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Biomedical subjects

S Khan

Publications and source records attributed to S Khan.

At least 325 records · Page 18Linked to original sources
PubMed1993

Beta 3 integrin derived peptide 217-230 inhibits fibrinogen binding and platelet aggregation: significance of RGD sequences and fibrinogen A alpha-chain.

beta 3 Integrin derived peptides 217-230 (DAPEGGFDAIMQAT) and 217-231 (Y) (DAPEGGFDAIMQATVY) at 100 microM inhibited 125I-fibrinogen binding to ADP-stimulated platelets and platelet aggregation. Peptide 217-231 (Y) (100 microM) significantly inhibited the binding of 125I-albolabrin (a disintegrin with a single RGD sequence) to ADP- and thrombin-activated platelets while it had only a slight effect on albolabrin binding to resting platelets. The 125I-beta 3 217-231 (Y) cross-linked selectively to the fibrinogen A alpha-chain. The interaction of the RGD sequence in the A alpha-chain of fibrinogen with beta 3 217-231 sequence appears to play a significant role in the events leading to platelet aggregation.

Adenosine Diphosphate↗
PubMed1993

Molecular mechanisms of nitrofurantoin-induced hepatocyte toxicity in aerobic versus hypoxic conditions.

We have previously reported that incubation of isolated rat hepatocytes with the antimicrobial drug nitrofurantoin causes toxic oxidative stress as a result of oxygen activation by futile one-electron redox cycling. In continuation of this work nitrofurantoin was found to cause rapid glutathione-protein mixed disulfide formation before GSSG had completely effluxed from the hepatocytes. Furthermore, the disulfide reductant dithiothreitol added up to 60 min later restored protein thiols and prevented cytotoxicity. In contrast, under hypoxic conditions nitrofurantoin-induced hepatocyte toxicity was associated with [14C]nitrofurantoin irreversible binding to protein, protein thiol depletion without glutathione-protein mixed disulfide formation, and GSH depletion. Furthermore, dithiothreitol did not have any antidotal properties and did not reverse covalent binding though some binding was prevented. These results suggest that under aerobic conditions nitrofurantoin-induced hepatocyte toxicity is due to the formation of glutathione-protein mixed disulfides, while under hypoxic conditions toxicity is associated with protein alkylation.

Aerobiosis↗
PubMed1993

Rationale for the use of clodronate in osteoporosis.

Bisphosphonates are widely used in disorders associated with increased resorption of bone, particularly in Paget's disease of bone and in the hypercalcemia of malignancy. Because of their undoubted efficacy and relatively low toxicity, bisphosphonates are attractive candidates for the management of osteoporosis. Clodronate, one of the many bisphosphonates being tested in osteoporosis, may be given intravenously or by mouth. In contrast to etidronate, even high doses of clodronate do not impair the mineralization of bone, making it suitable for long-term use in osteoporosis. As do all the bisphosphonates tested thus far, clodronate appears to delay the rate of bone loss in osteoporosis. Long-term studies are relatively few, so that its steady-state effects on bone mass are not yet known. Most data suggest clodronate is capable at least of delaying the rate of bone loss, but several pilot studies with this agent suggest that increments of bone mass might be sustainable for several years. Clodronate is likely to decrease the frequency of osteoporotic fractures, but there is no evidence for this at present. Well-controlled, long-term prospective studies are needed.

Bone Remodeling↗
PubMed1993

Failure of prostacyclin analog iloprost to sustain coronary blood flow after recombinant tissue-type plasminogen-induced thrombolysis in dogs.

The coronary artery often reoccludes soon after the flow has been restored with recombinant tissue-type plasminogen activator (TPA) in dogs with electrically-induced thrombosis. The coronary artery reocclusion relates to intense in situ platelet activation and thrombin generation in the reperfused coronary artery. To determine the effect of a potent platelet inhibitor, the prostacyclin analog iloprost, in the prevention of coronary artery reocclusion, an occlusive thrombus was created in the left anterior descending coronary artery in 23 dogs. Coronary artery reflow occurred in 17 dogs after TPA (1 mg/kg over 20 minutes intravenously) administration. After the reflow was established, 10 dogs were given saline and 7 dogs were given iloprost (4 micrograms/kg over 40 minutes). In the saline-treated group, the coronary artery reoccluded in 8 of 10 dogs over 90 minutes (reocclusion rate 80%). In the iloprost-treated group, the coronary artery reoccluded in five of seven dogs (reocclusion rate 71%; p = NS vs TPA alone). The magnitude of peak coronary blood flow and duration of flow were similar in dogs given saline or iloprost after TPA-induced thrombolysis. Scanning electron microscopy showed residual thrombus and the appearance of coronary arterial narrowing distal to the thrombus in all dogs examined. Thus residual thrombus formation and coronary artery narrowing continue to occur after TPA-induced thrombolysis in dogs whether the animals are treated with saline or iloprost. Administration of iloprost after reflow does not modulate the frequency of coronary artery reocclusion.

Animals↗
PubMed1993

Clinical validation of an RIA for natural and recombinant erythropoietin in serum and plasma.

A sensitive radioimmunoassay (RIA) for the detection of erythropoietin (EPO) was developed using antibody directed against EPO from human urine. With 100 microL of sample, the assay is sensitive to 7 U/L, well below the mean EPO level in normal males (15.1 +/- 3.5 U/L) or females (15.4 +/- 4.8 U/L). Dilutions of a variety of human serum samples show a parallel relationship with the standard EPO. Clinical validation of the RIA was confirmed by appropriate increases or decreases of EPO levels in various types of anemia and polycythemia. Serum EPO levels were also measured in volunteers participating in an autologous blood donation study. The RIA proved to be quite sensitive, detecting small increases even after a single unit phlebotomy. This RIA of human EPO meets all the requirements of a routine clinical assay in terms of specificity and clinical sensitivity and can be easily conducted in routine clinical laboratories.

Erythropoietin↗
PubMed1993

Characteristics of menopause in three socioeconomic urban groups in Karachi, Pakistan.

To determine age, symptoms and treatment choices in Pakistani women with spontaneous menopause, three groups in Karachi were interviewed using a structured questionnaire. The groups consisted of 250 poor slum dwellers, 250 middle class clinic attenders and 150 wives of retired military officers. Interviews were carried out in 1989 and 1990 by members of a team from the Aga Khan University consisting of a gynaecologist, a community health physician and two senior medical students. All interviewees had natural menopause at least 12 months previously. The results showed a mean age of 47 years for menopause in all groups. One in five women were symptomatic in the poorest group but one in two were in the other groups. Treatment was sought by 6% in the poor group, 26% of the middle class group and 38% of the most privileged group. Age at menopause was 4 years earlier than in most reports and fewer women had menopausal symptoms. These urban women may not represent the situation across the country but, as life expectancy in Pakistan is rising (now 56.4 years for women), menopausal problems may increase.

Adult↗
PubMed1993

Excitatory signaling in bacterial probed by caged chemoeffectors.

Chemotactic excitation responses to caged ligand photorelease of rapidly swimming bacteria that reverse (Vibrio alginolyticus) or tumble (Escherichia coli and Salmonella typhimurium) have been measured by computer. Mutants were used to assess the effects of abnormal motility behavior upon signal processing times and test feasibility of kinetic analyses of the signaling pathway in intact bacteria. N-1-(2-Nitrophenyl)ethoxycarbonyl-L-serine and 2-hydroxyphenyl 1-(2-nitrophenyl) ethyl phosphate were synthesized. These compounds are a 'caged' serine and a 'caged' proton and on flash photolysis release serine and protons and attractant and repellent ligands, respectively, for Tsr, the serine receptor. The product quantum yield for serine was 0.65 (+/- 0.05) and the rate of serine release was proportional to [H+] near-neutrality with a rate constant of 17 s-1 at pH 7.0 and 21 degrees C. The product quantum yield for protons was calculated to be 0.095 on 308-nm irradiation but 0.29 (+/- 0.02) on 300-350-nm irradiation, with proton release occurring at > 10(5) s-1. The pH jumps produced were estimated using pH indicators, the pH-dependent decay of the chromophoric aci-nitro intermediate and bioassays. Receptor deletion mutants did not respond to photorelease of the caged ligands. Population responses occurred without measurable latency. Response times increased with decreased stimulus strength. Physiological or genetic perturbation of motor rotation bias leading to increased tumbling reduced response sensitivity but did not affect response times. Exceptions were found. A CheR-CheB mutant strain had normal motility, but reduced response. A CheZ mutant had tumbly motility, reduced sensitivity, and increased response time to attractant, but a normal repellent response. These observations are consistent with current ideas that motor interactions with a single parameter, namely phosphorylated CheY protein, dictate motor response to both attractant and repellent stimuli. Inverse motility motor mutants with extreme rotation bias exhibited the greatest reduction in response sensitivity but, nevertheless, had normal attractant response times. This implies that control of CheY phosphate concentration rather than motor reactions limits responses to attractants.

Bacterial Proteins↗
PubMed1993

Visual/vestibular effects of inert gas narcosis.

Divers breathing compressed air at depths beyond 30 m experience a type of behavioural impairment known as inert gas narcosis. This condition degrades performance on a wide range of tasks and has the potential to compromise safety. Symptoms associated with narcosis include slowed response time, amnesia, and euphoria. Studies have also found disturbances to mechanisms regulating ocular control in response to vestibular stimulation; however, these experiments have been limited to very low frequency head movement (0.2 Hz). Thus, to further examine the effects of narcosis on visual/vestibular mechanisms, the vestibular ocular reflex (VOR) was assessed across a range of higher frequencies more representative of natural head movement (2.0-4.7 Hz). Seven subjects were tested prior to, during and after exposure to narcosis which was induced using 30% nitrous oxide. Standard room air was breathed as a control. The results indicated that narcosis decreased the velocity of compensatory eye movements in response to head rotation (decrease in VOR-gain), with more pronounced decreases occurring at the higher frequencies. The lag between eye and head position (phase lag) was also decreased by nitrous oxide; an effect that was again more pronounced at higher frequencies. These results indicate that narcosis disrupts ocular regulatory mechanisms which help to stabilize images on the retina during head movement.

Adult↗
PubMed1993

Spontaneous coronary artery dissection: a report of three cases and review of the literature.

We describe the clinical course of three patients who developed spontaneous coronary artery dissection. All patients were young women, one 9 weeks pregnant. All presented with chest pain; one died suddenly proving refractory to resuscitation, another developed unstable angina culminating in myocardial infarction, cardiogenic shock and death, and the third patient underwent coronary artery bypass grafting following diagnosis of a spontaneous coronary dissection of the left anterior descending artery at angiography. Pathological findings in the two fatal cases are reported. This condition, although rare, is a prominent cause of ischaemic coronary events in young women, when it is frequently associated with pregnancy or the puerperium. Most patients die suddenly, but a clinical spectrum is seen including stable and unstable angina, myocardial infarction and cardiogenic shock. The left anterior descending artery is most frequently affected. The classical histological finding is that of a large haematoma occupying the outer third of the media resulting in complete compression of the true lumen. The cause of spontaneous dissection remains unclear but theories of aetiology include a medial eosinophilic angiitis, pregnancy-induced degeneration of collagen in conjunction with the stresses of parturition, and rupture of the vasal vasorum. The diagnosis must be considered when a patient presents with a suggestive clinical profile. Urgent angiography should be undertaken to establish the diagnosis and consideration given to the need for coronary artery bypass grafting, which has been successfully employed in a number of patients. The uneventful long-term survival of cases treated conservatively has been reported.

Adult↗
PubMed1993

Reactive lysis--a phenomenon of delayed hemolytic transfusion reactions.

A 62-year-old female with Gaucher's disease demonstrated alloanti-c on pretransfusion testing. She was transfused with five units of c-negative red blood cells (RBCs) preoperatively and intraoperatively. The hemoglobin (Hb) level was slightly lower initially, hut was markedly lower on day 10 posttransfusion. Serologic results indicated a delayed hemolytic transfusion reaction (DHTR) due to alloanti-s, -Fya, and -Jkb, present both on the RBCs and in the serum. As late as day 35 posttransfusion, a mixed-field anti-IgG direct antiglobulin test (DAT) indicated that there were two cell populations present. The DAT remained positive with anti-C3b, -C3d throughout the course of the reaction. Because of the substantially lower Hb and the severity of symptoms, immunologic clearance of the antigen-positive donor RBCs was expected. However, we demonstrated their persistence. Our data corroborates the observation that complement activation occurring during DHTRs can result in the hemolysis of innocent bystander (autologous) cells.

Journal Article↗
PubMed1993

Morphological transformation, tumorigenicity and src-specific cytotoxic T-lymphocyte-mediated tumor immunity induced by murine 3T3 cells expressing src oncogenes encoding novel non-myristylated N-terminal domains.

We previously reported the development of a src-specific tumor regression system in chickens in which preinfection with rASV1702, a mutant of Rous sarcoma virus (RSV) encoding non-myristylated src product with a novel N-terminal domain, results in the immune suppression of challenge tumors induced by RSV. In order to adapt this system to the mouse, we have developed NIH3T3 and Balb/c3T3 (B3T3) cell lines that express 1702src, v-src, c-src, and other src variants, either by transfection or by infection with packaged recombinant Moloney virus (MLV) vectors. The sequence of the 1702 src cDNA, produced by reverse transcription-polymerase chain reaction (RT-PCR), confirmed the previously suggested 1702src N-terminal domain structure, fusing six amino acids from Pr76gag and 39 amino acids of env signal peptide sequence to Ala-76 of src. These cell lines were characterized for src expression and activity, cell compartmentalization of src product, tyrosine phosphorylation substrate specificity and transforming and tumorigenic potential. Based on these parameters, murine cell lines expressing 1702src were characteristically similar to chicken embryo fibroblasts (CEFs) infected with rASV1702. Finally, B3T3/1702src expressors, or membrane fractions of these cells, induced src-specific tumor protection in syngeneic mice against v-src-transformed tumor challenges. Splenic lymphocytes isolated from Balb/c mice inoculated with B3T3/1702src cells showed in vitro cytotoxicity against B3T3/v-src cells but not against untransformed B3T3 cells. Antibodies specific for Lyt2, mouse CD3 and H-2Dd blocked this cytotoxicity, whereas those specific for L3T4 did not, suggesting MHC class I-restricted, CD8-mediated cell killing. These data indicate that Balb/c3T3-expressed 1702src induces a cellular anti-tumor immunity based on src-specific tumor rejection antigens.

3T3 Cells↗
PubMed1993

Multiple drug resistant typhoid fever outbreak in Kashmir Valley.

We report the first ever report of multiple drug resistant salmonella typhi epidemic from Asia. The outbreak started in April 1988 and virtually ended by June 1988. The outbreak occurred in Baramullah town of Kashmir valley. In an epidemiological survey 230 cases were diagnosed as enteric fever. 46 cases (20%) were culture positive. A very rare multiple drug resistant strain of S. typhi was identified as phage type biotype II untypeable (UVS2). The strain was sensitive to Norfloxacin. This outbreak of S. typhi has many similarities with Mexico epidemic. Ingestion of contaminated water seems to be the possible cause for the outbreak.

Adolescent↗
PubMed1992

Dihydrolipoic acid--a universal antioxidant both in the membrane and in the aqueous phase. Reduction of peroxyl, ascorbyl and chromanoxyl radicals.

Thioctic (lipoic) acid is used as a therapeutic agent in a variety of diseases in which enhanced free radical peroxidation of membrane phospholipids has been shown to be a characteristic feature. It was suggested that the antioxidant properties of thioctic acid and its reduced form, dihydrolipoic acid, are at least in part responsible for the therapeutic potential. The reported results on the antioxidant efficiency of thioctic and dihydrolipoic acids obtained in oxidation models with complex multicomponent initiation systems are controversial. In the present work we used relatively simple oxidation systems to study the antioxidant effects of dihydrolipoic and thioctic acids based on their interactions with: (1) peroxyl radicals which are essential for the initiation of lipid peroxidation, (2) chromanoxyl radicals of vitamin E, and (3) ascorbyl radicals of vitamin C, the two major lipid- and water-soluble antioxidants, respectively. We demonstrated that: (1) dihydrolipoic acid (but not thioctic acid) was an efficient direct scavenger of peroxyl radicals generated in the aqueous phase by the water-soluble azoinitiator 2,2'-azobis(2-amidinopropane)-dihydrochloride, and in liposomes or in microsomal membranes by the lipid-soluble azoinitiator 2,2'-azobis(2,4-dimethylvaleronitrile); (2) both dihydrolipoic acid and thioctic acid did not interact directly with chromanoxyl radicals of vitamin E (or its synthetic homologues) generated in liposomes or in the membranes by three different ways: UV-irradiation, peroxyl radicals of 2,2'-azobis(2,4-dimethylvaleronitrile), or peroxyl radicals of linolenic acid formed by the lipoxygenase-catalyzed oxidation; and (3) dihydrolipoic acid (but not thioctic acid) reduced ascorbyl radicals (and dehydroascorbate) generated in the course of ascorbate oxidation by chromanoxyl radicals. This interaction resulted in ascorbate-mediated dihydrolipoic acid-dependent reduction of the vitamin E chromanoxyl radicals, i.e. vitamin E recycling. We conclude that dihydrolipoic acid may act as a strong direct chain-breaking antioxidant and may enhance the antioxidant potency of other antioxidants (ascorbate and vitamin E) in both the aqueous and the hydrophobic membraneous phases.

Animals↗
PubMed1992

Role of cytochrome P-450IIE1 in N-nitroso-N-methylaniline induced hepatocyte cytotoxicity.

1. The cytotoxicity of N-nitrosomethylaniline (NMA) towards hepatocytes isolated from rats was prevented by acetone or ethanol (inhibitors for cytochrome P-450IIE1) but not by metyrapone or SKF525A (inhibitors for cytochrome P-450IIB1/2). Various alcohols, secondary ketones and isothiocyanates that induced cytochrome P-450IIE1 were also found to be protective. Various aromatic and chlorinated hydrocarbon solvents that are substrates or inducers of cytochrome P-450IIE1 also prevented NMA cytotoxicity. Nitrogen-containing heterocycles that induced cytochrome P-450IIE1 were less effective. Further evidence that cytochrome P-450IIE1 was responsible for the activation of NMA was the marked increase in hepatocyte susceptibility if hepatocytes from pyrazole-induced rats were used. 2. NMA was more cytotoxic to hepatocytes isolated from phenobarbital-pretreated rats than uninduced rats. However, metyrapone now prevented and SKF525A delayed the cytotoxicity whereas ethanol, acetone, allyl isocyanate, isoniazid or trichloroethylene had no effect on the susceptibility of phenobarbital-induced hepatocytes. Furthermore, microsomes isolated from phenobarbital-pretreated rats had higher NMA-N-demethylase activity which was more inhibited by metyrapone and SKF525A than that of uninduced microsomal activity. By contrast the N-demethylase activity of phenobarbital induced microsomes was more resistant to acetone, ethanol, hexanal, trichloroethylene and toluene than uninduced microsome. 3. The above results suggest that cytochrome P-450IIE1 catalyses the cytotoxic activation of NMA in normal or pyrazole-induced hepatocytes whereas cytochrome P-450IIB1/2 is responsible for cytotoxicity in phenobarbital-induced hepatocytes.

Alcohols↗
PubMed1992

The cytoplasmic component of the bacterial flagellar motor.

We have used electron microscopy to examine freshly isolated Salmonella typhimurium and Escherichia coli basal flagellar fragments, purified without resort to extremes of pH or ionic strength. Such fragments contain the large bell-like basal structures visualized recently in freeze-substituted or fixed preparations. We have found mot (non-motile) mutants produced by lesions in fli genes (G, M, N) in which the bell structures do not coisolate with the flagellar basal body. The coisolation of the bell with the flagellar basal body was unaffected in strains lacking the genes for the motility-associated Mot proteins or for the Che family of proteins, which are necessary for chemotaxis. Proper assembly and interaction of the cytoplasmically located bell with the membrane-associated flagellar basal structures appears to be necessary for motor function. The FliG, FliM, and FliN proteins are thought to form a structural complex responsible for energization and switching of the flagellar motor. Our findings are consistent with the existence of such a complex and imply that it forms part of the flagellar bell.

Cell Fractionation↗