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Biomedical subjects

S Khan

Publications and source records attributed to S Khan.

At least 271 records · Page 15Linked to original sources
PubMed1996

Needle localization of non-palpable breast lesions.

Screening mammography identifies suspicious, non palpable mammary lesions. Mammographic needle localization (MNL) is currently being used to facilitate excision biopsy of these lesions. Thirty-two patients underwent biopsies of the breast after MNL for non-palpable lesions. Mammographic indications for biopsy consisted of microcalcifications (48%), mass or abnormal density (21%) or mass+abnormal density (24%). The carcinoma was identified in four cases (12%). Two of these were in situ, one was microinvasive and one was frankly invasive. Three were treated with a modified radical mastectomy. One of these non palpable lesion demonstrated nodal metastasis but none showed distant metastasis. All radiologically detected abnormalities were removed and confirmed with repeat radiology. No complications were identified. MNL effectively localizes non-palpable lesion of the breast and compliments accurate diagnosis and treatment of early carcinoma of the breast.

Adult↗
PubMed1996

Hematological and biochemical changes in acute leukemic patients after chemotherapy.

AIM: To study hematological and biochemical profiles in acute leukemic patients before and after chemotherapy. METHODS: Sera from 20 normal persons were compared with those from 40 patients of whom 20 patients were followed up after 6-8 months of treatment with cyclophosphamide, vincristine, and prednisolone. RESULTS: Hemoglobin, hematocrit and platelet count were decreased while reticulocyte count, blood sedimentation, total leukocyte count, bleeding time, bilirubin, blood coagulation time, alanine aminotransferase, lactate dehydrogenase, creatinine, and urea were increased in acute myelocytic patients compared to normal. A similar pattern was observed in acute lymphocytic patients except there was no significant increase in serum urea. CONCLUSION: In acute leukemic patients blood chemistry and hematology are useful during diagnosis and treatment. After 6-8 months of treatment 50% remission occurred.

Adolescent↗
PubMed1995

Oxygen dependence of hepatocyte susceptibility to mitochondrial respiratory inhibitors.

Most zone 3 specific hepatotoxins or their metabolites are mitochondrial toxins, and yet the susceptibility of hepatocytes to respiratory inhibitors at the low O2 concentrations found in zone 3 is not known. Potassium cyanide (CN) and antimycin A (AA) were found to be 5- and 2-fold more cytotoxic at 1% than at 95% O2, respectively. CN also inhibited the respiration of hepatocytes 36% more at 1% O2 than at 95% O2; however, AA inhibited the respiration to the same level at 1% and 95% O2. CN but not AA depleted ATP levels of hepatocytes more extensively at 1% than at 95% O2. The CN-trapping agents dihydroxyacetone, glyceraldehyde, alpha-ketoglutarate and pyruvate prevented CN-induced cytotoxicity more effectively at 95% O2 than at 1% O2. In contrast, thiosulfate was less effective in preventing CN toxicity at 95% than at 1% O2. Hepatocyte thiocyanate formation from CN and thiosulfate was much faster at 1% than at 95% O2, suggesting that rhodanese, the mitochondrial enzyme that forms thiocyanate from CN and thiosulfate, is more effective at 1% O2 than at 95% O2.

Adenosine Triphosphate↗
PubMed1995

Modulating hypoxia-induced hepatocyte injury by affecting intracellular redox state.

Hypoxia-induced hepatocyte injury results not only from ATP depletion but also from reductive stress and oxygen activation. Thus the NADH/NAD+ ratio was markedly increased in isolated hepatocytes maintained under 95% N2/5% CO2 in Krebs-Henseleit buffer well before plasma membrane disruption occurred. Glycolytic nutrients fructose, dihydroxyacetone or glyceraldehyde prevented cytotoxicity, restored the NADH/NAD+ ratio, and prevented complete ATP depletion. However, the NADH generating nutrients sorbitol, xylitol, glycerol and beta-hydroxybutyrate enhanced hypoxic cytotoxicity even though ATP depletion was not affected. On the other hand, NADH oxidising metabolic intermediates oxaloacetate or acetoacetate prevented hypoxic cytotoxicity but did not affect ATP depletion. Restoring the cellular NADH/NAD+ ratio with the artificial electron acceptors dichlorophenolindophenol and Methylene blue also prevented hypoxic injury and partly restored ATP levels. Ethanol which further increased the cellular NADH/NAD+ ratio increased by hypoxia also markedly increased toxicity whereas acetaldehyde which restored the normal cellular NADH/NAD+ ratio, prevented toxicity even though hypoxia induced ATP depletion was little affected by ethanol or acetaldehyde. The viability of hypoxic hepatocytes is therefore more dependent on the maintenance of normal redox homeostasis than ATP levels. GSH may buffer these redox changes as hypoxia caused cell injury much sooner with GSH depleted hepatocytes. Hypoxia also caused an intracellular release of free iron and cytotoxicity was prevented by desferoxamine. Furthermore, increasing the cellular NADH/NAD+ ratio markedly increased the intracellular release of iron. Hypoxia-induced hepatocyte injury was also prevented by oxypurinol, a xanthine oxidase inhibitor. Polyphenolic antioxidants or the superoxide dismutase mimic, TEMPO partly prevented cytotoxicity suggesting that reactive oxygen species contributed to the cytotoxicity. The above results suggests that hypoxia induced hepatocyte injury results from sustained reductive stress and oxygen activation.

Acetaldehyde↗
PubMed1995

Hepatocyte injury resulting from the inhibition of mitochondrial respiration at low oxygen concentrations involves reductive stress and oxygen activation.

By correlating lactate/pyruvate ratios and ATP levels, cytotoxicity induced by the mitochondrial respiratory inhibitors or hypoxia:reoxygenation injury can be attributed not only to ATP depletion but also to reductive stress and oxygen activation. Thus hypoxia, cyanide or antimycin markedly increases reductive stress, non-heme Fe release and H2O2 formation in hepatocytes. Cytotoxicity was partly prevented with the ferric chelator desferoxamine, the xanthine oxidase inhibitor oxypurinol and the hydrogen peroxide scavenger glutathione. No lipid peroxidation could be detected and phenolic anti-oxidants had little effect. However, polyphenolic antioxidants or the superoxide dismutase mimics TEMPO or TEMPOL partly prevented cytotoxicity. Furthermore, increasing the hepatocyte NADH/NAD+ ratio with NADH generating compounds such as ethanol, glycerol, or beta-hydroxybutyrate markedly increased cytotoxicity (prevented by desferoxamine) and further increased the intracellular release of non-heme iron. Cytotoxicity could be prevented by glycolytic substrates (eg. fructose, dihydroxyacetone, glyceraldehyde) or the NADH utilising substrates acetoacetate or acetaldehyde which decreased the reductive stress and prevented intracellular iron release. These results suggest that liver injury resulting from insufficient respiration involves reductive stress which releases intracellular Fe, converts xanthine dehydrogenase to xanthine oxidase and causes mitochondrial oxygen activation. The cell's antioxidant defences are compromised and ATP catabolism contributes to oxygen activation.

Adenosine Triphosphate↗
PubMed1995

Chemotactic signal integration in bacteria.

Chemotactic signaling in Escherichia coli involves transmission of both negative and positive signals. In order to examine mechanisms of signal processing, behavioral responses to dual inputs have been measured by using photoactivable "caged" compounds, computer video analysis, and chemoreceptor deletion mutants. Signaling from Tar and Tsr, two receptors that sense amino acids and pH, was studied. In a Tar deletion mutant the photoactivated release of protons, a Tsr repellent, and of serine, a Tsr attractant, in separate experiments at pH 7.0 resulted in tumbling (negative) or smooth-swimming (positive) responses in ca. 50 and 140 ms, respectively. Simultaneous photorelease of protons and serine resulted in a single tumbling or smooth-swimming response, depending on the relative amounts of the two effectors. In contrast, in wild-type E. coli, proton release at pH 7.0 resulted in a biphasic response that was attributed to Tsr-mediated tumbling followed by Tar-mediated smooth-swimming. In wild-type E. coli at more alkaline pH values the Tar-mediated signal was stronger than the Tsr signal, resulting in a strong smooth-swimming response preceded by a diminished tumbling response. These observations imply that (i) a single receptor time-averages the binding of different chemotactic ligands generating a single response; (ii) ligand binding to different receptors can result in a nonintegrated response with the tumbling response preceding the smooth-swimming response; (iii) however, chemotactic signals of different intensities derived from different receptors can also result in an apparently integrated response; and (iv) the different chemotactic responses to protons at neutral and alkaline pH may contribute to E. coli migration toward neutrality.

Bacterial Proteins↗
PubMed1995

Substance P-(1-7) and substance P-(5-11) locally modulate dopamine release in rat striatum.

The effects of substance P, substance P-(1-7) and substance P-(5-11) on endogenous dopamine outflow in rat striatal slices were investigated. The dose-response curves (0.01 nM to 10 microM) were bell-shaped, with significant increases at 0.1 and 1 nM but with no effect at higher concentrations. The tachykinin NK1 receptor agonist, [Sar9,Met(O2)11]substance P, significantly increased dopamine outflow at 10 and 100 nM. The effects of substance P or substance P-(5-11) and 25 mM KCl were additive. A negative interaction was observed with substance P-(1-7) and K+. The increase in dopamine outflow elicited by 1 nM substance P and substance P-(5-11) was reversed by the tachykinin NK1 receptor antagonist WIN 51,708 (17 beta-hydroxy-17 alpha-ethynyl-5 alpha-androstano[3,2-b]pyrimido[1,2- alpha]benzimidazole) (25 and 250 nM), whereas only partial reversal was observed for the effect of substance P-(1-7). These results show that substance P fragments locally modulate striatal dopamine outflow and the mechanisms underlying this modulation may differ between N- and C-terminal fragments.

Androstanes↗
PubMed1995

Structural effects of mutations in Salmonella typhimurium flagellar switch complex.

Mutations in Salmonella typhimurium fliG, fliM and fliN give rise either to non-flagellate, non-motile or non-chemotactic mutant bacteria. The FliG, FliM and FliN proteins form part of recently characterized extended flagellar basal structures, and have been postulated to form a mutually interacting structural complex. We have examined basal body preparations from non-motile or non-chemotactic fliG, fliM and fliN mutant strains by electron microscopy and immunoblot gel analysis. Most flagellar preparations isolated from the non-motile mutants lacked FliM, but contained FliG. The basal bodies lacked the belled morphology characteristic of the wild-type structures, but had protrusions which could be labelled with anti-FliG. Non-motile mutant preparations severely depleted of FliG but containing FliM were also obtained. These preparations contained extended, belled flagellar structures that were labelled with anti-FliM. Thus, FliM is part of the shell of the extended structures responsible for the belled morphology, while FliG may be part of the inner substructure. The extended basal structures from a FliG temperature-sensitive mutant strain rapidly lost FliM, as well as FliG, upon a shift to a non-permissive temperature, implying interaction between the FliG- and FliM-containing substructures. In dramatic contrast to non-motile mutants, extended basal structures isolated from non-chemotactic mutants were indistinguishable from wild-type structures. This difference may reflect the energetics of the different protein-protein interactions operative during torque generation and the switching of rotation sense.

Antibodies, Bacterial↗
PubMed1995

Properties of hemagglutinins newly separated from toxic phytoplankton.

Unique substances of the hemagglutinating activity were separated from unialgal cultures of the toxic phytoflagellates, Chattonella marina and Gymnodinium sp. Molecular masses of the substances were estimated to be 14,000 in Chattonella and 15,000 in Gymnodinium. These two substances contained phosphorus, hexose (galactose) and glycerol in the following molar ratios; 1.00:1.18:1.24 (Chattonella) and 1.00:1.07:1.10 (Gymnodinium). Hemagglutinating titres using rabbit red blood cells were inferred to be 25,000 in both preparations. In the presence of Chattonella hemagglutinin (0.10-0.50 microM), the growth of C. marina in Provasoli's ES media was little affected during 24 h of incubation, whereas a marked suppression took place in growth in Gymnodinium sp. (50% inhibition, 0.12 microM) or the diatom Nitzschia closterium (0.17 microM). On the other hand, Gymnodinium hemagglutinin inhibited the growth of the three species of phytoplankton. A 50% inhibition occurred at 0.12 microM in C. marina, at 0.22 microM in N. closterium or at 0.50 microM in Gymnodinium sp.

Animals↗
PubMed1995

5'-[4-(Pivaloyloxy)-1,3,2-dioxaphosphorinan-2-yl]-2'-deoxy-5-fluorouridine: a membrane-permeating prodrug of 5-fluoro-2'-deoxyuridylic acid (FdUMP).

5'-[4-(Pivaloyloxy)-1,3,2-dioxaphosphorinan-2-yl]-2'-deoxy-5 -fluorouridine (1c) was designed as a potential membrane-permeable prodrug of 2'-deoxy-5-fluorouridine 5'-monophosphate (FdUMP), a putative active metabolite of the antitumor drug 5-fluorouracil (FU). It was anticipated that 1c would be hydrolyzed in vivo by carboxylate esterase (E.C. 3.1.1.1) to the labile 4-hydroxy analogue 2a, which should penetrate cells by passive diffusion and ring open to the aldehyde 3a. Spontaneous elimination of acrolein from 3a would then generate the free nucleotide, FdUMP. 1c might also penetrate cells directly and undergo the same degradation sequence after hydrolysis by cellular esterases. 1c was prepared by condensing 2-hydroxy-2-oxo-4-(pivaloyloxy)-1,3,2-dioxaphosphorinane with 2'-deoxy-5-fluorouridine (FUdR) in the presence of triphenylphosphine and diethyl azodicarboxylate. 1c was moderately stable in aqueous buffers over the pH range 1-7.4 (T1/2 > 30 h). In the presence of carboxylate esterase, however, it was degraded, in a concentration-dependent manner, to FdUMP. No intermediates were detected in the incubation mixture. In mouse plasma, 1c was degraded first to FdUMP and then to FUdR. The latter is presumably formed by dephosphorylation of FdUMP by plasma 5'-nucleotidases or phosphatases. 1c and FU inhibited the growth of Chinese hamster ovary (CHO) cells in culture at a concentration of 5 x 10(-6) M. 1c was equally potent against a CHO variant that was 20-fold resistant to FU. Administered intraperitoneally for 5 consecutive days, 1c was as effective as FU at prolonging the life span of mice bearing P-388 leukemia. In the presence of 2-mercaptoehtanesulfonic acid, an acrolein scavenger, 1c was equally effective against a P-388 mutant cell line that was resistant to FU. Collectively, these data suggest that 1c acts as a membrane-permeable prodrug of FdUMP. This prodrug strategy may be generally useful for introducing dianionic phosphates and phosphonates into cells.

Animals↗
PubMed1995

The effects of intravenous alendronate in Paget's disease of bone.

We studied the effects of intravenous alendronate on disease activity in 36 patients with active Paget's disease of bone. Alendronate was administered to 3 groups of 12 patients at doses of 2.5, 5, and 10 mg intravenously daily for 5 consecutive days. The patients were matched for disease activity. Symptomatic improvement was seen in at least 10 patients in each treatment group. Alendronate induced a dose-dependent suppression of biochemical indices of bone turnover in all patients. A significant reduction in the mean fasting urinary excretion of hydroxyproline occurred within 2 days of starting treatment, reaching a nadir at 2-4 weeks, which was most marked in patients receiving 10 mg of alendronate (p < 0.05). There was a slower fall in serum alkaline phosphatase activity with maximal suppression occurring 3 months after the start of treatment. The degree of suppression was least for those receiving 2.5 mg of alendronate (p < 0.05) but no difference in response was observed for the other dosages. The duration of response was also dose-related. A significant fall in the serum calcium and urinary excretion of calcium occurred from the second day of treatment but returned to pretreatment values by 4 months. A transient fall in the mean lymphocyte count was observed, which was similar for each group. This was associated with a short-lived fever in 3 patients receiving 10 mg, in 4 patients receiving 5 mg, and in 2 patients receiving 2.5 mg.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1995

Effect of beta-endorphin on the contractile responses in mouse skeletal muscle.

Tension development in response to direct and indirect electrical stimulation was studied in an isolated phrenic nerve hemidiaphragm preparation of the mouse. beta-Endorphin (beta-EP) caused an increase in the amplitude and a decrease in the time to peak of muscle contractions in response to low frequency stimulation of the nerve. Upon direct stimulation of the muscle the peptide had no effect. The actions of beta-EP were abolished in the presence of the opioid antagonist naloxone and mimicked by delta opioid agonists. Upon high frequency stimulation of the nerve, beta-EP caused an increase in the initial, maximum, and mean tension. It also prevented the fall in the final tension seen in the control preparations with repeated periods of stimulation. The findings are consistent with beta-EP having a role to improve neuromuscular function and delay fatigue, and indicate the possible therapeutic potential of opioid substances in conditions where muscle weakness is present.

Animals↗
PubMed1995

Substrate specificity and inhibition of UDP-GlcNAc:GlcNAc beta 1-2Man alpha 1-6R beta 1,6-N-acetylglucosaminyltransferase V using synthetic substrate analogues.

UDP-GlcNAc:GlcNAc beta 1-2Man alpha 1-6R (GlcNAc to Man) beta 1,6- N-acetylglucosaminyltransferase V (GlcNAc-T V) adds a GlcNAc beta 1-6 branch to bi- and triantennary N-glycans. An increase in this activity has been associated with cellular transformation, metastasis and differentiation. We have used synthetic substrate analogues to study the substrate specificity and inhibition of the partially purified enzyme from hamster kidney and of extracts from hen oviduct membranes and acute myeloid leukaemia leukocytes. All compounds with the minimum structure GlcNAc beta 1-2Man alpha 1-6Glc/Man beta-R were good substrates for GlcNAc-T V. The presence of structural elements other than the minimum trisaccharide structure affected GlcNAc-T V activity without being an absolute requirement for activity. Substrates with a biantennary structure were preferred over linear fragments of biantennary structures. Kinetic analysis showed that the 3-hydroxyl of the Man alpha 1-3 residue and the 4-hydroxyl of the Man beta- residue of the Man alpha 1-6(Man alpha 1-3)Man beta-R N-glycan core are not essential for catalysis but influence substrate binding. GlcNAc beta 1-2(4,6-di-O-methyl-)Man alpha 1-6Glc beta-pnp was found to be an inhibitor of GlcNAc-T V from hamster kidney, hen oviduct microsomes and acute and chronic myeloid leukaemia leukocytes.

Animals↗
PubMed1995

Techniques for measuring renal transit time.

A variety of techniques have been used for quantitative estimation of renal transit time. We compared different indices of transit time in a group of 30 patients having baseline and ACE inhibitor technetium-99m mercaptoacetyltriglycine (MAG3) renography prior to arteriography: peak time, mean transit time, and the ratio of background-subtracted counts at 20 min to those at 3 min. Each index was calculated from whole-kidney ROI, cortical ROI, and cortical factor (by factor analysis). The strongest correlations between angiographic percent of stenosis and transit time index were observed for the peak time (Spearman p=0.469, n=53, P <0.005) and for the R20/3 (again p=0.469, n=53, P <0.005) using the whole-kidney ROI and using only the baseline data without captopril. (Spearman's p is simply the correlation coefficient calculated from rank in list, which allows for nonlinear correlation.) Thus simple indices of transit time (whole-kidney peak time and R20/3) correlated as well with the observed pathology as did more complicated methods that required deconvolution, factor analysis, or selection of a cortical ROI.

Adult↗
PubMed1995

p53 accumulation in benign breast biopsy specimens.

Several studies of benign breast lesions using methacran-fixed, paraffin-embedded tissues and cytological preparations have suggested that p53 accumulation in these lesions as detected by immunohistochemical (IHC) staining is rare to absent. As a result, several different investigators have suggested that p53 immunoreactivity in breast specimens infers a diagnosis of malignancy or may identify premalignant lesions. We immunostained 271 breast biopsy specimens from 271 patients with the monoclonal anti-p53 antibody BP-53-12 and found positive nuclear staining in seven of 23 malignant lesions (30%) and 39 of 248 benign biopsy specimens (16%). Of the benign lesions, 30% of fibroadenomas, nonpremalignant breast lesions, were positive. Long-term follow-up information was available on 48 patients with benign biopsy specimens and showed that 12% of those positive and 7% of those negative for p53 developed breast carcinoma. This difference was not significant (P > .2). We conclude that (1) p53 immunoreactivity in breast lesions should not be used as exclusive evidence of malignancy and (2) p53 immunoreactivity in benign breast lesions may not identify a subset of patients at increased risk for breast carcinoma.

Antibodies, Monoclonal↗
PubMed1995

Sustained response to intravenous alendronate in postmenopausal osteoporosis.

We studied the effects of alendronate (amino-hydroxybutylidene bisphosphonate) on biochemical indices of bone turnover and on lumbar spinal bone mineral density in 15 postmenopausal women with vertebral osteoporosis. Alendronate 7.5 mg daily was administered intravenously as a slow infusion for four consecutive days. Treatment was associated with a significant decrease in serum calcium (p < 0.01), fasting urinary calcium excretion (p < 0.01) and hydroxyproline excretion within several days followed a later decrease in serum alkaline phosphatase activity that showed a significant reduction at two months after treatment (p < 0.05). Serum calcium reverted to pretreatment values by the second week after infusion, but the decrease in alkaline phosphatase, urinary calcium, and hydroxyproline excretion persisted to six months after infusion. There was a 3% mean increase in lumbar bone mineral density at six months (p < 0.01). A transient lymphopenia or leucopenia was noted in eight patients and a short-lived fever in six. No other side effects were observed. This study demonstrates that shortterm exposure to high intravenous doses of alendronate induces suppression of bone resorption in osteoporosis that persists for at least 6 months after infusion. We conclude that a short exposure to high intravenous doses induces sustained effects on bone turnover in much the same manner as that observed in Paget's disease of bone.

Absorptiometry, Photon↗