Search PubMed⌕ Search

Biomedical subjects

J Khan

Publications and source records attributed to J Khan.

At least 37 records · Page 2Linked to original sources
PubMed2000

Stannyl radical-mediated cleavage of pi-deficient heterocyclic sulfones. Synthesis Of alpha-fluoro esters

Treatment of ethyl 2-(pyridin-2-ylsulfonyl)hexanoate with tributylstannane and azobis(2-methyl-2-propanitrile) (AIBN) in benzene at reflux for 36 h resulted in hydrogenolysis to give ethyl hexanoate (60%), whereas no reaction was observed after 48 h at reflux with ethyl 2-(phenylsulfonyl)hexanoate. Ethyl 2-(pyrimidin-2-ylsulfonyl)hexanoate underwent quantitative hydrogenolysis within 1 h under these conditions. This represents a mild new methodology for removal of the synthetically useful sulfone moiety. Substitution of Bu(3)SnD for Bu(3)SnH gave access to alpha-deuterium-labeled esters. Treatment of the alpha-(pyrimidin-2-ylsulfonyl) enolates derived from several esters with Selectfluor gave high yields of the 2-fluoro-2-(pyrimidin-2-ylsulfonyl)alkanoates, which were smoothly desulfonylated [Bu(3)SnH (2 equiv)/AIBN/benzene/Delta] to give 2-fluoroalkanoates. "Catalytic" tin hydride, generated from tribuytltin chloride (0.15 equiv) and excess polymethylhydrosiloxane in the presence of potassium fluoride, also effected removal of the pi-deficient alpha-(pyrimidin-2-ylsulfonyl) moiety from acid derivatives in high yields. Desulfonylation is suggested to proceed via alkoxy ketyl-type radicals and tin enolates.

Journal Article↗
PubMed2000

The nitration of platelet cytosolic proteins during agonist-induced activation of platelets.

The nitration of protein tyrosine residues by peroxynitrous acid has been associated with pathological conditions. Here it is shown, using a sensitive competitive enzyme-linked immunosorbent assay and immunoblotting for nitrotyrosine, that spontaneous nitration of specific proteins occurs during a physiological process, the activation of platelets by collagen. One of the main proteins nitrated is vasodilator-stimulated phosphoprotein. Endogenous synthesis of nitric oxide and activity of cyclo-oxygenase were required for the nitration of tyrosine. The nitration was mimicked by addition of peroxynitrite to unstimulated platelets, although the level of nitrotyrosine formation was greater and its distribution among the proteins was less specific.

Aspirin↗
PubMed2000

Doubly homologated dihalovinyl and acetylene analogues of adenosine: synthesis, interaction with S-adenosyl-L-homocysteine hydrolase, and antiviral and cytostatic effects.

Treatment of the 6-aldehyde derived by Moffatt oxidation of 3-O-benzoyl-1,2-O-isopropylidene-alpha-D-ribo-hexofuranose (2c) with the dibromo- or bromofluoromethylene Wittig reagents generated in situ with tetrabromomethane or tribromofluoromethane, triphenylphosphine, and zinc gave the dihalomethyleneheptofuranose analogues 3b and 3d, respectively. Acetolysis, coupling with adenine, and deprotection gave 9-(7,7-dibromo-5,6, 7-trideoxy-beta-D-ribo-hept-6-enofuranosyl)adenine (5a) or its bromofluoro analogue 5b. Treatment of 5a with excess butyllithium provided the acetylenic derivative 9-(5,6, 7-trideoxy-beta-D-ribo-hept-6-ynofuranosyl)adenine (6). The doubly homologated vinyl halides 5a and 5b and acetylenic 6 adenine nucleosides were designed as putative substrates of the "hydrolytic activity" of S-adenosyl-L-homocysteine (AdoHcy) hydrolase. Incubation of AdoHcy hydrolase with 5a, 5b, and 6 resulted in time- and concentration-dependent inactivation of the enzyme (K(i): 8.5 +/- 0.5, 17 +/- 2, and 8.6 +/- 0.5 microM, respectively), as well as partial reduction of enzyme-bound NAD(+) to E-NADH. However, no products of the "hydrolytic activity" were observed indicating these compounds are type I mechanism-based inhibitors. The compounds displayed minimal antiviral and cytostatic activity, except for 6, against vaccinia virus and vesicular stomatitis virus (IC(50): 15 and 7 microM, respectively). These viruses typically fall within the activity spectrum of AdoHcy hydrolase inhibitors.

Adenosylhomocysteinase↗
PubMed2000

Detection of gene amplification by genomic hybridization to cDNA microarrays.

Gene amplification is one of the major mechanisms of oncogene activation in tumorigenesis. To facilitate the identification of genes mapping to amplified regions, we have used a technique based on the hybridization of total genomic DNA to cDNA microarrays. To aid detection of the weak signals generated in this complex hybridization, we have used a tyramide-based technique that allows amplification of a fluorescent signal up to 1000-fold. Dilution experiment suggests that amplifications of 5-fold and higher can be detected by this approach. The technique was validated using cancer cell lines with several known gene amplifications, such as those affecting MYC, MYCN, ERBB2, and CDK4. In addition to the detection of the known amplifications, we identified a novel amplified gene, ZNF133, in the neuroblastoma cell line NGP. Hybridization of NGP cDNA on an identical array also revealed over expression of ZNF133. Parallel analysis of genomic DNA for copy number and cDNA for expression now provides rapid approach to the identification of amplified genes and chromosomal regions in tumor cells.

Cyclin-Dependent Kinase 4↗
PubMed2000

Comparison of mathematical models for exposure assessment with computational fluid dynamic simulation.

For many years exposure to airborne contaminants has been estimated by air or biological monitoring. In occupational settings, mathematical models increasingly are employed as adjuncts to monitoring, for instance, during process design or in retrospective epidemiological studies. Models can make predictions in a wide variety of scenarios, can be used for rapid screening, and may reduce the need for monitoring in exposure assessment. However, models make simplifying assumptions regarding air flow and contaminant transport. The errors resulting from these assumptions have not been systematically evaluated. Here we compare exposure estimates from the single-zone completely mixed (CM-1), two-zone completely mixed (CM-2), and uniform diffusivity (UD) models with workroom concentration fields predicted by computational fluid dynamics (CFD). The room air flow, concentration fields, and the breathing zone concentration of a stationary worker were computed using Fluent V4.3 for factorial combinations of three source locations, three dilution air flow rates and two emission rate profiles, constant and time-varying. These numerical experiments were used to generate plausible concentration fields, not to simulate exactly the processes in a real workroom. Thus, "error" is defined here as difference between model and CFD predictions. For both constant and time-varying emission sources, exposure estimates depended on receptor and source location. For the constant source case, ventilation rate was shown to be inconsequential to CM-1 model error. CM-1, CM-2, and UD models differed in their agreement with CFD. UD was closest to CFD for estimating concentration in the simulated breathing zone (BZ) near the source, although large errors resulted when the model was applied to the plane of possible breathing zones. CM-1 performed better for this plane but underestimated the near-source BZ exposure. For the near-source BZ location, CM-2 replicated CFD predictions more closely than CM-1 did, but less closely than UD did. Error in CM-1 model estimation of short-term average exposure to a time-varying source was highly dependent on ventilation rate. Error decreased as ventilation rate increased.

Air Movements↗
PubMed2000

Abciximab as an adjunct to high-risk carotid or vertebrobasilar angioplasty: preliminary experience.

OBJECTIVE: Abciximab, a platelet glycoprotein IIb/IIIa receptor inhibitor, has been shown to reduce the risk of ischemic events associated with coronary intervention. However, its role in neurointerventional procedures needs to be defined. We prospectively evaluated our initial experience with the use of abciximab in a series of high-risk patients undergoing carotid, basilar, or vertebral artery angioplasty. METHODS: Patients were given an intravenous abciximab bolus (0.25 mg/kg), followed by infusion (10 microg/min) for a period ranging from 12 to 24 hours, as an adjunct to angioplasty in 20 procedures (19 patients). These patients were considered to be at high risk for thromboembolic events because of recent ischemic symptoms and/or complex lesion morphology. Before, immediately after, and 24 hours after the procedure, each patient was evaluated by a neurologist for the presence of new neurological deficits. Any bleeding or other complications during hospitalization were also recorded. Bleeding was defined as major (hemoglobin decrease >5 g/dl), minor (hemoglobin decrease 3-5 g/dl), or insignificant. RESULTS: Angioplasty was performed in the internal carotid artery (n = 13), vertebral artery (n = 4), or basilar artery (n = 2). Stents were placed across 13 lesions. In one patient, angioplasty could not be performed owing to technical difficulties; however, abciximab was administered because of extensive lesion manipulation. Intraprocedural heparin was given in 19 procedures (35-86 U/kg intravenously) and partially reversed in 6 procedures. Low-dose intra-arterial thrombolytic agents were administered in seven patients before the lesion was crossed. Two patients experienced transient neurological deficits either during (n = 1) or immediately after (n = 1) the procedure. Another patient had complete occlusion of the right vertebral artery after angioplasty with complete recanalization after 24 hours of abciximab infusion. Major or minor bleeding was not observed in any patient. Insignificant bleeding was observed in eight patients. Thrombocytopenia was observed in one patient who received concomitant administration of intravenous heparin and abciximab infusion. CONCLUSION: We observed a low frequency of neurological events in high-risk patients undergoing angioplasty with or without stent placement. Abciximab seems to be a relatively safe adjunct for carotid or vertebrobasilar endovascular intervention either alone or in combination with low-dose thrombolytics. Partial reversal of intraprocedural heparin should be considered to reduce the risk of postprocedural bleeding.

Abciximab↗
PubMed2000

Automated quantitation of circulating neutrophil and eosinophil activation in asthmatic patients.

BACKGROUND: Asthma has been associated with eosinophil activation, measured in serum, sputum, bronchoalveolar lavage (BAL) fluid, and urine. A whole blood automated method was developed to assess eosinophil and neutrophil activity in terms of peroxidase content and cell morphology using the Bayer haematology analyser. The method was applied to an in vitro stimulation model when fMLP was added to whole blood and the samples were then analysed for changes in granularity and shape. In addition, cells stimulated with interleukin (IL)-8 were examined by electron microscopy. METHODS: A cross sectional analysis was performed on venous blood from non-atopic, non-asthmatic normal subjects (n = 37), mild (n = 46) and symptomatic (n = 22) asthmatic patients on inhaled beta(2) agonist only, and more severe asthmatic patients (n = 17) on inhaled and oral corticosteroid therapy. Samples were analysed by the haematology analyser and peroxidase leucograms gated using the WinMDI software program. RESULTS: There were significant differences in the amount of light scatter by the neutrophil populations in the symptomatic (p = 0.007) and severe asthmatic (p = 0.0001) groups compared with the control group. However, abnormalities in eosinophil populations were not observed. In vitro activation of whole blood with fMLP caused similar changes in neutrophil light scatter, suggesting that neutrophil activation is present in peripheral blood of symptomatic asthmatic patients. IL-8 caused a change in shape of the neutrophils seen using transmission electron microscopy. CONCLUSIONS: Evidence of neutrophil activation can be seen in whole blood from patients with asthma using a novel automated method. This may potentially be applied to other inflammatory diseases.

Adult↗
PubMed2000

Extraadrenal retroperitoneal paraganglioma causing malignant hypertension and permanent visual loss in an eleven-year-old girl.

We report a secretory paraganglioma in an eleven-year-old Trinidadian girl of East Indian descent who presented with malignant hypertension, proteinuria and modest elevation of urinary vanillylmandelic acid levels. The extra-adrenal mass was surgically removed without complications. The patient has been normotensive without evidence of recurrence of disease but with persistent visual sequel two years later. This case reinforces the observation that extraadrenal retroperitoneal paragangliomas can be functionally very active and early computed tomography or other imaging procedure is necessary for rapid noninvasive evaluation, timely surgery and prevention of permanent morbidity.

Child↗
PubMed2000

Laser incisional surgery.

Soft tissue surgery is more efficient, and sometimes more effective, using laser incisional surgery as opposed to standard techniques. The modern generation of lasers produces soft tissue incisions with a minimum amount of thermal damage at wound edges. The transition to laser incisional surgery requires a knowledge of methods, maneuvers, and safety information.

History, 20th Century↗
PubMed1999

cDNA microarrays detect activation of a myogenic transcription program by the PAX3-FKHR fusion oncogene.

Alveolar rhabdomyosarcoma is an aggressive pediatric cancer of striated muscle characterized in 60% of cases by a t(2;13)(q35;q14). This results in the fusion of PAX3, a developmental transcription factor required for limb myogenesis, with FKHR, a member of the forkhead family of transcription factors. The resultant PAX3-FKHR gene possesses transforming properties; however, the effects of this chimeric oncogene on gene expression are largely unknown. To investigate the actions of these transcription factors, both Pax3 and PAX3-FKHR were introduced into NIH 3T3 cells, and the resultant gene expression changes were analyzed with a murine cDNA microarray containing 2,225 elements. We found that PAX3-FKHR but not PAX3 activated a myogenic transcription program including the induction of transcription factors MyoD, Myogenin, Six1, and Slug as well as a battery of genes involved in several aspects of muscle function. Notable among this group were the growth factor gene Igf2 and its binding protein Igfbp5. Relevance of this model was suggested by verification that three of these genes (IGFBP5, HSIX1, and Slug) were also expressed in alveolar rhabdomyosarcoma cell lines. This study utilizes cDNA microarrays to elucidate the pattern of gene expression induced by an oncogenic transcription factor and demonstrates the profound myogenic properties of PAX3-FKHR in NIH 3T3 cells.

3T3 Cells↗
PubMed1999

DNA microarray technology: the anticipated impact on the study of human disease.

One can imagine that, one day, there will be a general requirement that relevant array data be deposited, at the time of publication of manuscripts in which they are described, into a single site made available for the storage and analysis of array data (modeled after the GenBank submission requirements for DNA sequence information). With this system in place, one can anticipate a time when data from thousands of gene expression experiments will be available for meta-analysis, which has the potential to balance out artifacts from many individual studies, thus leading to more robust results and subtle conclusions. This will require that data adhere to some type of uniform structure and format that would ideally be independent of the particular expression technology used to generate it. The pros and cons of various publication modalities for these large electronic data sets have been discussed elsewhere [12], but, practical difficulties aside, general depositing must occur for this technology to reach the broadest range of investigators. Finally, as mentioned at the beginning of this review, it is unfortunate that this important research tool remains largely restricted to a few laboratories that have developed expertise in this area and to a growing number of commercial interests. Ultimately the real value of microarray technology will only be realized when this approach is generally available. It is hoped that issues including platforms, instrumentation, clone availability, and patents [20] will be resolved shortly, making this technology accessible to the broadest range of scientists at the earliest possible moment.

Cell Line↗
PubMed1999

Indications for cholesterol-lowering medication: comparison of risk-assessment methods.

BACKGROUND: Recommendations for the prescription of lipid-lowering drugs emphasise the importance of an assessment of absolute coronary heart disease (CHD) risk based on all risk factors, rather than simply the serum cholesterol concentration. If, however, the methods recommended for risk assessment are inaccurate, recommended prescribing will not occur. We compared several sets of guidelines for such treatment in a series of patients referred to a lipid clinic, to assess the difference in degree of risk of CHD at which lipid-lowering medication is recommended by each set of guidelines. METHODS: For a series of 570 patients (50% men) without pre-existing clinical evidence of atherosclerosis referred to a lipid clinic, we compared the algorithms, charts, and tables used by the US National Cholesterol Education Program (NCEP), the joint guidelines of the European Society of Cardiology, the European Atherosclerosis Society, and the European Society of Hypertension, and the report of the UK Standing Medical Advisory Committee with the Framingham risk equation programmed into a computer. FINDINGS: In 386 patients for whom the NCEP and UK guidelines could be compared, 62% of the men and 72% of the women met NCEP criteria for lipid-lowering medication, whereas only 9% of the men and less than 1% of the women met the UK criteria. The Framingham equation estimated a CHD risk of more than 3% per year in 22% of the men and 7% of the women, which shows that the UK tables underestimated CHD risk. European guidelines could be applied to only 261 patients, and were reasonably accurate in assessment of a CHD risk of 2% per year. INTERPRETATION: Guidelines for the use of statin treatment in patients with CHD differ in their assessment of CHD risk. The method of risk assessment recommended in future guidelines for CHD prevention should be critically tested in relevant groups of patients.

Algorithms↗
PubMed1999

Expression profiling in cancer using cDNA microarrays.

Currently there are over 1,000,000 human expressed sequence tag (EST) sequences available on the public database, representing perhaps 50-90% of all human genes. The cDNA microarray technique is a recently developed tool that exploits this wealth of information for the analysis of gene expression. In this method, DNA probes representing cDNA clones are arrayed onto a glass slide and interrogated with fluorescently labeled cDNA targets. The power of the technology is the ability to perform a genome-wide expression profile of thousands of genes in one experiment. In our review we describe the principles of the microarray technology as applied to cancer research, summarize the literature on its use so far, and speculate on the future application of this powerful technique.

DNA, Complementary↗
PubMed1999

Nitric oxide synthase inhibitor attenuates intestinal damage induced by zinc deficiency in rats.

A nitric oxide synthase (NOS) inhibitor, NG-nitro-L -arginine methyl ester (L-NAME), was given to zinc-deficient (ZD) rats to determine whether it prevents the intestinal damage usually observed under these conditions. Weanling male rats were given free access to a ZD diet (2 mg zinc/kg), whereas control rats including pair-fed (PF) and ad libitum consumption (AL) groups were given a zinc-supplemented (50.8 mg zinc/kg) diet for 4 wk. Half of the ZD rats received L-NAME (0.3 g/L in drinking water) for 3 wk starting at the wk 2 of the deficient period. Plasma zinc concentration in ZD rats was significantly lower (P < 0.05) than that of AL and PF rats. Administration of L-NAME did not alter this concentration. Intestinal zinc concentration did not differ among groups. However, metallothionein-1 (MT-1) mRNA level was significantly lower in the intestine of ZD rats than in AL or PF rats. Treatment of ZD rats with L-NAME did not affect this level. Intestinal microvascular permeability evaluated by Evans blue showed significantly higher extravasation in ZD rats than in AL rats, whereas L-NAME administration inhibited the extravasation. Expression of inducible NOS mRNA was observed in intestine of ZD but not of AL or PF rats, and there was no significant difference between ZD rats, regardless of L-NAME treatment. The activity ratio of inducible NOS to total NOS in ZD rats not receiving L-NAME was significantly higher than that in AL rats or ZD rats treated with L-NAME (P < 0.05). The number of apoptotic-positive and goblet cells in intestinal villi was significantly higher in ZD rats compared with AL or PF rats. L-NAME administration in ZD rats reversed this effect. These results indicate that inhibition of NOS ameliorates zinc deficiency-induced intestinal damage in rats.

Animals↗
PubMed1999

Frequency and determinants of postprocedural hemodynamic instability after carotid angioplasty and stenting.

BACKGROUND AND PURPOSE: Hemodynamic instability can occur acutely after carotid angioplasty and stent placement (CAS). We performed this study to determine the frequency of hemodynamic instability in a series of patients who underwent CAS and to analyze factors associated with development of postprocedural hemodynamic events. METHODS: We reviewed medical records and angiograms in a series of 51 patients (mean age 68.3+/-8.9 years) who underwent CAS for symptomatic (n=29) or asymptomatic (n=22) carotid artery stenosis. Any episodes of hypotension (systolic blood pressure <90 mm Hg), hypertension (systolic blood pressure >160 mm Hg), or bradycardia (heart rate <60 bpm) that occurred in the acute postprocedural period were recorded. The effect of demographic, clinical, intraprocedural, and angiographic factors on subsequent development of hemodynamic instability was analyzed by logistic regression. RESULTS: The frequency of postprocedural hemodynamic complications in our patient series was as follows: hypotension, 22.4%; hypertension, 38.8%; and bradycardia, 27.5%. Intraprocedural hypotension (odds ratio [OR] 14.6, P=0.024) and history of myocardial infarction (OR 14.1, P=0.04) independently predicted postprocedural hypotension. Postprocedural hypertension was predicted by intraprocedural hypertension (OR 7.6, P=0.01) and previous ipsilateral carotid endarterectomy (OR 7.6, P=0.02). Postprocedural bradycardia was associated with intraprocedural hypotension (OR 74, P=0.001) and intraprocedural bradycardia (OR 12, P=0.008). All events had resolved at the conclusion of the intensive care unit monitoring period (mean 25.7 hours, range 18 to 43 hours). CONCLUSIONS: Postprocedural hemodynamic instability is frequent after CAS and supports the need for monitoring in settings suited to expeditious management of cardiovascular emergencies. Patients who have evidence of hemodynamic instability during the procedure are at highest risk.

Aged↗
PubMed1999

Prospective randomized trial of bilateral carotid endarterectomies: primary closure versus patching.

BACKGROUND AND PURPOSE: Although several studies have compared the results of carotid endarterectomy (CEA) with primary closure (PC) versus patch closure, none have compared the outcome of bilateral CEAs with patch versus PC performed on the same patient. This prospective randomized study compares the clinical outcome and incidence of recurrent stenosis (>/=80%) for CEA with PC versus patch closure in patients with bilateral CEAs. METHODS: This study includes 74 patients with bilateral CEAs with PC on one side and patching on the other. Patients were randomized to sequential operative treatment of either patching/PC or PC/patching. Postoperative duplex ultrasounds and clinical follow-up were done at 1, 6, and 12 months and every year thereafter. A Kaplan-Meier analysis was used to estimate the risk of significant restenosis (>/=80%). RESULTS: Demographic characteristics and the mean operative diameter of the internal carotid artery were similar for both PC and patching. The mean follow-up was 29 months (range, 6 to 65 months). The incidence of ipsilateral stroke was 4% for PC versus 0% for patching. PC had a significantly higher incidence of neurological complications (transient ischemic attacks and stroke combined) than patching (12% versus 1%; P=0.02). Operative mortality was 0%. PC had a higher incidence of recurrent stenosis (22% versus 1%; P<0.003) and total internal carotid artery occlusion (8% versus 0%; P=0.04) than patching. Restenoses necessitating a repeated CEA were also higher for PC (14%) than for patching (1%; P=0.01). The Kaplan-Meier analysis showed that patching had a significantly better cumulative patency rate than PC (P<0.01). This analysis also showed that freedom from recurrent stenosis at 24 months was 75% for PC and 98% for patching. CONCLUSIONS: Patch closure is less likely than PC to cause ipsilateral stroke, transient ischemic attacks, and recurrent carotid stenosis. The higher rate of unilateral recurrent stenosis may suggest that local factors play a more significant role than systemic factors in the etiology of recurrent carotid stenosis.

Carotid Arteries↗
PubMed1998

Gene expression profiling of alveolar rhabdomyosarcoma with cDNA microarrays.

Several forms of human sarcoma, lymphoma, and leukemia are characterized by somatically acquired chromosome translocations that result in fusion genes that encode chimeric transcription factors with oncogenic properties. We have used cDNA microarrays containing 1238 cDNAs to investigate the gene expression profile of a group of seven alveolar rhabdomyosarcoma (ARMS) cell lines characterized by the presence of the PAX3-FKHR fusion gene. Using the method of multidimensional scaling to represent the relationships among the cell lines in two-dimensional Euclidean space, we determined that ARMS cells show a consistent pattern of gene expression, which allows the cells to be clustered together. By searching across the seven ARMS cell lines, we found that 37 of 1238 genes were most consistently expressed in ARMS relative to a reference cell line. Only three of these genes have been previously reported to be expressed in ARMS. Among these 37 were genes related to both primary (PAX3-FKHR) and secondary (CDK4) genetic alterations in ARMS. These results in ARMS demonstrate the potential of cDNA microarray technology to elucidate tumor-specific gene expression profiles in human cancers.

Chromosomes, Human, Pair 13↗