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Biomedical subjects

N Khan

Publications and source records attributed to N Khan.

At least 19 recordsLinked to original sources
PubMed2016

Characterization of a novel adeno-associated viral vector with preferential oligodendrocyte tropism.

No adeno-associated virus (AAV) capsid has been described in the literature to exhibit a primary oligodendrocyte tropism when a constitutive promoter drives gene expression, which is a significant barrier for efficient in vivo oligodendrocyte gene transfer. The vast majority of AAV vectors, such as AAV1, 2, 5, 6, 8 or 9, exhibit a dominant neuronal tropism in the central nervous system. However, a novel AAV capsid (Olig001) generated using capsid shuffling and directed evolution was recovered after rat intravenous delivery and subsequent capsid clone rescue, which exhibited a >95% tropism for striatal oligodendrocytes after rat intracranial infusion where a constitutive promoter drove gene expression. Olig001 contains a chimeric mixture of AAV1, 2, 6, 8 and 9, but unlike these parental serotypes after intravenous administration Olig001 has very low affinity for peripheral organs, especially the liver. Furthermore, in mixed glial cell cultures, Olig001 exhibits a 9-fold greater binding when compared with AAV8. This novel oligodendrocyte-preferring AAV vector exhibits characteristics that are a marked departure from previously described AAV serotypes.

Animals↗
PubMed1998

Preparation of brain-derived neurotrophic factor- and neurotrophin-3-secreting Schwann cells by infection with a retroviral vector.

One reason that the central nervous system of adult mammals does not regenerate after injury is that neurotrophic factors are present only in low concentrations in these tissues. Recent studies have shown that the application of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) acts to encourage the regrowth of motor and sensory fibers after spinal cord injury. Other studies have reported that the regrowth of axons after injury was enhanced by the implantation of Schwann cells, which normally secrete BDNF and NT-3. The purpose of the present study was to genetically modify Schwann cells to secrete increased amounts of BDNF or NT-3 by infection with a retroviral vector. Retroviral vectors were constructed by the ligation of BDNF or NT-3 cDNA to the LXSN vector. Viruses were generated from the plasmid forms of the vectors by transient transfection of PA317 amphotrophic retroviral packaging cells. Viruses were harvested and used to infect the human Schwann cell line designated NF-1T. Northern blot analysis of poly (A+) RNA prepared from Schwann cells that were infected with BDNF- or NT-3-containing virus showed the presence of BDNF or NT-3 mRNA. An enzyme-linked immunosorbent assay (ELISA) for BDNF and NT-3 was performed on media the cells were grown in, and on cellular extracts prepared from the BDNF- and NT-3-infected Schwann cells. The ELISA results demonstrated that the Schwann cells were secreting increased levels of immunologically active BDNF or NT-3. Immunocytochemical staining of these cells revealed the presence of these two neurotrophic factors located in perinuclear granules. These neurotrophic factor-secreting Schwann cells are currently being evaluated for their efficacy in the treatment of spinal cord injury.

Adult↗
PubMed1998

Studies of endothelin-converting enzyme in bovine endothelial cells and vascular smooth-muscle cells: further characterization of the biosynthetic process.

Endothelin-1 (ET-1) is synthesized by a number of cell types, including endothelial, epithelial, and smooth muscle cells. Initial biosynthesis occurs as a protein precursor, preproendothelin-1 (preproET-1). This is processed intracellularly to the inactive intermediate big ET-1, which is hydrolyzed by endothelin-converting enzyme (ECE) to generate ET-1, but the precise identity of the physiologically relevant ECE has yet to be confirmed. Although ET-1 is synthesized in the constitutive secretory pathway, many features of the selective processing of proET-1 are comparable to those of peptide hormones. We describe here experimental investigations aimed at defining the regulation of ET-1 synthesis and its relationship to the biosynthesis of ECE.

Animals↗
PubMed1998

Temporal variability of asymptomatic embolization in carotid artery stenosis and optimal recording protocols.

BACKGROUND AND PURPOSE: Although asymptomatic embolization can be detected in patients with carotid artery stenosis, its temporal variability is unclear. An understanding of this is important in designing optimal recording protocols for future prospective studies of the predictive value of embolic signals (ES). We determined the effect of repeating and extending recording times in patients with symptomatic and asymptomatic carotid stenosis. METHODS: In 20 asymptomatic and 20 symptomatic subjects with > 60% carotid stenosis, we used transcranial Doppler ultrasound to record for ES in the ipsilateral middle cerebral artery. Three 1-hour recordings were performed on three separate days, and on one occasion (not necessarily the first) the recording was extended to 2 hours. The recordings were saved onto digital tape for subsequent blinded analysis. RESULTS: Marked temporal variability was seen in symptomatic patients in whom the cumulative proportion of subjects with ES increased from 10 (50%) after a single hour of recording to 12 (60%) and 15 (75%) after two and three recordings, respectively. Extending the recording to 2 hours increased the yield of ES-positive patients from 6 (30%) to 8 (40%). In symptomatic patients there was excellent agreement between whether patients were positive for ES during each of two consecutive 1-hour recordings (kappa = 0.78, P = 0.0003) but poor agreement between the results of two single-hour recordings performed on different days (kappa = 0.22, P = 0.27). In asymptomatic patients, 4 (20%) were ES positive during the first hour; this increased to 5 (25%) after the recording was repeated once, with no further increase after the third recording. Extending the recording to 2 hours increased the yield from 3 (15%) to 7 (35%). In contrast to symptomatic stenoses, in patients with asymptomatic stenoses there was fair agreement between whether patients were ES positive on two consecutive 1-hour recordings (kappa = 0.49, P = 0.01) or two single-hour recordings performed on different days (kappa = 0.48, P = 0.02). Symptomatic subjects were more likely to have ES (when all 1-hour recordings were considered, 24/60 versus 10/60; P = 0.0046). ES in symptomatic subjects had a higher relative intensity increase than in asymptomatic subjects (P = 0.01). CONCLUSIONS: The temporal variability of ES needs to be taken into account in the design of optimal recording protocols and comparisons of results from different studies. Extending the duration of recording beyond an hour in symptomatic stenoses is of less value, but repeating the recording on a different day will often identify additional subjects with ES. In intervention studies in symptomatic patients, the time since last symptoms must be considered. In asymptomatic stenosis, extending the duration of recording beyond an hour will increase the proportion of patients positive for ES.

Adult↗
PubMed1997

Identification of two glycoforms of the MUC5B mucin in human respiratory mucus. Evidence for a cysteine-rich sequence repeated within the molecule.

It has been demonstrated previously that respiratory secretions contain three oligomeric, gel-forming mucins; one of these was identified as the product of the MUC5AC gene (1). Here we demonstrate that the other two mucins are glycoforms of the MUC5B gene product. This was accomplished by trypsin treatment of the purified reduced mucin subunit populations and N-terminal sequencing of the liberated peptides. The products of trypsin digestion were separated by gel filtration into high molecular weight mucin glycopeptides and low molecular weight tryptic peptides. The latter were fractionated by reverse phase chromatography, and four of the major peptides were sequenced. Three of these peptides were identical to and contiguous within a 51-amino acid sequence deduced from a cDNA clone (JER57) encoding a portion of the MUC5B mucin. The other peptide is also present within this sequence but showed identity in only 9 of its 10 residues. A polyclonal antiserum raised against one of these peptides was reactive with the two putative MUC5B glycoforms. Analysis of the high molecular weight glycopeptides indicated that the MUC5B subunit contained different types and lengths of glycosylated domains; one domain of Mr 7.3 x 10(5), two domains of Mr 5.2 x 10(5), and a third domain of Mr 2.0 x 10(5). The amino acid composition of the larger two glycopeptides was similar in serine, threonine, and proline content but distinct from that of the smallest glycopeptide. Each of these domains in the mucin subunit is separated by a trypsin-sensitive region, and the relative abundance of the major peptides derived by proteolysis of these regions and their occurrence in a contiguous sequence suggest that they contain a common cysteine-rich motif.

Amino Acid Sequence↗
PubMed1997

The anterior and posterior selective temporal lobe amobarbital tests: angiographic, clinical, electroencephalographic, PET, SPECT findings, and memory performance.

The techniques, results, and problems of three types of selective temporal lobe (TL) amobarbital procedures (balloon technique with temporary occlusion of the internal carotid artery distal to the origin of the anterior choroidal artery (acha) [n = 19]; selective anterior catheterization of the acha [n = 20]; and selective catheterization of the peduncular P2-segment of the posterior cerebral artery [n = 5]) are described in a group of 40 patients with medically refractory complex partial seizures of mesial TL origin. Selective amobarbital tests were carried out before surgery to predict the memory deficit after an intended selective amygdalohippocampectomy. The effects of selective anaesthetization of TL were correlated with clinical data, pattern and duration of amobarbital induced EEG changes, and performance on verbal and nonverbal memory tasks measured during the test. In 4 patients the effect of selective amobarbital injection on regional and global metabolism was studied with 18F-FDG-PET, with the PET tracer being injected intravenously immediately after amobarbital. More recently in 2 patients the vascular territory perfused by amobarbital in the acha test was studied with SPECT using 99m Tc ECD injected immediately prior to the amobarbital into the acha. Whereas the PET studies showed a rather widespread and bilateral amobarbital-induced decrease of metabolism, the SPECT studies confirmed the selective distribution of the tracer in the vascular territory of the acha, i.e., in amygdala and hippocampus. The comparison of selective TL amobarbital test performance with postoperative neuropsychological performance showed that the predictive value of this test is rather good for the postoperative verbal memory but underestimates postoperative nonverbal ("figural") memory performance.

Adult↗
PubMed1997

Combining cultural, social and personality trait variables as predictors for drug use among adolescents in Zimbabwe.

A classroom survey among 3061 secondary school students in four provinces in Zimbabwe was conducted in 1994. This paper presents analyses of the relationship between a set of predictors including personality trait, social and cultural variables and drug use. A two-stage sampling strategy distinguished between four different socio-cultural groups. Multiple regression was applied to analyse the impact of sensation-seeking, addictive behaviour of significant others, and Global and Local cultural orientation on drug use, controlling for age, gender and socio-cultural subgroup. The model explained 29.7% of the variance in the dependent drug use variable and the two cultural orientation variables were found to contribute significantly in addition to the personality trait and the social variables.

Adolescent↗
PubMed1997

Presence of 11 beta-hydroxysteroid dehydrogenase in human semen: evidence of correlation with semen characteristics.

11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), the enzyme that catalyzes the conversion of biologically active glucocorticoids to their inactive metabolites, was shown to be located exclusively in Leydig cells of the rat testis, and its appearance was associated with the developmental rise in testosterone. Thus, 11 beta-HSD was suggested to play an important role in maintaining steroidogenesis by inactivating excess cortisol that inhibits testosterone production. Whether equivalent protection from glucocorticoids excess is necessary for spermatogenesis is not known, and we have, accordingly, investigated the 11 beta-HSD activity in ejaculated human semen. Both 11 beta-dehydrogenase (11 beta-DH) and 11 beta-oxoreductase (11-OR) activities of 11 beta-HSD were measurable in semen, although seminal plasma was devoid of 11 beta-HSD activity. Azoospermic specimens were associated with low 11 beta-dehydrogenase activity, indicating the presence of enzyme activity in cells other than spermatozoa. Pure spermatozoa separated on percoll gradient could oxidize corticosterone in the presence of NAD or NADP. Significantly higher 11 beta-DH activity is associated with semen specimens with low sperm count (p < .05) and higher level of morphologically abnormal spermatozoa (p < .05). The presence of 11 beta-HSD in human semen and its association with sperm characteristics thus suggests functional role for glucocorticoid exclusion in the sperm maturation process.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1997

Thalamic glucose metabolism in temporal lobe epilepsy measured with 18F-FDG positron emission tomography (PET).

Thalamic glucose metabolism has been studied in 24 patients suffering from temporal lobe epilepsy (TLE) using interictal 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET). A total of 17 patients had a unilateral TL seizure onset, 11 of these patients had a mesial temporal lobe epilepsy syndrome (MTLE), with mesial gliosis and a mesial TL seizure origin. Three patients had a lateral TL seizure origin, and 3 patients had mesial TL tumors. Bilateral TLE was assumed in 7 patients. Only in the patient group with MTLE (n = 11), the ipsilateral thalamic glucose uptake showed a statistically significant lower value when compared to the thalamus of the contralateral side (Wilcoxon paired sign test, P = 0.012). There was a more pronounced hypometabolism in right TLE compared to left TLE. A 'hypersynchronous seizure onset pattern' in ictal EEG was only seen in 6 (26%) patients (1 patient with bilateral, 5 with unilateral TLE). No correlation existed between the thalamic, temporal glucose metabolism and the 'hypersynchronous seizure onset pattern'.

Adult↗
PubMed1997

Dental fluorosis in 12-15-year-old rural children exposed to fluorides from well drinking water in the Hail region of Saudi Arabia.

To investigate the relationship between fluoride levels in well drinking water, severity of dental fluorosis and dental caries in the Hail region of Saudi Arabia, 2355 rural children aged 12-15 years were examined. Over 90% of the children had fluorosed teeth and chi-square tests showed a strong association (P < 0.001) between fluoride level (0.5-2.8 ppm) in well drinking water and severity of dental fluorosis. Although regression analysis showed a statistically significant relationship (P < 0.001) between fluoride concentration and caries experience, the amount of variation explained was very low (R2 = 0.9%). Since fluoride in well water had little influence on caries experience and is causing dental fluorosis, it should be removed by defluoridation or the rural population should be provided with an alternative source of drinking water with lower fluoride concentration.

Adolescent↗
PubMed1997

Identification of conserved aromatic residues essential for agonist binding and second messenger production at 5-hydroxytryptamine2A receptors.

Several models of agonist binding to G protein-coupled 5-hydroxytryptamine [5-HT] (serotonin) receptors have highlighted the potential importance of highly conserved aromatic residues for ligand binding and agonist efficacy. In this study, we tested these models by constructing and characterizing a number of point mutations of conserved and nonconserved aromatic residues using the 5-HT2A receptor as a model system. Mutations of three highly conserved tryptophans (W200A, W336A, and W367A) proposed to reside near the binding pocket markedly reduced agonist affinity and efficacy at 5-HT2A receptors. Mutations of two other highly conserved aromatic residues postulated to be near the agonist binding site (F340L and Y370A) also had dramatic effects on agonist binding and efficacy. Point mutations of neighboring conserved phenylalanines (F339L and F365L) had minimal effects on agonist binding, although the F365L mutation diminished agonist efficacy. Finally, mutations of two nonconserved aromatic residues (F125L and F383A) not predicted to be near the binding pocket had no effects on agonist binding, potency, or efficacy. Our results are best explained by models that suggest that helices III, V, VI, and VII can form a unit of interacting helices in which highly conserved aromatic residues are oriented toward the center of the helical aggregate to form an aromatic pocket. In addition, our novel results identify a series of aromatic residues essential for agonist-induced second messenger production. These results demonstrate that highly conserved aromatic residues residing in neighboring helices provide the optimum environment for both agonist binding and activation of 5-HT2A receptors.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1997

Cerebral metabolic changes (18F-FDG PET) during selective anterior temporal lobe amobarbital test.

Cerebral glucose utilisation using 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) was measured in 4 patients with temporal lobe epilepsy during a selective anterior temporal lobe (TL) amobarbital test (ATLAT) and compared with their baseline values. 18F-FDG was injected intravenously immediately after administration of amobarbital into the anterior choroidal artery (acha) in the case of the superselective ATLAT and into the territories of acha, posterior communicating artery, and ophthalmic artery in the case of the ATLAT using the temporary balloon occlusion technique. A decrease in glucose uptake as a result of amobarbital application was observed in ipsilateral temporolateral (4 patients), ipsilateral temporomesial (2 patients) and bilateral frontolateral (1 patient) cortices. All patients showed decreased glucose uptake in contralateral temporolateral regions. Cerebellar diaschisis was observed in 2 patients. In conclusion, although aimed at selective inactivation of the mesiobasal TL structures, the ATLAT does not result in exclusive selective glucose hypometabolism of these structures. Relatively widespread ipsilateral and contralateral effects were observed suggesting local and remote metabolic deafferentation. No association was observed between the glucose uptake, clinical or memory performance.

Adolescent↗
PubMed1997

Role of serotonin in fish immunomodulation

In the recent past, the importance of the fish brain monoaminergic system in aggression, mating and feeding has been documented. There are several apparent similarities between the functioning of the fish and mammalian monoaminergic systems. In fish, the hypermetabolism of catecholamines (norepinephrine and dopamine) and indoleamine (serotonin, 5-hydroxytryptamine, 5-HT) has been found to be associated with stressful conditions. In contrast to the situation in mammals, these monoamines can pass through the blood&shy;brain barrier in teleost fishes, contributing to the high levels of biogenic amines in the periphery. Hence, high levels of serotonin in the peripheral circulation, during different stressful conditions, may influence the functioning of other physiological systems, notably the immune system. Serotonin is also stored in considerable amounts by mast cells and platelets, and can be synthetized by chromaffin cells. In mammals, it has been established that 5-HT modulates immune function at a variety of levels. However, little is known about the role of serotonin in the functioning of the immune system in fish. In this perspective article, we will discuss our results and the findings of other laboratories, although meagre on this subject, on the possible role of serotonin in the functioning of immunocompetent cells in fish.

Journal Article↗
PubMed1997

Dental erosion associated with soft-drink consumption in young Saudi men.

This study reports on the causative factors of dental erosion in selected high- (n = 19) and low-erosion (n = 19) subgroups of a larger random sample (n = 95) of young male Saudi military inductees. By means of a questionnaire, the role of various possible factors related to oral health in general, and to dental erosion in particular, was assessed for each participant. Clinical examination included recordings of severity of dental erosion and fluorosis, presence of buccal cervical defects and first permanent molar 'cuppings', DMFT and DMFS, visible plaque index, and gingival bleeding index. In addition, bitewing radiographs, study casts, and intraoral color transparencies were obtained for each individual. Logistic regression analysis showed a strong correlation between the presence of dental erosion and a high level of consumption of cola-type soft drinks. Other statistically significant associated factors, although of less predictive strength, were type of cleaning aid and gingival bleeding index. In subgroup comparisons, dental problems (primarily pain), number of buccal cervical defects, and number of missing teeth were significantly greater in the high- than in the low-erosion subgroup.

Adult↗
PubMed1997

Serum creatine kinase kinetics after endomyocardial biopsy in cardiac transplant patients.

The objective of this study was to define the changes in serum creatine kinase (CK) and creatine kinase-MB isoenzyme (CK-MB) activities following endomyocardial biopsy. Ten cardiac transplant recipients underwent routine surveillance endomyocardial biopsy via the right internal jugular vein with single-use disposable bioptomes. Serum CK and CK-MB levels were measured at baseline and post-biopsy at 15, 30, and 45 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16, 20, and 24 hours. There was no significant increase in serum total CK after biopsy. No measurable change in CK-MB was observed in 40% of patients. CK-MB increased significantly in the remaining patients (N = 6) at 30 minutes (p < 0.05), and continued to rise to a peak at 4 hours post-biopsy, after which CK-MB gradually decreased to baseline. However, the increase in CK-MB did not meet criteria for the diagnosis of myocardial necrosis, hence should not be confused with the change in CK-MB occurring with myocardial infarction. These findings suggest that serum CK-MB activity is useful in the differential diagnosis of chest pain in cardiac transplant patients in the setting of recent biopsy.

Adult↗
PubMed1997

High-affinity agonist binding is not sufficient for agonist efficacy at 5-hydroxytryptamine2A receptors: evidence in favor of a modified ternary complex model.

In this study, the relationship between high-affinity agonist binding and second messenger production was examined at native and mutant 5-hydroxytryptamine2A receptors. At native 5-hydroxytryptamine2A receptors all agonists, with the exception of quipazine, discriminated between high- and low-affinity states of the receptor, as determined by analysis of competition binding assays. There was no correlation between the ability of selected agonists to label the high-affinity agonist state and to augment phosphoinositide hydrolysis. Quipazine, which did not discriminate between the affinity states of the receptor, behaved as a full agonist. Similar results were obtained when a point mutation (F340L) of a highly conserved phenylalanine located in transmembrane domain VI was examined. With the F340L mutant, most of the agonists tested labeled significantly fewer high-affinity sites, compared with the native receptor. There was no significant relationship between high-affinity agonist binding and second messenger production. Bufotenine and 4-iodo-3,5-dimethoxyphenylisopropylamine labeled similar percentages of high-affinity agonist binding sites (22% vs. 26%), but 4-iodo-3,5-dimethoxyphenylisopropylamine behaved as a full agonist, whereas bufotenine was devoid of detectable agonist activity. The inability of selected agonists to activate phosphoinositide hydrolysis was not due solely to lower agonist affinity for the mutant receptor, because the binding affinity of quipazine was unchanged by the F340L mutation but quipazine had no detectable agonist activity at the mutant receptor. Our results demonstrate that the ability of an agonist to promote the high-affinity state of the 5-hydroxytryptamine2A receptor is not correlated with its ability to augment second messenger production. These results are consistent with recent models of G protein-receptor functioning (e.g., modified ternary complex model) that predict that additional transition states of the receptor-ligand complex are essential for agonist efficacy.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1997

Comparative evaluation of breast lesions with the help of impression smears, histopathology and mammography.

A total of 148 surgically removed benign and malignant breast lesions were studied to correlate cytomorphologial features in impression smears and histopathological sections. Mammograms were taken prior to surgery. Role of mammography in detection of non-palpable breast lesions was enlightened. Impression smears helped in quick diagnosis (intraoperative) and overall accuracy obtained was 97.4%. Cluster predominant and Grade II nuclear grading on smear pattern was seen in 58.8% and 57.4% cases respectively amongst the 68 malignant cases. 45% cases revealed non-palpable breast lesions on mammography which was later confirmed on histopathology.

Breast Diseases↗