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Biomedical subjects

I M Khan

Publications and source records attributed to I M Khan.

At least 19 recordsLinked to original sources
PubMed2001

Expression of clusterin in the superficial zone of bovine articular cartilage.

OBJECTIVE: To investigate the differences between chondrocytes of the superficial and underlying zones of articular cartilage at the level of gene expression. METHODS: Messenger RNA (mRNA) was isolated from chondrocytes harvested from the superficial and deep zones of immature bovine articular cartilage. This mRNA was reverse transcribed, radiolabeled, and then each complementary DNA (cDNA) sample was used to screen duplicate filters of a bovine chondrocyte cDNA library. By comparing autoradiographic signals on matching filter sets, clones exclusively expressed in the superficial zone of articular cartilage were isolated and characterized further. RESULTS: Of the superficial-specific gene clones isolated, 25% were found to be a single gene product, clusterin. Northern hybridization was used to show that clusterin is expressed specifically in the superficial zone of articular cartilage and that its expression is up-regulated in mature cartilage. In situ hybridization was used to precisely localize clusterin transcripts in articular cartilage, where it was found that clusterin expression was confined to the articular surface in both immature and mature samples. CONCLUSION: The discovery of clusterin expression at the articular cartilage surface extends previous observations that superficial articular chondrocytes are highly specialized cells. Clusterin is a multifunctional, secreted glycoprotein that has been shown to be expressed in diverse locations that have in common a tissue-fluid boundary. Additionally, clusterin has been implicated in regulating complement activation and cell death in injured and degenerating tissues.

Animals↗
PubMed2001

Spinal nicotinic receptor activity in a genetic model of hypertension.

Intrathecal cytisine, a nicotinic receptor agonist, elicits greater dose-dependent increases in blood pressure, heart rate and nociceptive responses in SHR than normotensive rat strains. Similar to adult rats, cardiovascular and nociceptive responses were augmented in prehypertensive SHR than age-matched WKY. While hydralazine or captopril pretreatment significantly lowered blood pressure in both SHR and WKY rats, responses to i.t. cytisine were still greater in SHR. By contrast, i.t. cytisine elicited responses were not exaggerated in DOCA-salt hypertensive WKY rats. Pressor and irritation responses to i.t. cytisine can be divided into a transient, initial and persisting, late phases. Both are augmented in SHR. In F1 rats, only the late phase pressor and pain responses to i.t. cytisine are similar in magnitude to those observed in SHR suggesting a possible dominant trait in the SHR. Overall, our findings suggest that hyper-responsiveness in nociception and pressor activity to spinal cytisine in SHR may be pathogenetically associated, but not a consequence, of hypertension.

Alkaloids↗
PubMed2001

A-85380 and epibatidine each interact with disparate spinal nicotinic receptor subtypes to achieve analgesia and nociception.

Nicotinic agonists, such as epibatidine (EPI) and A-85380, when administered systemically, elicit analgesia. Intrathecal EPI also produces analgesia accompanied by nociceptive and pressor responses. Since spinal administration of drugs offers a well defined pathway connecting the site of administration with behavioral and autonomic responses, we have compared the responses to intrathecal epibatidine and A-85380 to delineate the role of nicotinic acetylcholine receptors in spinal neurotransmission. Following implantation of intrathecal catheters in rats, we monitored cardiovascular, nociceptive, and antinociceptive responses after administration of various nicotinic receptor agonists. Consistent with A-85380 displacement of epibatidine from isolated spinal cord membranes, A-85380 elicited pressor, nociceptive, and antinociceptive responses similar to EPI. Antinociception was preceded by nociception. Both antinociception and nociception were blocked by mecamylamine, methyllycaconitine, and alpha-lobeline, but dihydro-beta-erythroidine only blocked the antinociceptive response. Whereas prior administration of EPI desensitized the nociceptive and antinociceptive responses to EPI, A-85380 pretreatment only desensitized EPI-elicited nociception and not antinociception. 2-Amino-5-phosphopentanoic acid pretreatment blocked the nociceptive response to A-85380, indicating A-85380 stimulated release of glutamate onto N-methyl-D-aspartate receptors to produce the irritant response of nociception. Intrathecal phentolamine virtually abolished A-85380 antinociception, but had no effect on EPI antinociception. Hence, analgesia can be produced by stimulation of distinct spinal preterminal nicotinic receptor subtypes, resulting in the release of neurotransmitters. In the case of A-85380, these sites primarily appear to be localized on adrenergic bulbospinal terminals. Our data suggest that A-85380 and EPI act at separate preterminal spinal sites as well as on distinct nicotinic receptor subtypes to elicit an antinociceptive response at the spinal level.

Analgesics, Non-Narcotic↗
PubMed2000

Organization and conservation of the GART/SON/DONSON locus in mouse and human genomes.

The SON gene, which maps to human chromosome 21q22.1-q22.2, encodes a novel regulatory protein. Here we describe the organization of the Son locus in the mouse genome. The mouse Son gene spans a region of approximately 35 kb. The coding region is more than 8 kb in length and has been completely sequenced. The gene is organized into 11 coding exons and 1 noncoding 3'UTR exon, with over 70% of the coding region residing in one 5.7-kb exon. The gene contains at least one alternative exon, N/C exon 1, which can be used, by splicing, to generate a truncated form of the SON protein. Further investigation of the mouse Son locus has identified the genes directly flanking Son. The glycinamide ribonucleotide formyltransferase gene, Gart, is encoded 5' of Son in a head-to-head arrangement, with the start of both genes lying within 899 bp. Sequence comparison with the expressed sequence tagged database identified a novel gene within 65 bp of the 3' end of Son, which we have named Donson. In this unusually compact gene cluster, we have found overlap in the pattern of expression between Gart, Son, and Donson. However, at least two of these genes have very different functions. While GART is involved in purine biosynthesis, we find that SON shows the characteristics of "SR- type" proteins, which are involved in mRNA processing and gene expression.

Amino Acid Sequence↗
PubMed1998

Catalytic thiol and carboxylate: role of cysteine and glutamic acid in the xylosidic activity of endoxylanase from Chainia sp. (NCL 82-5-1).

Chemical modification of the endoxylanase from Chainia sp. with group-specific chemical modifiers in the absence and presence of substrate and kinetics of modification revealed the involvement of a thiol and a carboxylate in the catalytic function of the enzyme. The active-site peptides were chemically labeled and sequenced. The sequence alignment of the chemically labeled peptide with other family G/11 xylanases showed that the catalytic glutamate of Chainia xylanase is located in a highly homologous region and may function as an acid/base catalyst while thiol of the Cys may function as a nucleophile.

Amino Acid Sequence↗
PubMed1998

Nociceptive and antinociceptive responses to intrathecally administered nicotinic agonists.

Activation of spinal nicotinic receptors evokes a prominent algogenic response. Recently, epibatidine, a potent nicotinic agonist, was found to display an antinociceptive response after systemic administration. To examine the spinal component of this action, effects of three nicotinic agonists epibatidine, cytisine and nicotine--were given intrathecally (IT) and their antinociceptive activity was subsequently assessed. All agents elicited dose-dependent algogenic activity, characterized at lower doses by touch-evoked hyperactivity and at higher doses by intermittent vocalization and marked behavioral activity, with the rank order of potency being epibatidine > cytisine > nicotine. In addition, intrathecal epibatidine elicited a short-lasting, dose-dependent thermal antinociception. In contrast, the other nicotinic agonists at the highest usable dose failed to produce a significant antinociception. Mecamylamine, a nicotinic channel blocker, completely abolished the antinociceptive and algogenic responses of epibatidine. The competitive antagonist, alpha-lobeline, blocked both the analgesic and algogenic responses, but methyllycaconitine inhibited only the algogenic effects of epibatidine. Dihydro-beta-erythroidine, also a competitive antagonist, had no effect on the initial intense algogenic responses. The analgesic response to epibatidine was neither inhibited by naloxone nor by atropine. 2-Amino-5-phosphopentanoic acid, a competitive N-methyl-D-aspartate receptor antagonist, did not affect the analgesic response to intrathecal epibatidine or the intense initial algogenic response. Upon repeated administration (30-min interval), epibatidine (1 microg, IT) exhibited marked and rapid desensitization to both the analgesic and algogenic responses which recovered within 8 h. Pretreatment with two consecutive doses of cytisine (5 microg, IT, 30-min apart) inhibited the agitation and analgesic actions of intrathecal epibatidine. Thus, we contend that in addition to the typical nociceptive response elicited by spinal nicotinic agonists, intrathecal epibatidine also exhibits a pronounced but short-lasting antinociception. The analgesic and algogenic responses to intrathecal epibatidine may be mediated by distinct subtypes of spinal nicotinic receptors as suggested by the antagonist studies.

Alkaloids↗
PubMed1997

Epibatidine binding sites and activity in the spinal cord.

Epibatidine has been shown to be the most potent nicotinic agonist in several neuronal nicotinic receptor preparations. Similar to other nicotinic agonists, intrathecal (-)-epibatidine elicits dose-dependent increases in pressor, heart rate and pain responses in rats, as well as an increase in latency to withdraw from a noxious thermal stimulus. The latter response requires higher doses and is of shorter duration, suggesting interaction with multiple subtypes of spinal nicotinic receptors. In the present study, we relate the binding properties of (+/-)-[3H]epibatidine in spinal cord membrane preparations to the cardiovascular and behavioral responses. Unlike (-)-[3H]cytisine or (-)-[3H]nicotine, (+/-)-[3H]epibatidine reveals two sites; the ratio of high affinity to low affinity sites is 2:1. The rank ordering of potencies of the nicotinic agonists in displacing (+/-)-[3H]epibatidine binding from spinal cord membranes correlates with the potencies in eliciting cardiovascular and behavioral responses upon spinal administration. The nicotinic receptor antagonists, alpha-lobeline, dihydro-beta-erythroidine and methyllycaconitine, also displayed similar rank ordering of potencies in displacing (+/-)-[3H]epibatidine, (-)-[3H]cytisine or (-)-[3H]nicotine binding to spinal nicotinic receptors. Virtually all the nicotinic analogs exhibited a Hill coefficient of less than one in competing with (+/-)-[3H]epibatidine to spinal cord membranes indicating their interaction with at least two classes of binding sites. Intrathecal (-)-epibatidine, in addition to eliciting an initial and subsequently a sustained pressor and tachycardic response, also exhibited a transient intervening bradycardia which coincided temporally with the duration of the analgesia. Repeated administration of (-)-epibatidine desensitized its responses as well as the cardiovascular and behavioral responses to spinal nicotine and cytisine. Intrathecal alpha-lobeline showed selectivity for blocking the analgesic response, whereas methyllycaconitine exhibited selectivity for the pressor and irritation responses. The NMDA receptor antagonist, AP-5, inhibited the pressor, tachycardic and irritation responses elicited by intrathecal (-)-epibatidine, confirming a role for spinal excitatory amino acids released by the nicotinic agonist.

Animals↗
PubMed1996

Day-case laparoscopic hernia repair.

Some 114 patients (median age 52 years) underwent laparoscopic hernia repair as a day-case procedure. Twenty-one patients had bilateral and 11 recurrent hernias. Some 113 patients underwent transabdominal preperitoneal mesh repair but one required conversion to open operation. Mean operating time was 24 min for unilateral and 38 min for bilateral repair. In an operating session of 3.5 h, up to five patients (mean 4.4) underwent surgery and as many as seven hernias were repaired. More than 10 per cent of patients were found to have a previously undiagnosed hernia on the opposite side. A total of 111 patients were discharged home on the day of surgery. Major complications included one omental bleed and one small bowel obstruction. Seroma was the commonest minor complication and occurred in 7 per cent of patients. More than 35 per cent of patients needed no postoperative analgesia. To date there has been one recurrence (follow-up range 2-18 months).

Adult↗
PubMed1996

Carcinoma of the ampulla of Vater: a tumour with a poor prognosis?

OBJECTIVE: To assess the overall prognosis of patients with ampullary carcinomas and evaluate the presentation, diagnosis, pathology and management of these potentially highly curable tumours, attempting to relate these factors to overall survival. PATIENTS AND METHODS: Forty patients with ampullary carcinoma were reviewed. Age, Sex, nature and duration of history, laboratory information at admission, results of diagnostic radiology, endoscopic retrograde cholangiopancreatograms and pathological findings were considered. Both curative and palliative management strategies were reviewed. RESULTS: The overall median survival was 19 months. The median duration of history was 5.9 +/- 5.4. weeks, with no significant difference in survival between patients with short and those with long histories (P = 0.46). Twenty nine (73%) patients were potentially resectable, but only 15 (37%) underwent potentially curative surgery. The difference in survival between the Whipple's (13) and the endoscopically stented (20 ) groups was not significant (p = 0.08). The Whipple's group were significantly younger than the stented group (P = 0.001) and had a significant operative morbidity, re-operation rate (38%) and post-operative mortality (15%). Only five of 13 patients were alive following Whipple's treatment after a mean follow-up of 18.9 months. Sphincterotomy before Whipple's treatment improved survival significantly (P = 0.04); absence of jaundice, exophytic macroscopic appearance, well-differentiated tumours and early stage were also associated with good survival. Endoscopic retrograde cholangiopancreatography has a high diagnostic yield and a low associated morbidity and mortality, with endoscopic papillectomy aiding cannulation while effective palliation was provided through stenting, endoscopic papillectomy and laser debulking of obstructing tumours. Little benefit was obtained from chemoradiotherapy. CONCLUSION: Despite the potential for curative resection in patients with ampullary carcinoma, the majority of such patients are unsuitable for curative surgery on grounds of age, general health status or advanced disease; since only 37% of patients undergo potentially curative surgery the condition has a poor prognosis.

Aged↗
PubMed1996

Spinal nicotinic receptor expression in spontaneously hypertensive rats.

Intrathecal administration of nicotinic agonists previously has been shown to result in exaggerated pressor and heart rate responses as well as greater nociceptive behavior in adult (12-week-old) spontaneously hypertensive rats (SHR) than in age-matched normotensive Wistar-Kyoto rats (WKY). Paradoxical to these augmented responses to nicotinic agonists in SHR, nicotinic receptor number in the spinal cord as measured by cytisine binding sites is lower in adult SHR than normotensive WKY and Sprague-Dawley rats. Using the high-affinity agonist epibatidine, we found similar differences in receptor number between strains in both in vitro ligand binding experiments with spinal cord membranes and in situ autoradiographic analyses. Spinal nicotinic receptor number did not differ in 5-week-old prehypertensive SHR and age-matched WKY; however, receptor numbers were higher in young rats of both strains than in their adult counterparts. Antihypertensive treatment (25 mg/kg per day hydralazine PO) in 6-week-old SHR from 6 to 12 weeks of age markedly reduced the progressive rise in blood pressure yet did not alter nicotinic receptor number compared with untreated rats. Similar treatment of WKY with hydralazine produced a slight fall in blood pressure but no change in receptor number. Thus, normalization of blood pressure by hydralazine in SHR does not result in a return of receptor expression to levels seen in normotensive rats. Higher centrally mediated pressor activity or augmented postcoupling events after neuronal nicotinic receptor stimulation may slowly downregulate expression of spinal nicotinic receptors in this genetically hypertensive rat strain.

Animals↗
PubMed1996

Intrathecal nicotinic agonist-elicited release of excitatory amino acids as measured by in vivo spinal microdialysis in rats.

The nicotinic agonists, nicotine and cytisine, when administered intrathecally elicit an increase in blood pressure and heart rate as well as a nociceptive response. By using a novel microdialysis procedure, in which a 4-cm dialysis tubing is inserted proximal to the intrathecal injection site, we have examined the release of excitatory amino acids associated with agonist stimulation. The nicotinic agonists, nicotine, cytisine and epibatidine, elicit dose-dependent increases in spinal release of Asp and Glu. The rank order of potencies of the nicotinic agonists in eliciting the cardiovascular and irritation responses correlates with the order of agonist potency in inducing Asp and Glu release in spinal microdialysates. In addition, a correlation is observed between the nociceptive and blood pressure response evoked by the nicotinic agonists and the spinal release of the excitatory amino acids. By examining the position of the permeable dialysis surface in relation to the agonist injection port, we found that the response to nicotine is localized to 5 to 10 mm distances, whereas the cytisine response may be elicited over longer distances. The marked desensitization observed upon repeated administration of cytisine is also reflected in diminished amino acid release. Amino acid release by nicotine can be antagonized by a channel blocking antagonist, mecamylamine, and by a competitive antagonist, dihydro-beta-erythroidine. Mecamylamine also inhibited the amino acid release elicited by epibatidine and cytisine. Hence, excitatory amino acid release is an appropriate response marker for the cellular events associated with nicotinic receptor stimulation in the spinal cord.

Animals↗
PubMed1995

Conserved gene sequences for species identification: PCR analysis of the 3' UTR of the SON gene distinguishes human and other mammalian DNAs.

In this paper we show that the polymerase chain reaction (PCR) can be used on regions of highly conserved genes, such as the 3' untranslated region (3' UTR) of the SON gene, to identify the mammalian origin of a sample. Using this test, we have been able to distinguish human, monkey, cat, dog, mouse and hamster DNAs. We have also determined the DNA sequence of these different PCR products, which can be used to reinforce species identification. The advantages of this test are that: (i) no prior information is required on the possible species origin of a sample, (ii) the reaction produces a single PCR product which varies in size according to the species of origin, making the test simple to interpret, and (iii) the target region of DNA amplified in these experiments is small and can easily be sequenced and sized using automated techniques. This small size has enabled us to successfully amplify this product from DNA extracted from compromised material (human bone samples) and so demonstrate that the test is valuable for the characterisation of remains in which DNA is degraded.

Animals↗
PubMed1995

Brain kallikrein-kinin system abnormalities in spontaneously hypertensive rats.

The objective of the present study was to determine whether the brain kallikrein-kinin system differs between spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) and if so, whether any detected differences occur before the development of hypertension in SHR. We measured cerebrospinal fluid levels of various components of the system in adult and young prehypertensive SHR and WKY. Cerebrospinal fluid kinin concentration and appearance rate were higher in SHR. Cerebrospinal fluid active kallikrein level and kininogenase activity were also higher in adult SHR. In addition, cerebrospinal fluid kinin concentration and appearance rate were higher in prehypertensive, 5- to 6-week-old SHR compared with age-matched WKY. However, no differences in cerebrospinal fluid kallikrein or kininogenase activity were observed between the two strains of young rats. Cerebrospinal fluid kinin concentration was higher in young versus adult rats of the same strain. In WKY, cerebrospinal fluid kallikrein also decreased with age although cerebrospinal fluid kallikrein concentration did not decrease in young and adult SHR. Together, these data suggest that there is a hyperactive kallikrein-kinin system in the brain of SHR that may contribute to the hypertensive state in this animal model.

Aging↗
PubMed1994

The SON gene encodes a conserved DNA binding protein mapping to human chromosome 21.

We report the identification and characterization of a clone for the DNA binding protein SON, which we have isolated from a human keratinocyte cDNA library. Using this clone we have found that the SON gene is expressed in different cell types and that homologous sequences can be detected in vertebrate and insect genomic DNA. Using the polymerase chain reaction (PCR) to amplify SON sequences from a panel of somatic cell hybrids we have assigned the gene encoding human SON to chromosome 21. By use of hybrids containing regions of chromosome 21 the localization has been refined to 21q 22.1-q22.2.

Amino Acid Sequence↗
PubMed1994

Augmented responses to intrathecal nicotinic agonists in spontaneous hypertension.

Abnormal central cholinergic activity has been reported to be responsible in part for the pathogenesis of high blood pressure in spontaneously hypertensive rats (SHR). Administration of cholinergic agonists in brain and spinal cord results in exaggerated pressor responses in SHR. Studies to date have focused largely on the muscarinic cholinergic system. Recently, we demonstrated that intrathecal administration of nicotinic agonists results in pressor, tachycardic, and irritation responses. In the present study we examine the cardiovascular and behavioral responses to nicotine and cytisine administered intrathecally in La Jolla strain (LJ) SHRLJ and age-matched Wistar-Kyoto (WKYLJ) rats. Nicotinic agonists produced augmented pressor, heart rate, and irritation responses in SHRLJ compared with normotensive rats. In both SHRLJ and WKYLJ rats, cytisine elicited a greater nociceptive response and greater spinobulbar component to the pressor response than nicotine. SHRLJ and WKYLJ rats also differ in that the SHRLJ strain shows a diminished tendency for desensitization to cytisine. As in Sprague-Dawley rats, in SHRLJ and WKYLJ rats the cardiovascular and behavioral responses to intrathecal nicotine were significantly inhibited by mecamylamine, dihydro-beta-erthyroidine, and methyllycaconitine. However, methyllycaconitine, which effectively blocked cytisine-elicited cardiovascular and behavioral responses in Sprague-Dawley and WKYLJ rats, was unable to inhibit the maximal rise in cystine-elicited blood pressure, heart rate, and irritation responses in SHRLJ. In contrast to the heightened cardiovascular and behavioral responses, the number of nicotinic binding sites in spinal cord membranes was significantly decreased in the hypertensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Aconitine↗
PubMed1994

Stimulatory pathways and sites of action of intrathecally administered nicotinic agents.

Intrathecal (i.t.) administration of nicotinic agonists to rats elicits a receptor-mediated pressor response, a heart rate increase and irritation-nociceptive behavior. We examined the stimulatory pathways and sites of action of spinally administered nicotinic agonists. The thoracic region appears more sensitive to nicotine-elicited pressor actions than the lumbar or cervical regions of the spinal cord. Nicotinic receptors evoking a nociceptive response appear to be located over an area extending from the lumbar rostrally to the thoracic region. Similar to the pressor response, the thoracic spinal cord is the most sensitive region to nicotine in producing the heart rate increase. The cervical region is the least responsive to nicotine, suggesting sites of actions caudal to the brain stem. Intravenous infusion of trimethaphan inhibited the nicotine-elicited pressor response and tachycardia without affecting the irritation response. This suggests that the cardiovascular responses to spinal nicotinic agonists result from enhanced sympathetic outflow. Intrathecal morphine and MK-801 block spinal nicotine-elicited irritation and tachycardia but not the pressor response, indicating that pressor and irritation responses involve independent receptor-mediated pathways. Tachycardia may be associated with the irritation response. In contrast to nicotine, both pressor and irritation responses to cytisine were blocked by morphine with no effect on heart rate. Spinal transection at the T1-2 level eliminated the nociceptive response to nicotine but not the pressor response. Cytisine responses were similar to nicotine; however, cytisine was significantly less potent as a pressor agent in the transected compared with intact animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkaloids↗