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S Patel

Publications and source records attributed to S Patel.

At least 595 records · Page 33Linked to original sources

Quantitative autoradiographic analysis of glutamate binding sites in the hippocampal formation in normal and schizophrenic brain post mortem.

Using quantitative autoradiography, the anatomical distribution of the binding sites (kainate, N-methyl-D-aspartate and quisqualate) for the excitatory neurotransmitter glutamate has been established in the hippocampal formation from control and schizophrenic brains, post mortem. There is a loss of the kainate subtype particularly in schizophrenic hippocampi mainly from the CA4/CA3 mossy fibre termination zone of the cornu ammonis (CA4 and CA3; control and schizophrenic left hippocampus, respectively, 54.2 and 66.6 pmol/g; 18.3 and 17.9 pmol/g), as well as bilateral losses in the dentate gyrus (left 14.2 pmol/g and right 28.0 pmol/g; left 9.5 pmol/g and right 7.9 pmol/g, control and schizophrenic, respectively) and parahippocampal gyrus (left 50.8 pmol/g and right 41.7 pmol/g, left 27.7 pmol/g and right 25.3 pmol/g, control and schizophrenic, respectively). There is complete preservation of N-methy-D-aspartate sites in schizophrenic hippocampi, and a marginally significant loss of the quisqualate binding site in CA4/CA3 regions (left 249 fmol/g and right 306 fmol/g, left 157 fmol/g and right 148 fmol/g, control and schizophrenic, respectively). These findings reflect the possible importance of glutamate in the pathophysiology of schizophrenia and represent novel targets for therapeutic manipulation in schizophrenia.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

Amiloride inhibits contraction and serotonin modulation of Aplysia muscle.

1. Serotonin (5-HT) potentiates acetylcholine (ACh)-elicited contractions of Aplysia buccal muscles. Serotonin potentiation was significantly reduced by 0.03 mM, 0.1 mM, and 0.3 mM amiloride. 2. Unpotentiated ACh-elicited contractions were significantly reduced by 0.1 mM and 0.3 mM amiloride. 3. Amiloride reduced ACh-elicited depolarization. The reduction in contraction caused by 0.3 mM amiloride (to 16% of control) was larger than could be explained by the reduction in depolarization (86% of control). 4. Amiloride had no effect on tension in skinned muscle fibers, indicating that amiloride probably did not have a direct effect on contractile mechanisms. 5. Potentiation of contraction produced by zero sodium (Tris substituted, 0 Na-Tris) medium could be abolished by 0.3 mM amiloride. 6. Zero Na-Tris increased 45Ca influx 2.7-fold. In the presence of 0.3 mM amiloride, 0 Na-Tris increased 45Ca influx only 1.4-fold. 7. Amiloride (0.3 mM) reduced the elevation of muscle cAMP caused by 10(-6) M 5-HT by 60%. Zero Na-Tris did not cause a change in muscle cAMP.

Acetylcholine↗

A placebo-controlled trial of immunotherapy with two extracts of Dermatophagoides pteronyssinus in allergic rhinitis, comparing clinical outcome with changes in antigen-specific IgE, IgG, and IgG subclasses.

A double-blind, placebo-controlled trial of immunotherapy was conducted in patients with Dermatophagoides pteronyssinus rhinitis. Thirty patients received an extract with a high content of Der p I (Pharmalgen), 20 received a conventional mite extract (Allpyral), and 30 patients received histamine chloride (placebo). Specific IgG and subclasses were measured before and after 3 and 12 months of treatment by RIA and/or ELISA, and specific IgE by RAST. Clinical outcome was assessed by skin prick tests, nasal challenge, visual analogue, and diary-card symptom and drug scores; from these findings, a clinical index was derived. An IgG response occurred only in the Pharmalgen-treated group: D. pter IgG and IgG1 increased by 3 months (p less than 0.05) and then plateaued to 12 months (p less than 0.05). IgG4 levels increased throughout treatment (p less than 0.05 and p less than 0.01), as did the IgG/IgE ratio. A subclass switch from IgG1 to IgG4 occurred. D. pter IgE rose at 3 months (p less than 0.05). Clinical improvement occurred at 3 and 12 months in the Pharmalgen-treated group only. Pretreatment levels of IgE, IgG1, or IgG4 did not predict clinical outcome. Our findings are compatible with the hypothesis that IgG subclasses may modulate antigen-IgE interactions, although the antibody response to this potent extract need not be causally related to improvement.

Adolescent↗

Synthesis and muscarinic activities of 1,2,4-thiadiazoles.

A series of novel 1,2,4-thiadiazoles bearing a mono- or bicyclic amine at C5 were prepared. Quinuclidine and 1-azabicyclo[2.2.1]heptane derivatives were synthesized by reaction of the lithium enolate of the 3-methoxycarbonyl compounds followed by ester hydrolysis and decarboxylation. The receptor-binding affinity and efficacy of these compounds as muscarinic ligands was assessed by radioligand binding assays using [3H]-N-methylscopolamine and [3H]oxotremorine-M. Optimal agonist affinity was observed for 3'-methyl compounds. Smaller substituents (H) retained efficacy with reduced affinity while larger groups led to substantially lower efficacy. The observed binding affinity was influenced both by the conformational energy of rotation around the C3-C5' bond and the steric requirement of the mono- or bicyclic amine.

Animals↗

Factors influencing calcitriol metabolism in renal failure.

Metabolic clearance rate (MCR) and production rate (PR) of calcitriol is decreased in experimental renal failure. In this experiment, we studied uremia and secondary hyperparathyroidism as possible causes of the abnormal calcitriol metabolism. Normal rats were made uremic by infusing phosphorus-free urine for 24 hours. Both the MCR (0.22 +/- 0.01 ml/min/kg, N = 6 P less than 0.001) and the PR (16.6 +/- 1.97 ng/kg/day, P less than 0.01) of calcitriol were significantly suppressed in normal rats following urine infusion when compared to saline infused rats (MCR, 0.30 +/- 0.01; PR, 32.9 +/- 4.1, N = 6). Different levels of protein intake by rats with renal failure produced by subtotal nephrectomy also alter the PR but not the MCR of calcitriol. Thus, the synthesis of calcitriol was significantly lower in rats with renal failure fed a high protein (50% protein) diet (17.6 +/- 0.7 ng/kg/day, N = 8, P less than 0.001) than in rats with renal failure fed a normal protein (20% protein) diet (22.2 +/- 1.4, N = 7). Thyroparathyroidectomy (TPTX) did not alter the MCR of calcitriol in renal failure, even though parathyroid hormone, which may suppress the degradation enzyme, could be elevated in this model of renal failure. The MCR of TPTXed rats with renal failure (0.15 +/- 0.01 ml/min/kg, N = 7) remained lower than that of the TPTXed control rats (0.19 +/- 0.01, N = 7, P less than 0.001), and chronic infusion of PTH to TPTXed rats with renal failure did not change the MCR of calcitriol (0.15 +/- 0.01, vs. control, 0.24 +/- 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

The growth hormone independent insulin-like growth factor-I binding protein BP-28 is associated with serum insulin-like growth factor-I inhibitory bioactivity in adolescent insulin-dependent diabetics.

The relationship between the growth hormone independent insulin-like growth factor binding protein (BP-28) and serum insulin-like growth factor-I (IGF-I) inhibitory bioactivity observed in diabetic serum was investigated in five poorly controlled adolescent type I diabetics. We have measured the in-vitro effects of purified BP-28 from amniotic fluid on serum IGF-I stimulated and basal cartilage sulphation and compared serum IGF-I bioactivity obtained from 24-h serum profiles from each diabetic subject with serum concentrations of BP-28 and IGF-I measured by specific radioimmunoassays. Purified BP-28 inhibited serum IGF-I stimulated and basal cartilage sulphation in vitro, in a dose-dependent manner. Serum IGF-I bioactivity of diabetic sera showed a change in activity over the 24-h period, with peak inhibitory bioactivity observed in each subject between 0800 and 1000 h. BP-28 concentrations in each individual showed a marked circadian rhythm with maximum peak levels occurring at 0800 h. Long-acting insulin administered in the evening in two of the diabetic subjects blunted the maximum peak level attained compared to the three diabetics who had long-acting insulin administered in the morning. IGF-I concentrations did not change over the 24-h period in each individual. The data shows that BP-28 inhibits serum IGF-bioactivity on cartilage in vitro. The changes in inhibitory bioactivity observed in diabetic serum are associated with similar changes in serum concentrations of BP-28. We propose that BP-28 is one of the IGF-I inhibitors observed in diabetic serum and that it may play a role in retarded growth and delayed puberty often seen in the adolescent diabetic.

Adolescent↗

A novel series of non-quaternary oxadiazoles acting as full agonists at muscarinic receptors.

1 A novel series of non-quaternary oxadiazole-based muscarinic agonists demonstrated high affinity for muscarinic receptors. 2. These agonists possessed high efficacy in the nanomolar range at muscarinic receptors in the superior cervical ganglion, atrium and ileum but did not show selectivity across the tissue preparations. 3. Two amino oxadiazoles, one from a quinuclidine series (L-660,863) and one from a 1-azanorbornane series (L-670,207) possessed a high ratio of potency for displacing the binding of [3H]-N-methyl-scopolamine ([3H]-NMS) to potency for displacing the agonist [3H]-oxotremorine-M cortex. 4. The two azanorbornane derivatives L-670,548 and L-670,207 stimulated the turnover of phosphatidylinositol in the cortex with a potency higher than that obtained with any other known muscarinic agonist (ED50 0.26 and 0.18 microM respectively). 5. The maximum response obtained with L-670,207 was greater than that observed for carbachol but was comparable to that of the natural ligand acetylcholine. 6. These oxadiazole muscarinic agonists are among the most potent and efficacious non-quaternary muscarinic agonists ever described.

Animals↗

Lysosomal sorting mutants of coronavirus E1 protein, a Golgi membrane protein.

As a model for the intracellular sorting of Golgi membrane proteins, we are studying the E1 protein of the coronavirus Mouse Hepatitis Virus A59. The wild-type protein, when expressed from synthetic RNA, is localised in the Golgi complex. When the second and third of the three predicted membrane-spanning sequences were deleted from the protein, the resulting mutant was retained in the endoplasmic reticulum. In contrast, removal of the first and second membrane-spanning sequences allowed the protein to pass through the Golgi complex and reach the lysosomes. Likewise, when 40 amino acids were deleted from the C-terminal cytoplasmic part of E1, the truncated protein was transported to the lysosomes. We discuss the implications of these results for the structure of the E1 protein and the mechanism by which it is localised in the cell.

Amino Acid Sequence↗

Anticonvulsant action of the beta-carboline abecarnil: studies in rodents and baboon, Papio papio.

Abecarnil (ZK 112119; isopropyl-6-benzyloxy-4-methoxymethyl-beta-carboxylate) is a metabolically stable beta-carboline derivative with potent anxiolytic and few sedative and ataxic effects in rodents. The anticonvulsant and muscle relaxant actions of abecarnil have been evaluated in mice, rats, gerbils and baboons. Abecarnil raised the threshold for tonic electroconvulsions in mice after corneal but not after auricular application, had no effect on maximal electroshock-induced tonic convulsions triggered by either method, protected mice against the tonic hindlimb extension in PTZ-, picrotoxin- and 3-mercaptopropionate-induced seizures and blocked clonus after PTZ, DMCM (methyl-4-ethyl-6,7-dimethoxy-9H-pyrido-(3,4-b)-indol-3-carboxylate) and 3-mercaptopropionate. Abecarnil had no effect on convulsions induced by bicuculline and strychnine. Furthermore, abecarnil blocked kindled seizures after chronic administration of PTZ and FG 7142 (beta-carboline-3-carboxylic acid methylamide) and protected mice and rats against limbic convulsions induced by pilocarpine. Severity and afterdischarge duration of amygdala-kindled seizures were reduced in rats treated with abecarnil. Abecarnil also antagonized selectively convulsions induced by i.c.v. administration of kainate, but not those triggered by N-methyl-D-aspartate or quisqualate. In genetic models of reflex epilepsy, abecarnil was effective against sound-induced convulsions in DBA/2 mice, against air blast-induced generalized seizures in gerbils and against myoclonus in baboons Papio papio. The anticonvulsant effect of abecornil in a PTZ seizure model in mice was potentiated by ethosuximide, whereas no significant potentiation was found with diazepam, clonazepam, diphenylhydantoin, carbamazepine and phenobarbital. Electromyographic monitoring in a etorphine model of muscle rigidity in rats showed no or little muscle relaxant effect of abecarnil.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Development and properties of an etoposide-resistant human leukaemic CCRF-CEM cell line.

Etoposide (VP-16) and several other unrelated anti-tumour agents appear to act by inhibiting the enzyme DNA topoisomerase II. We report here the development and characterization of an etoposide-resistant human leukaemic CCRF-CEM cell line, CEM/VP-1. The cell line was 15-fold more resistant to etoposide than the parental CEM cells and exhibited cross-resistance to other topoisomerase II inhibitors including teniposide, m-AMSA, and doxorubicin. CEM/VP-1 cells exhibited only a low level cross-resistance to the Vinca alkaloids, vinblastine and vincristine, known inhibitors of mitotic spindle formation. As a first step in defining the mechanism of resistance to etoposide, we compared the levels of topoisomerase II activity and its drug sensitivity in nuclear extracts from the resistant and sensitive CEM cells. As determined by a kinetoplast DNA decatenation assay, the level of DNA topoisomerase II activity in CEM/VP-1 nuclear extracts was approximately 2-fold lower than that in CEM cells, and the activity appeared to be resistant to inhibition by etoposide. Furthermore, the DNA topoisomerase II activity in CEM/VP-1 nuclear extracts did not promote the etoposide-dependent cleavage of pBR322 DNA observed with extract from sensitive cells. These results suggest that etoposide resistance in the CEM/VP-1 cell line may at least in part be due to an altered topoisomerase II, or associated factor, resulting in a reduced ability to induce DNA cleavage in the presence of drug.

Cell Division↗

First-dose effects of enalapril and atenolol upon blood pressure and cerebral blood flow in patients with mild hypertension on diuretic therapy.

The present single-blind, randomised, cross-over, placebo-controlled study was set up to compare the first-dose effects upon blood pressure (BP) and cerebral blood flow (CBF, measured by Xenon inhalation) of a single oral dose of atenolol 50 mg and enalapril 5 mg in ten hypertensive patients receiving a thiazide diuretic. It was found that a) the timing and degree of fall in BP after the first dose of atenolol and enalapril on a diuretic background were similar and generally not associated with symptoms or a fall in CBF, and b) dizziness, which is sometimes associated with the first-dose effect of ACE inhibitors in hypertensives on diuretics, can occasionally occur accompanied by a substantial fall (43%) in CBF in the absence of marked falls in systolic blood pressure. It is suggested that the latter event may be linked to a disturbance of cerebral autoregulation in part dependent on localised renin-angiotensin systems.

Aged↗

Changes in geometrical and biomechanical properties of immature male and female rat tibia.

Tibial geometry and mechanical properties in male and female rapidly growing rats were measured to provide comparative data for spaceflight, exercise, or disease experiments that use immature rats as an animal model. A total of 68 immature Sprague-Dawley rats (43-58 d of age) were divided into 8 groups according to age and sex. Tibial length and middiaphysial cross-sectional data were analyzed, and tibial mechanical properties were obtained via three-point bending tests to failure. Results indicated that tibial geometry and mechanical properties were changed significantly during this 15-d period of rapid growth, with male rats having greater increases than female rats. Both male and female tibial lengths nevertheless increased significantly during this growth period, as did middiaphysical cross-sectional area. Tibial flexural rigidity increased significantly for both sexes during this growth period. The male tibiae changed primarily in structural characteristics, but some material properties also changed with age. In the female rats, however, the major changes in mechanical properties of the tibia were attributable only to structural changes in the bone.

Age Factors↗

Effect of polyamines, methylguanidine, and guanidinosuccinic acid on calcitriol synthesis.

Previous study from our laboratory has demonstrated that infusion of uremic plasma ultrafiltrate to normal rats suppressed their calcitriol synthesis. In order identify the uremic toxins responsible for the suppression of the calcitriol synthesis, we studied the effects of known uremic toxins: spermidine, spermine, methylguanidine (MG), and guanidinosuccinic acid (GSA) on calcitriol metabolism in the rats. Metabolic clearance rate (MCR) and production rate (PR) of calcitriol were measured in normal rats after they were infused for 24 hours with approximately 10 ml of normal saline containing one of the following substances: 0.8 mumoles spermidine, 0.3 mumoles spermine, 150 micrograms MG and 180 micrograms GSA. Control groups of rats were infused with 10 ml of normal saline for 24 hours. MCR of calcitriol was not altered by the infusion of each toxin; however, plasma concentration of calcitriol (controls, 105.3 +/- 6.7 pg/ml; versus GSA, 58.9 +/- 2.5 pg/ml, p less than 0.001) and PR of calcitriol (controls, 39.0 +/- 2.9 ng/kg/day, versus GSA, 22.5 +/- 1.62 ng/kg/day, p less than 0.001) were significantly suppressed by the infusion of GSA. The concentration (1.8 mg/dl) of GSA in the infusate was similar to that in the uremic plasma ultrafiltrate (2.32 +/- 1.41 mg/dl) used in the previous study, though the total amount of GSA infused to the rats was lower in the present study. GSA is, therefore, considered a uremic toxin that suppresses calcitriol synthesis.

Animals↗

Antroduodenal manometry in the evaluation of chronic functional gastrointestinal symptoms.

Intraluminal pressure in the gastric antrum and duodenum was studied in 44 children and adolescents referred for evaluation because of functional symptoms, including vomiting, abdominal distension, and abdominal pain. Manometric abnormalities were found in 39 patients (89%). Abnormalities during fasting included absence of the migrating motor complex; retrograde, phase 3-like episodes; increased frequency, decreased duration, and decreased amplitude of phase 3 episodes; tonic duodenal contractions; nonpropagated bursts of duodenal contractions; and consistently low-amplitude or absent contractions. Postprandial abnormalities included a phase 1-like pattern (postprandial hypomotility) and phase 3-like episodes (failure to induce a fed pattern). The presence or absence of the migrating motor complex was a predictor of disability. Parenteral alimentation was needed by only 4 of 28 patients with the migrating motor complex, but by 13 of 16 patients without the migrating motor complex (P less than .001). In 15 of 18 patients studied on consecutive days, oral cisapride was associated with increases in the number and amplitude of duodenal contractions after a complex-liquid meal (P less than .02). It is concluded that antroduodenal manometry is a useful technique that elucidates the underlying gastrointestinal motility disorder present in the majority of children and adolescents with severe functional symptoms.

Adolescent↗

25-Hydroxyvitamin D metabolism and its effect on calcitriol metabolism in experimental renal failure.

We studied 25-hydroxyvitamin D3 (25(OH)D3) metabolism and its effect on calcitriol metabolism in renal failure achieved by partial nephrectomy in rats. Metabolic clearance rates (MCRs) of 25(OH)D3 were significantly decreased in rats with renal failure (creatinine clearance, 0.21 +/- 0.02 ml/min/100 gm; MCR, 54.6 +/- 3.5 microliters/min/kg, n = 6) in comparison with normal control rats (creatinine clearance, 0.56 +/- 0.03 ml/min/100 gm; MCR, 73.4 +/- 1.6 microliters/min/kg, n = 5, both p less than 0.01). Because production rates (PRs) of 25(OH)D3 were not different between the two groups of rats (renal failure, 1.8 +/- 1.1; control, 1.8 +/- 0.42 microgram/kg/day), the decreased MCR resulted in elevation of plasma levels of 25(OH)D3 (22.7 +/- 1.6 vs control 17.1 +/- 0.28 ng/ml, p less than 0.01). Injection of 600 ng 25(OH)D3 per day for 6 days significantly increased the MCR of 25(OH)D3 in both normal rats (89.6 +/- 3.2 microliters/min/kg, n = 6, p less than 0.01) and rats with renal failure (84.9 +/- 9.7 microliters/min/kg, n = 6, p less than 0.01) when compared with normal rats (73.4 microliters/min/kg) and rats with renal failure (54.6 microliters/min/kg) injected with vehicle, respectively. To study the effect of 25(OH)D3 on calcitriol metabolism, MCRs of calcitriol were measured in normal rats and in rats with renal failure that received daily injection of 600 ng 25(OH)D3 for 6 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Direct measurement of muscarinic agents in the central nervous system of mice using ex vivo binding.

Muscarinic agents produce a range of side effects including hypothermia and tremor. Although these responses can be used to estimate the in vivo activity of these muscarinic agents in the central nervous system (CNS), the approach is limited by compensatory feedback mechanisms and the difficulty of equating degree of receptor occupancy to effect. We have developed an ex vivo assay to measure the potency and penetration of muscarinic agents into the CNS. The muscarinic antagonists scopolamine and N-methylscopolamine dose dependently inhibited the ex vivo binding of [3H]oxotremorine-M to homogenates of mouse whole brain membranes. Following intraperitoneal administration these compounds had ED50 values of 2.6 and 26 mg/kg respectively, which were comparable to the doses which inhibited RS86 induced hypothermia in mice. Three muscarinic agonists RS86, pilocarpine and arecoline also demonstrated CNS activity in this assay with ED50 values of 11, 23 and 220 mg/kg. RS86 and pilocarpine additionally showed good penetration into the CNS with estimated values of 1.5 and 0.31% of the administered dose. These values were comparable with the ability of these compounds to induce a centrally mediated hypothermic response. These studies demonstrate a simple, quick and reliable biochemical means of assessing a muscarinic agent's potency and penetration within the CNS.

Animals↗

Transscleral cyclophotocoagulation using a contact laser probe: a histologic and clinical study in rabbits.

Transscleral photocoagulation of the ciliary body was achieved in pigmented rabbits using a sapphire probe delivery system coupled to a commercial surgical continuous-wave Nd:YAG laser. This contact technique was found to be effective in reducing intraocular pressure (IOP); greater treatment energies were associated with a more prolonged reduction in IOP, and also correlated with a greater degree of histologic damage to the ciliary body. Treatment energies of 0.8-1.0 Joules produced substantial disruption of the ciliary body. This technique is easy to learn and offers ease in control and placement of the coagulation spots.

Animals↗