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Biomedical subjects

C Thornley

Publications and source records attributed to C Thornley.

13 recordsLinked to original sources
PubMed1999

Kallmann syndrome gene (KAL-X) is not mutated in schizophrenia.

Kallmann syndrome and schizophrenia share several clinical features, including dysfunctional olfactory ability, hypogonadotrophic hypogonadism, an excess of affected males, and psychiatric presentation. Because of this congruence, it has been proposed that up to 70% of male schizophrenics might have mutations affecting the function or expression of the gene mutated in Kallmann syndrome, KAL-X. We identified and studied 9 unrelated males with schizophrenia (as defined by DSM-IIIR criteria) who also have severe anosmia (first percentile of normal range) and low sex drive (seventh percentile of the normal range), and we sequenced the exons and the intron-exon junctions of the KAL-X gene for each. We found no mutations, and conclude that schizophrenia is rarely, if ever, due to a mutation in the coding sequence or splice junctions of KAL-X.

Extracellular Matrix Proteins↗
PubMed1997

Alterations in behavior and opioid gene expression induced by the novel tropane analog WF-31.

The effects of the acute administration of the serotonin-selective tropane analog, [2beta-propanoyl-3beta-(4-isopropylphenyl)-tropane, WF-31, on spontaneous locomotor activity were measured and compared to those of the highly selective serotonin uptake inhibitor, fluoxetine and cocaine, a non-selective re-uptake inhibitor of dopamine and serotonin. WF-31 (1, 10 and 30 mg/kg)-elicited increases in locomotor behaviors when compared to vehicle-treated rats. This increased activity was blocked by pre-treatment with the dopaminergic antagonist, flupenthixol, suggesting that these effects may be mediated by dopaminergic mechanisms. Cocaine, but not fluoxetine, also elicited increases in behaviors. In addition, the effects of these three compounds on opioid peptide gene expression were also assessed using in situ hybridization histochemistry in the same animals. The acute administration of both WF-31 and cocaine increased the expression of preprodynorphin mRNA in the dorsal striatum whereas fluoxetine had no effect. Expression of striatal preproenkephalin mRNA was augmented by all three compounds. Within the nucleus accumbens, PPD mRNA levels were affected only by treatment with WF-31, an effect that was blocked by pre-treatment with flupenthixol. In contrast, the acute administration of both WF-31 and fluoxetine, but not cocaine, increased the expression of preproenkephalin mRNA. These increases, however, were not reversed by pre-treatment with flupenthixol. Despite its profile in vitro as a relatively selective serotonin re-uptake inhibitor, some of the in vivo actions of WF-31 appear to be mediated by dopaminergic mechanisms. These data further suggest that the mechanisms underlying expression of the opioid peptides in the nucleus accumbens may vary from those in the dorsal striatum.

Animals↗
PubMed1997

Local cerebral metabolic effects of the novel cocaine analog, WF-31: comparisons to fluoxetine.

The effects of the acute administration of the selective serotonin uptake inhibitor, fluoxetine, on rates of local cerebral glucose utilization in rats were compared to those of the novel cocaine analog, [2beta-propanoyl-3beta-(4-isopropylphenyl)-tropane, WF-31, which has greater affinity for serotonin than dopamine transporters, using the quantitative autoradiographic 2-[14C]deoxyglucose method. Locomotor activity was assessed simultaneously. Fluoxetine administration resulted in dose-dependent decreases in locomotor behavior, as well as widespread reductions in rates of metabolic activity in brain areas including raphe nuclei, dorsal and ventral striatum, amygdala, hippocampus, limbic cortex, and thalamus. These effects were largely concentrated in brain regions containing high densities of serotonin transporters as revealed by in vitro autoradiography. In contrast, the acute administration of WF-31 produced more discrete changes in metabolic activity that were localized within the raphe nuclei and in portions of the hippocampal formation. Blockade of WF-31's dopaminergic effects by pretreatment with the antagonist, alpha-flupenthixol, resulted in a pattern of metabolic changes that closely resembled that observed with fluoxetine. These data suggest that the alterations in functional activity produced by both fluoxetine and WF-31 are largely the result of actions on serotonergic systems.

Animals↗
PubMed1997

Potential antidepressant effects of novel tropane compounds, selective for serotonin or dopamine transporters.

The forced swimming test (FST) predicts the efficacy of clinically effective antidepressants. In the present study, using the FST we examined the antidepressant potential of three novel tropane analogs: 8-methyl-2beta-propanoyl-3beta-(4-(1-methylethyl)phenyl)-8-azabicy clo[3.2.1] (WF-31) and 2beta-propanoyl-3beta-(4-(1-methylethyl)phenyl)-8-azabicyclo[3.2.1 ]octane (WF-50), selective inhibitors of serotonin uptake, and 8-methyl-2beta-propanoyl-3beta-(4-(1-methylphenyl)-8-azabicyclo[3. 2.1] octane (PTT, WF-11), a selective inhibitor of dopamine uptake. Fluoxetine and GBR 12909 were used as controls for selective inhibitors of serotonin and dopamine, respectively. Drugs were administered three times in a 24-hr period between pretest and test sessions. Intraperitoneal administration of WF-31 (0.1-10.0 mg/kg), WF-50 (0.3-10.0 mg/kg) and fluoxetine (0.3-10.0 mg/kg) dose-dependently decreased immobility while increasing swimming. In contrast, WF-11 (0.3-3.0 mg/kg) dose-dependently decreased immobility and increased both swimming and climbing, whereas GBR 12909 (3.0-30.0 mg/kg) decreased immobility, increased climbing but did not affect swimming. In a separate experiment, WF-11 (1.0 mg/kg) increased locomotor activity, whereas a higher dose of WF-11 (3.0 mg/kg) and GBR-12909 (30.0 mg/kg) produced stereotypic behaviors, suggesting that the effects in the FST may have been attributable to increases in general activity. However, the effects of WF-11 on swimming in the FST indicate that WF-11 produces antidepressant-like effects in addition to motor stimulation. These results confirm previous results that behavioral patterns manifested in the FST are characteristic of specific monoamine uptake inhibitors. In addition, these results demonstrate that WF-31 and WF-50 produce behavioral patterns similar to fluoxetine in the FST without accompanying decreases in motor activity, suggesting a potential antidepressant action. Based on comparisons with fluoxetine, the data suggest WF-31 and WF-50 may be therapeutically useful as potential antidepressant medications.

Animals↗
PubMed1996

Synthesis of 3 beta-aryl-8-azabicyclo[3.2.1]octanes with high binding affinities and selectivities for the serotonin transporter site.

A novel entry to tropane analogs of cocaine was developed based on the reaction of rhodium-stabilized vinylcarbenoids with pyrroles. These analogs were tested in binding to dopamine, serotonin (5-HT), and norepinephrine transporters in membranes from rat striatum and frontal cortex. In all the analogs, the aryl group at the 3 position was directly bound to the tropane ring and an ethyl ketone moiety was present at the 2 position. By appropriate modification of the aryl and nitrogen substituents, highly potent and 5-HT selective tropanes were prepared. The most potent and selective compound was 3 beta-[4-(1-methylethenyl)phenyl]-2 beta-propanoyl-8-azabicyclo[3.2.1]octane (13b) which had a Ki of 0.1 nM at 5-HT transporters and was 150 times more potent at 5-HT vs dopamine transporters and almost 1000 times more potent at 5-HT vs norepinephrine transporters.

Animals↗
PubMed1995

Novel 2-substituted cocaine analogs: uptake and ligand binding studies at dopamine, serotonin and norepinephrine transport sites in the rat brain.

A novel scheme utilizing vinylcarbenoid precursors has been developed for the synthesis of tropane analogs of cocaine. Specificities of these compounds for dopamine (DA), serotonin (5-HT) or norepinephrine (NE) transporters were determined by both uptake inhibition and binding assays. In each of the analogs, the aryl group at position 3 was bound directly to the tropane ring (as in WIN-35,428), and methyl or ethyl ketone moieties were present at position 2 in lieu of the ester linkage present in cocaine. The addition of methyl or ethyl ketone groups in position 2 did not affect potency compared to ester groups in the same position, but substituents on the benzene ring greatly affected potencies. The analogs could be categorized according to their relative specificity, which consisted of those selective for DA and NE transporters with little affinity for the 5-HT transporter (e.g., WF-39), those selective for only the DA transporter (e.g., WF-29) and those selective for the 5-HT transporter (e.g., WF-31) with much less affinity for the DA and NE transporters. There also were those analogs (e.g., WF-23) with high affinity, but with equal affinity at all three transporters. The analogs displayed significant correlation between uptake inhibition and binding displacement at DA, 5-HT and NE transport sites. These results suggest that large variations in the tropane structure do not result in a differentiation between binding at biogenic amine transporters and inhibition of amine uptake.

Adrenergic Uptake Inhibitors↗
PubMed1985

Human Tamm-Horsfall glycoprotein: urinary and plasma levels in normal subjects and patients with renal disease determined by a fully validated radioimmunoassay.

A recently developed, simple and sensitive radioimmunoassay has been used to examine 24 h excretion and plasma levels of Tamm-Horsfall glycoprotein (THG) in normal subjects, stone formers and patients with stable chronic renal disease. In normal subjects THG excretion ranged from 22 to 66 mg/24 h, with no sex difference and no correlation with creatinine clearance or body surface area. There was no correlation between 24 h THG excretion and urine volume, pH or osmolality, excretion of Na+, K+ or Ca2+ or free-water clearance. There was a small significant correlation between plasma THG concentration and urinary THG excretion. A good correlation was obtained between the THG/creatinine ratio in 24 h and random samples. This made possible the use of random samples to establish a reference range for THG excretion of 0.15-0.50 micrograms/ml of creatinine clearance which did not depend on sex or age. The excretion rate of THG in stone formers was generally within the reference range. It was not significantly different in those who were hypercalciuric or in those taking thiazides. In patients with chronic renal disease there was a good correlation between 24 h THG excretion, plasma THG concentration and creatinine clearance. The range of excretion of THG per ml of creatinine clearance was greater than in normal subjects, independent of the type of renal disease and unrelated to proteinuria. In patients with glomerulonephritis the excretion of THG per ml of creatinine clearance was significantly higher in those with well-preserved tubules compared with those with tubular atrophy.

Adolescent↗
PubMed1982

An improved radioimmunoassay for urinary Tamm-Horsfall glycoprotein. Investigation and resolution of factors affecting its quantification.

A rapid, specific radioimmunoassay has been used to measure Tamm-Horsfall glycoprotein (TH glycoprotein) in urine. The apparent concentration increased with increasing dilution of urine in water, reaching a plateau at 1 in 20. This increase was greater the higher the osmolality and TH glycoprotein concentration and the lower the pH of the original sample. A dilution of 1 in 100 was chosen for routine assay. Whole urine was centrifuged and the dissolved precipitate and supernatant assayed to quantify the proportion of TH glycoprotein of TH glycoprotein initially present in highly aggregated form. This correlated positively and significantly with increasing osmolality, decreasing pH and increasing TH glycoprotein concentration. When the urine was diluted 1 in 100 in water, no TH glycoprotein was precipitated by centrifugation and the measured concentrations were unaffected by alterations of urine pH or calcium concentration or by addition of sodium dodecyl sulphate. Parallelism was demonstrated between the diluted samples and the disaggregated standard preparation. Recovery of added standard to diluted urine varied between 96 and 114%. The apparent concentration of TH glycoprotein in neat or diluted urine was not affected by freezing or by storage at 4 degrees C or room temperature for at least 2 days. A physiological range for the urinary excretion rate was established as 22--56 mg/24 h, based on samples from 29 individuals with normal renal function, as defined by their creatinine clearance. There was no significant correlation between serum concentrations of TH glycoprotein and its urinary excretion rate, nor between urinary excretion rate and creatinine clearance.

Calcium↗
PubMedDate not supplied

Tamm-Horsfall glycoprotein excretion and aggregation during intravenous urography. Relevance to acute renal failure.

The effect of intravenous urography (IVU) on the excretion rate and precipitation of Tamm-Horsfall glycoprotein (THG) has been evaluated in 19 patients. Urine samples were collected immediately before the administration of contrast medium (U1) and then during the period of the excretion urogram (U2). The urinary THG: creatinine clearance ratio decreased in 15 patients by a mean of 28.2% (range 2.9-70.8) and increased in four by a mean of 22.8% (range 13.5-36.4). In 18 of 19 patients the amount of THG precipitated following the IVU decreased from an average of 75.6% of the total in U1 (range 2.2-100) to 19.5% (range 2.0-59) in U2. In the one exception the fraction precipitated was only 2.2% in U1 and 2.5% in U2. It is concluded that during routine IVU there is no marked increase in the excretion rate of THG. More importantly, the percentage of THG precipitated actually decreases.

Acute Kidney Injury↗
PubMedDate not supplied

Daylight robbery.

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Economics, Nursing↗