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Biomedical subjects

A Turner

Publications and source records attributed to A Turner.

At least 19 recordsLinked to original sources
PubMed1996

Radioimmunotherapy of colorectal carcinoma xenografts in nude mice with yttrium-90 A33 IgG and Tri-Fab (TFM).

The monoclonal antibody A33 recognises a tumour-associated antigen on human colorectal carcinoma, and has undergone preliminary evaluation in the clinic where selective localisation to hepatic metastases has been demonstrated [Welt et al. (1994) J. Clin. Oncol. 12, 1561-1571]. A33 and an A33 tri-fab fragment (TFM) were labelled with 90Y via a stable macrocyclic ligand for biodistribution and therapy studies in nude mice bearing SW1222 colon carcinoma xenografts. Biodistribution studies demonstrated tumour localisation for both A33 IgG and TFM with low bone, liver and kidney levels. Clearance of TFM from the blood was much faster than IgG and this led to lower tumour accumulation for TFM but superior tumour-blood ratios. The maximum per cent injected dose per g localised to tumour was 35.9% +/- 5.3% for A33 IgG and 12.9% +/- 4.6% for A33 TFM with tumour-blood ratios at 48 h after administration of 5.6 +/- 1.8 and 29.2 +/- 9.8 respectively. Autoradiography studies with 125I-labelled A33 IgG and TFM demonstrated a homogeneous distribution within tumour tissue which was not observed with other anti-colorectal tumour antibodies. TFM penetrated into the tumour tissue more rapidly than IgG. In therapy studies, a single dose of 90Y-A33 IgG (250 microCi per mouse) or 90Y-A33 TFM (300 microCi per mouse) led to complete regression of 2-week-old tumour xenografts with long-term tumour-free survivors. A transient drop in white blood cell count was observed with both IgG and TFM but was significantly more pronounced with IgG. The cell count fell to 8.4% of control for IgG, whereas with TFM cell counts fell to 51% of control before recovery. These results indicate that the more rapid blood clearance of 90Y-TFM confers reduced toxicity compared with 90Y-IgG although similar therapeutic effects are achieved. When the dose of 90Y-IgG was adjusted to give the same dose to tumour achieved with 300 microCi 90Y-TFM, a lesser therapeutic effect was observed. This may be owing to more rapid tumour penetration achieved with TFM. Both A33 IgG and TFM demonstrated potent anti-tumour effects against human tumour xenografts in this mouse model system. The stability of these 90Y-labelled conjugates and their effective tumour penetration are promising for the development of humanised reagents for clinical studies.

Animals↗
PubMed1996

A genetic linkage study of the D2 dopamine receptor locus in heavy drinking and alcoholism.

BACKGROUND: Reports of an association between restriction fragment length polymorphisms (RFLPs) at the dopamine D2 receptor (DRD2) locus and alcoholism have suggested involvement of that locus in the aetiology of alcoholism. METHOD: Sib pair linkage analyses were conducted in families multiply affected by alcoholism, using both the Taql 'A' RFLP and a microsatellite repeat polymorphism at the DRD2 locus. RESULTS: The 'Identical By Descent' analysis provided significant evidence of an effect of the DRD2 locus on the liability to develop heavy drinking (P < 0.0016) and Research Diagnostic Criteria alcoholism (P < 0.0003) in the first sample of families studied. However, this result was explicable by the segregation of alleles in a single large sibship, and it was not replicated in a second sample of families. CONCLUSIONS: The results do not support linkage between the DRD2 locus and alcoholism in most of the families studied. It remains possible that this locus influences the predisposition to alcoholism in some families.

Alcoholism↗
PubMed1996

Efficacy and safety of topical calcitriol (1,25-dihydroxyvitamin d3) for the treatment of psoriasis.

Plaque-type psoriasis has been successfully treated with topical calcitriol, but there has been no long-term follow-up study of the safety and efficacy of this calciotropic hormone. In a single-centre study, patients with plaque or erythrodermic psoriasis were enrolled in a double-blind, right/left comparison, placebo-controlled study, and received 1.5 micrograms of calcitriol (15 micrograms/g of Vaseline) per day, or a placebo consisting of Vaseline alone. A subset of these patients (n = 22), with at least 25% involvement, applied 0.1 g of calcitriol ointment/50 cm2 on an area of from 2,500 to 5,000 cm2. Of the 84 patients enrolled in the double-blind control study, 96.5% responded to topical calcitriol therapy, compared with 15.5% whose lesions improved with Vaseline alone, after 2.4 months. After completion of the double-blind study, 22 patients applied calcitriol ointment (15 micrograms/g Vaseline) to all of their lesions (up to 10 g of calcitriol ointment; 150 micrograms calcitriol lesions showed either excellent or moderate clearing in 90.9% of all cases. The remaining 9.1% of cases showed slight improvement of their lesions. No abnormalities in calcium metabolism were noted in any of the patients using topical calcitriol. None of the patients experienced any local cutaneous side-effects, including six patients who applied calcitriol ointment to the face. Topical calcitriol is safe and effective for the treatment of psoriasis.

Administration, Cutaneous↗
PubMed1996

Safety and efficacy of oral calcitriol (1,25-dihydroxyvitamin D3) for the treatment of psoriasis.

Plaque-type psoriasis has been successfully treated with oral calcitriol, but there has been no long-term follow-up on the safety and efficacy of this calciotropic hormone for psoriasis. In a single centre study, patients were enrolled in an open trial to evaluate the efficacy and safety of oral calcitriol for psoriasis. Of the 85 patients who received oral calcitriol, 88.0% had some improvement in their disease; 26.5, 36.2 and 25.3%, had complete, moderate and slight improvement in their disease, respectively. The mean baseline psoriasis area severity index score (PASI) of 18.4 +/- 1.0 was reduced to 9.7 +/- 0.8 and 7.8 +/- 1.3 after 6 and 24 months on oral calcitriol therapy. Serum calcium concentrations and 24 h urinary calcium excretion increased by 3.9% and 148.2%, respectively, but were not outside the normal range. Bone mineral density remained unchanged. The clearance of creatinine decreased by 13.4% from baseline during the first 6 months of treatment, and thereafter, remained unchanged after 3 years of follow up. An evaluation of creatinine, inulin and paraaminohypurate (PAH) clearance was performed in eight patients. After 6 months on oral calcitriol, there was a 22.5% decline in creatinine clearance but no significant changes were observed in either inulin or PAH clearance, suggesting that calcitriol alters creatinine metabolism or secretion but does not affect renal function. Oral calcitriol is effective and safe for the treatment of psoriasis.

Administration, Oral↗
PubMed1995

A 500-kilobase region containing the tuberous sclerosis locus (TSC1) in a 1.7-megabase YAC and cosmid contig.

A complete overlapping clone map of a 1.7-Mb region from DBH to D9S67 that includes the TSC1 candidate region has been constructed. The map includes YAC and cosmid clones, contains STS approximately every 50 kb on average, and establishes the order of five previously unordered loci. The overall physical length of this segment of chromosome 9q34 (1.7 Mb) is significantly less than expected compared to its estimated genetic length (approximately 10 cM). Consequently, the physical length of the TSC1 candidate region is substantially less than predicted by a genetic distance of approximately 2 cM.

Base Sequence↗
PubMed1995

Differentiating between orchiectomized rats and controls using measurements of trabecular bone density: a comparison among DXA, histomorphometry, and peripheral quantitative computerized tomography.

In studies of rat bone metabolism, trabecular bone density should be measured. Three established methods of measuring trabecular bone include trabecular bone volume by histomorphometry (BV/TV%), trabecular bone density by peripheral quantitative computerized tomography (pQCT), and areal bone density of trabecular-rich regions by dual x-ray absorptiometry (DXA). We compared the ability of these three methods to discriminate between orchiectomized (orchidectomized) rats and controls. Sixteen male Sprague-Dawley rats (400-425 g) were orchiectomized, and 16 others were controls. In vivo spine bone mineral density (BMD) was measured at the beginning of the study and again after 11 weeks. Rats were sacrificed, and ex vivo BMDs of the right femur and tibia were measured by DXA, followed by trabecular bone density of the right proximal tibia by pQCT. BT/TV% of the left proximal tibia was measured by histomorphometry. Differences between groups were detected by all three methods, but both the magnitude of the difference between groups and the variance of the measurements was much greater for histomorphometry and pQCT than for DXA. Consequently, the statistical significance for the difference between groups was comparable for all three methods. Of the sites measured with DXA, the proximal tibia had the greatest statistical significance for the difference between groups. In summary, all three methods can demonstrate the effect of orchiectomy on trabecular bone. The large differences between groups seen by histomorphometry are also seen by pQCT but not by DXA. We conclude that trabecular bone density by pQCT may be a reasonable surrogate for measurements by histomorphometry.

Absorptiometry, Photon↗
PubMed1995

Relation between meconium concentration of the cocaine metabolite benzoylecgonine and fetal growth.

Among 95 term infants with benzoylecgonine, the cocaine metabolite, detectable in their meconium, there was an inverse relation between the concentration of benzoylecgonine and birth weight, length, and head circumference. Multiple regression analysis confirmed these relations after controlling for gestational age and maternal use of marijuana, cigarettes, and alcohol. These data suggest a dose-response relation between the magnitude of prenatal cocaine exposure and impaired fetal growth.

Birth Weight↗
PubMed1995

Postprandial sympatho-adrenal activity: its relation to metabolic and cardiovascular events and to changes in meal frequency.

1. Sympatho-adrenal activity was measured after the consumption of a 3.15 MJ mixed meal. Whole-body noradrenaline spillover rates, forearm plasma noradrenaline spillover and adrenaline secretion rates were derived using isotope dilution methodology. Heart rate and blood pressure spectral analysis measurements were also made. The relation of sympathoadrenal activity to thermogenic and cardiovascular events was studied. Sympathetic nervous and thermogenic responses were measured for 120 min after the single 3.15 MJ meal and compared with those after three 1.05 MJ meals, given 30 min apart. 2. Whole-body and forearm plasma noradrenaline spillover, and the 0.1 Hz component of systolic pressure power all increased significantly postprandially, while the 0.1 Hz component of heart rate variability, an indirect index of cardiac sympathetic nervous activity, remained unaltered. Adrenaline secretion was unaltered postprandially. Whole-body plasma noradrenaline spillover and thermogenesis during the 120 min postprandial period were 37% and 36% higher after the single meal as compared with the multiple meals, although this was not statistically significant. 3. The sympathetic neural responses were delayed in relation to peak plasma insulin levels and sustained in the face of declining insulin levels. Energy expenditure increased significantly postprandially, but there was no direct quantitative relationship to plasma noradrenaline spillover. Forearm oxygen consumption did not increase postprandially despite significant increases in regional noradrenaline spillover. Thus, no close relation was demonstrated between postprandial sympathetic nervous activation and either insulin secretion or thermogenesis.

Adult↗
PubMed1995

Comparison of three methods for culture confirmation of Neisseria gonorrhoeae strains currently circulating in the UK.

AIMS: To establish the current sensitivity of two commercial kits for culture confirmation of Neisseria gonorrhoeae strains circulating in the UK. METHODS: A total of 544 strains were studied (199 gonococci from male patients attending hospitals in the county of Avon, 204 unselected N gonorrhoeae isolates from male patients in Leeds, 20 strains referred to the Gonococcus Reference Unit because of difficulties with the Syva fluorescent antibody test (FAT), and 121 strains collected over a four year period which had not reacted with serotyping antibodies). Strains were tested by sugar utilisation in cysteine trypticase base agar (CTA test), the Phadebact Monoclonal GC Test and Syva MicroTrak Neisseria gonorrhoeae Culture Confirmation Test. The auxotype and serovar of each strain were also determined. RESULTS: The sugar utilisation test confirmed the identity of 99% (197/199) of gonococci from Avon and 97% (198/204) of those from Leeds. The Syva FAT confirmed 76% (151/199) of isolates from Avon and 84% (171/204) of those from Leeds. The Phadebact test confirmed all but one isolate from the 403 strains from both cities. Half of the 20 referred FAT negative isolates also give a negative result in the Syva FAT; however, only 10% of the remainder gave a strong reaction in our laboratory. All serotyping antibody negative strains were negative in the FAT, although all these and all of the 20 strains that give a negative result in the FAT gave positive reactions in the other culture confirmation tests. Typing tests revealed a greater diversity amongst the FAT negative strains from Leeds than those from Avon. CONCLUSIONS: Considerable differences in the sensitivity of the MicroTrak but not with the Phadebact or CTA tests were found for the identification of isolates from two geographically distinct areas of the UK. Our results suggest that the Syva FAT would not be suitable, if used alone, for culture confirmation in Avon or Leeds.

Agglutination Tests↗
PubMed1995

Regional epinephrine kinetics in human heart failure: evidence for extra-adrenal, nonneural release.

A number of neurohumoral processes are activated in heart failure, including an increase in the plasma concentration of epinephrine. Radiotracer methods were applied in 42 patients with severe heart failure and 31 healthy volunteers to ascertain the rate at which epinephrine is released to plasma and to evaluate the contribution of extra-adrenal sources. The increase in arterial plasma epinephrine observed in the heart failure patients was explained principally by a 34% (P < 0.001) reduction in the whole body clearance rate of epinephrine from plasma. Regional venous sampling from the heart, lungs, and hepatomesenteric beds was performed in a subgroup of the study population, revealing a significant increase in the release rate of epinephrine to plasma from these organs in heart failure which accounted for 26% of the whole body plasma epinephrine appearance rate. To establish whether the cardiac epinephrine release was of neuronal origin, a physical (cycling) or mental (difficult mental arithmetic) stressor was applied as a sympathoexcitatory stimulus, given that a proportional release of norepinephrine and epinephrine could be expected if sympathetic nerves were the source. These interventions caused significant increases in the regional spillover of norepinephrine to plasma but not that of epinephrine. These findings suggest that nonadrenal tissues contribute significantly to the whole body epinephrine release rate in heart failure and that this may arise from a site other than sympathetic neurons.

Adrenal Glands↗
PubMed1995

Effects of aging on epinephrine secretion and regional release of epinephrine from the human heart.

In contrast to the sympathetic nervous system, which is activated by aging in at least some sympathetic nervous outflows, epinephrine release from the adrenal medulla appears to be either normal or low in the elderly. Using isotope dilution methodology, we studied the effect of aging on the secretion of epinephrine in 19 men, aged 20-30 yr, and 15 men, aged 60-75 yr. Measurements were made both at rest and during the application of laboratory stressors, as diminished adrenal medullary responsiveness possibly contributes to the impairment of some cardiovascular and metabolic responses to stress described previously in the elderly. Epinephrine secretion at rest was lower in the older men (mean +/- SEM, 0.86 +/- 0.10 nmol/min) than in the younger men (1.45 +/- 0.17 nmol/min; P < 0.05). Due to 20% lower plasma epinephrine clearance in the older men (P < 0.01), the reduction in the plasma concentration of epinephrine (0.37 +/- 0.03 vs. 0.52 +/- 0.06 nmol/L; P = 0.06) was proportionally less than that in epinephrine secretion. In the younger men, epinephrine secretion doubled or tripled during mental stress, isometric exercise, and dynamic exercise. Epinephrine responses to the stressors were reduced in older men, being equivalent to only 44% (P < 0.05), 44% (P = 0.1), and 33% (P = 0.01) of the corresponding responses in the younger men. After uptake from plasma, in some circumstances epinephrine is released from sympathetic nerves as a cotransmitter, where it can augment the release of the major sympathetic transmitter, norepinephrine. We also measured regional extraadrenal release of epinephrine from the heart to test whether the previously described increased release of norepinephrine from the cardiac sympathetic nerves with aging might result from facilitator effects of epinephrine released as a cotransmitter. At rest, epinephrine was released from the heart (9.4 +/- 2.6 pmol/min) in older men only (P < 0.01) despite the fact that adrenal medullary secretion of epinephrine was reduced. Failure of epinephrine and norepinephrine spillover from the heart to increase in parallel in the elderly during the sympathetic excitation accompanying exercise suggested that epinephrine lay outside the sympathetic nerves, perhaps arising from extraneuronal synthesis in the heart. We have not yet tested whether extraneuronal, in contrast to neuronal, epinephrine release in the heart could contribute to the observed higher rates of norepinephrine release in the elderly.

Adult↗
PubMed1995

Characterization of a multidrug resistant human erythroleukemia cell line (K562) exhibiting spontaneous resistance to 1-beta-D-arabinofuranosylcytosine.

We have assessed the response of a previously characterized multidrug resistant (MDR) human erythroleukemia cell line (K562R) to the nucleoside analog antimetabolite 1-beta-D-arabinofuranosylcytosine (ara-C). This cell line has been subjected to selection pressure by intermittent exposure to daunorubicin, but not ara-C, since its initial isolation. In comparison to the parental line (K562S), K562R were approximately 15-fold more resistant to ara-C as determined by 3H-dThd incorporation, MTT dye reduction and clonogenicity. Following a 4-h exposure to 10 microM ara-C, K562S accumulated approximately seven times more ara-CTP, and incorporated approximately 250% more ara-C into DNA than their resistant counterparts. The intracellular generation of ara-CTP was not significantly influenced by the cytidine deaminase inhibitor THU or the deoxycytidylate deaminase inhibitor dTHU (1 mM each) in either cell line. Rates of dephosphorylation of ara-CTP were equivalent in sensitive and resistant cells, as were intracellular levels of both ribonucleotide and deoxyribonucleotide triphosphates. However, K562R displayed a significant (ie 70%) reduction in the level of activity of the pyrimidine salvage pathway enzyme, deoxycytidine kinase (dCK), compared to K562S cells. In contrast to U937 leukemic cells, DNA extracted from K562S and K562R cells following exposure to 10 microM ara-C for 6 h did not exhibit the characteristic internucleosomal DNA cleavage on agarose gel electrophoresis typical of drug-induced apoptosis. Lastly, Northern analysis revealed equivalent levels of dCK message in the two cell lines. K562R represents an unusual example of a classical multidrug resistant human leukemic cell line exhibiting spontaneous cross-resistance to the antimetabolite ara-C, and may prove of value in attempts to understand the mechanism(s) by which human leukemic myeloblasts survive in vivo exposure to combination chemotherapeutic regimens containing drugs that are not classically associated with the multidrug resistance phenomenon.

Arabinofuranosylcytosine Triphosphate↗