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Biomedical subjects

A M Taylor

Publications and source records attributed to A M Taylor.

At least 109 records · Page 6Linked to original sources
PubMed1994

A haplotype common to intermediate radiosensitivity variants of ataxia-telangiectasia in the UK.

In a study of ataxia-telangiectasia (A-T) in the UK, patients in 10 out of 60 families were shown to have a much lower level of chromosomal radiosensitivity compared with the majority of patients. In some patients the level of radiosensitivity was hardly distinguishable from normal. Patients in this group, however, could be distinguished clinically from the majority either by the later onset of severe cerebellar features or the slower rate of progress of the disorder. By using highly polymorphic microsatellite repeat markers a chromosome 11q22-23 haplotype common to the majority of these patients, and not occurring in any non-A-T chromosome in 60 families, was identified on one chromosome. The haplotype probably defines the region of the A-T gene in these families and the mutation associated with this haplotype may be much less severe than the second mutation thereby producing the slightly milder phenotype.

Adolescent↗
PubMed1994

Genetic and physical mapping of the ataxia-telangiectasia locus on chromosome 11q22-q23.

The identification of A-T gene(s) using both positional and functional cloning techniques has been a major objective in A-T research over the past 10 years. Functional cloning, using complementation of the radiosensitivity phenotype, has met with some success, although technical problems remain to be overcome. Recent progress, however, in both genetic and physical mapping of the A-T locus on chromosome 11q22-q23, described in this review, suggests that the positional cloning of candidate genes should be achieved in the very near future. The region of the chromosome containing the gene(s) has been identified, and is no more than 1.6 Mb in size. The detailed physical characterization of this region, as a preliminary to candidate gene isolation, is now underway. There are, however, still some unresolved issues, most notably the existence of four A-T complementation groups, with the resulting supposition that these equate to a number of different genes. Although genetic linkage evidence does not support the hypothesis of genetic heterogeneity, the possibility of a cluster of genes at the 11q22-23 locus cannot be ruled out. It is likely that the explanations for this and other problems such as discrepancies in expected levels of consanguinity, and difficulties in the classification of atypical phenotypes will become much more obvious once a gene or genes have been cloned.

Ataxia Telangiectasia↗
PubMed1994

Clonal evolution of malignant and non-malignant T cells carrying t(14;14) and t(X;14) in patients with ataxia telangiectasia.

People with ataxia telangiectasia (AT) are at a higher than normal risk of T cell leukaemia and often have either non-malignant or malignant T cells with chromosomal abnormalities, typically t(14;14), inversion 14 or more rarely t(X;14). This provides a chance to study the pre-leukaemic phase of the disease. T cells have been studied with either t(14;14)(q11;q32.1) or t(X;14)(q28;q11) from two AT sisters of which the latter developed T cell leukaemia. The telomeric breakpoint of the t(14;14) was cloned and found to occur at 14q32.1 where known tumour-associated breakpoints are located, but the patient remains asymptomatic for leukaemia. Analysis of T cell populations in both patients showed that the cells containing the translocation became oligoclonal with respect to T cell receptor beta rearrangement and complete T cell receptor beta clonality was only established in the patient with t(X;14) by onset of overt disease. Therefore in these chronic diseases, chromosomal translocations can precede T cell receptor rearrangement suggesting a role for these abnormalities as early events of malignant outgrowth.

Ataxia Telangiectasia↗
PubMed1994

A gene on chromosome Xq28 associated with T-cell prolymphocytic leukemia in two patients with ataxia telangiectasia.

A t(X;14)(q28;q11) translocation was present for many years in T cells in two patients with ataxia telangiectasia (A-T), who subsequently developed T-prolymphocytic leukemia. We describe here the relationship between the translocation breakpoints in these patients with respect to two recently described genes, c6.1A and c6.1B, on Xq28 which are transcribed in opposite directions from the same CpG island. In our first patient, the Xq28 breakpoint disrupts the c6.1A gene which is consequently transcribed as a fusion mRNA with the TCR C alpha chain gene. In the second case, the Xq28 breakpoint lies within the adjacent gene c6.1B, and c6.1A is not transcribed. We show that the c6.1B gene is transcribed in both of our patients. c6.1B may be important in the initial clonal proliferation of T lymphocytes which commonly precedes transformation to T-PLL in ataxia telangiectasia patients. The same gene may also be involved in the development of T-PLL in the non-A-T population.

Adult↗
PubMed1993

Finasteride, a steroid 5 alpha-reductase inhibitor, does not affect the oxidative metabolism of antipyrine.

A single-blind study was conducted to investigate the effect of multiple doses of finasteride, a 5 alpha-reductase inhibitor for the treatment of benign prostatic hyperplasia, on the single-dose pharmacokinetics of antipyrine. Twelve patients with benign prostatic hyperplasia received a total of four single oral doses of 18 mg/kg antipyrine before, during, and after treatment with 10 mg/day of finasteride for 28 days. Finasteride had no effect on antipyrine concentration profiles. There were also no changes in urinary excretion of three principal antipyrine metabolites. A slight increase in renal clearance of antipyrine was observed; however, this is not considered relevant because excretion of unchanged antipyrine represents a minor fraction of total elimination and is not directly related to oxidative metabolism. These results imply that significant interactions between finasteride and drugs metabolized by these cytochrome P-450 enzymes are unlikely.

Administration, Oral↗
PubMed1993

Irradiation hybrids for human chromosome 11: characterization and use for generating region-specific markers in 11q14-q23.

High-dose irradiation hybrids containing fragments of chromosome 11 have been generated, with a view to isolating new region-specific markers. Forty-seven lines were scored for 34 markers: average retention was 6%. Fourteen lines contain markers from 11q14 to 11q23. One of these, Jo12, has 11q markers extending from tyrosinase (q14-q21) to PBGD (q23.3) plus one marker (TYRL, p11.2) from 11p. In situ hybridization using Alu PCR products from Jo12 as probe confirmed that the human DNA is derived from two regions, one in proximal 11p and a second, larger region in 11q23. Plasmid libraries of Alu PCR products from this and three other hybrids have been made. Six of eight recombinants identified as having single-copy inserts were mapped back to the regions of 11q22-q23 detected in the originating hybrid; only one mapped to a region not originally detected, and one was of hamster origin. These six clones provide new markers in 11q22-q23 that can be used directly for polymorphism studies. This series of hybrids is therefore a valuable resource for the rapid generation of markers from specific, defined regions of chromosome 11.

Animals↗
PubMed1993

The order and orientation of a cluster of metalloproteinase genes, stromelysin 2, collagenase, and stromelysin, together with D11S385, on chromosome 11q22-q23.

A cluster of metalloproteinase genes, stromelysin, fibroblast collagenase, and stromelysin 2 together with the anonymous DNA marker D11S385, was mapped using pulsed-field gel electrophoresis to a 135-kb region of chromosome 11q22-q23. The physical proximity of these markers was subsequently confirmed using two YAC clones, and their relative order was established as stromelysin 2-collagenase-stromelysin-D11S385. The pattern of marker representation in a panel of radiation-reduced chromosome 11 hybrids suggests that the metalloproteinase gene/D11S385 cluster is orientated with STMY2 closest to the centromere.

Animals↗
PubMed1993

The effects of recombinant insulin-like growth factor I administration on growth hormone levels and insulin requirements in adolescents with type 1 (insulin-dependent) diabetes mellitus.

Type 1 (insulin-dependent) diabetes mellitus in adolescence is associated with reduced levels of insulin-like growth factor I, elevated growth hormone concentrations and insulin resistance. In order to determine whether restoring insulin-like growth factor I levels to normal might lead to a reduction in growth hormone levels and insulin requirements, we undertook a double-blind placebo controlled study of a single s.c. dose of recombinant insulin-like growth factor I (40 micrograms/kg body weight) in nine late pubertal subjects with Type 1 diabetes. After administration of placebo or insulin-like growth factor I at 18.00 hours, a variable rate insulin infusion was used to maintain euglycaemia overnight. Plasma insulin-like growth factor I, growth hormone, free insulin, and intermediate metabolite concentrations were monitored throughout the study. Recombinant insulin-like growth factor I led to a rise in plasma concentrations which reached a peak at 5.5 h (413.1 +/- 28.2 ng/ml, mean +/- SEM). Mean growth hormone levels between 20.00 and 08.00 hours were significantly reduced after recombinant insulin-like growth factor I (19.4 +/- 4.0 compared with 33.6 +/- 5.8 mU/l; p = 0.01), as were the insulin requirements for euglycaemia (0.25 +/- 0.02 compared with 0.31 +/- 0.04 mU.kg-1.min-1; p = 0.03). Plasma free insulin levels were lower after recombinant insulin-like growth factor I administration (31.9 +/- 2.7 compared with 67.9 +/- 16.0 mU/l; p = 0.001) but no significant differences in ketone or lactate levels were detected.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

Contrasting distributions of patched and hedgehog proteins in the Drosophila embryo.

The segment polarity genes patched (ptc) and hedgehog (hh) are thought to encode a receptor and signal molecule respectively, components of a signal transduction pathway that regulates the transcription of the wingless gene in the Drosophila embryo. Here we describe the production of antibodies specific for the products of these two genes and the patterns of protein distribution that they reveal in the developing embryo. The results are consistent with the hh protein being secreted by cells in which it is expressed and support a role for ptc in the reception of the putative hh encoded signal.

Animals↗
PubMed1993

The kindling model of alcohol dependence: similar persistent reduction in seizure threshold to pentylenetetrazol in animals receiving chronic ethanol or chronic pentylenetetrazol.

Rats on a chronic intermittent ethanol (CIE) regimen showed a persistent reduction in seizure threshold to the convulsant drug pentylenetetrazol (PTZ). CIE rats were given ethanol by intubation on an alternate day schedule and tested at selected intervals for seizure threshold with PTZ. A significant reduction in seizure threshold, a sign of withdrawal, was observed 20 hr after the first dose. The severity of withdrawal intensified on repetition of the ethanol administration and depression-hyperexcitability cycle, with the seizure threshold reaching a maximum decrease after 12 doses and remaining reduced up to 60 doses. The reduction in seizure threshold persisted for at least 40 days of no alcohol following the 60th dose. The long-lasting decrease in seizure threshold following CIE treatment resembled the "kindling" phenomenon produced by chronic administration of PTZ (25 mg/kg, 3 times/week). The CIE rats developed, in addition, a tolerance to the anticonvulsant action of ethanol, which occurred well after the decrease in PTZ seizure threshold, and a tolerance to the hypothermic effect of ethanol, which developed rapidly. PTZ kindled rats that had never been exposed to ethanol also exhibited tolerance to the hypothermic effect of ethanol. We propose that kindling contributes to the mechanism of the development of dependence on central nervous system depressants like benzodiazepines, barbiturates, and alcohol, drugs that act on the gamma-aminobutyric acid-A receptor chloride ion channel complex. Repeated episodes of depression and withdrawal hyperexcitability are postulated to produce kindling during the repeated withdrawal episodes.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Withdrawal Delirium↗
PubMed1993

A family showing no evidence of linkage between the ataxia telangiectasia gene and chromosome 11q22-23.

We have studied an inbred family in which two cousins presented with the same clinical features of ataxia telangiectasia (AT). Both patients are still ambulatory at ages 25 and 20. Cellular features of both patients are typical of AT and include increased radiosensitivity and an increased level of spontaneously occurring chromosome aberrations in peripheral blood lymphocytes. Linkage studies and haplotype analysis show no clear evidence that the gene for AT in this family is on chromosome 11q22-23. As previously reported AT families from complementation groups AB, C, and D have all shown linkage to this region of 11q22-23. Our study is of importance in suggesting additional locus heterogeneity.

Adult↗
PubMed1993

Effects of hypothyroidism and hyperthyroidism on insulin-like growth factors (IGFs) and growth hormone- and IGF-binding proteins.

Normal thyroid status is a prerequisite for the normal growth and development of many tissues. The interrelationships between the thyroid and pituitary-GH-insulin-like growth factor (IGF) axes are complex and not yet fully understood. We have studied the effects of hypothyroidism (n = 22) and hyperthyroidism (n = 17) on levels of serum immunoreactive IGF-I and II, IGF-binding proteins (IGFBP-1 and -3), and IGF bioactivity before and during treatment. We have also assessed changes in GH-binding activity (GHBP). Mean immunoreactive (IR) IGF-I levels in the hypothyroid group rose from 106.6 +/- 10.6 micrograms/L at diagnosis to 139.9 +/- 12.7 micrograms/L (P = 0.009) on normalization of thyroid function. In hyperthyroidism, mean IGF-I levels (258.9 +/- 33.9 micrograms/L) were high initially and fell to 188.7 +/- 14.8 micrograms/L (P = 0.04) after treatment. IR IGF-I levels correlated positively with free T3 and free T4 and negatively with TSH levels. Mean serum IGF-II levels were low in hypothyroid patients (375.2 +/- 37.3) and rose during treatment (516.9 +/- 59.4 micrograms/L; P = 0.04). In the hyperthyroid subjects, however, there was no significant change during therapy (625.0 +/- 66.9 vs. 621.9 +/- 120.8 micrograms/L; P = 0.98). IGF bioactivity potency ratios were low in the hypothyroid group (0.26 +/- 0.03 U/mL) and rose to 0.71 +/- 0.10 U/mL (P = 0.01) during treatment. IGF bioactivity in the hyperthyroid group was also low (0.38 +/- 0.05 U/mL) and rose significantly during treatment (0.81 +/- 0.06 U/mL; P = 0.003). Mean IGFBP-1 levels (29.8 +/- 5.7 micrograms/L) were unaltered by treatment of hypothyroid subjects (28.4 +/- 4.8 micrograms/L). In contrast, IGFBP-1 levels in the hyperthyroid subjects were high at diagnosis (134.6 +/- 26.6 micrograms/L) and fell significantly (71.3 +/- 14.3 micrograms/L; P = 0.04) during treatment. In the hypothyroid group, IGFBP-3 levels rose from an initial mean of 1.98 +/- 0.17 to 2.67 +/- 0.27 mg/L (P = 0.04) during treatment. The higher mean pretreatment levels in the thyrotoxic group (3.46 +/- 0.32 mg/L) were unaltered by treatment (3.20 +/- 0.51 mg/L; P = 0.71). GHBP was low in the hypothyroid group at diagnosis (28.5 +/- 2.5%) and rose during treatment to 40.6 +/- 3.9% (P = 0.02). We have confirmed that IR IGF-I levels are low in hypothyroidism and have demonstrated a reduction in IGF bioactivity and IGF-II and IGFBP-3 levels, and low GH-binding activity, which may reflect a reduction in the processing of GH receptors.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1993

Endocrine and cardiac paracrine actions of insulin-like growth factor-I (IGF-I) during thyroid dysfunction in the rat: is IGF-I implicated in the mechanism of heart weight/body weight change during abnormal thyroid function?

Thyroid hormones are essential for the normal growth and development of many tissues. In the rat, hypothyroidism is associated with growth impairment, and hyperthyroidism with the development of a hypercatabolic state and skeletal muscle wasting but, paradoxically, cardiac hypertrophy. The mechanism by which thyroid hormone produces cardiac hypertrophy and myosin isoenzyme changes remains unclear. The role of IGF-I, an anabolic hormone with both paracrine and endocrine actions, in producing cardiac hypertrophy was investigated during this study in hyperthyroid, hypothyroid and control rats. A treated hypothyroid group was also included in order to assess the effect of acute normalization of thyroid function. Body weight was significantly lower in the hyperthyroid (mean +/- S.E.M.; 535.5 +/- 24.9 g, P < 0.05), hypothyroid (245.3 +/- 9.8 g, P < 0.001) and treated hypothyroid (265.3 +/- 9.8 g, P < 0.001) animals when compared with controls (618.5 +/- 28.6 g). Heart weight/body weight ratios were, however, significantly increased in the hyperthyroid (2.74 +/- 0.11 x 10(-3), P < 0.01) and treated hypothyroid (2.87 +/- 0.07 x 10(-3), P < 0.001) animals when compared with controls (2.26 +/- 0.03 x 10(-3). Serum IGF-I concentrations were similar in the control and hyperthyroid rats (0.91 +/- 0.07 vs 0.78 +/- 0.04 U/ml, P = 0.26), but bioactivity was reduced by 70% in hyperthyroid serum, suggesting a circulating inhibitor of IGF. Serum IGF-I levels (0.12 +/- 0.03 U/ml, P < 0.001) and bioactivity (0.12 +/- 0.04 U/ml, P < 0.001) were significantly lower in the hypothyroid group. Liver IGF-I mRNA levels were not statistically different in the control and hyperthyroid animals, but were significantly reduced in the hypothyroid animals (P < 0.05 vs control). Heart IGF-I mRNA levels were similar in the control and hypothyroid rats, but were significantly increased in the hyperthyroid and treated hypothyroid animals (increased by 32% in hyperthyroidism, P < 0.05; increased by 57% in treated hypothyroidism, P < 0.01). Cardiac IGF-I was significantly elevated in hyperthyroidism (0.16 +/- 0.01 U/mg heart tissue, P < 0.01), was low in hypothyroidism (0.08 +/- 0.01 U/mg, P < 0.01) and was normalized in the treated hypothyroid group (0.11 +/- 0.01 U/mg vs control, 0.13 +/- 0.01 U/mg). Low body mass during both hypothyroidism and hyperthyroidism is therefore associated with reduced systemic IGF bioactivity. In hypothyroidism there is a primary defect in the endocrine function of IGF-I, while in hyperthyroidism serum IGF bioactivity is reduced in the presence of normal endocrine production of this anabolic hormone.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

The effects of dexamethasone treatment on immunoreactive and bioactive insulin-like growth factors (IGFs) and IGF-binding proteins in normal male volunteers.

Glucocorticoids inhibit somatic growth in man and laboratory animals, and have long been regarded as suppressors of both stimulated GH secretion and insulin-like growth factor (IGF) activity. Recent evidence suggests, however, that glucocorticoids can be potent GH secretagogues in their own right with concomitant increases in circulating IGF-I levels. IGFs circulate tightly bound to a group of high-affinity binding proteins (IGFBPs) which modulate their actions. In order to investigate the effects of glucocorticoids on serum levels of IGFs and IGFBPs, normal male volunteers were sampled over 24-h periods before and directly after treatment with dexamethasone (2 mg twice daily) for 96 h. Following dexamethasone administration, all volunteers showed a marked increase in mean +/- S.E.M. IGF-I levels over the 24-h sampling period (292.2 +/- 31.8 before dexamethasone, 425.9 +/- 37 micrograms/l after dexamethasone, P < 0.005); there was no change in mean IGF-II levels. Integrated mean insulin levels were raised by dexamethasone treatment (50 +/- 4.6 before dexamethasone, 117 +/- 13.4 mU/l after dexamethasone, P = 0.002) and IGFBP-1 was significantly suppressed (42.9 +/- 8.2 before dexamethasone, 28.0 +/- 7.9 micrograms/l after dexamethasone, P < 0.001). IGFBP-2 levels were similarly suppressed after dexamethasone (319.5 +/- 24.5 before dexamethasone, 214.8 +/- 8.5 micrograms/l after dexamethasone, P = 0.002), and there was a significant increase in IGFBP-3 levels from 3.24 +/- 0.25 to 3.67 +/- 0.32 mg/l (P = 0.0153). Mean IGF bioactivity over the sampling period after dexamethasone was reduced by approximately 60% (0.93 +/- 0.39 before dexamethasone, 0.39 +/- 0.05 U/ml after dexamethasone, P < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Genetic analysis of hedgehog signalling in the Drosophila embryo.

The segment polarity genes play a fundamental role in the patterning of cells within individual body segments of the Drosophila embryo. Two of these genes wingless (wg) and hedgehog (hh) encode proteins that enter the secretory pathway and both are thought to act by instructing the fates of cells neighbouring those in which they are expressed. Genetic analysis has identified the transcriptional activation of wg as one of the targets of hh activity: here we present evidence that transduction of the hh-encoded signal is mediated by the activity of four other segment polarity genes, patched, fused, costal-2 and cubitus interruptus. The results of our genetic epistatsis analysis together with the molecular structures of the products of these genes where known, suggest a pathway of interactions leading from reception of the hh-encoded signal at the cell membrane to transcriptional activation in the cell nucleus. We have also found that transcription of patched is regulated by the same pathway and describe the identification of cis-acting upstream elements of the ptc transcription unit that mediate this regulation.

Animals↗
PubMed1993

A comparison of in vitro assay systems for the measurement of drug sensitivity of Trypanosoma evansi.

Two in vitro assay systems were investigated for their effectiveness in detecting the sensitivity of Trypanosoma evansi stocks to the trypanocide suramin. These assay systems measured 1) incorporation of radiolabelled nucleic acid precursor, hypoxanthine; and 2) pyruvate production. They were compared with the direct counting method in which numbers of motile trypanosomes were estimated using a Neubauer haemocytometer chamber. Three stocks of T. evansi were tested-2 suramin sensitive stocks from Indonesia, TREU 1840 and TREU 1981, and a suramin resistant stock from the Sudan, TREU 2136. Each assay system distinguished between the suramin sensitive and resistant stocks. However, inhibition compared to untreated control cultures was less when assessed from pyruvate concentration in culture supernatants than by direct counting. The length of incubation with drug before addition of radio-label was the most important variable in the hypoxanthine incorporation assay. A pre-incubation time of 16 hours with the drug before adding the label for the further 8 hours of the assay was found to be the most sensitive. Under these conditions, the IC50 values (drug concentrations causing 50% inhibition) were similar to those obtained from direct counts. Pre-incubation of parasites with drug before adding the label resulted in a decrease of the IC50. These results suggest that the discrepancy between the levels of pyruvate production and relative growth at inhibitory concentrations of the drug are due to metabolism by the parasites during the initial stages of the assay, before the drug has began to inhibit cell growth.

Animals↗
PubMed1992

Molecular analysis of a new translocation, t(X;14)(q28;q11), in premalignancy and in leukaemia associated with ataxia telangiectasia.

The disease ataxia telangiectasia (A-T) is a multifaceted disorder in which patients have an increased chance of developing a T-cell leukaemia, often with abnormalities of chromosome 14, but sometimes with rare translocations, like t(X;14)(q28;q11). We describe the cloning of the breakpoint of one such novel t(X;14) from an A-T patient. The translocation breaks within the T cell receptor alpha chain gene on chromosome 14 at band q11 and in a region of the X chromosome, within about 1 Mb of the telomere of the long arm. The patient subsequently developed T-cell prolymphocytic leukaemia (T-PLL), and molecular examination showed that the tumour cells carried the same t(X;14) breakpoint as that cloned from the premalignant cells. The same breakpoint could be detected in blood samples taken as much as 5 years prior to diagnosis of T-PLL. This suggests a role for the abnormality in the tumour development in this patient but implies that other mutational events were necessary for overt disease to become manifest.

Adult↗