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K Talbot

Publications and source records attributed to K Talbot.

At least 37 records · Page 2Linked to original sources
PubMed1996

Evidence for compound heterozygosity causing mild and severe forms of autosomal recessive spinal muscular atrophy.

Spinal muscular atrophy is an autosomal recessive disease of motor neurone degeneration which shows a variable phenotype. Two candidate genes show deletions in affected subjects but with no distinction between different forms of the disease. We report an unusual family in which mild and severe SMA coexists and patients are deleted for the SMN gene. The father is affected with late onset SMA; therefore this family shows pseudodominant inheritance. When typed using closely linked flanking markers the severely affected son does not share the same haplotype as his sib, who is deleted for SMN but shows no signs yet of SMA. This supports the hypothesis that differences in SMA phenotype can be explained by a multiple allele model.

Adult↗
PubMed1996

Gene deletions in spinal muscular atrophy.

Two candidate genes (NAIP and SMN) have recently been reported for childhood onset spinal muscular atrophy (SMA). Although affected subjects show deletions of these genes, these deletions can lead to either a very mild or a severe phenotype. We have analysed a large number of clinically well defined patients, carriers, and normal controls to assess the frequency and extent of deletions encompassing both of these genes. A genotype analysis indicates that more extensive deletions are seen in the severe form of SMA than in the milder forms. In addition, 1 center dot 9% of phenotypically normal carriers are deleted for the NAIP gene; no carriers were deleted for the SMN gene. Our data suggest that deletions in both of these genes, using the currently available assays, are associated with both a severe and very mild phenotype.

Chromosomes, Human, Pair 5↗
PubMed1995

Deletions in the survival motor neuron gene on 5q13 in autosomal recessive spinal muscular atrophy.

Autosomal recessive spinal muscular atrophy is a motor neuron disease which affects about 1 in 10,000 births. Recent evidence shows that the candidate region contains multiple copies of genes and pseudogenes and is characterised by genome instability. We have analysed the frequency of deletions in a recently characterised candidate survival motor neuron (SMN) gene. Our data confirm previous analyses and show that this gene is disrupted by deletion in SMA patients. The same deletion frequency is observed in the milder variants of the disease as in patients with the severe form. In addition, we observed one case of a new mutation in a family previously thought not to be segregating for a chromosome 5 linked form of SMA. This assay is a very good diagnostic for SMA although no direct correlation between phenotype and genotype is apparent and carrier status cannot be determined. The implications for the identification of the gene or genes causing the disease are discussed.

Chromosomes, Human, Pair 5↗
PubMed1993

Vasoactive intestinal peptide, but not pituitary adenylate cyclase-activating peptide, modulates the responsiveness of the gonadotroph to LHRH in man.

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) are hypothalamic peptides sharing considerable sequence homology which are postulated to be hypophysiotrophic releasing factors. When infused into man, PACAP has no effect on anterior pituitary hormone levels, while VIP causes a significant increase in circulating prolactin concentrations. However, PACAP has recently been shown to augment the release of LH and FSH in response to LHRH in rat anterior pituitary cell culture. In order to ascertain if either peptide has a similar effect in man, PACAP and VIP were infused at 3.6 pmol/kg per min into six healthy male volunteers, and an LHRH test was performed 30 min after the infusion was commenced. Infusion of PACAP did not alter the gonadotrophin response to LHRH significantly. However, VIP augmented the release of LH significantly, both during the infusion and for 30 min thereafter, although there was no effect on FSH release. Thus VIP, but not PACAP, potentiates the release of LH after LHRH injection in man.

Follicle Stimulating Hormone↗
PubMed1988

Feline islands of Calleja complex: I. Cytoarchitectural organization and comparative anatomy.

Cytoarchitectural analyses demonstrated that the islands of Calleja complex (ICC) is highly developed and discretely organized in the cat. The feline complex is clearly divided into morphological units, each containing a granular Callejal island and a population of satellite neurons. These ICC units change progressively in cytoarchitecture from the lateral to the medial edge of the olfactory tubercle. In particular, the islands flatten, sink into the tubercular molecular layer, and increase in cell density, while their satellite neurons increase in number and decrease in size. The lateromedial transformation was judged to take place in five stages, resulting in the successive appearance of lateral, lateral transitional, central, medial transitional, and medial ICC units. The first two unit types display prominently two additional components of the feline ICC-namely, clusters of dwarf cells and small pyramidal-like neurons constituting the densocellular layer cupping the base of lateral Callejal islands. All of the various types of ICC units contact the tubercular molecular layer via their dwarf and/or granule cell components, raising the possibility of direct olfactory input to the entire Callejal complex (apart from the isla magna). Output from the complex is presumed to arise from the satellite neurons, which are distinguished from adjoining cell populations by their close association with Callejal islands, typical chromophilic character, and relatively large size (15-42 micron in soma length). In the tubercular ICC, these neurons are most numerous immediately above Callejal islands in a fiber-rich zone continuous with the supratubercular zone and hence with the ventral pallidum. In the accumbal ICC, satellite neurons are most conspicuous in granule-cell-poor spaces within the isla magna, where many non-granular neurons are uncharacteristically small and chromophobic. The isla magna itself is unusual not only for its large size but for lateral extensions encircling a group of accumbal neurons far caudally. Such extensions are one of several indications that the isla magna is intimately associated with the nucleus accumbens. A comparative anatomical survey of the ICC in rats, cats, and macaque monkeys demonstrated a number of species differences. Of particular interest is the finding that the complex is unambiguously divided into discrete island-satellite cell units only in cats and macaques. In these species, the complex is also distinguished by a predominance of superficial islands and an especially prominent isla magna. ICC units, however, were most conspicuous in cats.

Animals↗
PubMed1988

Feline islands of Calleja complex: II. Cholinergic and cholinesterasic features.

Histochemical analyses demonstrated that the islands of Calleja complex (ICC) in the cat is exceptionally rich in choline acetyltransferase (ChAT) and acetylcholinesterase (AChE). Both enzymes are found in neuropil throughout the complex, as well as in a subset of the satellite neurons accompanying Callejal islands. Lateromedial changes in these cholinergic and cholinesterasic tissue elements were consistent with our previous finding that the feline ICC is cytoarchitecturally divided into five successively more medial types of island-satellite cell ensembles or units. In particular, satellite neurons reactive for ChAT and AChE diminished progressively in size and increased steadily in number from the most lateral to the most medial units. A concomitant increase in neuropil levels of both enzymes suggested that the strong cholinergic innervation of the feline ICC is at least partially derived from satellite cells. This possibility gained further credibility from the additional observation that very fine processes from some ChAT and AChE satellite neurons projected into the terminal-like cholinergic field permeating the granular Callejal islands. The granule cells themselves lacked ChAT and (apart from potentially artifactual cases) AChE, as did adjoining groups of dwarf cells and small pyramidal like neurons. The cholinergic and cholinesterasic satellite neurons were preferentially located above tubercular Callejal islands and in otherwise cell-poor spaces within the isla magna. Such neurons appeared to be isodendritic: they commonly had ovoidal somata with one or two processes lacking enzyme-reactive spines. Depending on the type of ICC unit involved, their mean soma length ranged from 15 to 24 micron, all but the largest of which was distinctly smaller than that of ChAT and AChE cells in striatal or basal nuclear structures. Not all the cholinesterase neurons in the feline ICC are cholinergic, judging from the finding that there are a significantly greater number of satellite neurons containing AChE than ChAT. Three cholinergic features of the feline ICC are especially noteworthy. First, each of the island-satellite cell ensembles in the complex is unified by AChE neuropil often denser than that of adjacent striatal areas. Second, cholinergic neuropil is exceptionally dense in the isla magna and in a subpial band under medial Callejal islands. Third, ChAT neurons in the isla magna are among the smallest cholinergic cells found in the brain.

Acetylcholinesterase↗
PubMed1987

Characterization of a cDNA defining a gene family encoding TM30p1, a human fibroblast tropomyosin.

We have isolated a cDNA that contains the complete coding sequence of a 3.0 X 10(3) base human fibroblast mRNA together with a large part of its 3' untranslated sequence. The deduced protein sequence is very similar if not identical to the sequence of horse platelet tropomyosin, a 247 amino acid protein. In vitro translation of an SP6 transcript of this cDNA reveals that the protein product of the 3.0 X 10(3) base mRNA is TM30p1, one of the five proteins in human fibroblasts that have been shown to possess the physical and chemical characteristics of tropomyosin. This mRNA is encoded by a gene family that consists of a functional gene and multiple RNA-copy pseudogenes. This family of sequences is distinct from the gene family encoding TM30nm, a cytoskeletal tropomyosin very similar in electrophoretic mobility to TM30p1, but which shows significant differences in primary structure.

Base Sequence↗
PubMed1986

The mRNA and RNA-copy pseudogenes encoding TM30nm, a human cytoskeletal tropomyosin.

We have determined the sequence of a 2.5 kb mRNA in human fibroblasts encoding a 248 amino acid cytoskeletal tropomyosin. The protein product of this mRNA is TM30nm, one of five tropomyosin-like proteins in human fibroblasts. The structural gene encoding this mRNA can also produce a 1.3 kb mRNA encoding a 285 amino acid skeletal muscle alpha-tropomyosin by tissue-specific alternative mRNA splicing. However, the multiple RNA-copy pseudogenes of this gene family are derived largely if not exclusively from transcripts processed according to the pattern observed in non-muscle cells.

Amino Acid Sequence↗
PubMed1986

CB 1954 revisited. I. Disposition kinetics and metabolism.

Although it has been the subject of considerable interest for 15 years, originally as a cytotoxic agent and more recently as a radiosensitizer, there is very little pharmacokinetic information on CB 1954 (2,4-dinitro-5-aziridinylbenzamide). We have developed a rapid high-performance liquid chromatography assay for the drug and its metabolites and applied it to detailed examination of the pharmacokinetics of CB 1954 in mice and dogs. With IV administration a dose of 50 mg/kg gave peak blood concentrations of 100 micrograms/ml in mice, while 25 mg/kg gave peak plasma concentrations of 27 micrograms/ml in dogs. Peak concentrations were 3 to 5-fold lower for the IP route in mice and the oral route in dogs, and the bioavailabilities were 85% and 40%, respectively. Elimination t1/2 values were 1.4-2 h in mice and 2.5-4 h in dogs and were independent of route of administration. Plasma protein binding was 57% but tissue penetration in mice was generally good. Tumour: plasma ratios were 50%-90%, while brain: plasma ratios were lower, at 37%-50%. The parent drug and several metabolites were identified and quantified in mouse urine, the total recovery being 24%-29%, of which 16%-25% was parent drug. The metabolites were also found in the circulation and in tissues. No changes in pharmacokinetics were seen with repeated dosing in mice or with administration of the protective agent phenyl AIC. Phenobarbitone pretreatment produced a small reduction in elimination t1/2, mainly by accelerating aziridine ring removal. Allopurinol increased the blood levels of the 5-amino nitroreduction product. These studies provide a pharmacokinetic basis for interpreting the antitumour activity and toxicity of CB 1954, as well as for the development of new 'mixed-function' sensitizers.

Allopurinol↗
PubMed1986

CB 1954 revisited. II. Toxicity and antitumour activity.

We have assessed the antitumour activity of the nitrophenylaziridine CB 1954 in vitro and in vivo. For EMT6 mouse mammary tumour multicellular spheroids under hypoxic conditions in vitro, a 6-h exposure to 40 micrograms/ml reduced the surviving fraction to as low as 10(-3) and the growth delay was 5.4 days. Oxic cells were twofold less sensitive. Phenyl AIC protected oxic and hypoxic cells equally. Under oxic conditions minimal cell killing was seen with HT29 cells, either in multicellular spheroids or in monolayer; a 6-h exposure to 40 micrograms/ml gave a spheroid growth delay of 1.5-1.7 days. No growth delay was seen with single maximum tolerated doses of CB 1954 against HT29 grown as a xenograft in immunosuppressed mice. Only minimal growth delays of 1-2 days were seen with similar doses against the EMT6 tumour and the RIF-1 and KHT sarcomas in mice. Little activity was seen with maximum tolerated doses given once a day for 5 days against EMT6 and RIF-1. No chemosensitization was measurable with CCNU, cyclophosphamide or melphalan in the KHT tumour.

Animals↗
PubMed1985

A muscle-type tropomyosin in human fibroblasts: evidence for expression by an alternative RNA splicing mechanism.

We have isolated a cDNA clone from a human fibroblast cDNA library that contains the entire protein-coding region of a 1.1-kilobase mRNA. This mRNA encodes a 284-amino acid tropomyosin, the primary structure of which most closely resembles smooth muscle tropomyosin. Thus, the expression of both 284-amino acid muscle-type and 247-amino acid non-muscle-type tropomyosins appears to be a normal feature of human non-muscle cells. We also present evidence to suggest that this cytoskeletal tropomyosin and a human skeletal muscle beta-tropomyosin are derived from a common structural gene by an alternative RNA splicing mechanism.

Amino Acid Sequence↗
PubMed1984

Evidence that efferents from the basolateral amygdala innervate the dorsolateral neostriatum in rats.

The dorsolateral precommissural caudate-putamen complex has been characterized recently as a 'non-limbic' region of the neostriatum. In the present study, however, it was found that numerous neurons in the basolateral amygdala were labeled retrogradely following infusions of Evans Blue into that neostriatal region. Control infusions demonstrated that such labeling could not be attributed to the spread of the red fluorescent tracer into surrounding neocortical areas. On the basis of these data, it is proposed that: (1) the amygdalo-neostriatal pathway may be more extensive than previously believed, and (2) the basolateral amygdala may serve as an important link between the limbic and extrapyramidal motor systems.

Acetylcholinesterase↗
PubMed1983

A processed gene defining a gene family encoding a human non-muscle tropomyosin.

We have isolated and characterized a human genomic DNA sequence that defines a family of closely related sequences. At least one member of this family expresses a 2.5 X 10(3) base messenger RNA transcript encoding a 30,000 molecular weight tropomyosin in human fibroblasts. The coding sequence of this mRNA but not the non-coding sequence is also related to that of a 1.1 X 10(3) base mRNA encoding a 36,000 molecular weight non-muscle tropomyosin. This demonstrates the existence of at least two functional genes encoding human non-muscle tropomyosins.

Amino Acid Sequence↗
PubMed1983

Novel form of non-muscle tropomyosin in human fibroblasts.

The cytoskeletal extracts of cultured human fibroblasts were found to contain at least four distinct polypeptides, each of which demonstrated the resistance to denaturation and the acidic isoelectric point characteristic of tropomyosin. One of these, hscp 36 (heat-stable cytoskeletal protein having an apparent molecular weight of 36,000), cross-reacted efficiently with an antiserum to chicken skeletal muscle tropomyosin. Furthermore, the messenger RNA coding for hscp 36 was selected by a chicken complementary DNA clone containing a tropomyosin sequence. The abundance of mRNA coding for hscp 36 was found to be similar in both normal and simian virus 40 (SV40) transformed human fibroblasts. The apparent molecular weight of hscp 36 is different from non-muscle tropomyosins previously isolated from human sources, which show the apparent molecular weight of 30,000 normally associated with non-muscle tropomyosin. This, together with the complexity of the heat-stable cytoskeletal proteins present in human fibroblasts, suggests the existence of multiple genes coding for human non-muscle tropomyosins.

Base Sequence↗