Biomedical subjects

J F Powell

Publications and source records attributed to J F Powell.

At least 55 records · Page 3Linked to original sources

PubMed1997

Autism and multiple exostoses associated with an X;8 translocation occurring within the GRPR gene and 3' to the SDC2 gene.

An X;8 translocation was identified in a 27-year-old female patient manifesting multiple exostoses and autism accompanied by mental retardation and epilepsy. Through molecular analysis using yeast artificial chromosomes (YACs) and cosmid clones, the translocation breakpoint was isolated and confirmed to be reciprocal within a 5'-GGCA-3' sequence found on both X and 8 chromosomes without gain or loss of a single nucleotide. The translocation breakpoint on the X chromosome occurred in the first intron of the gastrin-releasing peptide receptor (GRPR) gene and that on chromosome 8 occurred approximately 30 kb distal to the 3' end of the Syndecan-2 gene (SDC2), also known as human heparan sulfate proteoglycan or fibroglycan. The GRPR gene was shown to escape X-inactivation. A dosage effect of the GRPR and a position effect of the SDC2 gene may, however, contribute the phenotype observed in this patient since the orientation of these genes with respect to the translocation was incompatible with the formation of a fusion gene. Investigation of mutations in these two genes in unrelated patients with either autism or multiple exostoses as well as linkage and association studies is needed to validate them as candidate genes.

Adult↗

PubMed1997

Familial amyotrophic lateral sclerosis. Molecular pathology of a patient with a SOD1 mutation.

We report the clinical, genetic, and neuropathologic findings in a patient with rapidly progressive familial amyotrophic lateral sclerosis (ALS). We detected a point mutation at codon 48 of the Cu/Zn superoxide dismutase gene (SOD1) leading to a substitution of histidine by glutamine in the copper-binding domain. The histopathologic features are consistent with those described in rapidly progressive sporadic ALS and do not support claims that sporadic and familial disease are different pathologic entities. Neurofilamentous accumulations, hyaline, and ubiquitinated inclusions were present in the motor cortex, brainstem, and anterior horn cells, but there was no evidence of abnormal SOD1 immunoreactivity. This confirms that the cytoskeletal pathology specific to ALS is secondary to an unknown biochemical disturbance caused by mutant SOD1 molecules and not its toxic accumulation.

Amyotrophic Lateral Sclerosis↗

PubMed1997

Evidence that gonadotropin-releasing hormone (GnRH) functions as a prolactin-releasing factor in a teleost fish (Oreochromis mossambicus) and primary structures for three native GnRH molecules.

Three forms of gonadotropin-releasing hormone (GnRH) are isolated and identified here by chemical sequence analysis for one species of tilapia, Oreochromis niloticus, and by HPLC elution position for a second species of tilapia, O. mossambicus. Of the three GnRH forms in O. mossambicus, chicken GnRH-II (cGnRH-II) and sea bream GnRH (sbGnRH) are present in greater abundance in the brain and pituitary than salmon GnRH (sGnRH). These three native forms of GnRH are shown to stimulate the release of prolactin (PRL) from the rostral pars distalis (RPD) of the pituitary of O. mossambicus in vitro with the following order of potency: cGnRH-II > sGnRH > sbGnRH. In addition, a mammalian GnRH analog stimulated the release of PRL from the pituitary RPD incubated in either iso-osmotic (320 mosmol/l) or hyperosmotic (355 mosmol/l) medium, the latter normally inhibiting PRL release. The response of the pituitary RPD to GnRH was augmented by co-incubation with testosterone or 17 beta-estradiol. The effects of GnRH on PRL release appear to be direct effects on PRL cells because the RPD of tilapia contains a nearly homogeneous mass of PRL cells without intermixing of gonadotrophs. Our data suggest that GnRH plays a broad role in fish, depending on the species, by affecting not only gonadotropins and growth hormone, but also PRL.

Amino Acid Sequence↗

PubMed1996

Altered expression of group I metabotropic glutamate receptors in the hippocampus of amygdala-kindled rats.

Kindling is a well documented model of acquired focal epilepsy and synaptic plasticity in the nervous system. Previous biochemical studies have indicated an increase in mGluR-mediated phosphoinositide hydrolysis in the amygdala or hippocampus of fully kindled animals. In this study we have used in situ hybridisation techniques to examine the mRNA expression of group I metabotropic glutamate receptors (mGluR1 and mGluR5 both linked to phosphoinositide hydrolysis) in the hippocampus of amygdala-kindled animals sacrificed 24 h, 7 days or 28 days following the last electrically evoked stage 5 seizure, and in implanted non-stimulated control rats. Results indicate an initial up-regulation in mGluR1 mRNA (expressed as percentage of control) bilaterally in the DG (35-40%) and CA3 (16-48%), and unilaterally in CA4 (12%) in the 24 h post-kindled group. In kindled animals studied 7 days after the last seizure, these changes were either reduced or had returned to control levels. By 28 days mGluR1 mRNA levels had returned to control levels, with only a persistent increase in expression unilaterally in the DG (14%). In contrast, an initial down-regulation in mGluR5 mRNA was observed bilaterally in CA4 (-45 and -25%) and CA1 (-46 and -45%), and unilaterally in DG and CA3 (-27 and -42% respectively) 24 h after the last kindled seizure. In the 7 and 28 day kindled groups significant alterations in expression of mGluR5 mRNA were still apparent. These data show that the mRNAs for mGluR1 and mGluR5 are differentially regulated by kindling, indicating that the expression of each of these receptors is under independent regulatory control. These perturbations in mRNA expression may contribute to kindling epileptogenesis but are unlikely to account for the maintenance of the kindled state.

Amygdala↗

PubMed1996

Linkage studies in bipolar affective disorder with markers on chromosome 21.

Straub et al. (1994: Nature Genet. 8. 291-296) have suggested that a susceptibility gene for bipolar affective disorder is located at chromosome 21q22.3, on the basis of linkage analysis in one large family. This result has been supported by Gurling et al. (1995: Nature Genet. 10, 8-9) who also found some evidence for linkage to this region under locus heterogeneity. In order to investigate the validity of these results and to estimate how broadly applicable they are, we performed a linkage study between bipolar affective disorder and two DNA markers (D21S171 and PFKL) from 21q22.3 using 60 bipolar pedigrees from three European centres and Brazil. The most positive result obtained was a maximised admixture lod score of 1.2 for the marker PFKI, under the assumption of locus heterogeneity, dominant transmission and a diagnostic classification which included recurrent unipolar depression. However, since lod scores obtained for both markers were substantially negative overall, we conclude that there is no common major gene for bipolar affective disorder at 21q22.3. It remains possible that a gene of major effect in this region operates in a minority of families.

Bipolar Disorder↗

PubMed1996

A linkage study of schizophrenia with DNA markers from chromosome 8p21-p22 in 25 multiplex families.

Two recent genome-wide searches for linkage (Lasseter et al., 1994; Moises et al., 1995) suggested that a susceptibility gene for schizophrenia might be located at chromosome 8p21-p22. We attempted to replicate these findings by performing a linkage study of schizophrenia with four DNA markers from this region using 25 multiply affected families. Neither the lod score method nor non-prametric extended sib-pair analysis yielded any evidence for linkage, even under the assumption of locus heterogeneity. We conclude that there is unlikely to be a major gene in the 8p21-p22 region which confers susceptibility to schizophrenia in our set of families. However we cannot exclude the possibility of a major gene present in other families, or of a susceptibility gene with a moderate but widespread effect which we cannot detect.

Autoradiography↗

PubMed1996

Two new forms of gonadotropin-releasing hormone in a protochordate and the evolutionary implications.

The neuropeptide gonadotropin-releasing hormone (GnRH) is the major regulator of reproduction in vertebrates. Our goal was to determine whether GnRH could be isolated and identified by primary structure in a protochordate and to examine its location by immunocytochemistry. The primary structure of two novel decapeptides from the tunicate Chelyosoma productum (class Ascidiacea) was determined. Both show significant identity with vertebrate GnRH. Tunicate GnRH-I (pGlu-His-Trp-Ser-Asp-Tyr-Phe-Lys-Pro-Gly-NH2) has 60% of its residues conserved, compared with mammalian GnRH, whereas tunicate GnRH-II (pGlu-His-Trp-Ser-Leu-Cys-His-Ala-Pro-Gly-NH2) is unusual in that it was isolated as a disulfide-linked dimer. Numerous immunoreactive GnRH neurons lie within blood sinuses close to the gonoducts and gonads in both juveniles and adults, implying that the neuropeptide is released into the bloodstream. It is suggested that in ancestral chordates, before the evolution of the pituitary, the hormone was released into the bloodstream and acted directly on the gonads.

Amino Acid Sequence↗

PubMed1996

Circadian changes of glutamate decarboxylase 65 and 67 mRNA in the rat suprachiasmatic nuclei.

Gaba has been implicated in the regulation of the circadian clock within the suprachiasmatic nuclei (SCN). In the present study in situ hybridization histochemistry was used to assess expression of mRNA for the two isoforms of the enzyme governing GABA synthesis, glutamic acid decarboxylase (GAD) 65 and 67, within the rat SCN during a 24 h cycle in constant darkness. GAD 65 mRNA exhibited a monophasic rhythm, with a peak at the beginning of the subjective day and a nadir early in the subjective night. In contrast, there was a biphasic variation in GAD 67 expression, with peaks at the beginning of the subjective day and early in the subjective night. No significant variation in the mRNAs for GAD 65 or GAD 67 was observed in the cingulate cortex. These results suggest that the clock intrinsic to the SCN controls the expression of the mRNAs encoding GAD 65 and GAD 67 in both a coordinated and a differential manner.

Animals↗

PubMed1996

Rapid identification of novel genes expressed in a circadian manner in rat suprachiasmatic nuclei.

The circadian clock in mammals is located in the suprachiasmatic nuclei (SCN). There is evidence that changes in gene expression are central to its mechanism. We are engaged in identifying the genes involved. The small size of the SCN, the large number of mammalian genes and the need to identify those differentially expressed over 24 h have required novel experimental procedures. mRNA differential display and an improved tissue micropunching method have been used to examine temporal changes in gene expression in the SCN of rats maintained in constant darkness. Several of the displayed cDNA species were found to be differentially expressed; they show no homology with published sequences. Riboprobes of these cDNA species were used for in situ hybridization. Emulsion-dipped sections confirmed that at least two of these differentially displayed mRNAs are expressed in a circadian manner.

Animals↗

PubMed1996

Association of apolipoprotein E epsilon 4 allele with bulbar-onset motor neuron disease.

BACKGROUND: Variants of the apolipoprotein E (APOE) gene influence the age of onset of Alzheimer's disease. APOE may influence the presentation of other neurological diseases. We investigated the relationship between the allelic variants of apolipoprotein E and clinical presentation in motor neuron disease. METHODS: 123 patients with motor neuron disease and 121 controls were studied. Diagnosis, location of onset and date of onset were recorded prospectively. Genotyping was performed blind to clinical information. FINDINGS: Possession of at least one epsilon 4 allele was significantly more common in patients with bulbar onset motor neuron disease (14/33, 42%) than in limb onset patients (20/90, 22%) and controls (26/121, 21%) (chi 2 = 4.93, p = 0.026 and chi 2 = 5.91, p = 0.015, respectively). INTERPRETATION: These results suggest that the apolipoprotein E epsilon 4 allele may influence the pattern of motor neuron loss in motor neuron disease and that it may affect neuronal function in ways unrelated to the deposition of beta-amyloid or accumulation of neurofibrillary tangles.

Age of Onset↗

PubMed1996

Reproduction in the Mexican leaf frog, Pachymedusa dacnicolor. VI. Presence and distribution of multiple GnRH forms in the brain.

The presence and distribution of gonadotropin-releasing hormone (GnRH) has been investigated in the Mexican leaf frog, Pachymedusa dacnicolor, brain during development and in the adult. The ontogenetic pattern of GnRH neurons illustrates their extracranial as well as intracranial sites. Immunohistochemical analysis indicates that GnRH-immunoreactive neurons appear during the metamorphic climax. They are located in the mesencephalon and subsequently other GnRH neurons appear in the peripheral terminal nerve and anterior preoptic area of the brain. Use of specific antisera and homologous combined with heterologous preabsorption tests indicate that mammalian and chicken GnRH-II-like peptide-containing neurons are differentially located within the brain, the former in the anterior preoptic area and peripheral terminal nerve and the latter in the mesencephalon. HPLC and RIA data suggest the presence of three forms of immunoreactive GnRH in the P. dacnicolor brain. A mammalian GnRH-like molecule and a chicken GnRH-II-like molecule are present. A third form, suspected to be [hydroxyproline9]mGnRH elutes before the mammalian GnRH.

Animals↗

PubMed1996

Circadian variation of EAAC1 glutamate transporter messenger RNA in the rat suprachiasmatic nuclei.

Using in situ hybridization, we examined temporal changes of the EAAC1 glutamate transporter mRNA within the suprachiasmatic nuclei (SCN) of rats in constant darkness. Film autoradiographs showed that the SCN and supraoptic nuclei (SON) contained a marked density of hybridization signal. Analysis of silver grains per cell in emulsion-dipped sections indicated that cellular expression of EAAC1 mRNA in the SCN was elevated during the latter part of the subjective night and at the beginning of the subjective day, with a peak at circadian time 23.1 as determined by cosinor analysis. The times at which EAAC1 mRNA is highest correspond to the time points at which extracellular glutamate, a neurotransmitter that putatively mediates photic entrainment, has been reported to be low within the SCN. The presence of EAAC1 mRNA in the SCN and SON may partially explain the resistance of these nuclei to glutamate receptor-mediated excitotoxins; furthermore, the raised level preceding subjective dawn in the SCN may ensure sub-toxic levels of extracellular glutamate at the onset of photic stimulation during the LD cycle. In contrast, cellular expression of EAAC1 mRNA in the cingulate cortex and reticular thalamus remained constant at all time points studied. These results suggest that there is circadian control of the EAAC1 mRNA by the clock intrinsic to the SCN.

Amino Acid Transport System X-AG↗

PubMed1996

The effects of hypoxaemia and recommendations for postoperative oxygen therapy.

Hypoxaemia following surgery is common and may be prolonged and severe. The thresholds for deleterious effects of hypoxaemia on the heart and central nervous system are reviewed and the problems of assessment of the adequacy of tissue oxygenation are outlined. Recommendations for postoperative oxygen therapy are made.

Brain↗

PubMed1996

Apolipoprotein E: non-cognitive symptoms and cognitive decline in late onset Alzheimer's disease.

OBJECTIVES: To determine the association between the epsilon2 and epsilon4 alleles of apolipoprotein E (ApoE) and independent measures of cognitive decline and non-cognitive symptomatology in late onset Alzheimer's disease. METHODS: The frequency of the epsilon2 and epsilon4 alleles of ApoE and their association with measures of cognitive decline and non-cognitive symptomatology were assessed in a population based case register study of 164 patients with late onset Alzheimer's disease from the east Lambeth and south Southwark districts of south London. RESULTS: Analysis of a wide range of non-cognitive symptoms against ApoE epsilon4 genotype showed no significant association but a positive relation was found between ApoE epsilon2 genotype and depressive symptomatology (P = 0.004). No relation was found between measurements of cognitive decline and the presence of the ApoE epsilon4 allele. A trend for decreasing age at onset of 3 to 4 years in carriers of the ApoE epsilon4 allele was found, confirming earlier studies. CONCLUSION: Presence of the epsilon4 allele of ApoE is associated with an earlier age at onset but does not seem to be related to either a more severe psychopathology or a more rapid progression of the illness. The epsilon2 allele of ApoE is associated with depressive symptomatology in late onset Alzheimer's disease.

Age of Onset↗

PubMed1996

Molecular forms of GnRH in three model fishes: rockfish, medaka and zebrafish.

Three species of fish have become important in the study of reproduction and development. Rockfish are a model for developmental studies of live-bearing perch-like fish, whereas medaka and zebrafish are models for developmental and genetic studies. The forms of GnRH are identified in the brains of each of these fish and in the pituitary of the rockfish to investigate the role of GnRH in reproduction. Here, we report that grass rockfish (Sebastes rastrelliger) have three forms of GnRH in brain extracts as determined by HPLC elution position and RIA. These forms are identified as sea bream GnRH, chicken GnRH-II and salmon GnRH. In contrast, only two forms of GnRH were detected in brain extracts of medaka (Oryzias latipes) and zebrafish (Brachydanio rerio): salmon GnRH and chicken GnRH-II. Rockfish is distinct from medaka and zebrafish in that the most abundant form of GnRH in the rockfish pituitary is sea bream GnRH, whereas this form is absent in the other two fishes. The identification of sea bream GnRH in the rockfish brain and pituitary extracts indicates that the phylogenetic emergence of sea bream GnRH is earlier than the order Perciformes.

Animals↗

PubMed1995

Regulation of intracellular free calcium levels by the cellular prion protein.

A rat brain synaptosomal model was used to investigate the possible role of the cellular prion protein (PrP) in the regulation of intracellular free calcium levels ([Ca2+i). Treatment of synaptosomes with bacterially derived recombinant human PrP in the range 20-100 micrograms ml-1 resulted in dose-dependent elevations of [Ca2+]i. These increases were dependent on extracellular calcium and were inhibited by gadolinium chloride, a potent blocker of voltage-sensitive calcium channels. Conversely, when calcium channels were activated by synaptosomal depolarization, treatment with monoclonal antibody to PrP in the range 200-320 ng IgG ml-1 resulted in a dose-dependent reduction of [Ca2+i, which was blocked by competition with PrP preparations. These results indicate that PrP is associated with regulation of intracellular free calcium levels through an interaction with voltage-sensitive calcium channels.

Animals↗

PubMed1995

Systematic search for major genes in schizophrenia: methodological issues and results from chromosome 12.

We describe a method of systematically searching for major genes in disorders of unknown mode of inheritance, using linkage analysis. Our method is designed to minimize the probability of missing linkage due to inadequate exploration of data. We illustrate this method with the results of a search for a locus for schizophrenia on chromosome 12 using 22 highly polymorphic markers in 23 high density pedigrees. The markers span approximately 85-90% of the chromosome and are on average 9.35 cM apart. We have analysed the data using the most plausible current genetic models and allowing for the presence of genetic heterogeneity. None of the markers was supportive of linkage and the distribution of the heterogeneity statistics was in accordance with the null hypothesis.

Chromosomes, Human, Pair 12↗

PubMed1995

Primary structure of solitary form of gonadotropin-releasing hormone (GnRH) in cichlid pituitary; three forms of GnRH in brain of cichlid and pumpkinseed fish.

GnRH is a decapeptide family with at least nine distinct structures. Vertebrates, except for most placental mammals, have more than one of these GnRH forms within the brain. We report chromatographical and immunological evidence that three forms of GnRH are in the brains of both cichlid (Haplochromis burtoni) and pumpkinseed (Lepomis gibbosus) fishes. We argue that the three forms correspond to those previously described as sea bream GnRH (sbGnRH), chicken GnRH-II and salmon GnRH. In contrast, only one GnRH form was present in the pituitary of the cichlid and is identified as sbGnRH by amino acid sequence. This is the first report in which the primary structure of GnRH is determined from pituitary tissue. The N-terminus was identified by monitoring the digestion of the peptide by pyroglutamate aminopeptidase with matrix assisted laser desorption/ionization (MALDI) mass spectrometry (MS). The amidation of the C-terminus was established using an esterification procedure for monitoring with MALDI-MS. This report supports the idea that three forms of GnRH within one species is widespread in the order Perciformes. The present study establishes sbGnRH as the third GnRH form in H. burtoni and predicts that sbGnRH is synthesized in preoptic neurons, then transported to the pituitary in the preoptic-hypophyseal axons for the release of one or both gonadotropins.

Amino Acid Sequence↗