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Biomedical subjects

J F Powell

Publications and source records attributed to J F Powell.

At least 19 recordsLinked to original sources
PubMed2004

No association of the SOD1 locus and disease susceptibility or phenotype in sporadic ALS.

Mutations in the copper zinc superoxide dismutase gene (SOD1) are found in 20% of familial and 3% of sporadic ALS patients. SOD1 protein aggregation can be detected in motor neurons of mutation-negative sporadic cases but a pathogenic role for wild-type SOD1 in ALS has not been demonstrated. In this study of 233 ALS cases and 248 controls the authors found no significant association between four individual single nucleotide polymorphisms and a deletion spanning the SOD1 locus (or their combined haplotypes), and disease susceptibility, or phenotype.

Amyotrophic Lateral Sclerosis↗
PubMed2004

Cognitive and psychological correlates of smoking abstinence, and predictors of successful cessation.

The neural circuitry implicated in addictive drug use, which appears to be down-regulated in early abstinence, corresponds closely with brain reward pathways. A literature review suggests that responses to incentive stimuli and the ability to inhibit reflexive responses, both of which have been associated with normal functioning in these pathways, might be weakened during acute abstinence from chronic drug use. In an ongoing study, 82 smokers, abstinent overnight before two separate testing occasions, have been assessed after administration of nicotine and placebo lozenges (order of sessions counterbalanced). Nicotine administration is associated with a significant reduction in anhedonia, a near-significant increase in response to financial incentive, enhanced ability to inhibit reflexive eye movements, and increased attentional bias to words with appetitive significance. Fifty-nine participants then initiated a quit attempt and 19 reported relapsing within 7 days. Comparing their performance in the two prequit lozenge assessment sessions, relapsers showed a stronger effect of nicotine on enhancing their ability to inhibit reflexive eye movements and a near-significant trend towards greater nicotine-induced increases in attentional bias toward appetitive words.

Adult↗
PubMed2003

beta-1,3-Glucuronyltransferase-1 gene implicated as a candidate for a schizophrenia-like psychosis through molecular analysis of a balanced translocation.

We have mapped and sequenced both chromosome breakpoints of a balanced t(6;11)(q14.2;q25) chromosome translocation that segregates with a schizophrenia-like psychosis. Bioinformatics analysis of the regions revealed a number of confirmed and predicted transcripts. No confirmed transcripts are disrupted by either breakpoint. The chromosome 6 breakpoint region is gene poor, the closest transcript being the serotonin receptor 1E (HTR1E) at 625 kb telomeric to the breakpoint. The chromosome 11 breakpoint is situated close to the telomere. The closest gene, beta-1,3-glucuronyltransferase (B3GAT1 or GlcAT-P), is 299 kb centromeric to the breakpoint. B3GAT1 is the key enzyme during the biosynthesis of the carbohydrate epitope HNK-1, which is present on a number of cell adhesion molecules important in neurodevelopment. Mice deleted for the B3GAT1 gene show defects in hippocampal long-term potentiation and in spatial memory formation. We propose that the translocation causes a positional effect on B3GAT1, affecting expression levels and making it a plausible candidate for the psychosis found in this family. More generally, regions close to telomeres are highly polymorphic in both sequence and length in the general population and several studies have implicated subtelomeric deletions as a common cause of idiopathic mental retardation. This leads us to the hypothesis that polymorphic or other variation of the 11q telomere may affect the activity of B3GAT1 and be a risk factor for schizophrenia and related psychoses in the general population.

Base Sequence↗
PubMed2002

Diagnostic strategies in CADASIL.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited autosomal dominant condition characterized by migraine, recurrent stroke, and dementia. It results from mutations in the notch3 gene but mutations may occur at multiple sites making molecular diagnosis time consuming. It has been suggested that the presence of granular osmiophilic material (GOM) on skin biopsy and involvement of the anterior temporal lobe and external capsule on MRI may help in diagnosis. METHODS: The authors identified 83 potential index cases from the British population and screened exons 2 to 23 of notch3. MRI scans were scored using a modified Scheltens scale. Skin biopsy was performed in a subgroup. RESULTS: Fifteen different point mutations were identified in 48 families, 73% of which were in exon 4, 8% in exon 3, and 6% in each of exons 5 and 6. Moderate or severe involvement of the anterior temporal pole on MRI had a sensitivity of 89% and specificity of 86% for diagnosis of CADASIL, whereas external capsule involvement had a high sensitivity of 93% but a low specificity of 45%. Skin biopsy, performed in 18 cases, had a sensitivity of 45% and specificity of 100%. CONCLUSIONS: The spectrum of mutations in this study can be used to plan appropriate screening protocols; a suggested protocol is to screen exon 4, and proceed to exons 3, 5, and 6 where indicated. GOM on skin biopsy is diagnostic but can be negative. Anterior temporal pole involvement on MRI is a useful diagnostic marker.

Adult↗
PubMed2002

Identification of genomic organisation, sequence variants and analysis of the role of the human dishevelled 1 gene in late onset Alzheimer's disease.

Alzheimer's disease (AD) is a disorder characterised by a progressive deterioration in memory and other cognitive functions. Neurofibrillary tangles (NFT) are a major pathological hallmark of AD, these are aggregations of paired helical filaments (PHF) comprised of the hyperphosphorylated microtubule associated protein tau. Several kinases, such as glycogen synthase kinase 3 beta (GSK3beta) and c-Jun N-terminal kinase (JNK), phosphorylate tau at sites that are phosphorylated in PHF. Dishevelled 1 (DVL1) is thought to act as a positive regulator of the wnt signalling pathway, and inhibits GSK3beta activity preventing beta-catenin degradation and thus allowing wnt target gene expression. JNK activation is also regulated by DVL1, however it is unclear if this is via the wnt signalling pathway. These observations suggest a central role for DVL1 in tau phosphorylation and AD and led us to investigate DVL1 as a candidate gene for this disorder. We determined the genomic structure of the DVL1 gene by sequencing and data mining and searched for sequence variations in the coding sequences and flanking introns. The DVL1 gene spans a region of approximately 13.8 kb (not including the 5' untranslated region) and is encoded by 15 exons. Analysis of over 4.3 kb of sequence, including 98% of exonic sequences and introns 2, 3, 6, 7, 9, 10, 11 and 12, revealed there to be six rare (< or =6%) sequence variations. None of these had any association with late onset AD. This would suggest that polymorphic variations in the coding sequences of DVL1 are not important in AD. However further analysis of regulatory regions may lead to the identification of other sequence variations which may be implicated in AD.

Adaptor Proteins, Signal Transducing↗
PubMed2001

The microtubule associated protein Tau gene and Alzheimer's disease--an association study and meta-analysis.

Several studies have suggested an association between polymorphisms and an extended haplotype of the microtubule associated protein tau gene and Alzheimer's disease (AD) in synergy with apolipoprotein E (APOE) epsilon 4 status. However these findings have not been consistently replicated. We investigated the role of the tau haplotype in AD by conducting an association study as well as a meta-analysis of all the studies conducted to date. We examined six polymorphisms known to be in the extended tau haplotypes, one in exon 7 and five in and around exon 9 in 200 late onset AD and 189 control samples. All the polymorphisms examined fell into the recognised tau haplotypes. There was no statistical significant association with any of the polymorphisms and late onset AD. Stratification of data by APOE epsilon 4 status also produced no strongly significant association. The meta-analysis showed no significant differences between AD cases and controls, however stratification of data by APOE epsilon 4 status showed a small significant decrease in the H1 haplotype in AD before correction for multiple testing.

Aged↗
PubMed2001

MRI hyperintensities of the temporal lobe and external capsule in patients with CADASIL.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited, autosomal dominant condition caused by mutations of the Notch3 gene. Affected individuals have migraine, mood disturbance, and recurrent strokes, often progressing to subcortical dementia and premature death. MRI findings include focal lacunar infarcts and diffuse T2-weighted hyperintensity, or leukoaraiosis. However, such findings are seen much more commonly in patients with cardiovascular risk factors, particularly hypertension, where they are believed to represent cerebral small vessel disease. No previous study has sought to identify specific radiologic markers of CADASIL. METHODS: MRI scans from 20 consecutive patients with CADASIL and 20 patients with sporadic leukoaraiosis due to presumed small-vessel disease were compared using the previously validated semiquantitative MRI rating scale devised by Scheltens et al. Analysis was blinded to clinical category. RESULTS: Scores for hyperintensities of the temporal white matter and external capsule-insula region were significantly higher in patients with CADASIL. Hyperintensity confined to the pole of the temporal lobe was a characteristic finding in CADASIL, occurring in 19 patients with CADASIL but no patients with ischemic leukoaraiosis. Involvement of the external capsule, though less specific, was seen early in the disease course. In a few patients with CADASIL, involvement of the corpus callosum was observed. CONCLUSIONS: Temporal pole hyperintensity is a radiologic marker of CADASIL. Involvement of the external capsule and corpus callosum are also characteristic findings that may help to distinguish the disease.

Adult↗
PubMed2001

The extended haplotype of the microtubule associated protein tau gene is not associated with Pick's disease.

Pick's disease (PiD) is a rare neurodegenerative condition and is a member of a heterogeneous group of disorders known as tauopathies, so-called because of the predominantly neuronal aberrant tau accumulations found in these diseases. The tauopathy, familial frontotemporal dementia (FTD), is caused by mutations in the tau gene. Moreover, progressive supranuclear palsy (PSP) is associated with the tau H1 haplotype. In certain familial forms of FTD and in PSP the microtubule-binding four repeat tau isoform principally accumulates in neuropathological lesions. However, in PiD three repeat tau accumulations are found. We therefore investigated whether either the tau H1 or H2 haplotype was associated with PiD. Our results indicate a slight increase in H2H2 frequency in Pick's cases which is not statistically significant.

Aged↗
PubMed2001

Association study of the 5-HT(2A) receptor gene polymorphism, T102C and essential hypertension.

BACKGROUND: Serotonin dysfunction has been implicated in hypertension due to its ability to induce vasoconstriction via stimulation of 5-HT(2) receptors and due to the antihypertensive effect of ketanserin, an antagonist at the 5-HT(2A) receptor subtype, expressed both on arteries and the brain. The silent T102C polymorphism in the 5-HT(2A) gene is in absolute linkage disequilibrium with a polymorphism in the promoter and may contribute to genetic predisposition possibly by modifying the transcription of the gene. OBJECTIVE: To examine the genetic contribution of the T102C 5-HT(2A)polymorphism in essential hypertension in a case-control sample of UK residents. DESIGN: The hypertensive group consisted of 342 subjects over 75 years and the community-based control group consisted of 319 subjects. Subjects were genotyped for the T102C polymorphism by Mspl restriction enzyme digestion following PCR amplification. RESULTS: Sex-specific association analysis revealed significant differences between hypertensive and normotensive subjects in the genotypes distribution (P = 0.016) and allelic frequencies (P = 0.007) in the female group. The direction of significance was increased frequency of the 102-C allele in the hypertensive subjects. There were no association between haplotype and age or body mass index, which suggest that the effect of the T102C variant is not influenced by these variables. CONCLUSION: This data indicates that the T102C polymorphism in the 5-HT(2A) gene might be an independent risk factor for increased blood pressure in female individuals with essential hypertension.

Age Distribution↗
PubMed2001

Identification of sequence variants and analysis of the role of the glycogen synthase kinase 3 beta gene and promoter in late onset Alzheimer's disease.

Alzheimer's disease (AD) is a disorder characterised by a progressive deterioration in memory and other cognitive functions. Glycogen synthase kinase 3 beta (GSK3 beta) phosphorylates the microtubule associated protein tau at sites that are aberrantly phosphorylated in AD. GSK3 beta binds to presenilin 1 and plays a role in wnt and insulin signalling cascades, both of which have been proposed to be linked to AD. Moreover GSK3 beta activity may be altered in AD brain. These observations suggest a central role for GSK3 beta in AD and led us to investigate GSK3 beta as a candidate gene for AD. We sought to identify sequence variations in the gene and its promoter, as these could have an effect on activity and expression leading to abnormal function. Sequencing over 3000 bp of the GSK3 beta putative promoter revealed there to be five sequence variations, two of which were common (>10%). However on further examination none of these, either alone or in synergy, had any association with late onset AD. Stratification of the data by APOE epsilon 4 status also produced no significant association. Sequencing of the GSK3 beta coding region revealed no variations. This would suggest that the aberrant phosphorylation of tau by GSK3 beta in AD is not due to sequence variations in the gene or its promoter.

Age of Onset↗
PubMed2001

Mutations in the lysyl oxidase gene are not associated with amyotrophic lateral sclerosis.

BACKGROUND: There is an urgent need to identify genes involved in familial ALS (FALS), as mutations in the CuZn superoxide dismutase (SOD1) gene can account for 20% of FALS cases. The mechanisms by which the many mutations in the SOD1 gene lead to motoneuron degeneration are unknown, although current experimental evidence supports a toxic gain of function, possibly through copper-induced cytotoxicity. Copper is an integral component of a number of enzymes as well as SOD1. Since abnormalities in connective tissue cross-linking have been reported in ALS patients, an enzyme of possible relevance is lysyl oxidase (LOX), a copper-containing enzyme which catalyses the crosslinking of collagens and elastin. The aim of this study was to investigate the hypothesis that allelic variants or mutants of LOX gene result in altered function of LOX in ALS patients. METHODS: The coding regions of the LOX gene were screened for polymorphism and mutations in a cohort of sporadic and familial ALS patients. RESULTS: A novel polymorphism, Pro159Gln, was identified in eight individuals with sporadic ALS (5.0%) and five controls (3.6%). The previously identified Arg158Gln polymorphism was also detected in ALS patients and controls. These polymorphisms were genotyped in 192 ALS patients, including 31 unrelated familial cases and 138 controls, and no association was found between any of these polymorphisms and amyotrophic lateral sclerosis or its phenotype. CONCLUSION: Mutations in the LOX gene are unlikely to be directly causative of ALS.

Adult↗
PubMed2001

Examination of variation in sternal rib end morphology relevant to age assessment.

The morphology of the sternal end of the right fourth rib has been proffered as an accurate age assessor in skeletonized individuals of both sexes. This technique was tested for its applicability on left and right II, III, V-IX. Tests were performed between phase scores obtained from right and left ribs; right rib IV phase scores and scores obtained from the others in the right rib series; and between right rib IV scores and a composite score composed of the average of an individual's phase scores (omitting rib IV). Left ribs IV-IX were found not to vary significantly from their right counterparts. Although only right rib II was found to vary significantly from rib IV, use of the other ribs in the series should be undertaken with caution due to questions concerning their statistical significance. A composite score is therefore recommended for use instead.

Adolescent↗
PubMed2001

Intron 7 retention and exon 9 skipping EAAT2 mRNA variants are not associated with amyotrophic lateral sclerosis.

Glutamate-mediated excitotoxicity is implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). The astroglial glutamate transporter EAAT2 plays a major role in maintaining low levels of extracellular glutamate in the central nervous system. Multiple EAAT2 mRNA transcripts have been described, but those retaining intron 7 or skipping exon 9 are reported to be specific to the motor cortex, spinal cord, and cerebrospinal fluid of ALS patients. We sought to verify these findings using a TaqMan (Elmer Biosystems, Warrington, UK) real-time reverse transcriptase polymerase chain reaction assay, which provides a sensitive and reliable quantitative measure of EAAT2 transcript copy ratios. We analyzed RNA extracted from frozen postmortem tissue from affected and unaffected central nervous system regions dissected from 17 sporadic ALS patients, 7 Alzheimer's disease patients, and 19 control subjects. We have demonstrated unequivocally that intron 7 retaining and exon 9 skipping variants can be detected in all individuals and in all central nervous system regions studied. The mean ratio of "variant" to "normal" transcripts did not differ significantly between patient and control groups. Although our assay could detect transcript concentrations in cerebrospinal fluid as low as 10 pg/ml, none were detected in 17 ALS and 8 control samples. We conclude that ALS is not associated with elevated levels of EAAT2 transcripts retaining intron 7 and skipping exon 9. An alternative explanation must be sought for the disturbance of glutamate homeostasis reported in ALS.

Aged↗
PubMed2000

Systematic screening of the 14-3-3 eta (eta) chain gene for polymorphic variants and case-control analysis in schizophrenia.

The neuronal protein 14-3-3 eta is a candidate gene for schizophrenia because it maps chromosome 22q12, a region implicated in the disease by linkage analysis, and is involved in brain development. We systematically screened this gene for polymorphic variants by comparison of public EST sequence data (five cDNAs and 72 ESTs, 21,155 bp of sequence) in parallel with single-stranded conformational polymorphism analysis, and we compared these methods by using a simple power calculation. Twelve potential polymorphisms were identified from EST sequence comparison, and two of these (a 5'-VNTR and 753G/A) were confirmed by SSCP analysis and sequencing. Three additional infrequent polymorphisms (-408T/G; 177 C/G; and 989 A/G) were found by SSCP only. We next examined these variants for association with schizophrenia. One variant in untranslated region of exon 1 (-408 T/G) was found to occur more frequently in the schizophrenic subjects (8%) than the controls (3%; P = 0.01). After fivefold correction of the P value for multiple testing, marginal association was found. Haplotype analysis of pairs of polymorphisms provided no evidence for association of this gene with schizophrenia in the population studied. Am. J. Med. Genet. (Neuropsychiatr. Genet. ) 96:736-743, 2000.

14-3-3 Proteins↗
PubMed2000

Primary structure and function of three gonadotropin-releasing hormones, including a novel form, from an ancient teleost, herring.

The evolution of GnRH and the role of multiple forms within the brain are examined. Three forms of GnRH were purified from the brain of Pacific herring (Clupea harengus pallasi) and characterized using Edman degradation and mass spectrometry. Two forms correspond with the known structures of chicken GnRH-II and salmon GnRH that are found in many vertebrate species. The third form, designated herring GnRH (hrGnRH), has a primary structure of pGlu-His-Trp-Ser-His-Gly-Leu-Ser-Pro-Gly-NH2. This novel peptide is a potent stimulator of gonadotropin II and GH release from dispersed fish pituitary cells. The content of hrGnRH in the pituitary was 8-fold that of salmon GnRH and 43-fold that of chicken GnRH-II, which provides supporting evidence that hrGnRH is involved in the release of gonadotropin. Herring is the most phylogenetically ancient animal in which three forms of GnRH have been isolated and sequenced. Our evidence suggests that the existence of three GnRHs in the brain of one species 1) is an ancestral condition for teleosts, 2) has the potential for separate regulation of the distinct GnRHs, and 3) may be an evolutionary advantage for refined control of reproduction in different environments.

Amino Acid Sequence↗
PubMed2000

Skeletal manifestations of bear scavenging.

In many partially or fully skeletonized forensic cases, postmortem animal damage is simply attributed to rodents or carnivores; little effort is made to determine the general size or assign a genus to the scavenger. As one of the largest wild carnivores to inhabit mountainous and forested areas throughout the continental United States, Alaska, and Canada, black bears (Ursus americanus) must be considered possible suspects when skeletonized remains are located showing marks of carnivore damage. Since 1995, three cases of known bear scavenging have been referred to the Maxwell Museum's Laboratory of Human Osteology by the New Mexico Office of the Medical Investigator for skeletal analysis. These cases comprise a total of seven individuals, and all of the remains were deposited in high altitude forests of New Mexico along the western border with Arizona with a minimum of 4 months exposure before recovery. When analyzed, all cases shared a similar pattern of element survivorship and damage. We suggest that bears can be distinguished from members of the canid family, the other common scavenger of human remains, based on the representation of skeletal elements at the scene. Rates and patterns of damage are not as accurate as element recovery in the discrimination of scavenger genus. Use of this information should allow forensic anthropologists to better understand the postmortem taphonomic processes that shaped the skeletal remains, and hopefully prevent misdiagnoses of perimortem trauma on elements not typically scavenged by canids.

Adult↗
PubMed1999

Mutations in the gene encoding human persyn are not associated with amyotrophic lateral sclerosis or familial Parkinson's disease.

The synucleins are a family of small proteins expressed in nervous tissue, which have been implicated in neurodegeneration. Using single strand conformation polymorphism analysis we screened for polymorphisms and mutations in the gene encoding human persyn, a recently discovered member of the synuclein family, in controls, patients with sporadic or familial amyotrophic lateral sclerosis (ALS) or familial Parkinson's disease (PD). Six polymorphisms in the genomic sequence of persyn were detected; A590C (5' untranslated region), G1943C (exon 3), G2049A (intron 3), T4502C (intron 3), T4552A (exon 4) and C5019T (3' untranslated region). However no associations with disease state were found in our sample group.

Amyotrophic Lateral Sclerosis↗