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Biomedical subjects

John Powell

Publications and source records attributed to John Powell.

At least 37 records · Page 2Linked to original sources
PubMed2005

Nicastrin gene polymorphisms, cognitive ability level and cognitive ageing.

The hypothesis that polymorphisms in the gene for nicastrin (NCSTN) are associated with differences in cognitive level and ageing was tested in 462 relatively healthy surviving participants of the Scottish Mental Survey 1932. None had a history of dementia. They were tested on the Moray House Test of verbal reasoning at age 11 in 1932 and at age 79 between 1999 and 2001. At age 79 they also took tests of non-verbal reasoning, short- and long-term verbal declarative memory, Verbal Fluency, and a short screening test for dementia. Subjects who possessed at least one copy of the NCSTN B haplotype (Hap B) had higher scores on the Moray House Test (a test principally of verbal reasoning) at age 11 (p=0.036) and age 79 (p=0.027). The effect of Hap B on cognition at age 79 was non-significant after adjusting for the effect at age 11. Therefore, the effect of Hap B in this sample is on the life-long stable trait of cognitive ability, and not on age-related cognitive change. The possibility that this result might be a selection effect was not supported by the samples being in Hardy-Weinberg equilibrium with respect to the distribution of NCSTN genotypes.

Aged↗
PubMed2005

Candidate gene association studies of genes involved in neuronal cholinergic transmission in Alzheimer's disease suggests choline acetyltransferase as a candidate deserving further study.

Consistent deficits in the cholinergic system are evident in the brains of Alzheimer's Disease (AD) patients, including reductions in the activities of acetylcholine, acetylcholinesterase (AChE), and choline acetyltransferase (ChAT), increased butyrylcholinesterase (BChE) activity, and a selective loss of nicotinic acetylcholine receptors (nAChRs). Accordingly, we have analyzed polymorphisms in the genes encoding AChE, ChAT, BChE, and several of the subunit genes from neuronal nAChRs, for genetic associations with late-onset AD. A significant association for disease was detected for a non-coding polymorphism in ChAT (allele chi(1) (2) = 12.84, P = 0.0003; genotype chi(2) (2) = 11.89, P = 0.0026). Although replication analysis did not confirm the significance of this finding when the replication samples were considered alone (allele chi(1) (2) = 1.02, P = 0.32; genotype chi(2) (2) = 1.101, P = 0.58) the trends were in the correct direction and a significant association remained when the two sample sets were pooled (allele chi(1) (2) = 12.37, P = 0.0004; genotype chi(2) (2) = 11.61, P = 0.003). Previous studies have reported significant disease associations for both the K-variant of BChE and the coding ChAT rs3810950 polymorphism with AD. Replication analyses of these two loci failed to detect any significant association for disease in our case-control samples.

Aged↗
PubMed2005

Glycogen synthase kinase-3 is increased in white cells early in Alzheimer's disease.

Alzheimer's disease (AD) is a disorder without a molecular marker in peripheral tissues or a disease modifying treatment. As increasing evidence has suggested a role for glycogen synthase kinase-3 (GSK-3) in the pathogenesis of the condition we measured total GSK-3 protein (alpha and beta isoforms) and GSK-3 activity (serine 9 phosphorylation) in a group of healthy elderly people, in AD and in mild cognitive impairment (MCI). Total GSK-3 protein was increased in both AD and in MCI without a compensatory decrease in activity. These data suggest that GSK-3 assays might be a useful diagnostic marker in a readily available tissue and moreover that GSK-3 activity is increased in the prodromal phase of the disorder suggesting that inhibition of GSK-3 might be a useful therapeutic strategy.

Aged↗
PubMed2005

Genetic association of the APP binding protein 2 gene (APBB2) with late onset Alzheimer disease.

Alzheimer disease (AD) is a complex neurodegenerative disorder predisposed by multiple genetic factors. Mutations in amyloid beta precursor protein (APP) are known to be associated with autosomal dominant, early onset familial AD and possibly also late onset AD (LOAD). A number of genes encoding proteins capable of binding to APP have been identified, but their contribution to AD pathobiology remains unclear. Conceivably, mutations in these genes may play a role in affecting AD susceptibility, which appears to be substantiated by some genetic studies. Here we report results of the first genetic association study with APBB2, an APP binding protein (also known as FE65L), and LOAD, in three independently collected case-control series totaling approximately 2,000 samples. Two SNPs were significantly associated with LOAD in two sample series and in meta-analyses of all three sample sets (for rs13133980: odds ratio [OR](hom)=1.36 [95% CI: 1.05-1.75], OR(het)=1.32 [95% CI: 1.04-1.67], minor allele frequency=43%, P=0.041; and for hCV1558625: OR(hom)=1.37 [95% CI: 1.06-1.77], OR(het)=1.02 [95% CI: 0.82-1.26], minor allele frequency=48%, P=0.026). One of these SNPs, located in a region conserved between the human and mouse genome, showed a significant interaction with age of disease onset. For this marker, the association with LOAD was most pronounced in subjects with disease onset before 75 years of age (OR(hom)=2.43 [95% CI: 1.61-3.67]; OR(het)=2.15 [95% CI: 1.46-3.17]; P=0.00006) in the combined sample set. Our data raise the possibility that genetic variations in APBB2 may affect LOAD susceptibility.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells.

BACKGROUND: Patients with follicular lymphoma may survive for periods of less than 1 year to more than 20 years after diagnosis. We used gene-expression profiles of tumor-biopsy specimens obtained at diagnosis to develop a molecular predictor of the length of survival. METHODS: Gene-expression profiling was performed on 191 biopsy specimens obtained from patients with untreated follicular lymphoma. Supervised methods were used to discover expression patterns associated with the length of survival in a training set of 95 specimens. A molecular predictor of survival was constructed from these genes and validated in an independent test set of 96 specimens. RESULTS: Individual genes that predicted the length of survival were grouped into gene-expression signatures on the basis of their expression in the training set, and two such signatures were used to construct a survival predictor. The two signatures allowed patients with specimens in the test set to be divided into four quartiles with widely disparate median lengths of survival (13.6, 11.1, 10.8, and 3.9 years), independently of clinical prognostic variables. Flow cytometry showed that these signatures reflected gene expression by nonmalignant tumor-infiltrating immune cells. CONCLUSIONS: The length of survival among patients with follicular lymphoma correlates with the molecular features of nonmalignant immune cells present in the tumor at diagnosis.

Adult↗
PubMed2004

Association of late-onset Alzheimer's disease with genetic variation in multiple members of the GAPD gene family.

Although several genes have been implicated in the development of the early-onset autosomal dominant form of Alzheimer's disease (AD), the genetics of late-onset AD (LOAD) is complex. Loci on several chromosomes have been linked to the disease, but so far only the apolipoprotein E gene has been consistently shown to be a risk factor. We have performed a large-scale single-nucleotide polymorphism (SNP)-based association study, across the region of linkage on chromosome 12, in multiple case-control series totaling 1,089 LOAD patients and 1,196 control subjects and report association with SNPs in the glyceraldehyde-3-phosphate dehydrogenase (GAPD) gene. Subsequent analysis of GAPD paralogs on other chromosomes demonstrated association with two other paralogs. A significant association between LOAD and a compound genotype of the three GAPD genes was observed in all three sample sets. Individually, these SNPs make differential contributions to disease risk in each of the casecontrol series, suggesting that variants in functionally similar genes may account for series-to-series heterogeneity of disease risk. Our observations raise the possibility that GAPD genes are AD risk factors, a hypothesis that is consistent with the role of GAPD in neuronal apoptosis.

Age of Onset↗
PubMed2004

Association of ABCA1 with late-onset Alzheimer's disease is not observed in a case-control study.

Genetic association of ABCA1 or the ATP-binding cassette A1 transporter with late-onset Alzheimer's disease (LOAD) has recently been proposed for a haplotype comprised of three single nucleotide polymorphisms (SNPs). We have genotyped these and other ABCA1 SNPs in a LOAD case-control series of 796 individuals (419 cases versus 377 controls) collected at Washington University. While our sample series is larger and thus presumably has greater power than any of the series used to implicate ABCA1, we were unable to replicate the published association, using either single markers or multiple marker haplotypes. Further, we did not observe significant and replicated association of other ABCA1 SNPs we examined with the disease, thus these ABCA1 variants do not appear to influence the risk of LOAD in this study.

ATP Binding Cassette Transporter 1↗
PubMed2004

Health related virtual communities and electronic support groups: systematic review of the effects of online peer to peer interactions.

OBJECTIVE: To compile and evaluate the evidence on the effects on health and social outcomes of computer based peer to peer communities and electronic self support groups, used by people to discuss health related issues remotely. DESIGN AND DATA SOURCES: Analysis of studies identified from Medline, Embase, CINAHL, PsycINFO, Evidence Based Medicine Reviews, Electronics and Communications Abstracts, Computer and Information Systems Abstracts, ERIC, LISA, ProQuest Digital Dissertations, Web of Science. SELECTION OF STUDIES: We searched for before and after studies, interrupted time series, cohort studies, or studies with control groups; evaluating health or social outcomes of virtual peer to peer communities, either as stand alone interventions or in the context of more complex systems with peer to peer components. MAIN OUTCOME MEASURES: Peer to peer interventions and co-interventions studied, general characteristics of studies, outcome measures used, and study results. RESULTS: 45 publications describing 38 distinct studies met our inclusion criteria: 20 randomised trials, three meta-analyses of n of 1 trials, three non-randomised controlled trials, one cohort study, and 11 before and after studies. Only six of these evaluated "pure" peer to peer communities, and one had a factorial design with a "peer to peer only" arm, whereas 31 studies evaluated complex interventions, which often included psychoeducational programmes or one to one communication with healthcare professionals, making it impossible to attribute intervention effects to the peer to peer community component. The outcomes measured most often were depression and social support measures; most studies did not show an effect. We found no evidence to support concerns over virtual communities harming people. CONCLUSIONS: No robust evidence exists of consumer led peer to peer communities, partly because most peer to peer communities have been evaluated only in conjunction with more complex interventions or involvement with health professionals. Given the abundance of unmoderated peer to peer groups on the internet, research is required to evaluate under which conditions and for whom electronic support groups are effective and how effectiveness in delivering social support electronically can be maximised.

Clinical Trials as Topic↗
PubMed2004

The use of intradiscal steroid therapy for lumbar spinal discogenic pain: a randomized controlled trial.

STUDY DESIGN: A prospective randomized study of the therapeutic effect of intradiscal steroid injection compared to a saline placebo. OBJECTIVES: To determine whether intradiscal steroid injection influences the clinical outcome at 1 year in patients with chronic low back pain of discogenic origin. SUMMARY OF BACKGROUND DATA: Steroids have been used empirically in the treatment of back pain. They have been used in the epidural space and around nerve roots and have been used as an alternative to chymopapain within the disc. Previous studies have, however, shown variable results. METHODS: A total of 120 patients with chronic low back pain of discogenic origin were enrolled in the study. At discography, if they had concordant pain, they were randomized to injection of normal saline or methylprednisolone into the disc space. These patients were prospectively followed up for 12 months, and they were asked to report pain according to a visual analogue score and their Oswestry Disability Index was recorded. The primary outcome measure was determined as a percentage change in disability, and the results were analyzed using independent samples t test. The secondary outcome measure was a change in the pain score, and this was analyzed using the Mann-Whitney U test. RESULTS: There was no significant difference in the primary outcome between the two groups (P = 0.71). The steroid group had a mean change of 2.28 (SE 2.49) in percentage disability, while the saline group had a mean change of 3.42 (SE 1.79). With respect to the change in pain score, there was no significant difference between the two groups (P = 0.72). Those patients who had saline injection had a median change in pain score of 0 (interquartile range -1 to 1), whereas those given steroid treatment had a median change in pain score of 0 (interquartile range -0.25 to 1). CONCLUSIONS: This study demonstrates that intradiscal steroid injections do not improve the clinical outcome in patients with discogenic back pain compared with placebo.

Chronic Disease↗
PubMed2004

Candidate gene association studies of the alpha 4 (CHRNA4) and beta 2 (CHRNB2) neuronal nicotinic acetylcholine receptor subunit genes in Alzheimer's disease.

Consistent deficits in the cholinergic system are evident in Alzheimer's disease (AD) patients, including selective loss of alpha4beta2 nicotinic acetylcholine receptors in the brains of AD patients. Knockout mice for the beta2 subunit have impaired neuronal survival in ageing. Accordingly, we have analysed polymorphisms in the genes that encode the alpha4 and beta2 subunits, CHRNA4 and CHRNB2 respectively, for genetic associations with late-onset AD. A significant association for disease was observed for a non-coding polymorphism in CHRNB2 (odds ratio=0.57, 95% confidence interval=0.35-0.95, P=0.024). Replication analysis was performed in two further sample sets. While these did not individually yield significant results, a significant association remained when all samples were pooled (odds ratio=0.70, 95% confidence interval=0.52-0.95, P=0.019). These data suggest that this variant warrants further examination in large case-control series.

Aged↗
PubMed2004

Contribution of eotaxin-1 to eosinophil chemotactic activity of moderate and severe asthmatic sputum.

The CC chemokine eotaxin-1 (CCL11) is chemotactic for eosinophils, basophils, and type 2 helper T cells and may play a role in allergic inflammation. We investigated its contribution as an eosinophil chemoattractant in asthmatic airway secretions (sampled as induced sputum), which possess chemotactic activity for eosinophils and T cells. Sputum samples collected from healthy subjects and subjects with mild, stable-moderate, unstable-moderate, and severe asthma were processed with phosphate-buffered saline and assayed for eotaxin by ELISA and for eosinophil chemotactic activity by fluorescence-based chemotaxis assay. The contribution of eotaxin to chemotactic activity was studied by using a high-affinity neutralizing human anti-eotaxin antibody, CAT-213. Sputum eotaxin concentration was significantly raised in moderate and severe asthma (p < 0.05 versus healthy control subjects) but not in mild asthma. Chemotactic activity was significantly increased in all asthmatic groups relative to healthy subjects (p < 0.05) and was significantly inhibited by CAT-213 (100 nM) in subjects with moderate and severe asthma, with median inhibition of 52% (p < 0.05), 78% (p < 0.0001), and 86% (p < 0.0001), respectively, in samples representing stable-moderate, unstable-moderate, and severe asthma. Eotaxin contributed to the eosinophil chemotactic activity of sputum from subjects with more severe forms of asthma but not mild asthma, suggesting that its contribution is more important in more severe disease. This activity is inhibited significantly by CAT-213.

Adult↗
PubMed2004

Concussion in professional football: injuries involving 7 or more days out--Part 5.

OBJECTIVE: A 6-year study was conducted to determine the signs, symptoms, and outcome of concussions with 7 or more (7+) days out from play or extended postconcussion recovery in the National Football League (NFL). METHODS: From 1996 to 2001, reporting of concussion was performed by NFL teams using a special standardized reporting form filled out by team physicians. Signs and symptoms were grouped by general symptoms, somatic complaints, cranial nerve effects, cognition problems, memory problems, and unconsciousness. Medical action taken and management were recorded. In all, 887 concussions were reported in practices and games. RESULTS: There were 72 concussions (8.1%) involving 7+ days out from play. The highest frequency occurred in quarterbacks (14.8%), the return unit on special teams (11.8%), and secondary (10.8%). Quarterbacks had the highest odds ratio (OR) of 7+ days out with concussion (OR = 2.10, P = 0.049), whereas running backs had the lowest relative risk (OR = 0.13, P = 0.021). The greatest fraction of 7+ days out occurred in passing plays (36.1%) and kickoffs (22.2%). Many signs and symptoms occurred at a greater frequency on initial examination in players 7+ days out; the average number per player was 4.64 with 7+ days out versus 2.58 with fewer days out (t = 6.02, df = 77.1). The signs and symptoms with the highest incidence for 7+ days out were disorientation to time (chi(2) = 51.2, P = 001), retrograde amnesia (chi(2) = 33.2, P = 0.001), fatigue (chi(2) = 28.1, P = 0.001), and the general category of cognition problems (chi(2) = 21.7, P = 0.001). Loss of consciousness for more than 1 minute was a predictor of 7+ days out (chi(2) = 33.5, P = 0.001), although it occurred in only 7.9% of cases. Of players with 7+ days out, 72.2% were removed from the game and 12.5% were hospitalized. These frequencies were significantly greater than for players with fewer than 7 days out (chi(2) = 68.03, df = 3, P < 0.0001). Approximately 90% of players were managed by rest, irrespective of days out, but a greater fraction were given drug or medical therapies with prolonged days out. CONCLUSION: The most vulnerable players for 7+ days out with concussion were quarterbacks and the secondary in professional football. Although 8.1% of concussions involved 7+ days out, only 1.6% involved a prolonged postconcussion syndrome. They recovered from symptoms and had a consistent return to play in the NFL.

Adult↗
PubMed2004

Alpha-T-catenin is expressed in human brain and interacts with the Wnt signaling pathway but is not responsible for linkage to chromosome 10 in Alzheimer's disease.

The gene encoding alpha-T-catenin, CTNNA3, is positioned within a region on chromosome 10, showing strong evidence of linkage to Alzheimer's disease (AD), and is therefore a good positional candidate gene for this disorder. We have demonstrated that alpha-T-catenin is expressed in human brain, and like other alpha-catenins, it inhibits Wnt signaling and is therefore also a functional candidate. We initially genotyped two single-nucleotide polymorphisms (SNPs) in the gene, in four independent samples comprising over 1200 cases and controls but failed to detect an association with either SNP. Similarly, we found no evidence for association between CTNNA3 and AD in a sample of subjects showing linkage to chromosome 10, nor were these SNPs associated with Abeta deposition in brain. To comprehensively screen the gene, we genotyped 30 additional SNPs in a subset of the cases and controls (n > 700). None of these SNPs was associated with disease. Although an excellent candidate, we conclude that CTNNA3 is unlikely to account for the AD susceptibility locus on chromosome 10.

Aged↗
PubMed2003

Cross-sectional survey of users of Internet depression communities.

BACKGROUND: Internet-based depression communities provide a forum for individuals to communicate and share information and ideas. There has been little research into the health status and other characteristics of users of these communities. METHODS: Online cross-sectional survey of Internet depression communities to identify depressive morbidity among users of Internet depression communities in six European countries; to investigate whether users were in contact with health services and receiving treatment; and to identify user perceived effects of the communities. RESULTS: Major depression was highly prevalent among respondents (varying by country from 40% to 64%). Forty-nine percent of users meeting criteria for major depression were not receiving treatment, and 35% had no consultation with health services in the previous year. Thirty-six percent of repeat community users who had consulted a health professional in the previous year felt that the Internet community had been an important factor in deciding to seek professional help. CONCLUSIONS: There are high levels of untreated and undiagnosed depression in users of Internet depression communities. This group represents a target for intervention. Internet communities can provide information and support for stigmatizing conditions that inhibit more traditional modes of information seeking.

Adult↗
PubMed2003

Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma.

Using current diagnostic criteria, primary mediastinal B cell lymphoma (PMBL) cannot be distinguished from other types of diffuse large B cell lymphoma (DLBCL) reliably. We used gene expression profiling to develop a more precise molecular diagnosis of PMBL. PMBL patients were considerably younger than other DLBCL patients, and their lymphomas frequently involved other thoracic structures but not extrathoracic sites typical of other DLBCLs. PMBL patients had a relatively favorable clinical outcome, with a 5-yr survival rate of 64% compared with 46% for other DLBCL patients. Gene expression profiling strongly supported a relationship between PMBL and Hodgkin lymphoma: over one third of the genes that were more highly expressed in PMBL than in other DLBCLs were also characteristically expressed in Hodgkin lymphoma cells. PDL2, which encodes a regulator of T cell activation, was the gene that best discriminated PMBL from other DLBCLs and was also highly expressed in Hodgkin lymphoma cells. The genomic loci for PDL2 and several neighboring genes were amplified in over half of the PMBLs and in Hodgkin lymphoma cell lines. The molecular diagnosis of PMBL should significantly aid in the development of therapies tailored to this clinically and pathogenetically distinctive subgroup of DLBCL.

Adult↗
PubMed2003

Sequence variation in the CHAT locus shows no association with late-onset Alzheimer's disease.

There is substantial evidence for a susceptibility gene for late-onset Alzheimer's disease (AD) on chromosome 10. One of the characteristic features of AD is the degeneration and dysfunction of the cholinergic system. The genes encoding choline acetyltransferase (ChAT) and its vesicular transporter (VAChT), CHAT and SLC18A3 respectively, map to the linked region of chromosome 10 and are therefore both positional and obvious functional candidate genes for late-onset AD. We have screened both genes for sequence variants and investigated each for association with late-onset AD in up to 500 late-onset AD cases and 500 control DNAs collected in the UK. We detected a total of 17 sequence variants. Of these, 14 were in CHAT, comprising three non-synonymous variants (D7N in the S exon, A120T in exon 5 and L243F in exon 8), one synonymous change (H547H), nine single-nucleotide polymorphisms in intronic, untranslated or promoter regions, and a variable number of tandem repeats in intron 7. Three non-coding SNPs were detected in SLC18A3. None demonstrated any reproducible association with late-onset AD in our samples. Levels of linkage disequilibrium were generally low across the CHAT locus but two of the coding variants, D7N and A120T, proved to be in complete linkage disequilibrium.

Aged↗
PubMed2003

Depression in Alzheimer's disease: the effect of serotonin receptor gene variation.

This study investigated possible associations between selected polymorphisms in the serotonin receptor genes, 5-HT2A and 5-HT2C, with the presence of co-morbid depressive illness at baseline in a community based cohort of 158 patients with late onset patients with Alzheimer's disease (AD). An association was found between the presence of major depressive illness at baseline and both the 5-HT2A and 5-HT2C polymorphisms. Specifically, homozygous carriers of the 5-HT2A C102 allele were five times more likely to have major depressive illness than heterozygotes. In addition, homozygous or hemizygous carriers of the 5-HT2C Ser allele were 12 times more likely to have major depressive illness than homozygous or hemizygous carriers of the 5-HT2C Cys allele.

Age of Onset↗