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| 2. |
- Ismail, AA, et al.
(författare)
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Incidence of limb fracture across Europe: Results from the European Prospective Osteoporosis Study (EPOS)
- 2002
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Ingår i: Osteoporosis International. - : Springer Science and Business Media LLC. - 1433-2965 .- 0937-941X. ; 13:7, s. 565-571
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this population-based prospective study was to determine the incidence of limb fracture by site and gender in different regions of Europe. Men and women aged 50-79 years were recruited from population registers in 31 European centers. Subjects were invited to attend for an interviewer-administered questionnaire and lateral spinal radiographs. Subjects were subsequently followed up using an annual postal questionnaire which included questions concerning the occurrence of new fractures. Self-reported fractures were confirmed where possible by radiograph, attending physician or subject interview. There were 6451 men and 6936 women followed for a median of 3.0 years. During this time there were 140 incident limb fractures in men and 391 in women. The age-adjusted incidence of any limb fracture was 7,3/1000 person-years [pyrs] in men and 19 per 1000 pyrs in women, equivalent to a 2,5 times excess in women. Among women, the incidence of hip, humerus and distal forearm fracture, though not 'other' limb fracture, increased with age, while in men only the incidence of hip and humerus fracture increased with age. Among women, there was evidence of significant variation in the occurrence of hip, distal forearm and humerus fractures across Europe, with incidence rates higher in Scandinavia than in other European regions. though for distal forearm fracture the incidence in east Europe was similar to that observed in Scandinavia. Among men, there was no evidence of significant geographic variation in the occurrence of these fractures. This is the first large population-based study to characterize the incidence of limb fracture in men and women over 50 years of age across Europe. There are substantial differences in the descriptive epidemiology of limb fracture by region and gender.
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| 3. |
- Cockerill, W, et al.
(författare)
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Health-related quality of life and radiographic vertebral fracture
- 2004
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Ingår i: Osteoporosis International. - : Springer Science and Business Media LLC. - 1433-2965 .- 0937-941X. ; 15:2, s. 113-119
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Tidskriftsartikel (refereegranskat)abstract
- Background: Vertebral fractures are associated with back pain and disability; however, relatively little is known about the impact of radiographic vertebral fractures on quality of life in population samples. The aim of this study was to determine the impact of a recent radiographic vertebral fracture on health-related quality of life (HRQoL). Methods: Men and women aged 50 years and over were recruited from population registers in 12 European centers. Subjects completed an interviewer-administered questionnaire and had lateral spine radiographs performed. Subjects in these centers were followed prospectively and had repeat spinal radiographs performed a mean of 3.8 years later. Prevalent deformities were defined using established morphometric criteria, and incident vertebral fractures by both morphometric criteria and qualitative assessment. For each incident fracture case, three controls matched for age, gender, and center were selected: one with a prevalent deformity (at baseline) and two without prevalent deformities. All subjects were interviewed or completed a postal questionnaire instrument which included Short Form 12 (SF-12), the EQ-5D (former EuroQol), and the quality of life questionnaire of the International Osteoporosis Foundation (QUALEFFO). The median time from the second spinal radiograph until the quality of life survey was 1.9 years. Comparison between cases and their matched controls was undertaken using the signed rank test. Results: 73 subjects with incident vertebral fracture (cases), mean age 64.8 years (of whom 23 had a baseline deformity), and 196 controls, mean age 63.9 years (of whom 60 had a baseline deformity), were studied. There were strong correlations between the domain scores for each of the three instruments. There was no statistically significant difference in any of the domain scores between cases and those controls with a prevalent deformity. However, compared with the controls without a prevalent deformity the cases had significantly impaired quality of life as determined using the total QUALEFFO score (38.2 vs 33.7), the physical component score of the SF-12 (39.9 vs 43.7) and the health status score of the EQ-5D (62.3 vs 69.9). When the analysis was repeated after stratification of the cases by baseline deformity status (i.e., cases with and without a prevalent deformity at baseline), cases with a prevalent deformity had impaired quality of life compared with their matched controls, both with and without a prevalent deformity. In contrast there was no significant difference in quality of life among the cases without a prevalent deformity and either control group. Conclusion: In this population-based study a recent vertebral fracture was associated with impairment in quality of life, though this was mainly among those who had sustained a previous vertebral deformity.
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| 4. |
- Cowburn, RF, et al.
(författare)
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Receptor-G-protein signalling in Alzheimer's disease
- 2001
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Ingår i: Biochemical Society symposium. - : Portland Press Ltd.. - 0067-8694 .- 1744-1439. ; 67:67, s. 163-175
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Tidskriftsartikel (refereegranskat)abstract
- Based on radioligand binding studies, it has long been assumed that the neurochemical pathology of Alzheimer's disease (AD) does not involve widespread changes in post-synaptic neurotransmitter function. However, more recent studies suggest that receptor function in AD may be compromised due to disrupted post-receptor signal transduction, in particular that mediated by the G-protein regulated phosphoinositide hydrolysis and adenylate cyclase (AC) pathways. The phosphoinositide hydrolysis pathway has been shown to be altered at a number of levels in AD post-mortem brains, including impaired agonist and G-protein regulation of phospholipase C, decreased protein kinase C (PKC) levels and activity, and a reduced number of receptor sites for the second messenger, Ins(1,4,5)P3. Of these, loss of Ins(1,4,5)P3 receptors and PKC in the entorhinal cortex and hippocampus correlates with AD-related neurofibrillary changes, as staged according to Braak's protocol. Disregulation of the phosphoinositide hydrolysis pathway may therefore have consequences for the progression of AD pathology. In contrast to the extensive pattern of disruption seen with the phosphoinositide hydrolysis pathway, changes to AC signalling in AD appear more circumscribed. Disruptions include a lesion at the level of Gs-protein stimulation of AC and, at least in the hippocampus, reduced enzyme activities in response to forskolin stimulation. Of these, the latter change has been shown to precede neurofibrillary changes. Apart from a loss of calcium/calmodulin sensitive AC isoforms, other components of this signalling pathway, including G-protein levels, Gi-protein mediated inhibition and protein kinase A levels and activity, remain relatively preserved in the disorder.
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| 5. |
- Dunne, Aisling, et al.
(författare)
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Structural complementarity of Toll/interleukin-1 receptor domains in Toll-like receptors and the adaptors Mal and MyD88
- 2003
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Ingår i: Journal of Biological Chemistry. - : American Society for Biochemistry and Molecular Biology. - 0021-9258 .- 1083-351X. ; 278:42, s. 41443-41451
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Tidskriftsartikel (refereegranskat)abstract
- The Toll/interleukin 1 receptor (TIR) domain is a region found in the cytoplasmic tails of members of the Toll-like receptor/interleukin-1 receptor superfamily. The domain is essential for signaling and is also found in the adaptor proteins Mal (MyD88 adaptor-like) and MyD88, which function to couple activation of the receptor to downstream signaling components. Experimental structures of two Toll/interleukin 1 receptor domains reveal a alpha-beta-fold similar to that of the bacterial chemotaxis protein CheY, and other evidence suggests that the adaptors can make heterotypic interactions with both the receptors and themselves. Here we show that the purified TIR domains of Mal and MyD88 can form stable heterodimers and also that Mal homodimers and oligomers are dissociated in the presence of ATP. To identify structural features that may contribute to the formation of signaling complexes, we produced models of the TIR domains from human Toll-like receptor 4 (TLR4), Mal, and MyD88. We found that although the overall fold is conserved the electrostatic surface potentials are quite distinct. Docking studies of the models suggest that Mal and MyD88 bind to different regions in TLRs 2 and 4, a finding consistent with a cooperative role of the two adaptors in signaling. Mal and MyD88 are predicted to interact at a third non-overlapping site, suggesting that the receptor and adaptors may form heterotetrameric complexes. The theoretical model of the interactions is supported by experimental data from glutathione S-transferase pull-downs and co-immunoprecipitations. Neither theoretical nor experimental data suggest a direct role for the conserved proline in the BB-loop in the association of TLR4, Mal, and MyD88. Finally we show a sequence relationship between the Drosophila protein Tube and Mal that may indicate a functional equivalence of these two adaptors in the Drosophila and vertebrate Toll pathways.
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| 6. |
- Lewis, Cathryn M, et al.
(författare)
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Genome scan meta-analysis of schizophrenia and bipolar disorder, part II : Schizophrenia
- 2003
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Ingår i: American Journal of Human Genetics. - 0002-9297 .- 1537-6605. ; 73:1, s. 34-48
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Tidskriftsartikel (refereegranskat)abstract
- Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studies (R(avg)) and then weighted for sample size (N(sqrt)[affected casess]). A permutation test was used to compute the probability of observing, by chance, each bin's average rank (P(AvgRnk)) or of observing it for a bin with the same place (first, second, etc.) in the order of average ranks in each permutation (P(ord)). The GSMA produced significant genomewide evidence for linkage on chromosome 2q (PAvgRnk<.000417). Two aggregate criteria for linkage were also met (clusters of nominally significant P values that did not occur in 1,000 replicates of the entire data set with no linkage present): 12 consecutive bins with both P(AvgRnk) and P(ord)<.05, including regions of chromosomes 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p, and 19 consecutive bins with P(ord)<.05, additionally including regions of chromosomes 16q, 18q, 10p, 15q, 6q, and 17q. There is greater consistency of linkage results across studies than has been previously recognized. The results suggest that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.
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| 7. |
- O'Neill, C, et al.
(författare)
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Dysfunctional intracellular calcium homoeostasis: a central cause of neurodegeneration in Alzheimer's disease
- 2001
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Ingår i: Biochemical Society symposium. - : Portland Press Ltd.. - 0067-8694 .- 1744-1439. ; 67:67, s. 177-194
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Tidskriftsartikel (refereegranskat)abstract
- The clinical symptoms of all forms of Alzheimer's disease (AD) result from a slowly progressive neurodegeneration that is associated with the excessive deposition of ϐ-amyloid (Aϐ) in plaques and in the cerebrovasculature, and the formation of intraneuronal neurofibrillary tangles, which are composed primarily of abnormally hyperphosphorylated tau protein. The sequence of cellular events that cause this pathology and neurodegeneration is unknown. It is, however, most probably linked to neuronal signal transduction systems that become misregulated in the brains of certain individuals, causing excessive Aϐ to be formed and/or deposited, tau to become aggregated and hyperphosphorylated and neurons to degenerate. We hypothesize that a progressive alteration in the ability of neurons to regulate intracellular calcium, particularly at the level of the endoplasmic reticulum, is a crucial signal transduction event that is linked strongly to the initiation and development of AD pathology. In this chapter we will discuss the key findings that lend support to this hypothesis.
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| 8. |
- O'Neill, TW, et al.
(författare)
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Back pain, disability, and radiographic vertebral fracture in European women: a prospective study
- 2004
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Ingår i: Osteoporosis International. - : Springer Science and Business Media LLC. - 1433-2965 .- 0937-941X. ; 15:9, s. 760-765
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Tidskriftsartikel (refereegranskat)abstract
- Vertebral fractures are associated with back pain and disability. There are, however, few prospective data looking at back pain and disability following identification of radiographic vertebral fracture. The aim of this analysis was to determine the impact of radiographically identified vertebral fracture on the subsequent occurrence of back pain and disability. Women aged 50 years and over were recruited from population registers in 18 European centers for participation in the European Prospective Osteoporosis Study. Participants completed an interviewer-administered questionnaire which included questions about back pain in the past year and various activities of daily living, and they had lateral spine radiographs performed. Participants in these centers were followed prospectively and had repeat spine radiographs performed a mean of 3.7 years later. In addition they completed a questionnaire with the same baseline questions concerning back pain and activities of daily living. The presence of prevalent and incident vertebral fracture was defined using established morphometric criteria. The data were analyzed using logistic regression with back pain or disability (present or absent) at follow-up as the outcome variable with adjustment made for the baseline value of the variable. The study included 2,260 women, mean age 62.2 years. The mean time between baseline and follow-up survey was 5.0 years. Two hundred and forty participants had prevalent fractures at the baseline survey, and 85 developed incident fractures during follow-up. After adjustment for age, center, and the baseline level of disability, compared with those without baseline prevalent fracture, those with a prevalent fracture (odds ratio [OR]=1.4; 95% confidence interval [CI] 1.0 to 2.0) or an incident fracture (OR=1.7; 95% CI, 0.9 to 3.2) were more likely to report disability at follow-up, though the confidence intervals embraced unity. Those with both a prevalent and incident fracture, however, were significantly more likely to report disability at follow-up (OR=3.1; 95% CI, 1.4 to 7.0). After adjustment for age, center, and frequency of back pain at baseline, compared with those without baseline vertebral fracture, those with a prevalent fracture were no more likely to report back pain at follow-up (OR=1.2; 95%CI, 0.8 to 1.7). There was a small increased risk among those with a preexisting fracture who had sustained an incident fracture during follow-up (OR=1.6; 95%CI, 0.6 to 4.1) though the confidence intervals embraced unity. In conclusion, although there was no significant increase in the level of back pain an average of 5 years following identification of radiographic vertebral fracture, women who suffered a further fracture during follow-up experienced substantial levels of disability with impairment in key physical functions of independent living.
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| 9. |
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| 10. |
- O'Neill, Luke A. J., et al.
(författare)
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Mal and MyD88 : adapter proteins involved in signal transduction by Toll-like receptors
- 2003
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Ingår i: Journal of Endotoxin Research. - : Maney Publishing. - 0968-0519 .- 1743-2839. ; 9:1, s. 55-59
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Tidskriftsartikel (refereegranskat)abstract
- Signal transduction processes activated by Toll-like receptors (TLRs) include the important transcription factor NF-kappaB and 2 MAP kinases, p38 and Jun N-terminal kinase. These signals ultimately give rise to increased expression of a multitude of pro-inflammatory proteins. Receptor-proximal proteins involved in signalling by all TLRs include the adapter MyD88, 3 IRAKs (IRAK-4, IRAK and IRAK-2), Tollip, Traf-6 and TAK-1. Differences between signals generated by TLRs are emerging, with both TLR4 and TLR2 signalling requiring an additional adapter termed MyD88-adapter-like (Mal; also known as TIRAP). MyD88 and Mal both have a homologous Toll/IL-1 receptor (TIR) domain although they differ in their N-termini, with MyD88 possessing a death domain. In addition, structural models reveal marked differences in surface charges which, when taken with surface charge differences between TLR2 and TLR4 TIR domains, may indicate that TLR4 but not TLR2 recruits Mal directly. Another difference is that Mal can become phosphorylated. Future studies on Mal will reveal specificities in signal transduction by different TLRs, which may ultimately provide molecular explanations for specificities in the innate immune response to infection.
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