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Biomedical subjects

Michael Doherty

Publications and source records attributed to Michael Doherty.

At least 19 recordsLinked to original sources
PubMed2007

Sex and ethnic differences in the association of ASPN, CALM1, COL2A1, COMP, and FRZB with genetic susceptibility to osteoarthritis of the knee.

OBJECTIVE: To assess whether the association of genetic polymorphisms with osteoarthritis (OA) in other populations could be replicated in a large, multicenter, mixed-sex, case-control study of clinical knee OA. METHODS: Genetic polymorphisms in OA candidate genes were genotyped in 298 men and 305 women, ages 50-86 years, all of whom had a diagnosis of knee OA as assessed clinically and radiographically, and in 300 male and 299 female control subjects matched for age and ethnicity. Allele and haplotype frequencies for 5 genes (ASPN, CALM1, COL2A1, COMP, and FRZB) previously tested for association with hip and/or knee OA in other populations were compared between patients and control subjects, analyzing men and women separately. RESULTS: The same FRZB 2-marker single-nucleotide polymorphism (SNP) haplotype associated with hip OA in other populations of Caucasian women was shown to increase the risk of knee OA among the women (but not the men) in the current study (odds ratio [OR] 2.87, P < 0.04). The CALM1 SNP, which affects the risk of hip OA in Japanese individuals, was not shown to be associated with susceptibility to OA in men or women. COL2A1 haplotypes were demonstrated to be associated with a decreased risk of knee OA in men (OR 0.68, P < 0.005) but not in women. COMP haplotypes that were associated with susceptibility to knee OA were different in men and women (P < 0.014 and P < 0.032, respectively). A meta-analysis of these data and those from previously published reports indicated a strong association between the FRZB G324 allele (P < 0.0003) and suggested that an ASPN allele is protective against the risk of knee OA in Caucasians (P < 0.02). CONCLUSION: Our results indicate that genetic polymorphisms affecting knee OA vary between populations (Japanese versus Caucasian) and sexes and indicate a role for ASPN, COMP, FRZB, and COL2A1 in Caucasians.

Aged↗
PubMed2006

Reproducible genetic associations between candidate genes and clinical knee osteoarthritis in men and women.

OBJECTIVE: Osteoarthritis (OA) is recognized to have a genetic component, and in this study, we aimed to replicate in a case-control study of men and women with clinical knee OA genetic associations in 12 candidate genes previously reported to be associated with OA. METHODS: Twenty-five single-nucleotide polymorphisms were genotyped in 298 men and 305 women ages 50-86 who were diagnosed as having knee OA, as assessed both clinically and radiographically, and in 297 men and 299 women matched for age and ethnicity (controls). Standardized anteroposterior radiographs of the knee in extension were performed on each of the cases, and all cases met the American College of Rheumatology criteria for OA of the knee. Genotype and haplotype frequencies in cases and controls were compared separately in men and women. The 12 genes tested were AACT, ADAM12, BMP2, CD36, CILP, COX2, ESR1, NCOR2, OPG, TNA, TNFAIP6, and VDR. RESULTS: Eight of the candidate genes were associated in women and 5 in men, and only 3 genes (TNFAIP6, NCOR2, and CD36) were not significantly associated in either sex. The strongest associations in terms of odds ratios (ORs) were a haplotype in ADAM12 (OR 7.1 [95% confidence interval (95% CI) 3.3-33.8]) and a haplotype in ESR1 (OR 3.6 [95% CI 1.18-10.98]) in women. The same ADAM12 haplotype (OR 2.54 [95% CI 1.2-5.4]) and a haplotype in the CILP gene (OR 0.38 [95% CI 0.23-0.62]) were the strongest associations in men. CONCLUSION: We found that genes previously identified by their association with subclinical features of knee OA or progression were also associated with clinical knee OA. These genetic associations may identify individuals at a particularly high risk of developing knee OA.

Aged↗
PubMed2006

Association between a variation in LRCH1 and knee osteoarthritis: a genome-wide single-nucleotide polymorphism association study using DNA pooling.

OBJECTIVE: To perform a large-scale association analysis of single-nucleotide polymorphisms (SNPs) in patients with radiographically defined osteoarthritis (OA) of the knee. METHODS: We examined >25,000 SNPs located within approximately 14,000 genes for associations with radiographically defined knee OA, using polymerase chain reaction and MassExtend amplification techniques. Allele frequencies were estimated initially in DNA pools from 335 female patients with knee OA and 335 asymptomatic and radiographically negative female control subjects. All were of northern European ancestry. Significant allele frequency differences were validated by genotyping of individual DNA samples. Confirmed significant findings were verified in 2 additional case-control samples from the UK (443 cases and 303 controls) and Newfoundland (346 cases and 264 controls). Chondrosarcoma cell lines were used to test for potential differences in gene expression. RESULTS: The marker most strongly associated with the risk of knee OA was rs912428, a C/T polymorphism in intron 1 of LRCH1, a gene on chromosome 13q14 that encodes a novel protein of as-yet-unknown function. The frequency of the T allele compared with controls was consistently increased by 40% across all 3 case-control groups. Additional subanalyses in case-control samples with hip OA and hand OA suggested similar trends, but did not reach statistical significance. Association fine-mapping using 10 additional SNPs in LRCH1 confirmed intron 1 as the region of highest association but failed to reveal variations with significance stronger than the marker SNP, as did the haplotype analysis. LRCH1 was not up-regulated or overexpressed in chondrosarcoma cell lines exposed to inflammatory stimuli, suggesting a possible structural role. CONCLUSION: A genetic variant in LRCH1 was consistently associated with knee OA in 3 samples from 2 populations. Our results also suggest that the same association with OA may exist at other sites. Additional genetic and experimental work is needed to elucidate the precise mechanism by which the LRCH1 gene influences OA risk.

Aged↗
PubMed2006

Changing life-styles and osteoarthritis: what is the evidence?

Life-style modification, particularly exercise and weight reduction, is a core component of the management of osteoarthritis. In this chapter, the evidence for the efficacy of exercise, weight reduction and footwear is reviewed. Caveats to the evidence and the areas where further research is needed are highlighted. Long-term adherence to exercise and weight reduction is a key predictor of response, and strategies for increasing adherence are reviewed. Our discussion focuses predominantly on knee OA, to which most of the evidence relates but refers to other sites where appropriate.

Exercise↗
PubMed2006

Evidence-based clinical guidelines: a new system to better determine true strength of recommendation.

RATIONALE, AIMS AND OBJECTIVES: Clinical practice guidelines often grade the 'strength' of their recommendations according to the robustness of the supporting research evidence. The existing methodology does not allow the strength of recommendation (SOR) to be upgraded for recommendations for which randomized controlled trials are impractical or unethical. The purpose of this study was to develop a new method of determining SOR, incorporating both research evidence and expert opinion. METHODS: A Delphi technique was employed to produce 10 recommendations for the role of exercise therapy in the management of osteoarthritis of the hip or knee. The SOR for each recommendation was determined by the traditional method, closely linked to the category of research evidence found on a systematic literature search, and on a visual analogue scale (VAS). Recommendations were grouped A-D according to the traditional SOR allocated and the mean VAS calculated. Difference across the groups was assessed by one-way ANOVA variance analysis. RESULTS: Mean VAS scores for the traditional SOR groups A-D and one proposition which was 'not recommended' showed significant linearity on one-way ANOVA. However, certain recommendations which, for practical reasons, could not assessed in randomized controlled trials and therefore could not be recommended strongly by the traditional methodology, were allocated a strong recommendation by VAS. CONCLUSIONS: This new system of grading strength of SOR is less constrained than the traditional methodology and offers the advantage of allowing SOR for procedures which cannot be assessed in RCTs for practical or ethical reasons to be upgraded according to expert opinion.

Analysis of Variance↗
PubMed2005

Lack of support for the presence of an osteoarthritis susceptibility locus on chromosome 6p.

OBJECTIVE: To replicate, in a Northern Irish population, the previously reported association between a locus on chromosome 6 and hip osteoarthritis (OA). METHODS: Patients with hip OA were identified from a registry of patients who had undergone total hip replacement surgery over an 8-year period at a single large orthopedic unit in Northern Ireland. Patients identified as index cases were contacted by mail and asked to reply only if another family member also had undergone total hip replacement surgery. Using this approach, we identified 288 sibling pairs concordant for primary hip OA. DNA was extracted from peripheral blood, and microsatellite markers were amplified by polymerase chain reaction and subsequently genotyped. RESULTS: No evidence of linkage to this region was demonstrated by either 2-point analysis or multipoint analysis of 17 microsatellites. CONCLUSION: The reported association between a locus on chromosome 6 and hip OA could not be confirmed in this population. Different methods of ascertainment and phenotyping of OA may contribute to the current inability to replicate genetic associations for hip OA.

Arthroplasty, Replacement, Hip↗
PubMed2005

Joint aspiration and injection.

Joint aspiration/injection is an invaluable procedure for the diagnosis and treatment of joint disease. The knee is the commonest site to require aspiration although any non-axial joint is accessible for obtaining synovial fluid. Septic arthritis and crystal arthritis can be readily diagnosed by aspirating synovial fluid. Intra-articular injection of long-acting insoluble corticosteroids produces rapid resolution of inflammation in most injected joints and is a well established procedure in rheumatological practice. The technique involves only a knowledge of basic anatomy and should not be unduly painful for the patient. Provided sterile equipment and a sensible, aseptic approach are used it is a safe procedure. This chapter addresses the indications, technical principals, expected benefits and risks of intra-articular corticosteroid injection. The use of other intra-articular injections including osmic acid, radioisotopes and hyaluronic acid, which are less universally utilised than intra-articular corticosteroid, will also be addressed.

Glucocorticoids↗
PubMed2004

Efficacy of topical non-steroidal anti-inflammatory drugs in the treatment of osteoarthritis: meta-analysis of randomised controlled trials.

OBJECTIVE: To assess the efficacy of topical non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of osteoarthritis. DATA SOURCES: Medline, Embase, Scientific Citation Index, CINAHL, Cochrane Library, and abstracts from conferences. REVIEW METHODS: Inclusion criterion was randomised controlled trials comparing topical NSAIDs with placebo or oral NSAIDs in osteoarthritis. Effect size was calculated for pain, function, and stiffness. Rate ratio was calculated for dichotomous data such as clinical response rate and adverse event rate. Number needed to treat to obtain the clinical response was estimated. Quality of trial was assessed, and sensitivity analyses were undertaken. RESULTS: Topical NSAIDs were superior to placebo in relieving pain due to osteoarthritis only in the first two weeks of treatment. Effect sizes for weeks 1 and 2 were 0.41 (95% confidence interval, 0.16 to 0.66) and 0.40 (0.15 to 0.65), respectively. No benefit was observed over placebo in weeks 3 and 4. A similar pattern was observed for function, stiffness, and clinical response rate ratio and number needed to treat. Topical NSAIDs were inferior to oral NSAIDs in the first week of treatment and associated with more local side effects such as rash, itch, or burning (rate ratio 5.29, 1.14 to 24.51). CONCLUSION: Randomised controlled trials of short duration only (less than four weeks) have assessed the efficacy of topical NSAIDs in osteoarthritis. After two weeks there was no evidence of efficacy superior to placebo. No trial data support the long term use of topical NSAIDs in osteoarthritis.

Administration, Topical↗
PubMed2004

Distribution of radiographic osteoarthritis between the right and left hands, hips, and knees.

OBJECTIVE: To investigate whether radiographic osteoarthritis (OA) is asymmetric and greater on the right side than on the left side in the hands, hips, and knees. METHODS: Participants were 489 individuals with posteroanterior hand radiographs from a family study of nodal OA, 1,715 community-derived individuals who had undergone intravenous urography with views of both hips, and 1,729 community-derived individuals with weight-bearing fully extended tibiofemoral (TF) joint and skyline patellofemoral (PF) joint radiographs. All radiographs were evaluated for global OA grade, osteophytes, and joint space narrowing (JSN). Minimum joint space width (JSW) was measured at the hip and knee. Odds ratios (ORs) for global OA on the right side versus the left side were calculated. Osteophytes and JSN were compared by Wilcoxon's signed rank test, and the JSW was compared by paired t-test. RESULTS: Global OA was more prevalent on the right side at the distal interphalangeal joints (OR 1.57; 95% confidence interval 1.22, 2.02) and the TF joint (OR 1.24; 95% confidence interval 1.01, 1.52). Osteophyte scores for the fingers were greater on the right side, but JSN was symmetric. At the hip, there were no right-left differences in osteophytosis or JSN, but the JSW was smaller on the left. At the TF joint, the medial compartment was narrower and the lateral compartment wider on the right side, and osteophyte scores were greater on the right side. At the PF joint, there were no right-left differences in osteophytes, and for lone PF joint OA, there were no differences in JSN or the JSW. CONCLUSION: This discordance in symmetry suggests that the relative importance of biomechanical factors in the pathogenesis of OA is site-specific and may be discordant for cartilage and bone.

Aged↗
PubMed2004

Autosomal dominant early childhood seizures associated with chondrocalcinosis and a mutation in the ANKH Gene.

We describe the pattern of early childhood seizures within a family with autosomal dominant chondrocalcinosis (CCAL, which causes adult-onset arthritis). All affected family members with CCAL experienced seizures in early childhood, usually, but not always, associated with fever. Similarities exist to the syndrome of generalized epilepsy with febrile seizures plus (GEFS+). A mutation within the ANKH gene on chromosome 5p has been found previously in this family; other patients with familial CCAL (but without seizures) have mutations in the same gene. ANKH codes for a transmembrane protein involved in the regulation of extracellular pyrophosphate ion levels, although its precise mechanism of action remains unclear. It is highly expressed in the brain, and its expression may be influenced by seizure activity. The mutation within this family creates a premature initiation codon, adding four amino acids to the N-terminus of the protein. We postulate that this may lead to a gain of function, causing seizure susceptibility as well as chondrocalcinosis. Mutations within this gene may underlie other forms of genetic epilepsy and febrile seizures.

Arthritis↗
PubMed2003

Age and sex differences in hip joint space among asymptomatic subjects without structural change: implications for epidemiologic studies.

OBJECTIVE: The prevalence of hip osteoarthritis (OA) increases significantly with age. Although it is not clear whether joint space loss at the hip is a feature of normal aging or a reflection of the OA process, epidemiologic criteria for OA are based on narrowing alone. The aim of this study was to determine whether changes in joint space width occur with age, and whether there are sex differences, in asymptomatic subjects without hip OA. METHODS: We identified a total of 1,806 subjects who had undergone intravenous urography between 1994 and 1996 and sent a questionnaire to the 1,527 of these subjects who were alive in 1998; 1,031 replies (68%) were received. All radiographs were read by an observer blinded to age, sex, and pain status. Individual radiographic features of OA (narrowing, osteophyte, sclerosis, and cysts) were graded, and an overall qualitative grade was allocated, according to a standard atlas. Minimum joint space width (JSW) was measured by metered caliper to within 0.1 mm. A total of 276 women (mean age 63 years) and 257 men (mean age 64 years) were identified who had never had hip pain (defined as having ever had pain on most days for at least 1 month) and who had no evidence of either joint space narrowing or osteophyte (grade 0, no structural changes). The minimum JSW in either hip was tabulated according to age. RESULTS: JSW measurement was reproducible (95% confidence limits of agreement) to within +/-0.5 mm. At all ages, men had larger JSW than women (3.85 mm in women, 4.19 mm in men, mean difference 0.34 mm; 95% confidence interval [95% CI] 0.24, 0.44). A significant decline in JSW with age was seen in women, with a mean difference between ages 45-54 and 75-84 years of 0.36 mm (95% CI 0.15, 0.58; P = 0.001). No significant change in JSW with age was seen in men (mean difference 0.16 mm; 95% CI -0.11, 0.43). Analysis of an additional 64 women and 61 men who were without hip pain and had overall qualitative grade 1-2 changes gave similar results. Implementing these results to alter the threshold for definition of hip OA in women from < or =2.5 mm to < or =2.2 mm reduced the prevalence of hip OA from 10.6% to 5.6%. CONCLUSION: These sex differences in joint space have significant implications in terms of the major emphasis on joint space narrowing in definitions of hip OA. Women also have a significant progressive decline in joint space with age that is not seen in men. This suggests that in women, loss of cartilage may be an age-related phenomenon that is independent of other aspects of structural change. Consideration should be given to the development of sex-specific definitions of hip "OA."

Age Factors↗
PubMed2003

Mutations in the amino terminus of ANKH in two US families with calcium pyrophosphate dihydrate crystal deposition disease.

OBJECTIVE: To analyze ANKH in families with calcium pyrophosphate dihydrate crystal deposition disease (CPPD) for disease-causing mutations. METHODS: Two US families (one of British ancestry and the other of German/Swiss ancestry) with autosomal-dominant CPPD, whose disease phenotypes were found to be linked to chromosome 5p15.1 (locus symbol CCAL2), were screened by direct sequencing for mutations in ANKH, a gene in the CCAL2 candidate interval that has been shown to harbor mutations in other families with CPPD. Observed sequence variants were confirmed by antisense sequencing, and expression of the mutant allele was verified by reverse transcriptase-polymerase chain reaction amplification of messenger RNA followed by direct sequencing. RESULTS: The two US families displayed the same mutation at position 5 of the ANKH gene product (P5T). All affected members were heterozygous for the P-to-T variant, and the mutation was not seen in 204 control alleles. The two families displayed distinct disease haplotypes, suggesting that they were unrelated to each other. CONCLUSION: These observations represent the fourth and fifth families with heritable CPPD whose disease phenotypes are linked to the CCAL2 locus and who have missense mutations in the amino terminus of ANKH. This same position (P5) was the site of a missense mutation in an Argentine family of northern Italian ancestry; however, the sequence variant in that family generated a P5L mutation. The distinct disease haplotypes among the 3 families with P5 mutations suggest that the mutations arose independently and that the evolutionarily conserved P5 position of ANKH may represent a hot spot for mutation in families with autosomal-dominant CPPD.

Chondrocalcinosis↗
PubMed2003

Guidelines for management of osteoarthritis published by the American College of Rheumatology and the European League Against Rheumatism: why are they so different?

Because of different methodology the ACR and EULAR guidelines differ significantly in their recommendations despite an identical evidence base. Guidelines that use a strictly evidence-based approach are less likely to incur bias than those that rely more on expert consensus. Although expert consensus is useful in areas in which there are little trial data, clear delineation should be made between evidence-based statements and expert opinion. Following the dissemination of guidelines for the management of OA, emphasis should now be placed on discussion and implementation of the recommendations and subsequent revision of guidelines as new evidence comes to light.

Clinical Trials as Topic↗