Search PubMed⌕ Search

Biomedical subjects

Michael Doherty

Publications and source records attributed to Michael Doherty.

At least 19 recordsLinked to original sources
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↗
PubMed2002

Mutations in ANKH cause chondrocalcinosis.

Chondrocalcinosis (CC) is a common cause of joint pain and arthritis that is caused by the deposition of calcium-containing crystals within articular cartilage. Although most cases are sporadic, rare familial forms have been linked to human chromosomes 8 (CCAL1) or 5p (CCAL2) (Baldwin et al. 1995; Hughes et al. 1995; Andrew et al. 1999). Here, we show that two previously described families with CCAL2 have mutations in the human homolog of the mouse progressive ankylosis gene (ANKH). One of the human mutations results in the substitution of a highly conserved amino acid residue within a predicted transmembrane segment. The other creates a new ATG start site that adds four additional residues to the ANKH protein. Both mutations segregate completely with disease status and are not found in control subjects. In addition, 1 of 95 U.K. patients with sporadic CC showed a deletion of a single codon in the ANKH gene. The same change was found in a sister who had bilateral knee replacement for osteoarthritis. Each of the three human mutations was reconstructed in a full-length ANK expression construct previously shown to regulate pyrophosphate levels in cultured cells in vitro. All three of the human mutations showed significantly more activity than a previously described nonsense mutation that causes severe hydroxyapatite mineral deposition and widespread joint ankylosis in mice. These results suggest that small sequence changes in ANKH are one cause of CC and joint disease in humans. Increased ANK activity may explain the different types of crystals commonly deposited in human CCAL2 families and mutant mice and may provide a useful pharmacological target for treating some forms of human CC.

Cells, Cultured↗
PubMed2002

Assisted suicide and human rights.

The case of R (Pretty) v. Director of Public Prosecutions, gave the House of Lords the opportunity to comment on the issues surrounding the application of the European Convention on Human Rights to the crime of assisted suicide in the case of the terminally ill. A conservative approach was taken in relation to both this issue and indeed in relation to the possibilities of judicial control of the Law Officers of the Crown.

Human Rights↗