Showing papers by "Guy's and St Thomas' NHS Foundation Trust published in 1996"

The association of obesity with osteoarthritis of the hand and knee in women: a twin study.

Abstract: Objective. To examine the association of obesity and osteoarthritis (OA) at various sites in middle aged women and to estimate the magnitude of the weight difference associated with OA. Methods. A co-twin control study was performed within a population based twin study of women aged 48-70. OA was defined radiologically using site specific features and a standard atlas. Twin pairs discordant for OA disease traits were analyzed. Results. The mean weight differences (95% CI) within twin pairs discordant for different OA traits were : tibiofemoral osteophytes 3.75 (1.29, 6.21) kg ; patellofemoral osteophytes 3.05 (0.96, 5.15) kg ; carpometacarpal (CMC) osteophytes 3.06 (0.83, 5.28) kg. There was no significant difference in weight within twin pairs discordant for osteophytes at the distal interphalangeal (DIP) or proximal interphalangeal (PIP) joints or for joint space narrowing at all sites examined except the patellofemoral joint, 4.73 (1.61, 7.84) kg. For each kg increase in weight the increased likelihood of developing different OA traits [OR (95% CI)] was : tibiofemoral osteophytes 1.14 (1.01-1.28), patellofemoral osteophytes 1.32 (1.09-1.59), patellofemoral narrowing 1.15 (1.01-1.30), and CMC osteophytes 1.09 (1.02-1.17). Conclusion. Obesity is an important risk factor for development of OA at the tibiofemoral and patellofemoral joints of the knee and CMC joints of the hands, with significant increases of 9-13% in risk of OA per kg increase in body weight. This emphasizes the potential importance of even minor weight reduction as a preventive health measure for OA.

Down-Regulation of Transcripts for Na Channel α -SNS in Spinal Sensory Neurons Following Axotomy

Abstract: Spinal sensory (dorsal root ganglion; DRG) neurons display slowly inactivating, tetrodotoxin-resistant (TTX-R), and rapidly inactivating, TTX-sensitive (TTX-S) Na currents. Attenuation of the TTX-R Na current and enhancement of TTX-S Na current have been demonstrated in cutaneous afferent DRG neurons in the adult rat after axotomy and may underlie abnormal bursting. We show here that steady-state levels of transcripts encoding the α-SNS subunit, which is associated with a slowly inactivating, TTX-R current when expressed in oocytes, are reduced significantly 5 days following axotomy of DRG neurons, and continue to be expressed at reduced levels, even after 210 days. Steady-state levels of α-III transcripts, which are present at low levels in control DRG neurons, show a pattern of transiently increased expression. In situ hybridization using α-SNS- and α-III-specific riboprobes showed a decreased signal for α-SNS, and an increased signal for α-III, in both large and small DRG neurons following axotomy. Reduced levels of α-SNS may explain the selective loss of slowly inactivating, TTX-R current. The abnormal electrophysiological properties of DRG neurons following axonal injury thus appear to reflect a switch in Na channel gene expression.

Captopril reduces the risk of nephropathy in IDDM patients with microalbuminuria

Abstract: In insulin-dependent diabetes mellitus (IDDM), microalbuminuria predicts renal and cardiovascular disease. We report a combined analysis of 235 normotensive IDDM patients with microalbuminuria who participated in two 24-month double-blind, randomised, placebo-controlled trials to assess the effects of captopril 50 mg twice daily on the progression to overt clinical albuminuria. Of the 225 patients who were evaluable on an intent to treat basis, 25 of 114 placebo-treated patients (21.9%) and 8 of 111 captopril-treated patients (7.2%) progressed to persistent clinical albuminuria. The risk of progression over 24 months was significantly reduced by captopril (p = 0.004) with a risk reduction of 69.2% (95% confidence interval (CI): 31.7 to 86.1%). This degree of risk reduction remained at the same level (62.9% [16.1-83.6%], p = 0.017) after adjustment for differences in time-varying mean arterial blood pressure. Albumin excretion rate increased by an average of 14.2% [3.1-26.5%] per year in the placebo-treated group compared with a reduction of 9.6% [-18.6-0.4%] per year in the captopril-treated group (p = 0.002). The rate of fall of creatinine clearance tended to be faster in the placebo-treated group than in the captopril-treated group (-6.4 [-10.2--2.5] vs -1.4 [-5.3-2.6] ml . min(-1). 1.73 m(-2), p = 0.07). Baseline albumin excretion rate (p < 0.0001) and glycated haemoglobin (p = 0.03) were independent predictors of progression to clinical albuminuria and changes in mean arterial blood pressure (p = 0.02) and serum cholesterol level (p = 0.003) were significantly associated with percentage changes in albumin excretion rate. Captopril reduces the risk of progression to overt nephropathy in IDDM patients with microalbuminuria, an effect partly independent of its blood pressure-lowering effects.

Genetics of osteoarthritis.

Abstract: The available evidence suggests that genetic factors have a major role in osteoarthritis. It has been believed for over 50 years that a strong genetic component to certain forms of osteoarthritis is present. This genetic influence has now been estimated to be up to 65% in a recent twin study. The nature of the genetic influence in osteoarthritis is speculative and may involve either a structural defect (that is, collagen), alterations in cartilage or bone metabolism, or alternatively a genetic influence on a known risk factor for osteoarthritis such as obesity. Exciting work has showed that mutations in the collagen type 2 are important in some rare, familial forms of osteoarthritis. Further work is needed on isolating the gene or genes involved in the pathogenesis of this common, disabling condition.

Early age-dependent growth impairment in chronic renal failure

Abstract: We report early linear growth in 73 children (51 boys, 22 girls) with early onset of chronic renal failure (CRF). The inclusion criteria was onset of CRF before 6 months of age, two or more height measurements during the 1st year of life, follow-up for at least 3 years and continuously impaired renal function with a glomerular filtration rate below 50 ml/min per 1.73 m2 at 1 year or later. Only height measurements taken during conservative treatment or dialysis were included. The data were analysed in terms of the infancy-childhood-puberty growth model. There was an age-dependent growth failure in early life leading to an attained height of −3 standard deviation score (SDS) at 3 years of age. Approximately one-third of the reduction in height occurred during fetal life and one-third during the first postnatal months. Between 0.75 and 1.5 years of age height also decreased by 1 SD as a consequence of a delayed onset of the second, the “childhood’, phase of growth in 36% of the patients and by an ‘offset childhood’ growth pattern — i.e. a return to the infancy phase pattern after onset of the childhood phase — in 60% of the patients. Growth between 0.25–0.75 and 1.5–5 years of age was generally percentile parallel and thus less likely to be affected in CRF with early disease onset. The glomerular filtration rate was not related to the height gain in early life. We speculate that the growth failure during fetal life and the first postnatal months reflects metabolic and/or nutritional influences and the impaired growth at 0.75–1.5 years of age is related to a partial insensitivity to growth hormone.

Choosing the best method for radiological assessment of patellofemoral osteoarthritis.

Abstract: OBJECTIVE: To assess the reproducibility of different methods of radiological assessment of patellofemoral osteoarthritis (OA) and to determine which is the best view as a research tool in epidemiological studies of knee OA requiring explicit diagnostic criteria to classify the disease in the general population. METHODS: A population based study of 252 unrelated, normal individuals (504 knees) was performed. Lateral and skyline radiographs from each individual were graded for joint space narrowing and osteophytes using a standard atlas. Reproducibility was assessed by two observers on 50 knees. Radiographic features were assessed on their ability to predict knee pain. RESULTS: The skyline views performed better than the lateral views in the assessment of patellofemoral joint OA. The reproducibility for osteophytes was high (kappa > 0.8) and that for joint space narrowing moderate (kappa > 0.6) for both lateral and skyline views. Although the specificity for detecting knee pain was similar in both views, the sensitivity of skyline views in the assessment of knee pain was greater (52.8% versus 30%). The odds ratio for skyline osteophytes as a predictor of knee pain was 7.66 (95% confidence interval (CI) 3.68 to 15.90); that for osteophytes seen on lateral view was 1.83 (95% CI 0.96 to 3.49). Narrowing on both views was a poor predictor of pain. There was frequent disagreement between the lateral and skyline views for detecting osteophytes. CONCLUSION: In a community based study, skyline views performed better than lateral views in terms of reproducibility and for identifying symptomatic patellofemoral joint OA. Skyline radiographs should be the preferred method for examining the patellofemoral joint in such studies.

Serological and molecular evidence of enterovirus infection in patients with end-stage dilated cardiomyopathy.

Abstract: OBJECTIVE: To study the relative diagnostic value of enterovirus-specific molecular biological and serological assays in patients with end-stage dilated cardiomyopathy, and to investigate the possible role of other cardiotropic viruses in dilated cardiomyopathy. DESIGN: Analysis of recipient myocardial tissue and serum from patients with dilated cardiomyopathy and controls undergoing cardiac transplantation for end-stage cardiac disease. SETTING: University virology department and transplantation unit. METHODS: Reverse transcriptase-polymerase chain reaction and nucleotide sequence analysis of myocardial RNA and DNA; enterovirus-specific in situ hybridization; enterovirus-specific immunoglobulin M detection. RESULTS: Enterovirus RNA was detected in myocardial tissue from only a small proportion of (five of 75) hearts. However, although enterovirus-specific immunoglobulin M responses were detected in 22 (28%) of 39 controls patients, a significantly higher prevalence was observed among patients with dilated cardiomyopathy (22 (56%) of 39 patients; P < 0.005). All enteroviruses detected in myocardium showed greatest nucleotide sequence homology with coxsackievirus type B3. Detection of enterovirus RNA in myocardium by the polymerase chain reaction and by in situ hybridisation gave comparable results. Other potentially cardiotropic virus genomes, including human cytomegalovirus, influenzaviruses, and coronaviruses were not detected in myocardium. CONCLUSION: This study found that enterovirus-specific immunoglobulin M responses provided the strongest evidence of enterovirus involvement in patients with end-stage dilated cardiomyopathy. However, the high background prevalence of these responses limits their diagnostic value. The finding that enteroviruses detected in myocardium were coxsackievirus type B3 accords with recent findings in patients with acute myocarditis, and indicates that this serotype is the major cardiotropic human enterovirus.

Don't forget sickled cells in the urine when investigating a patient for haematuria.

Abstract: Haematuria is a well-known complication of sickle cell disease. A South African coloured patient with repeated episodes of gross haematuria is described in whom the diagnosis of sickle cell disease was suggested after the finding of sickled erythrocytes in the urine sediment. The diagnosis was then confirmed by haemoglobin electrophoresis, which revealed sickle cell trait (Hb-AS). It is concluded that sickled erythrocytes must be looked for when urine is microscopically scrutinized to determine the source of a haematuria.

The genetics of osteoarthritis.

Abstract: Osteoarthritis is the most frequent cause of musculoskeletal disability in developed countries. Although the multifactorial nature of osteoarthritis is well recognised,' the role of genetic factors in the development of osteoarthritis has recently received considerable attention with the development of molecular biology techniques. For over 50 years certain forms of osteoarthritis have been thought to have a strong genetic component. Early studies by Stecher in 19412 demonstrated that Heberden's nodes of the fingers were three times as common in the sisters of 64 affected subjects as in the general population. Family studies in the early 1 960s of individuals with generalised osteoarthritis suggested that first degree relatives were twice as likely to have radiographic generalised disease too.3 Further suggestive evidence for a genetic predisposition to osteoarthritis has come from the association of osteoarthritis with some HIA haplotypes4 and a-1-antitrypsin isoform patterns.4 However, not all studies supported this.5 There are also a number of rare subtypes of osteoarthritis, including familial calcium pyrophosphate deposition disease, Stickler syndrome and some chondrodysplasis, that have a genetic basis and are associated with severe, early onset osteoarthritis. Recently, a clear genetic influence on osteoarthritis was demonstrated in a study of 500 unselected female twins aged 45-70 years who were screened radiologically for osteoarthritis of the hands and knees.6 The correlations of osteoarthritis disease status were consistently twofold higher in 130 pairs of identical compared with 120 non-identical twin pairs. The influence of genetic factors was estimated to be between 35 and 65%, independent of known environmental or demographic confounders. Genetic linkage analysis of large kindred populations has been performed to examine some potential candidate genes in osteoarthritis. Several unrelated families have demonstrated co-inheritance of primary generalised osteoarthritis with specific alleles of the gene for type II procollagen (COL2A1) on chromosome 12.7 This allele has now been cloned and found to be normal except for a single base mutation at position 519 of the ctl (II) chain,8 which was found in all affected members of a family but in none of the unaffected or unrelated individuals. Linkage analysis of several Stickler syndrome kindreds has also demonstrated that this disease is linked to COL2A1 in about 25-50% of families.9 Despite these exciting developments, there is currently little evidence that the common forms of osteoarthritis are due to collagen mutations. The families described earlier are extremely rare and associated with mild chondrodysplasias. A recent study used gene specific highly polymorphic markers and affected sibling pair analyses to investigate genetic linkage between generalised osteoarthritis and three cartilage matrix genes: COL2A1, which encodes type II collagen; CRTL1, which encodes the cartilage link protein; and CRTM, which encodes the cartilage matrix protein.'0 No linkage between generalised osteoarthritis and these genes was shown, suggesting that these genes are not major susceptibility loci for generalised osteoarthritis. A recent study which analysed blood leucocyte DNA to detect mutations in the gene for COL2A1 showed that mutations could be detected in up to 2% of patients with early onset familial osteoarthritis.\" This suggests that only a small proportion of cases of osteoarthritis can be explained by this genetic abnormality. Recently, promising new data has suggested an association between polymorphisms of the vitamin D receptor, which has recently been associated with osteoporosis, and early knee osteoarthritis. 12 As some evidence suggests an inverse association between these two common conditions, it may be that some genes may have a number of effects on bone and cartilage. Primary generalised osteoarthritis is likely to be a heterogeneous disease at the genetic level and mutations in genes other than COL2A1 are likely to be responsible for this phenotype. Yet to be explored is the role of mutations in the genes encoding the minor collagen types (for example, IX, X, XI). For example, transgenic mouse models with a central deletion in the al chain of the type IX collagen gene suggest that this gene may be important as heterozygotes develop osteoarthritis with no signs of chondrodysplasia.13 Also, the role of the other extracellular matrix proteins such as aggrecan, decorin and the link protein will need to be investigated. In summary, genetic factors have a major role in osteoarthritis. This genetic influence has now been estimated to lie between 39 and 65% based on a recent female twin study. The nature of the genetic influence in osteoarthritis is speculative and may involve either a structural defect (that is, collagen) or alterations in cartilage or bone metabolism. Exciting work has identified mutations in type II collagen to be important in some rare, familial forms of osteoarthritis but the genetic basis of the common forms of osteoarthritis is currently unknown. Finding the genes involved is likely to lead to important new therapeutic targets and diagnostic advances in this common, disabling disease.

IgA-associated renal diseases.

Abstract: IgA nephropathy and Schonlein-Henoch purpura nephritis are common renal diseases. Recent studies have provided new insights into the factors that contribute to the initiation and progression of renal injury. Approaches to therapy, although still limited and largely empirical, show some encouraging results.