Showing papers by "St Thomas' Hospital published in 2004"

Female genital mutilation.

Abstract: The purpose of this review is to provide an up to date account of recent papers and attitude on female genital mutilation in the past year. It is aimed at all professionals caring and supporting women/girls with female genital mutilation and to identify gaps. Worldwide there are approximately 13 million refugees and asylum seekers and human rights violations are seen as contributing factors to people fleeing their homeland. In the United States those seeking asylum or refugee status are asked about their life experiences. African women are asked about ritual genital surgery as it may be an indicator of their gynaecological obstetric and sexual health. Health and social care professionals in host countries in Europe Australia Canada the USA and the UK for example are increasingly encountering this vulnerable client group in their practice and are finding that they are ill-prepared to deal with presenting complex health needs and challenges. (excerpt)

Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials

Abstract: This study evaluates the efficacy of capecitabine using data from a large, well-characterised population of patients with metastatic colorectal cancer (mCRC) treated in two identically designed phase III studies. A total of 1207 patients with previously untreated mCRC were randomised to either oral capecitabine (1250 mg m(-2) twice daily, days 1-14 every 21 days; n=603) or intravenous (i.v.) bolus 5-fluorouracil/leucovorin (5-FU/LV; Mayo Clinic regimen; n=604). Capecitabine demonstrated a statistically significant superior response rate compared with 5-FU/LV (26 vs 17%; P<0.0002). Subgroup analysis demonstrated that capecitabine consistently resulted in superior response rates (P<0.05), even in patient subgroups with poor prognostic indicators. The median time to response and duration of response were similar and time to progression (TTP) was equivalent in the two arms (hazard ratio (HR) 0.997, 95% confidence interval (CI) 0.885-1.123, P=0.95; median 4.6 vs 4.7 months with capecitabine and 5-FU/LV, respectively). Multivariate Cox regression analysis identified younger age, liver metastases, multiple metastases and poor Karnofsky Performance Status as independent prognostic indicators for poor TTP. Overall survival was equivalent in the two arms (HR 0.95, 95% CI 0.84-1.06, P=0.48; median 12.9 vs 12.8 months, respectively). Capecitabine results in superior response rate, equivalent TTP and overall survival, an improved safety profile and improved convenience compared with i.v. 5-FU/LV as first-line treatment for MCRC. For patients in whom fluoropyrimidine monotherapy is indicated, capecitabine should be strongly considered. Following encouraging results from phase I and II trials, randomised trials are evaluating capecitabine in combination with irinotecan, oxaliplatin and radiotherapy. Capecitabine is a suitable replacement for i.v. 5-FU as the backbone of colorectal cancer therapy.

Early response to immunosuppressive therapy predicts good renal outcome in lupus nephritis: Lessons from long-term followup of patients in the Euro-Lupus Nephritis Trial

Abstract: OBJECTIVE: In the Euro-Lupus Nephritis Trial (ELNT), 90 patients with lupus nephritis were randomly assigned to a high-dose intravenous cyclophosphamide (IV CYC) regimen (6 monthly pulses and 2 quarterly pulses with escalating doses) or a low-dose IV CYC regimen (6 pulses of 500 mg given at intervals of 2 weeks), each of which was followed by azathioprine (AZA). After a median followup of 41 months, a difference in efficacy between the 2 regimens was not observed. The present analysis was undertaken to extend the followup and to identify prognostic factors. METHODS: Renal function was prospectively assessed quarterly in all 90 patients except 5 who were lost to followup. Survival curves were derived using the Kaplan-Meier method. RESULTS: After a median followup of 73 months, there was no significant difference in the cumulative probability of end-stage renal disease or doubling of the serum creatinine level in patients who received the low-dose IV CYC regimen versus those who received the high-dose regimen. At long-term followup, 18 patients (8 receiving low-dose and 10 receiving high-dose treatment) had developed permanent renal impairment and were classified as having poor long-term renal outcome. We demonstrated by multivariate analysis that early response to therapy at 6 months (defined as a decrease in serum creatinine level and proteinuria <1 g/24 hours) was the best predictor of good long-term renal outcome. CONCLUSION: Long-term followup of patients from the ELNT confirms that, in lupus nephritis, a remission-inducing regimen of low-dose IV CYC followed by AZA achieves clinical results comparable with those obtained with a high-dose regimen. Early response to therapy is predictive of good long-term renal outcome.

Adverse drug reactions to azathioprine therapy are associated with polymorphism in the gene encoding inosine triphosphate pyrophosphatase (ITPase).

Abstract: Adverse drug reactions to azathioprine (AZA), the pro-drug of 6-mercaptopurine (6-MP), occur in 15% to 28% of patients and the majority are not explained by thiopurine methyltransferase (TPMT) deficiency. Inosine triphosphate pyrophosphatase (ITPase) deficiency results in the benign accumulation of the inosine nucleotide ITP. 6-MP is activated through a 6-thio-IMP intermediate and, in ITPase deficient patients, potentially toxic 6-thio-ITP is predicted to accumulate. The association between polymorphism in the ITPA gene and adverse drug reactions to AZA therapy was studied in patients treated for inflammatory bowel disease. Sixty-two patients with inflammatory bowel disease suffering adverse drug reactions to AZA therapy were genotyped for ITPA 94C>A and IVS2 + 21A>C polymorphisms, and TPMT*3A, *3C, *2 polymorphisms. Genotype frequencies were compared to a consecutive series of 68 controls treated with AZA for a minimum of 3 months without adverse effect. The ITPA 94C>A deficiency-associated allele was significantly associated with adverse drug reactions [odds ratio (OR) 4.2, 95% confidence interval (CI) 1.6-11.5, P = 0.0034]. Significant associations were found for flu-like symptoms (OR 4.7, 95% CI 1.2-18.1, P = 0.0308), rash (OR 10.3, 95% CI 4.7-62.9, P = 0.0213) and pancreatitis (OR 6.2, CI 1.1-32.6, P = 0.0485). Overall, heterozygous TPMT genotypes did not predict adverse drug reactions but were significantly associated with a subgroup of patients experiencing nausea and vomiting as the predominant adverse reaction to AZA therapy (OR 5.5, 95% CI 1.4-21.3, P = 0.0206). Polymorphism in the ITPA gene predicts AZA intolerance. Alternative immunosuppressive drugs, particularly 6-thioguanine, should be considered for AZA-intolerant patients with ITPase deficiency. (C) 2004 Lippincott Williams Wilkins.

Automated detection of diabetic retinopathy in digital retinal images: a tool for diabetic retinopathy screening.

Abstract: Aims To develop a system to detect automatically features of diabetic retinopathy in colour digital retinal images and to evaluate its potential in diabetic retinopathy screening. Methods Macular centred 45° colour retinal images from 1273 patients in an inner city diabetic retinopathy screening programme. A system was used involving pre-processing to standardize colour and enhance contrast, segmentation to reveal possible lesions and classification of lesions using an artificial neural network. The system was trained using a subset of images from 500 patients and evaluated by comparing its performance with a human grader on a test set of images from 773 patients. Results Maximum sensitivity for detection of any retinopathy on a per patient basis was 95.1%, accompanied by specificity of 46.3%. Specificity could be increased as far as 78.9% but was accompanied by a fall in sensitivity to 70.8%. At a setting with 94.8% sensitivity and 52.8% specificity, no cases of sight-threatening retinopathy were missed (retinopathy warranting immediate ophthalmology referral or re-examination sooner than 1 year by National Institute for Clinical Excellence criteria). If the system was implemented at 94.8% sensitivity setting over half the images with no retinopathy would be correctly identified, reducing the need for a human grader to examine images in 1/3 of patients. Conclusion This system could be used when screening for diabetic retinopathy. At 94.8% sensitivity setting the number of normal images requiring examination by a human grader could be halved.

Oxidative Stress and Preeclampsia: Rationale for Antioxidant Clinical Trials

Abstract: Preeclampsia remains a frequent and potentially dangerous complication of pregnancy. The cause remains largely unknown, but oxidative stress and a generalized inflammatory state are features of the maternal syndrome. The placenta appears to be the principal source of free radical synthesis but maternal leukocytes and the maternal endothelium are also likely contributors. Recent reports have suggested an important role for placental trophoblast NAD(P)H oxidase in free radical generation in preeclampsia. The antioxidant vitamin E is now known to have multiple actions in addition to prevention of lipid peroxidation (ie, inhibition of NAD(P)H oxidase activation and the inflammatory response). In view of the abnormally low plasma vitamin C concentrations in preeclampsia, a combination of vitamins C and E is a promising prophylactic strategy for prevention of preeclampsia. Several multicenter randomized clinical trials are now underway. The potential use of antioxidants and the recognized, albeit modest, benefit of low-dose aspirin prophylaxis have heightened the need for a reliable predictive test for preeclampsia. A combination test involving several relevant biomarkers is likely to provide the best predictive potential.

Structural, psychological, and genetic influences on low back and neck pain: a study of adult female twins.

Abstract: Objective To assess genetic and environmental influences on low back and neck pain in a classic twin design and to examine the extent to which these are explained by structural changes seen on magnetic resonance imaging (MRI) and psychological and lifestyle variables. Methods The subjects comprised 1,064 unselected women (181 monozygotic [MZ] and 351 dizygotic [DZ] twin pairs) recruited from a national registry of twin volunteers. Outcome measures included lifetime history of low back and neck pain (using a range of increasingly stringent definitions), MRI scores of disc degeneration in the lumbar and cervical spine, psychological distress as assessed by the General Health Questionnaire (GHQ), and lifestyle variables assessed by questionnaire. Results For all definitions of pain, there was a consistent excess concordance in MZ when compared with DZ twins, equating to a heritability for low back pain in the range of 52–68% and for neck pain in the range of 35–58%. The strongest associations were between low back pain and MRI change (odds ratio [OR] 3.6, 95% confidence interval [95% CI] 1.8–7.3]) and between neck pain and response on the GHQ (OR 3.3, 95% CI 2.1–5.0). These associations were mediated genetically. Conclusions Genetic factors have an important influence on back and neck pain reporting in women. These factors include the genetic determinants of structural disc degeneration and an individual's inherited tendency toward psychological distress. MRI changes are the strongest predictor of low back pain.

Major depression in outpatients attending a regional cancer centre: screening and unmet treatment needs

Abstract: A screening programme designed to identify cases of Major Depressive Disorder (MDD) in patients attending a Regional Cancer Centre outpatient department was established. It comprised two stages: (1) The Hospital Anxiety and Depression Scale (HADS) self-rating questionnaire administered by a touch-screen computer; (2) we interviewed patients with high scores on the HADS (15 or more total score) over the telephone using the depression section of the Structured Clinical Interview for DSMIV (SCID). A large consecutive sample (5613) of oncology clinic attenders was screened, and practical difficulties in the screening process were identified. The estimated prevalence of major depressive disorder (MDD) in the sample surveyed was approximately 8% (7.8%; 95% confidence intervals 6.9-8.5%). We assessed a consecutive series of 150 patients identified as having MDD to determine how many had received evidence-based treatment for MDD. Only half had discussed their low mood with their general practitioner, only one-third had been prescribed any antidepressant medication, and very few had taken a therapeutic dose for an adequate period. Very few had received psychological treatment or had been referred to mental health services. Most were receiving no potentially effective therapy.

EuroSCORE: a systematic review of international performance.

Abstract: The validity of the cardiac surgical scoring system, EuroSCORE, has been assessed by several individual cardiac centres within and outside Europe. We chose to assess the overall international performance by systematic review of peer-reviewed literature. There were six studies meeting our criteria for assessment. Internationally, the evidence is highly suggestive that additive EuroSCORE performance generally over-estimates mortality at lower EuroSCOREs (EuroSCORE 13). The effect of this could have serious misrepresentations for surgeons and hospitals operating on differing case-mixes. We suggest that further studies need to be performed on the logistic EuroSCORE calculation to ascertain whether predictive ability is improved. Overall, however, EuroSCORE is the most rigorously evaluated scoring system in cardiac surgery.

The pivotal role of phosphatidylinositol 3-kinase-Akt signal transduction in virus survival

Abstract: Over the course of evolution, viruses have developed the ability to modulate a variety of host cell signalling pathways Inhibition of apoptosis, in particular, has become recognized as an important contributory factor in virus survival Apoptotic inhibition contributes to the establishment of latent and chronic infections and has been implicated in viral oncogenesis The phosphatidylinositol 3-kinase (PI3K)–Akt pathway is utilized by many cell types for inhibition of apoptosis and cellular survival Virus modulation of this pathway provides an alternative to the expression of viral oncogenes or the direct inhibition of pro-apoptotic proteins It has become evident that many viruses require up-regulation of this pathway to sustain long-term infections and it is modulated, in some cases, by specific viral products to create an environment favourable for cellular transformation In other cases, PI3K–Akt signalling simply helps to create an environment favourable for virus replication and virion assembly This review details the modulation and function of PI3K–Akt signalling for virus survival

Quantitative “magnetic resonance immunohistochemistry” with ligand‐targeted 19F nanoparticles

Abstract: Unstable atherosclerotic plaques exhibit microdeposits of fibrin that may indicate the potential for a future rupture. However, current methods for evaluating the stage of an atherosclerotic lesion only involve characterizing the level of vessel stenosis, without delineating which lesions are beginning to rupture. Previous work has shown that fibrin-targeted, liquid perfluorocarbon nanoparticles, which carry a high payload of gadolinium, have a high sensitivity and specificity for detecting fibrin with clinical (1)H MRI. In this work, the perfluorocarbon content of the targeted nanoparticles is exploited for the purposes of (19)F imaging and spectroscopy to demonstrate a method for quantifiable molecular imaging of fibrin in vitro at 4.7 T. Additionally, the quantity of bound nanoparticles formulated with different perfluorocarbon species was calculated using spectroscopy. Results indicate that the high degree of nanoparticle binding to fibrin clots and the lack of background (19)F signal allow accurate quantification using spectroscopy at 4.7 T, as corroborated with proton relaxation rate measurements at 1.5 T and trace element (gadolinium) analysis. Finally, the extension of these techniques to a clinically relevant application, the evaluation of the fibrin burden within an ex vivo human carotid endarterectomy sample, demonstrates the potential use of these particles for uniquely identifying unstable atherosclerotic lesions in vivo.

A Susceptibility Locus for Myopia in the Normal Population Is Linked to the PAX6 Gene Region on Chromosome 11: A Genomewide Scan of Dizygotic Twins

Abstract: Myopia is a common, complex trait with considerable economic and social impact and, in highly affected individuals, ocular morbidity. We performed a classic twin study of 506 unselected twin pairs and inferred the heritability of refractive error to be 0.89 (95% confidence interval 0.86–0.91). A genomewide scan of 221 dizygotic twin pairs, analyzed by use of optimal Haseman-Elston regression methods implemented by use of generalized linear modeling, showed significant linkage (LOD >3.2) to refractive error at four loci, with a maximum LOD score of 6.1 at 40 cM on chromome 11p13. Evidence of linkage at this locus, as well as at the other linkage peaks at chromosomes 3q26 (LOD 3.7), 8p23 (LOD 4.1), and 4q12 (LOD 3.3), remained the same or became stronger after model fit was checked and outliers were downweighted. Examination of potential candidate genes showed the PAX6 gene directly below the highest peak at the 11p13 locus. PAX6 is fundamental to identity and growth of the eye, but reported mutations usually result in catastrophic congenital phenotypes such as aniridia. Haplotype tagging of 17 single-nucleotide polymorphisms (SNPs), which covered the PAX6 gene and had common minor allele frequencies, identified 5 SNPs that explained 0.999 of the haplotype diversity. Linkage and association analysis of the tagging SNPs showed strong evidence of linkage for all markers with a minimum χ21 of 7.5 (P=.006) but no association. This suggests that PAX6 may play a role in myopia development, possibly because of genetic variation in an upstream promoter or regulator, although no definite association between PAX6 common variants and myopia was demonstrated in this study.

Quality of life and disease severity are correlated in children with atopic dermatitis.

Abstract: Summary Background Atopic dermatitis (AD) in children may affect their daily activities and normal development. It can have a negative impact on the child's behaviour. Little is known about the quality of life (QOL) in children and its relationship to disease severity, especially from a community-based study. Objectives To document the impact of AD on children's QOL and its relationship to disease severity. Methods The targeted population, before recruitment, comprised children with AD aged 5–10 years from a primary care setting. Their general practitioners identified potential patients and the U.K. diagnostic criteria for AD were used to verify the diagnosis. Eczema severity was assessed using the SCORAD (SCORing Atopic Dermatitis) index. The Children's Dermatology Life Quality Index (CDLQI) was used to quantify the impact of AD on children's QOL. These two parameters were evaluated on two occasions 6 months apart. The Spearman correlation coefficient and multiple regressions were used in statistical analysis. Results Of the 116 children attending the first QOL assessment visit, 78 (mean age 8·6 years, 44 girls and 34 boys) were able to complete the CDLQI. Of these 78 children, 71 (91%) attended the second visit, and were included in the analysis. The children's QOL was affected in 65 (92%) and 55 (77%) children attending the first and second visits, respectively. The CDLQI was significantly correlated with the SCORAD at the first and second visits (r = 0·52, P < 0·001 and r = 0·59, P < 0·001, respectively). Each unit change in the SCORAD was associated with a 0·12 (95% confidence interval 0·04–0·19, P = 0·004) unit change in the children's QOL. Conclusions We have shown a positive correlation between children's QOL and disease severity on cross-sectional and over time observation. This highlights the impact of AD on children's life. It also draws attention to the long-term effect on children's behaviour and development. In addition, these findings may imply that the CDLQI could be used as an extra measure of disease assessment in clinical practice and research studies.

Association study of candidate genes for the prevalence and progression of knee osteoarthritis.

Abstract: Objective Osteoarthritis (OA), characterized by late-onset degeneration of articular cartilage, is recognized to have a genetic component. We examined the role of 26 single-nucleotide polymorphisms (SNPs) from 24 candidate genes in OA susceptibility and progression. Methods We compared human complementary DNA libraries from OA-affected and normal cartilage and synovium and selected 22 genes in addition to the estrogen receptor α and vitamin D receptor genes. Based on the availability of polymorphisms, we proceeded to test whether genetic variation at those genes affected susceptibility to or progression of radiographic knee OA over a 10-year period in 749 women (mean age 64 years) from the longitudinal Chingford Study. Results After adjusting for age and body mass index, we observed significant associations at ADAM12, BMP2, CD36, COX2, and NCOR2 with 3 OA susceptibility traits (presence/absence of joint space narrowing [JSN], presence/absence of osteophytes, and Kellgren/Lawrence [K/L] score). For the OA progression traits (change over 10 years in the K/L score, osteophyte grade, and JSN grade), we found significant associations with ADAM12, CILP, OPG, and TNA. Overall, we observed 15 associations with nominal significance (P < 0.05) and, by permutation analysis, found that such a number would be observed by chance only 3.8% of the time. Although these tests require replication, the stronger genetic associations observed are unlikely to be attributable simply to multiple comparisons. Conclusion Our results suggest that OA severity and progression have a multigenic and feature-specific nature. These findings should encourage the development of genetic diagnostics for OA progression based on multiple SNPs and help unravel some of the complex disease mechanisms in OA.

Anti-C1q antibodies in nephritis: correlation between titres and renal disease activity and positive predictive value in systemic lupus erythematosus

Abstract: Objective: To investigate antibodies to complement 1q (anti-C1q) and investigate the correlation between anti-C1q titres and renal disease in systemic lupus erythematosus (SLE). Methods: 151 SLE patients were studied. In patients with biopsy proven lupus nephritis (n = 77), activity of renal disease was categorised according to the BILAG renal score. Sera were tested for anti-C1q by enzyme immunoassay. Serum samples were randomly selected from 83 SLE patients who had no history of renal disease, and the positive and negative predictive value of the antibodies was studied. Results: Patients with active lupus nephritis (BILAG A or B) had a higher prevalence of anti-C1q than those with no renal disease (74% v 32%; relative risk (RR) = 2.3 (95% confidence interval, 1.6 to 3.3)) (p<0.0001). There was no significant difference in anti-C1q prevalence between SLE without nephritis and SLE with non-active nephritis (BILAG C or D) (32% v 53%, p = 0.06) or between active and non-active nephritis (74% v 53%, p = 0.06). Patients with nephritis had higher anti-C1q levels than those without nephritis (36.0 U/ml (range 4.9 to 401.0) v 7.3 U/ml (4.9 to 401.0)) (p<0.001). Anti-C1q were found in 33 of 83 patients (39%) without history of renal disease. Nine of the 33 patients with anti-C1q developed lupus nephritis. The median renal disease-free interval was nine months. One patient with positive anti-C1q was diagnosed as having hypocomplementaemic urticarial vasculitis syndrome during follow up. Conclusions: Anti-C1q in SLE are associated with renal involvement. Monitoring anti-C1q and their titres in SLE patients could be important for predicting renal flares.

Genetic effects on baseline values of C-reactive protein and serum amyloid a protein: a comparison of monozygotic and dizygotic twins

Abstract: Background: C-Reactive protein (CRP) and serum amyloid A protein (SAA) are exquisitely sensitive acute-phase reactants, but their baseline values are surprisingly constant in individuals in the general population These values, especially of CRP, are associated with future atherothrombotic events, and the determinants of baseline CRP and SAA concentration are therefore of considerable interest Methods: CRP and SAA concentrations were measured by well-validated automated microparticle capture enzyme immunoassays, standardized on the respective WHO International Reference Standards, in serum from 146 monozygotic and 164 dizygotic healthy female UK twin pairs from the general population, with mean (range) ages of 580 (40–696) and 557 (40–703) years, respectively, who were also very closely matched for height, weight, body mass index, blood pressure, and lifestyle variables Statistical modeling based on variance components analysis was used to estimate the genetic contribution to the observed values Results: As reported previously, CRP values were associated with body mass index, smoking, and hormone replacement therapy After exclusion of the few samples with CRP concentrations >10 mg/L, which indicate an ongoing acute-phase response rather than baseline values, and inclusion of adjustments for all known confounding variables, there was significantly higher correlation of CRP and SAA results among monozygotic than among dizygotic twins The estimated hereditability (95% confidence interval) of baseline values was 52% (40–62%) for CRP and 59% (49–67%) for SAA Conclusion: There is a substantial genetic contribution to baseline serum concentrations of CRP and SAA

Circulating Humoral Factors and Endothelial Progenitor Cells in Patients With Differing Coronary Collateral Support

Abstract: Background—The mechanisms underlying the variation in collateral formation between patients, even with similar patterns of coronary artery disease, remain unclear. This study investigates whether circulating humoral or cellular factors can provide an insight into this variation. Methods and Results—Thirty patients with isolated left anterior descending coronary artery disease underwent percutaneous coronary intervention with collateral flow index (CFI) determined using a pressure wire. Patients with inadequate (CFI 0.25) compared with those with adequate (CFI0.25) collateral support had, or tended to have, lower concentrations of coronary sinus growth factors and plasma exerting a weaker effect on endothelial cell migration and angiogenesis in vitro. However, there was an inverse correlation between serum mitogenicity and CFI (r0.61, P0.01). No significant differences were detected between the 2 groups in plasma levels of total vascular endothelial growth factor, vascular endothelial growth factor 165, or placental growth factor. There was a strong positive correlation between numbers of CD34/CD133-positive circulating hemopoietic precursor cells and CFI (r0.75, P0.001). In patients with inadequate, compared with those with adequate, CFI, the numbers of differentiated endothelial progenitor cells (EPCs) appearing in the circulation and in culture were significantly reduced by 75% (P0.05) and 70% (P0.05), respectively. Conclusions—In this study, inadequate coronary collateral development is associated with reduced numbers of circulating EPCs and impaired chemotactic and proangiogenic but not mitogenic activity. These findings are consistent with current efforts to enhance collateral formation by augmentation of circulating EPCs. (Circulation. 2004;109:2986-2992.)

Dietary sources of inorganic microparticles and their intake in healthy subjects and patients with Crohn's disease.

Abstract: Dietary microparticles are non-biological, bacterial-sized particles. Endogenous sources are derived from intestinal Ca and phosphate secretion. Exogenous sources are mainly titanium dioxide (TiO2) and mixed silicates (Psil); they are resistant to degradation and accumulate in human Peyer's patch macrophages and there is some evidence that they exacerbate inflammation in Crohn's disease (CD). However, whether their intake differs between those with and without CD has not been studied. We aimed to identify dietary microparticle sources and intakes in subjects with and without CD. Patients with inactive CD and matched general practice-based controls (ninety-one per group) completed 7 d food diaries. Intake data for dietary fibre and sucrose were compared as positive controls. All foods, pharmaceuticals and toothpastes were examined for microparticle content, and intakes of Ca and exogenous microparticles were compared between the two groups. Dietary intakes were significantly different between cases and controls for dietary fibre (12 (SD 5) v. 14 (SD 5) g/d; P=0.001) and sucrose (52 (SD 27) v. 45 (SD 18) g/d; P=0.04) but not for Ca. Estimated median TiO2 and Psil intakes (2.5 and 35 mg/individual per d respectively, totalling 10(12)-10(13) microparticles/individual per d) were broadly similar to per capita estimates and while there was wide variation in intakes between individuals there was no significant difference between subjects with CD and controls. Hence, if exposure to microparticles is associated with the inflammation of CD, then the present study rules out excess intake as the problem. Nonetheless, microparticle-containing foods have now been identified which allows a low-microparticle diet to be further assessed in CD.

Strategies for the rapid prenatal diagnosis of chromosome aneuploidy.

Abstract: Rapid diagnosis of common chromosome aneuploidies in raised risk pregnancies, usually prior to full karyotype analysis, is now carried out in a number of European genetic centres; several techniques for detecting genomic copy number changes have been described. Prenatal diagnosis of genetic disease requires accurate and robust assays; the invasive procedures are associated with a risk of pregnancy loss and an abnormal result may lead to termination of the pregnancy. The testing of prenatal material (amniotic fluid, chorionic villi or, more rarely, fetal blood) is associated with specific problems, including the quality and quantity of the tissue and difficulties of interpretation due to phenomena such as maternal cell contamination and mosaicism. In addition, there are 24-h, high-throughput demands on centres offering such a service. The extent to which existing and proposed strategies, including different PCR-based assays, a multiplex ligation-dependent probe amplification approach, and microarrays, fulfil the requirements of rapid prenatal testing is discussed. In the past 3 years, we have tested 7720 prenatal samples for trisomies 13, 18 and 21 using a quantitative fluorescence-PCR (QF-PCR) approach. The abnormality rate was 5.7%. There were no misdiagnoses for nonmosaic trisomy, the amplification failure rate was 0.09% of samples, and 97% of samples received a report on the working day following sample receipt. Maternal cell contamination and mosaicism were also detected. Our data recommend a QF-PCR approach as the current method of choice for rapid aneuploidy testing.

Non-contact left ventricular endocardial mapping in cardiac resynchronisation therapy

Abstract: Background: Up to 30% of patients with heart failure do not respond to cardiac resynchronisation therapy (CRT). This may reflect placement of the coronary sinus lead in regions of slow conduction despite optimal positioning on current criteria. Objectives: To characterise the effect of CRT on left ventricular activation using non-contact mapping and to examine the electrophysiological factors influencing optimal left ventricular lead placement. Methods and results: 10 patients implanted with biventricular pacemakers were studied. In six, the coronary sinus lead was found to be positioned in a region of slow conduction with an average conduction velocity of 0.4 m/s, v 1.8 m/s in normal regions (p < 0.02). Biventricular pacing with the left ventricle paced 32 ms before the right induced the optimal mean velocity time integral and timing for fusion of depolarisation wavefronts from the right and left ventricular pacing sites. Pacing outside regions of slow conduction decreased left ventricular activation time and increased cardiac output and dP/dtmax significantly. Conclusions: In patients undergoing CRT for heart failure, non-contact mapping can identify regions of slow conduction. Significant haemodynamic improvements can occur when the site of left ventricular pacing is outside these slow conduction areas. Failure of CRT to produce clinical benefits may reflect left ventricular lead placement in regions of slow conduction which can be overcome by pacing in more normally activating regions.

The genetic epidemiology of joint hypermobility: a population study of female twins.

Abstract: Objective To estimate the genetic influence on joint hypermobility in an unselected population using a classic twin study design. Methods A self-report questionnaire on joint hypermobility as well as data on age, height, weight, estrogen replacement therapy, and menopause status were obtained from 483 monozygotic (MZ) and 472 dizygotic (DZ) unselected female twin pairs ages 21–81 years who were registered with the St Thomas' Adult Twin Registry in the UK. Results The overall prevalence of hypermobility was 19.5% in MZ twins and 22.1% in DZ twins. The prevalence of hypermobile joints declined with age, falling from 34% in subjects ages 20–30 years to 18.4% in those ages 60 years or older. Significantly greater concordance for joint hypermobility was observed in the MZ twins when compared with the DZ twins (60% versus 36%), consistent with a genetic influence. In variance components analysis, the age- and body mass index–adjusted heritability of joint hypermobility was estimated to be 70% (95% confidence interval 57–89%). Conclusion Genetic factors have a substantial contribution to joint hypermobility in the adult female population.