Changes in stool frequency following chicory inulin consumption, and effects on stool consistency, quality of life and composition of gut microbiota.

Inulin is a soluble dietary fibre, also classified as a prebiotic, extracted from chicory roots. The present study aimed to determine the effect of consumption of native chicory inulin on the stool frequency of middle-aged to older adults (40-75 years old) with uncomfortably but not clinically relevant low stool frequency, specified as two to four days without bowel movements per week. Two randomised, double blind, placebo-controlled crossover trials were conducted using similar protocols in differing populations. Trial A was conducted in Amsterdam, The Netherlands and subsequently Trial B was conducted in Newcastle, United Kingdom. Both trials involved supplementation for 5 weeks with 10 g per day of inulin or placebo, a washout period of 2 weeks, and then crossed over to receive the other treatment. In Trial B, faecal gut microbiota composition was assessed using 16S rRNA gene sequencing. In Trial A, which 10 volunteers completed, the stool frequency was significantly increased to an average 4.9 ±â€¯0.23 (SEM) times per week during inulin periods versus 3.6 ±â€¯0.25 in the periods with placebo (p = 0.01). In contrast, in Trial B which 20 volunteers completed, there was no significant effect of the inulin on stool frequency (7.5 ±â€¯2.1 times per week with inulin, 8.1 ±â€¯3.0 with placebo, p = 0.35). However, many subjects in Trial B had a stool frequency >5 per week also for the placebo period, in breach of the inclusion criteria. Combining the data of 16 low stool frequency subjects from Trials A and B showed a significant effect of inulin to increase stool frequency from 4.1 to 5.0 per week (p = 0.032). Regarding secondary outcomes, stool consistency was significantly softer with inulin treatment compared to placebo periods, it increased 0.29 on the Bristol stool scale (p = 0.008) when data from all subjects of Trials A and B were combined. No other differences in bowel habit parameters due to inulin consumption were significant. None of the differences in specific bacterial abundance, alpha or beta diversity were significant, however the trends were in directions consistent with published studies on other types of inulin. We conclude that 10 g per day of native chicory inulin can increase stool frequency in subjects with low stool frequency.

Assessment of the efficacy of a novel tailored vitamin K dosing regimen in lowering the International Normalised Ratio in over-anticoagulated patients: a randomised clinical trial.

Current guidelines advocate using fixed-doses of oral vitamin K to reverse excessive anticoagulation in warfarinised patients who are either asymptomatic or have minor bleeds. Over-anticoagulated patients present with a wide range of International Normalised Ratio (INR) values and response to fixed doses of vitamin K varies. Consequently a significant proportion of patients remain outside their target INR after vitamin K administration, making them prone to either haemorrhage or thromboembolism. We compared the performance of a novel tailored vitamin K dosing regimen to that of a fixed-dose regimen with the primary measure being the proportion of over-anticoagulated patients returning to their target INR within 24 h. One hundred and eighty-one patients with an index INR > 6·0 (asymptomatic or with minor bleeding) were randomly allocated to receive oral administration of either a tailored dose (based upon index INR and body surface area) or a fixed-dose (1 or 2 mg) of vitamin K. A greater proportion of patients treated with the tailored dose returned to within target INR range compared to the fixed-dose regimen (68·9% vs. 52·8%; P = 0·026), whilst a smaller proportion of patients remained above target INR range (12·2% vs. 34·0%; P < 0·001). Individualised vitamin K dosing is more accurate than fixed-dose regimen in lowering INR to within target range in excessively anticoagulated patients.

Association between CYP4F2 genotype and circulating plasma vitamin K concentration in children on chronic warfarin therapy: Possible long-term implications for bone development and vascular health.

Vitamin K is essential, for the activation of clotting proteins, as well as the biosynthesis of osteocalcin in bones and the activation of matrix-Gla protein needed in maintaining vasculature health. Cytochrome p450 4F2 (CYP4F2) enzyme is involved in vitamin K catabolism. Genetic polymorphism in CYP4F2 is thus likely to affect vitamin K systemic availability. We show that children on chronic warfarin therapy have low levels of vitamin K and vitamin K levels are linked to CYP4F2 genotype. Long-term low levels of vitamin K, influenced by CYP4F2 genotype, might affect bone development and vascular health in children on chronic warfarin therapy.

Vitreoretinal interface abnormalities in patients treatedwith ranibizumab for diabetic macular oedema.

PURPOSE: Intravitreal anti-vascular endothelial growth factor (VEGF) agents are effective in the treatment of central involving diabetic macular oedema (DMO). Vitreoretinal interface abnormalities (VRIA) are common in patients with DMO, and the effect of these on the response to anti-VEGF treatment is unclear. Furthermore the effect of anti-VEGF agents on the VRIA itself is uncertain. METHOD: Prospective study of consecutive patients treated with ranibizumab (RZB) for DMO as part of routine clinical care in one eye unit over a 1-year period. Visual acuity (Va), central retinal thickness (CRT) and injection frequency data was recorded on an electronic database. Treatment was initiated with four monthly RZB injections and then a monthly PRN regime. All patients underwent high-density spectral-domain optical coherence tomography (SDOCT) at baseline and 12 months. The SDOCTs were graded by two observers masked to the outcome. RESULTS: One hundred and four eyes (77 patients) were included in the analysis. The mean age was 62 years, and 62% were male. The mean presenting vision was 62 letters and CRT 472 µm. Eighty eyes retained stable Va, and 17 had an improvement in Va. At baseline, 39 eyes had associated focal vitreomacular adhesion (VMA) and by 12 months this reduced to 30 (p = 0.04), with 12 releasing VMA and three developing it. Patients with VMA had significantly better final Va than those without VMA. Improvement in CRT was greatest in those where VMA released during the study. Forty-five eyes had some degree of foveal involving epiretinal membrane (ERM) at baseline, and 28 were considered to have clinically significant ERM. There was no clinically relevant change in ERM during the study. Patients with significant ERM at baseline had a lower final vision. Multivariate analysis showed that ERM and more severe retinopathy at baseline were predictive of less visual improvement (p < 0.01). Shorter intraretinal cyst length, ERM and the absence of VMA at baseline were predictive of a worsened anatomical response (p < 0.001). CONCLUSION: VRIA are related to outcome in patients treated with RZB. ERM was associated with a worsened visual and anatomic response, and VMA with an improved anatomical response particularly when spontaneous VMA release occurred during treatment. The presence and severity of ERM was not affected by RZB treatment.

VKORC1 and CYP2C9 genotype and patient characteristics explain a large proportion of the variability in warfarin dose requirement among children.

Although genetic and environmental factors explain approximately half of the interindividual variability in warfarin dose requirement in adults, there is limited information available in children. In a cross-sectional study of anticoagulated children from 5 tertiary care centers, 120 children with a stable warfarin dose were genotyped for VKORC1 (-1639G > A; rs9923231), CYP2C9 (*2 and *3 alleles; rs1799853 and rs1057910), and CYP4F2 (V433M; rs2108622) polymorphisms. Clinical and demographic features were recorded. Multiple regression analysis of the data showed that, although CYP4F2 made no contribution to the dose model, 72.4% of the variability in warfarin dose requirement is attributed to by patient height, genetic polymorphisms in VKORC1 and CYP2C9, and indication for warfarin. The recently published International Warfarin Pharmacogenetics Consortium pharmacogenetic-based warfarin dosing algorithm (based on data derived from anticoagulated adults) consistently overestimated warfarin dose for our cohort of children. A similar proportion of the interindividual variability in warfarin dose is explained by genetic factors in children compared with adult patients, although height is a greater predictor in children. A pharmacogenomic approach to warfarin dosing has the potential to improve the efficacy and safety of warfarin therapy in children. However, algorithms should be derived from data in children if their potential benefit is to be realized.

Early PROMs following total knee arthroplasty--functional outcome dependent on patella resurfacing.

Patella resurfacing during primary total knee arthroplasty (TKA) remains controversial. Variation in published results for patella resurfacing may potentially be explained by differences in design between TKA brands. We interrogated NJR-PROMs data to ascertain whether there is an early functional benefit to resurfacing the patella, both overall and for each of the five most popular primary knee designs through use of the Oxford Knee Score. A total of 8103 resurfaced TKAs and 15,290 nonresurfaced TKAs were studied. There was a large variation in the proportion of knees undergoing patella resurfacing by brand (Nexgen=16% versus Triathlon=52%). Patellar resurfacing did not significantly influence the magnitude of improvement in overall knee function or anterior knee-specific function irrespective of TKA brand or for cruciate retaining versus sacrificing designs.

English Premiership Academy knee injuries: lessons from a 5 year study.

This study addresses the epidemiology of knee injuries in adolescent males. Data were collected prospectively from 41 Premiership soccer academies over a 5 year period from July 2000 to June 2005. A total of 12,306 player seasons were registered in the U9 to the U16 age categories with a total of 1750 recordable injuries specific to the knee joint. There was a mean incidence of 0.71 (95% confidence interval ± 0.05) knee injuries per player per year, and a median of 17 (inter-quartile range 9-38) training days and 2 (inter-quartile range 1-4) matches missed per knee injury. Knee injuries were found to be most common in the 14-16 year age group. Six hundred and nine (35% of total) injuries were classed as severe resulting in more than 28 days' absence. Injuries were more likely to be sustained in a competitive or match-play environment (862 or 52%) than in training (796 or 48%), and a non-contact mechanism was implicated in 823 (55%) of recorded cases. Peaks in injury numbers were seen in early season and subsequent to the winter break. Sprain was the most common diagnosis recorded, with the medial collateral ligament affected in 23% of all knee injuries. Knee injuries are common in elite youth footballers. In this uninsured age group, it could be argued that earlier medical intervention may reduce long-term damage to the immature skeleton.

STK39 polymorphisms and blood pressure: an association study in British Caucasians and assessment of cis-acting influences on gene expression.

BACKGROUND: Blood pressure (BP) has significant heritability, but the genes responsible remain largely unknown. Single nucleotide polymorphisms (SNPs) at the STK39 locus were recently associated with hypertension by genome-wide association in an Amish population; in vitro data from transient transfection experiments using reporter constructs suggested that altered STK39 expression might mediate the effect. However, other large studies have not implicated STK39 in hypertension. We determined whether reported SNPs influenced STK39 expression in vivo, or were associated with BP in a large British Caucasian cohort. METHODS: 1372 members of 247 Caucasian families ascertained through a hypertensive proband were genotyped for reported risk variants in STK39 (rs6749447, rs3754777, rs35929607) using Sequenom technology. MERLIN software was used for family-based association testing. Cis-acting influences on expression were assessed in vivo using allelic expression ratios in cDNA from peripheral blood cells in 35 South African individuals heterozygous for a transcribed SNP in STK39 (rs1061471) and quantified by mass spectrometry (Sequenom). RESULTS: No significant association was seen between the SNPs tested and systolic or diastolic BP in clinic or ambulatory measurements (all p > 0.05). The tested SNPs were all associated with allelic expression differences in peripheral blood cells (p < 0.05), with the most significant association for the intronic SNP rs6749447 (P = 9.9 x 10-4). In individuals who were heterozygous for this SNP, on average the G allele showed 13% overexpression compared to the T allele. CONCLUSIONS: STK39 expression is modified by polymorphisms acting in cis and the typed SNPs are associated with allelic expression of this gene, but there is no evidence for an association with BP in a British Caucasian cohort.

The C-532T polymorphism of the angiotensinogen gene is associated with pulse pressure: a possible explanation for heterogeneity in genetic association studies of AGT and hypertension.

BACKGROUND: Many previous studies have investigated whether there is an association between genotypes at the angiotensinogen (AGT) gene and hypertensive status, but few have incorporated quantitative data. Although meta-analyses support a possible effect of AGT variants on blood pressure (BP), substantial unexplained between-study heterogeneity has been observed. We hypothesized that a primary effect of AGT variants on arterial stiffness (and thus pulse pressure) might explain such heterogeneity, and tested for such an effect in a family study. METHODS: We studied 1425 individuals from 248 families ascertained through a proband with essential hypertension. BP was measured using 24 h ambulatory monitoring, and polymorphisms of the AGT gene that had been previously associated with hypertension and/or plasma angiotensinogen levels were typed. Pulse pressure was used as a measurement of arterial stiffness. RESULTS: We observed a highly significant association between genotypes at the AGT C-532T polymorphism and pulse pressure (p = 0.00006). Each T allele was associated with a 5% lower pulse pressure (that is, an additive effect). This resulted from opposing genotypic effects to (slightly) lower systolic BP and (slightly) elevate DBP. CONCLUSIONS: These results suggest that genetic variation at the angiotensinogen locus may primarily affect arterial stiffness, and therefore pulse pressure. The heterogeneity between previous genetic studies of AGT and hypertension status could in part be explained by this finding, since case selection criteria based on systolic BP, diastolic BP, or both would result in different levels of selection for the -532T allele.

The relationship between a dissociated optic nerve fibre layer appearance after macular hole surgery and Muller cell debris on peeled internal limiting membrane.

PURPOSE: A dissociated optic nerve fibre layer (DONFL) is a characteristic change noted in inner retinal morphology after internal limiting membrane (ILM) peeling. It is thought to be due to trauma to Muller cells as the ILM is peeled from their attached end plates. In this study, we aimed to determine the extent and size of Muller cell debris on the retinal side of excised ILM and assess whether this correlated with the extent of DONFL observed postoperatively. METHOD: Prospective single centre study of a consecutive series of patients undergoing macular hole surgery. Transmission electron microscopy of the ILM was used to assess Muller cell debris and postoperative spectral domain optical coherence tomography (SD-OCT) to assess the extent of DONFL. A variety of other pre- and postoperative features was also included. RESULTS: Thirty-nine patients were analysed. There were retinal dimples characteristic of DONFL detected on SD-OCT in all 39 eyes. The portion of the retinal side of the ILM specimen covered by cellular debris ranged from 12% to 49%, with a median of 28%. Using linear regression, the percentage of retinal debris, the size of the debris and the postoperative visual acuity were significantly positively associated with the DONFL score. The total R squared for the model was 63.9%. CONCLUSION: The extent of DONFL observed postoperatively can be partly explained by the amount of retinal side cellular debris on the retinal side of the peeled ILM. Surgical strategies which minimize this material could reduce the extent of DONFL.

Association between aldosterone production and variation in the 11beta-hydroxylase (CYP11B1) gene.

CONTEXT: Variation in the region of chromosome 8 including the genes steroid 11beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) influences mineralocorticoid and glucocorticoid metabolism. However, the relative importance of polymorphisms in CYP11B1 and CYP11B2 in determining these phenotypes is unknown. OBJECTIVE: Our objective was to investigate genetic influences of the CYP11B1 and CYP11B2 genes on mineralocorticoid metabolism. DESIGN: We measured 24-h urinary excretion of the key metabolites of the principal mineralocorticoids, glucocorticoids and androgens secreted by the adrenal cortex. We genotyped polymorphisms spanning the CYP11B1 and CYP11B2 genes, which together capture all common variations at the locus. PARTICIPANTS: Participants included 573 members of 105 British Caucasian families ascertained on a hypertensive proband. MAIN OUTCOME MEASURES: We assessed heritability of urinary tetrahydroaldosterone (THAldo) excretion and association of THAldo excretion with genotype. RESULTS: The heritability of THAldo excretion was 52% (P < 10(-6)). There was significant association between THAldo and genotype at several of the CYP11B1/B2 polymorphisms. The strongest association was observed at the rs6387 (2803A/G) polymorphism in intron 3 of CYP11B1 (P = 0.0004). Association followed a codominant model with a 21% higher THAldo excretion per G allele. Genotype at rs6387 accounted for 2.1% of the total population variability of THAldo. We found significant association between THAldo excretion and urinary total androgen excretion, urinary tetrahydrodeoxycortisol level, and urinary cortisol metabolites (all P < 0.001). CONCLUSIONS: Aldosterone synthesis is highly heritable and is affected by genotype at CYP11B1. Our findings support the hypothesis that genetically determined differences in 11-hydroxylation efficiency can have downstream effects on mineralocorticoid synthesis. Such effects may be of relevance to the development of low-renin essential hypertension.

Association between common polymorphisms of the proopiomelanocortin gene and body fat distribution: a family study.

Rare mutations in the proopiomelanocortin (POMC) gene cause severe early-onset childhood obesity. However, it is unknown whether common variants in POMC are responsible for variation in body weight or fat distribution within the commonly observed range in the population. We tested for association between three polymorphisms spanning the POMC gene and obesity phenotypes in 1,428 members of 248 families. There was significant association between genotypes at the C8246T (P < 0.0001) and C1032G (P = 0.003) polymorphisms and waist-to-hip ratio (WHR) corrected for age, sex, smoking, exercise, and alcohol consumption. Each T allele at C8246T (or G allele at C1032G) was associated with a 0.2-SD-higher WHR in a codominant fashion. When WHR was additionally corrected for BMI, thus providing a measure of body fat distribution throughout the range of BMI, there remained significant evidence for association with both markers that was of similar magnitude and statistical significance. There was no association between genotype at any polymorphism and BMI or plasma leptin level. These data show that genetic variants at the POMC locus influence body fat distribution within the normal range, suggesting a novel role for POMC in metabolic regulation.

INSIG-2 promoter polymorphism and obesity related phenotypes: association study in 1428 members of 248 families.

BACKGROUND: Obesity is a major public health problem. Body mass index (BMI) is a highly heritable phenotype but robust associations of genetic polymorphisms to BMI or other obesity-related phenotypes have been difficult to establish. Recently a large genetic association study showed evidence for association of the single nucleotide polymorphism (SNP) rs7566605, which lies 10 Kb 5' to the first exon of the insulin-induced gene 2 (INSIG-2), with obesity in several cohorts. We tested this polymorphism for association with body mass related phenotypes in a large family study whose mean BMI was consistent with moderate overweight. METHODS: We studied 1428 members of 248 British Caucasian families who had been ascertained through a proband with hypertension. We measured BMI, waist and hip circumference, and plasma levels of leptin. We genotyped the rs7566605 SNP using a restriction fragment length polymorphism assay, and carried out a family-based association test for quantitative traits related to obesity using the statistical programs MERLIN and QTDT. RESULTS: We observed no significant association between genotype at rs7566605 and covariate-adjusted (for age, sex, alcohol consumption, smoking and exercise habit) log-transformed BMI, waist measurement, hip measurement, waist-to-hip ratio, or plasma levels of leptin. CONCLUSION: There was no association between genotype at rs7566605 and obesity-related phenotypes in this British Caucasian population. These families were in general moderately overweight, few members being severely obese. Our result indicates that this polymorphism has little if any effect on BMI within the normal to moderately overweight range. The effects of this polymorphism on body mass may be restricted to those already predisposed to at least moderate obesity as a result of environmental factors and other predisposing genotypes.

Genotype at the -174G/C polymorphism of the interleukin-6 gene is associated with common carotid artery intimal-medial thickness: family study and meta-analysis.

BACKGROUND AND PURPOSE: Studies in unrelated individuals have produced conflicting findings concerning the putative association between the interleukin-6 (IL-6) -174G/C polymorphism and carotid intimal-medial thickness (IMT). We have used a family-based genetic association design to assess the heritability of carotid IMT and to investigate the hypothesized association of carotid IMT with the IL-6 to -174G/C polymorphism. METHODS: We studied 854 members of 224 white British families. The heritability of carotid IMT was determined using Multipoint Engine for Rapid Likelihood Inference. Genetic association analyses were carried out using ANOVA and family-based tests of association implemented in Quantitative Transmission Disequilibrium Test. A meta-analysis of previous studies of the association was conducted to place our result in context. RESULTS: The heritability of carotid IMT was 24%. Under a recessive model (GG+GC versus CC), there was significant evidence of association between IL-6 to the -174G/C genotype and adjusted log(e) maximal carotid IMT (F=5.469; P=0.02). Family-based analyses using Quantitative Transmission Disequilibrium Test showed no evidence of population stratification as a cause of the observed association (chi2(1)=0.469; P=0.4934). The CC genotype was associated with a 4.8% increase in maximal carotid IMT and accounted for 0.6% of the observed variation in the trait, which is equivalent to 2.5% of the heritable component. A meta-analysis of the present and 2 previous large studies, which enrolled a total of 2930 subjects, confirmed the recessive effect of the C allele on carotid IMT (P=0.0014). CONCLUSIONS: The genotype at the IL-6 to -174G/C polymorphism is associated with common carotid artery IMT, although the size of the genetic effect is small.

Does the timing of presentation of neck of femur fractures affect the outcome of surgical intervention.

OBJECTIVES: There is growing emphasis on minimizing surgical delay for neck of femur fractures. Surgery within 36 h of diagnosis by the emergency department (ED) is classed as a key performance indicator. We aimed to determine the influence of the effect of time of presentation to the ED on surgical delay and 90-day mortality. The influence of age (<85 vs. ≥85 years) on these outcomes was also examined. METHODS: A retrospective study was carried out. Data on 663 patients admitted over 30 months to a single unit were analysed for times of presentation to ED, radiographs in ED, admission to trauma ward and surgery. The delays to admission and surgery were calculated. The patients were divided into four 'time classes' depending on their time of presentation in the ED (i.e. 00:00-06:00, 06:00-12:00, 12:00-18:00 and 18:00-00:00) and into two 'age cohorts' (i.e. <85 and ≥85 years). RESULTS: The four 'time classes' included 58, 157, 259 and 189 patients, respectively. Patients who presented between 00:00 and 06:00 had a significantly reduced surgical interval and delay (P<0.001). There were no significant differences in the outcome measures, that is 36-h operation and 90-day mortality rates between the four classes. Overall, 386 patients were aged below 85 years and 277 were aged at least 85 years. Admission and surgical delays were similar between the two age cohorts, as were the 36-h operation rates. The 90-day mortality rates were 5.7 and 17.7%, respectively (P<0.0001). CONCLUSION: This study showed that the time of presentation to the ED could influence surgical delay. However, there was no direct relationship between surgical delay and 90-day mortality.

Common variation neighbouring micro-RNA 22 is associated with increased left ventricular mass.

AIMS: Previous genome-wide linkage analysis has suggested that chromosomal region 17p13.3 may harbour genes influencing left ventricular mass (LVM) in man. To date, the genetic factors accounting for LVM variability remain largely unknown but a non-coding RNA gene within this region, micro-RNA 22 (miR-22), has been implicated in cardiac hypertrophy and heart failure in animal models. We thus investigated the relationship between common genetic polymorphisms surrounding miR-22 and left ventricular mass in a family-based association study. METHODS AND RESULTS: We studied a cohort of 255 families comprising 1,425 individuals ascertained via a hypertensive proband. Ten single nucleotide polymorphisms which together tagged common genetic variation surrounding the miR-22 gene were genotyped. There was evidence of association between the rs7223247 polymorphism, which lies within the 3'UTR of a gene of unknown function, TLCD2, immediately downstream from miR-22, and left ventricular mass determined by Sokolow-Lyon voltage (Bonferroni corrected p-value = 0.038). The T allele at rs7223247 was associated with an 0.272 standard deviation higher Sokolow-Lyon voltage. Genotype was responsible for ~1% of the population variability in LVM. CONCLUSIONS: Genotype at the rs7223247 polymorphism affects left ventricular mass determined by Sokolow-Lyon voltage. The neighbouring genes miR-22 and TLCD2 are strong candidates to account for this observation.

Revision for unexplained pain following unicompartmental and total knee replacement.

BACKGROUND: Unicompartmental knee arthroplasty has been associated with consistently worse implant survival rates than total knee arthroplasty in worldwide arthroplasty registers. The rate of revision and the proportion of revisions performed for unexplained knee pain after either a unicompartmental or total knee arthroplasty were studied to assess if there is evidence to support the hypothesis that the numbers of revisions performed for unexplained knee pain differ between these two implant types. METHODS: Using data from the National Joint Registry (NJR) of England and Wales, we identified 402,714 primary knee arthroplasties (366,965 total knee arthroplasties and 35,749 unicompartmental knee arthroplasties) that were consecutively entered from April 2003 to December 2010. The status of all implants was assessed as of December 2010, at which time 6075 implants (4503 total knee implants and 1572 unicompartmental knee implants) had been revised at a maximum of eight years. Survival analysis and Cox regression analysis with adjustment of differences in age, sex, American Society of Anesthesiologists (ASA) grade, and indication for arthroplasty were performed with use of the end points of revision for any reason, revision for unexplained pain, and revision for other reasons. RESULTS: Revision for unexplained pain was more common after unicompartmental knee arthroplasty than after total knee arthroplasty (representing 23% of revisions as compared with 9% of revisions; p < 0.001). The five-year rate of revision for unexplained pain was 1.6% for the unicompartmental knee arthroplasty group and 0.2% for the total knee arthroplasty group. With use of Cox regression, the hazard ratio (HR) for unicompartmental knee arthroplasty relative to total knee arthroplasty with the end points of revision for any reason, revision for unexplained pain, and revision for all other reasons were 2.82 (95% confidence interval [CI], 2.66 to 2.99; p < 0.001), 6.76 (95% CI, 5.84 to 7.83; p < 0.001), and 2.39 (95% CI, 2.24 to 2.56; p < 0.001), respectively. The mean time from primary implantation to revision was similar for both implant types. CONCLUSIONS: While more unicompartmental knee implants than total knee implants were revised for unexplained pain, when these revisions for unexplained pain were discounted, unicompartmental knee arthroplasty still had a significantly greater risk of revision from other reasons than did total knee arthroplasty. The revision rate in isolation may not be a reliable way to compare different implant designs and should instead be considered in the context of the reason for failure.

Common variation in the CD36 (fatty acid translocase) gene is associated with left-ventricular mass.

AIMS: Genetic variation in the fatty acid translocase (CD36) gene has been shown in animal models to affect several risk factors for the development of left-ventricular hypertrophy, but this phenotype has not, thus far, been investigated in humans. We examined the relationship between common genetic polymorphisms in the CD36 gene and left-ventricular mass. METHODS AND RESULTS: We studied a cohort of 255 families comprising 1425 individuals ascertained via a hypertensive proband. Seven single-nucleotide polymorphisms which together tagged common genetic variation in the CD36 gene were genotyped using a SEQUENOM MALDI-TOF instrument. There was evidence of association between the rs1761663 polymorphism in intron 1 of the CD36 gene and left-ventricular mass determined either by echocardiography (P=0.003, N=780) or electrocardiography (P=0.001, N=814). There was also association between rs1761663 genotype and body mass index (P<0.001, N=1354). Genotype was associated with between 2 and 8% differences in these phenotypes per allele. After adjustment for the effect of body mass index, there remained significant associations between genotype and left ventricular mass measured either by echo (P=0.017) or ECG (P=0.007). CONCLUSIONS: Genotype at the rs1761663 polymorphism has independent effects both on body mass index and left-ventricular mass. Genes with such pleiotropic effects may be particularly attractive therapeutic targets for interventions to modify multiple risk factors for cardiovascular events.

Common variation at the 11-ß hydroxysteroid dehydrogenase type 1 gene is associated with left ventricular mass.

BACKGROUND: Polymorphisms in 11-ß hydroxysteroid dehydrogenase type 1 (11ß-HSD1, encoded by HSD11B1) have been reported to be associated with obesity-related cardiovascular risk factors, such as type II diabetes and hypertension. Left ventricular hypertrophy (LVH) is an independent risk factor for cardiovascular death associated with these factors but has significant additional heritability, the cause of which is undetermined. The 11ß-HSD1 is believed to maintain tonic inhibition of the mineralocorticoid receptor in cardiomyocytes, and mineralocorticoid receptor activation is involved in the pathophysiology of LVH. We assessed the association between polymorphisms in the HSD11B1 gene and left ventricular mass (LVM) in 248 families ascertained through a proband with hypertension. METHODS AND RESULTS: LVM was measured by electrocardiography and echocardiography in 868 and 829 participants, respectively. Single-nucleotide polymorphisms (SNPs) tagging common variation in the HSD11B1 gene were genotyped by mass spectrometry. The rs846910 SNP, which lies in the flanking region 5' to exon 1B of HSD11B1, was associated with LVM both by electrocardiography (≈5% lower LVM per copy of the rare allele, P=0.02) and by echocardiography (≈10% lower LVM per copy of the rare allele, P=0.003). Genotype explained 1% to 2% of the population variability in LVM, or approximately 5% of the heritable fraction. There were no significant associations between any HSD11B1 SNP and blood pressure or body mass index that could have confounded the association with LVM. CONCLUSIONS: Genotype at HSD11B1 has a small, but significant effect on LVM, apparently independently of any effect on obesity-related traits. These findings suggest a novel action of 11ß-HSD1 in the human cardiomyocyte, which may be of therapeutic importance.