Genome-wide meta-analysis of variant-by-diuretic interactions as modulators of lipid traits in persons of European and African ancestry.

Hypertension (HTN) is a significant risk factor for cardiovascular morbidity and mortality. Metabolic abnormalities, including adverse cholesterol and triglycerides (TG) profiles, are frequent comorbid findings with HTN and contribute to cardiovascular disease. Diuretics, which are used to treat HTN and heart failure, have been associated with worsening of fasting lipid concentrations. Genome-wide meta-analyses with 39,710 European-ancestry (EA) individuals and 9925 African-ancestry (AA) individuals were performed to identify genetic variants that modify the effect of loop or thiazide diuretic use on blood lipid concentrations. Both longitudinal and cross sectional data were used to compute cohort-specific interaction results, which were then combined through meta-analysis in each ancestry. These ancestry-specific results were further combined through trans-ancestry meta-analysis. Analysis of EA data identified two genome-wide significant (p < 5 × 10-8) loci with single nucleotide variant (SNV)-loop diuretic interaction on TG concentrations (including COL11A1). Analysis of AA data identified one genome-wide significant locus adjacent to BMP2 with SNV-loop diuretic interaction on TG concentrations. Trans-ancestry analysis strengthened evidence of association for SNV-loop diuretic interaction at two loci (KIAA1217 and BAALC). There were few significant SNV-thiazide diuretic interaction associations on TG concentrations and for either diuretic on cholesterol concentrations. Several promising loci were identified that may implicate biologic pathways that contribute to adverse metabolic side effects from diuretic therapy.

Association of complement receptor 1 gene polymorphisms with cognitive function.

Previous evidence suggest involvement of the complement receptor 1 (CR1) in development of Alzheimer's disease. We investigated the association of CR1 gene polymorphisms with cognitive function in older subjects. Single nucleotide polymorphisms (SNPs) within the CR1 region on chromosome 1 ( n = 73) were assessed in 5,244 participants in the PROspective Study of Pravastatin in the Elderly at Risk (51.9% female, mean age 75.3 yr). Linear regression, adjusted for age, sex, country, and use of pravastatin, was used to assess the association between the SNPs and cognitive function. All 73 SNPs within the genomic region of the CR1 gene on chromosome 1 were extracted. Eighteen were independent, according to a relatively stringent R2 threshold of >0.8 with LDlink. Twelve of the 18 investigated CR1 SNPs were significantly associated with a decline in cognitive function (all P < 0.05). These data indicate that genetic variation within the CR1 gene is associated not only with Alzheimer's disease, but also with general cognitive function during late life.

Large-scale pharmacogenomic study of sulfonylureas and the QT, JT and QRS intervals: CHARGE Pharmacogenomics Working Group.

Sulfonylureas, a commonly used class of medication used to treat type 2 diabetes, have been associated with an increased risk of cardiovascular disease. Their effects on QT interval duration and related electrocardiographic phenotypes are potential mechanisms for this adverse effect. In 11 ethnically diverse cohorts that included 71 857 European, African-American and Hispanic/Latino ancestry individuals with repeated measures of medication use and electrocardiogram (ECG) measurements, we conducted a pharmacogenomic genome-wide association study of sulfonylurea use and three ECG phenotypes: QT, JT and QRS intervals. In ancestry-specific meta-analyses, eight novel pharmacogenomic loci met the threshold for genome-wide significance (P<5 × 10-8), and a pharmacokinetic variant in CYP2C9 (rs1057910) that has been associated with sulfonylurea-related treatment effects and other adverse drug reactions in previous studies was replicated. Additional research is needed to replicate the novel findings and to understand their biological basis.

Maternal hemodynamics in normal pregnancy and in pregnancy affected by pre-eclampsia.

OBJECTIVES: To determine if, in a high-risk group of women in the first half of pregnancy, those who develop pre-eclampsia (PE) with fetal growth restriction (FGR) demonstrate distinct hemodynamics compared with those with PE in the absence of FGR (PE only). METHODS: Cardiac output (CO), peripheral vascular resistance (PVR) and mean arterial pressure (MAP) were measured at the first hospital visit at 9-24 weeks' gestation in 69 women who had chronic hypertension and 67 who had had a hypertensive disorder in a previous pregnancy. These women were divided into five groups according to pregnancy outcome. In total, 19 subsequently developed PE only, 22 developed PE with FGR, 17 developed pregnancy-induced hypertension, 39 had chronic hypertension without PE or FGR and 39 had had a hypertensive disorder in a previous pregnancy without PE, pregnancy-induced hypertension or FGR in the index pregnancy. The hemodynamic values in each of these groups were compared with those in a cohort of 300 low-risk women with normal pregnancy. RESULTS: In all the high-risk groups, PVR and MAP were higher than in women with a normal pregnancy, but CO was lower in the group of women with PE and FGR, whereas in the other high-risk groups, it was not significantly different from normal. CONCLUSIONS: In women who develop PE, there is evidence of high PVR and MAP from the first half of pregnancy, whilst PE and FGR are associated with failure in physiological expansion of CO. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Study protocol: a randomised controlled trial on the clinical effects of levothyroxine treatment for subclinical hypothyroidism in people aged 80 years and over.

BACKGROUND: Subclinical hypothyroidism is common in older people and its contribution to health and disease needs to be elucidated further. Observational and clinical trial data on the clinical effects of subclinical hypothyroidism in persons aged 80 years and over is inconclusive, with some studies suggesting harm and some suggesting benefits, translating into equipoise whether levothyroxine therapy provides clinical benefits. This manuscript describes the study protocol for the Institute for Evidence-Based Medicine in Old Age (IEMO) 80-plus thyroid trial to generate the necessary evidence base. METHODS: The IEMO 80-plus thyroid trial was explicitly designed as an ancillary experiment to the Thyroid hormone Replacement for Untreated older adults with Subclinical hypothyroidism randomised placebo controlled Trial (TRUST) with a near identical protocol and shared research infrastructure. Outcomes will be presented separately for the IEMO and TRUST 80-plus groups, as well as a pre-planned combined analysis of the 145 participants included in the IEMO trial and the 146 participants from the TRUST thyroid trial aged 80 years and over. The IEMO 80-plus thyroid trial is a multi-centre randomised double-blind placebo-controlled parallel group trial of levothyroxine treatment in community-dwelling participants aged 80 years and over with persistent subclinical hypothyroidism (TSH ≥4.6 and ≤ 19.9 mU/L and fT4 within laboratory reference ranges). Participants are randomised to levothyroxine 25 or 50 micrograms daily or matching placebo with dose titrations according to TSH levels, for a minimum follow-up of one and a maximum of three years. Primary study endpoints: hypothyroid physical symptoms and tiredness on the thyroid-related quality of life patient-reported outcome (ThyPRO) at one year. Secondary endpoints: generic quality of life, executive cognitive function, handgrip strength, functional ability, blood pressure, weight, body mass index, and mortality. Adverse events will be recorded with specific interest on cardiovascular endpoints such as atrial fibrillation and heart failure. DISCUSSION: The combined analysis of participants in the IEMO 80-plus thyroid trial with the participants aged over 80 in the TRUST trial will provide the largest experimental evidence base on multimodal effects of levothyroxine treatment in 80-plus persons to date. TRIAL REGISTRATION: Nederlands (Dutch) Trial Register: NTR3851 (12-02-2013), EudraCT: 2012-004160-22 (17-02-2013), ABR-41259.058.13 (12-02-2013).

Longitudinal maternal hemodynamics in pregnancies affected by fetal growth restriction.

OBJECTIVE: Fetal growth restriction (FGR) is a powerful determinant of poor perinatal outcome. From our previous work in pregnancies at high risk of development of hypertension we found impaired cardiovascular adaptation early in gestation in those destined to deliver growth-restricted infants. In this study, we monitored serially maternal hemodynamics from the first to third trimester in a similar high-risk cohort, in order to determine whether this distinct hemodynamic profile found at presentation persisted throughout pregnancy in those complicated by FGR. METHODS: This was a prospective observational study based at a specialist antenatal hypertension clinic at a tertiary hospital in London. Maternal hemodynamics were evaluated serially using a non-invasive bioreactance method in pregnant women referred to the clinic with a history of chronic hypertension or a history of hypertensive disorder in a previous pregnancy. Differences in maternal hemodynamic parameters were compared between women who delivered a baby with a birth weight ≥ 10th vs < 10th percentile and ≥ 5th vs < 5th percentile. RESULTS: Eighty-four pregnant women were included in the study. Mean gestational age at presentation was 14.3 weeks. Sixteen women delivered babies with a birth weight < 10th percentile and 11 with a birth weight < 5th percentile. In pregnancies with a birth weight ≥ 10th percentile, longitudinal maternal hemodynamics showed a pattern consistent with well-established physiological changes in pregnancy, i.e. a reduction in vascular resistance and an increase in cardiac output with advancing gestation until mid-pregnancy. However, women who delivered babies with a birth weight < 10th percentile showed a static pattern with no change during gestation and lower cardiac output and higher peripheral vascular resistance. Similar differences were seen when the 5th percentile was used to discriminate between appropriately-grown and growth-restricted babies. CONCLUSION: Serial assessment of maternal hemodynamics in high-risk women identifies distinctive trends associated with pregnancies destined to deliver babies with birth weights < 10th and < 5th percentiles. These pregnancies have a suppressed and static maternal cardiac output and stroke volume, and have consistently raised peripheral vascular resistance. This suggests that, in women with chronic hypertension or a history of hypertensive disorder in a previous pregnancy, FGR is associated with a primary and persistent failure of maternal cardiovascular adaptation in pregnancy. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Serial hemodynamic monitoring to guide treatment of maternal hypertension leads to reduction in severe hypertension.

OBJECTIVES: To examine whether treatment for hypertension in pregnancy that is guided by serial monitoring of maternal central hemodynamics leads to a reduction in the rate of severe hypertension, defined as blood pressure ≥ 160/110 mmHg; and to assess the distinct longitudinal hemodynamic profiles associated with beta-blocker monotherapy, vasodilator monotherapy and dual agent therapy, and their relationships with outcomes, including fetal growth restriction. METHODS: This was a prospective observational study at a dedicated antenatal hypertension clinic in a tertiary UK hospital. Fifty-two untreated women presenting with hypertension were recruited consecutively and started on treatment, either with a beta-blocker or a vasodilator. The choice of initial antihypertensive agent was determined according to a model constructed previously to predict the response to the beta-blocker labetalol in pregnant women needing antihypertensive treatment. At presentation, the demographic and maternal hemodynamic variables associated with a therapeutic response to labetalol, defined as blood pressure control < 140/90 mmHg with labetalol monotherapy throughout pregnancy, were ascertained and analyzed with logistic regression to create a model to predict sustained blood pressure control as described above. The women were reviewed regularly until delivery and underwent serial hemodynamic monitoring throughout pregnancy. If their blood pressure was elevated, the prediction model was referred to again to determine if alternative antihypertensive therapy, either with additional beta-blocker or a vasodilator, should be added. RESULTS: Treatment by referring to results of serial hemodynamic monitoring reduced the rate of severe antenatal hypertension from 18% to 3.8%. Seventy-seven percent of women were initially prescribed a beta-blocker and 23% a vasodilator. The group that maintained good blood pressure control with beta-blocker monotherapy had the best fetal and maternal outcomes. They had lower blood pressures at presentation and throughout gestation, demonstrated well-maintained cardiac output and had the lowest rates of fetal growth restriction. The groups that required dual therapy to control their blood pressure had persistently higher blood pressure and rate of fetal growth restriction. The groups that required vasodilator therapy due to high levels of peripheral vascular resistance, either at presentation or later in pregnancy, accounted for 81% of cases with fetal growth restriction. CONCLUSION: Using serial hemodynamic monitoring in pregnancy to guide treatment of hypertension significantly reduces the rate of severe hypertension and allows identification of high-resistance, low-output hypertensive pregnancies that are associated with an increased rate of fetal growth restriction. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd. RESUMEN OBJETIVOS: Examinar si el tratamiento para la hipertensión en el embarazo guiado por un seguimiento en serie de las principales constantes hemodinámicas de la madre conduce a una reducción en la tasa de hipertensión grave, definida como presión arterial ≥ 160/110 mmHg; y evaluar los diferentes perfiles hemodinámicos longitudinales asociados a la monoterapia con beta-bloqueantes, la monoterapia con vasodilatadores y la terapia dual, y su relación con los resultados, como la restricción del crecimiento fetal. MÉTODOS: Se realizó un estudio observacional prospectivo en una clínica especializada en hipertensión prenatal de un hospital de atención terciaria del Reino Unido. Se reclutaron consecutivamente a cincuenta y dos mujeres no tratadas que presentaban hipertensión y se comenzó a tratarlas, bien con un beta-bloqueante o bien con un vasodilatador. La elección del agente antihipertensivo inicial se determinó de acuerdo con un modelo elaborado previamente para predecir la respuesta al beta-bloqueante labetalol en mujeres embarazadas que necesitaban tratamiento antihipertensivo. Al inicio se registraron las características demográficas y las variables hemodinámicas maternas asociadas con una respuesta terapéutica al labetalol, definida como un control de la presión arterial < 140/90 mmHg con monoterapia de labetalol durante todo el embarazo que se analizó mediante regresión logística para crear un modelo con el que pronosticar un control sostenido de la presión arterial, como se describe arriba. Las mujeres fueron sometidas a revisiones regulares hasta el momento del parto y se les hizo un seguimiento hemodinámico en serie durante todo el embarazo. Si la presión arterial era elevada, se empleó de nuevo el modelo de predicción para determinar si se debería añadir un tratamiento antihipertensivo alternativo, ya sea con un beta-bloqueante adicional o con un vasodilatador. RESULTADOS: El tratamiento que tuvo en cuenta los resultados del seguimiento hemodinámico en serie redujo la tasa de hipertensión prenatal grave del 18% al 3,8%. Al 77% de las mujeres se les recetó inicialmente un y al 23% un vasodilatador. El grupo que mantuvo un buen control de la presión arterial con monoterapia de beta-bloqueantes logró mejores resultados fetales y maternos. Este grupo tuvo menor presión arterial al inicio y durante toda la gestación, mostró un gasto cardíaco en buen estado y tuvo las tasas más bajas de restricción del crecimiento fetal. Los grupos que requirieron terapia dual para controlar su presión arterial mostraron persistentemente una mayor presión arterial y un mayor ritmo de restricción del crecimiento fetal. Los grupos que requirieron tratamiento vasodilatador debido a los altos niveles de resistencia vascular periférica, tanto al inicio como durante el embarazo, representaron el 81% de los casos con restricción del crecimiento fetal. CONCLUSIÓN: El uso de un seguimiento hemodinámico en serie en el embarazo como guía para el tratamiento de la hipertensión reduce significativamente la tasa de hipertensión severa y permite la identificación de embarazos con hipertensión de alta resistencia y malos resultados, asociados con una mayor tasa de restricción del crecimiento fetal. : (≥ 160/110 mmHg);ß、,()。 : 。52、,ß。ß。,(<140/90 mmHg),logistic,。,。,(ß)。 : ,18%3.8%。77%ß,23%。ß。,,。,。,81%。 : ,,、。.

Longitudinal hemodynamics in acute phase of treatment with labetalol in hypertensive pregnant women to predict need for vasodilatory therapy.

OBJECTIVE: Hypertensive pregnant women who do not respond to treatment with labetalol to control blood pressure (BP), but require vasodilatory therapy, progress rapidly to severe hypertension. This could be delayed by early recognition and individualized treatment. In this study, we sought to create prediction models from data at presentation and at 1 h and 24 h after commencement of treatment to identify patients who will not have a sustained response to labetalol and therefore need vasodilatory therapy. METHODS: The study population comprised 134 women presenting with hypertension at a UK hospital. Treatment with oral labetalol was administered when BP was > 150/100 mmHg or > 140/90 mmHg with systemic disease. BP and hemodynamic parameters were recorded at presentation and at 1 h and 24 h after commencement of treatment. Labetalol doses were titrated to maintain BP around 135/85 mmHg. Women with unresponsive BP, despite labetalol dose maximization (2400 mg/day), received additional vasodilatory therapy with nifedipine. Binary logistic and longitudinal (mixed-model) data analyses were performed to create prediction models anticipating the likelihood of hypertensive women needing vasodilatory therapy. The prediction models were created from data at presentation and at 1 h and 24 h after treatment, to assess the value of central hemodynamics relative to the predictive power of BP, heart rate and demographic variables at these intervals. RESULTS: Twenty-two percent of our cohort required additional vasodilatory therapy antenatally. These women had higher rates of severe hypertension and delivered smaller babies at earlier gestational ages. The unresponsive women were more likely to be of black ethnicity, had higher BP and peripheral vascular resistance (PVR), and lower heart rate and cardiac output (CO) at presentation. Those who needed vasodilatory therapy showed an initial decrease in BP and PVR, which rebounded at 24 h, whereas BP and PVR in those who responded to labetalol showed a sustained decrease at 1 h and 24 h. Stroke volume and CO did not decrease during the acute phase of treatment in either group. The best model for prediction of the need for vasodilators was provided at 24 h by combining ethnicity and longitudinal BP and heart rate changes. The model achieved a detection rate of 100% for a false-positive rate of 20% and an area under the receiver-operating characteristics curve of 0.97. CONCLUSION: Maternal demographics and hemodynamic changes in the acute phase of labetalol monotherapy provide a powerful tool to identify hypertensive pregnant patients who are unlikely to have their BP controlled by this therapy and will consequently need additional vasodilatory therapy. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd. RESUMEN OBJETIVO: Las embarazadas hipertensas que no responden al tratamiento con labetalol para el control de la presión arterial (PA), pero que requieren terapia vasodilatadora, evolucionan rápidamente hacia una hipertensión severa. Ésta se puede retrasar mediante un diagnóstico precoz y un tratamiento individual. En este estudio se ha tratado de crear modelos de predicción a partir de datos al inicio del tratamiento y al cabo de 1 hora y de 24 horas después del mismo, para identificar a las pacientes que no mostrarán una respuesta constante al labetalol y que por lo tanto necesitarán terapia vasodilatadora. MÉTODOS: La población de estudio incluyó 134 mujeres con hipertensión en un hospital del Reino Unido. El tratamiento con labetalol por vía oral se administró cuando la PA fue >150/100 mm de Hg o >140/90 mm de Hg con enfermedad multisistémica. Se registró la PA y los parámetros hemodinámicos tanto al inicio como al cabo de 1 h y de 24 h después del inicio del tratamiento. Las dosis de Labetalol se ajustaron para mantener la PA en torno a los 135/85 mm de Hg. Las mujeres cuya PA no produjo respuesta, a pesar de haberles administrado la dosis máxima de labetalol (2400 mg/día), recibieron terapia vasodilatadora adicional con nifedipino. Se realizaron análisis de datos mediante logística binaria y longitudinal (modelo mixto), para crear modelos de predicción con los que pronosticar la probabilidad de la necesidad de terapia vasodilatadora en mujeres hipertensas. Los modelos de predicción se crearon a partir de datos al inicio y al cabo de 1 hora y 24 horas del tratamiento, para evaluar el valor de los parámetros hemodinámicos principales con respecto a la capacidad predictiva de la PA, la frecuencia cardíaca y las variables demográficas en estos intervalos. RESULTADOS: El 22 % de la cohorte necesitó terapia vasodilatadora adicional antes del parto. Estas mujeres tuvieron tasas más altas de hipertensión grave y neonatos más pequeños en edades gestacionales más tempranas. Las mujeres que no respondieron al tratamiento fueron con más frecuencia de raza negra, tuvieron la PA y la resistencia vascular periférica (RVP) más alta, y la frecuencia cardíaca y el gasto cardíaco (GC) más bajos al inicio del tratamiento. Aquellas que necesitaron terapia vasodilatadora mostraron un descenso inicial de la PA y la RVP, que se recuperó al cabo de 24 h, mientras que la PA y la RVP en las que respondieron al labetalol mostraron una disminución constante al cabo de 1 h y de 24 h. El volumen sistólico y el GC no disminuyeron durante la fase aguda del tratamiento en ninguno de los grupos. El mejor modelo para la predicción de la necesidad de vasodilatadores se obtuvo a las 24 h mediante la combinación de la etnia con los cambios longitudinales de la PA y la frecuencia cardíaca. El modelo alcanzó una tasa de detección del 100% para una tasa de falsos positivos del 20% y un área bajo la curva de características operativas del receptor de 0,97. CONCLUSIÓN: Los datos demográficos maternos y los cambios hemodinámicos en la fase aguda de la monoterapia con labetalol constituyen una herramienta poderosa para identificar a las pacientes embarazadas hipertensas con pocas probabilidades de que se les pueda controlar su PA mediante esta terapia y que por lo tanto necesitarán terapia vasodilatadora adicional. : 、(blood pressure,BP),。。,1 h24 h,。 : 134。BP>150/100 mmHgBP>140/90 mmHg。1 h24 hBP。,BP135/85 mmHg。BP,()。logistic(),。1 h24 h,,BP、。 : 22%。。,BP(peripheral vascular resistance,PVR),(cardiac output,CO)。BPPVR,24 h,1 h24 hBPPVR。CO。24hBP。100%,20%,0.97。 : ,BP。.

Non-response to (statin) therapy: the importance of distinguishing non-responders from non-adherers in pharmacogenetic studies.

PURPOSE: In pharmacogenetic research, genetic variation in non-responders and high responders is compared with the aim to identify the genetic loci responsible for this variation in response. However, an important question is whether the non-responders are truly biologically non-responsive or actually non-adherent? Therefore, the aim of this study was to describe, within the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER), characteristics of both non-responders and high responders of statin treatment in order to possibly discriminate non-responders from non-adherers. METHODS: Baseline characteristics of non-responders to statin therapy (≤10 % LDL-C reduction) were compared with those of high responders (>40 % LDL-C reduction) through a linear regression analysis. In addition, pharmacogenetic candidate gene analysis was performed to show the effect of excluding non-responders from the analysis. RESULTS: Non-responders to statin therapy were younger (p = 0.001), more often smoked (p < 0.001), had a higher alcohol consumption (p < 0.001), had lower LDL cholesterol levels (p < 0.001), had a lower prevalence of hypertension (p < 0.001), and had lower cognitive function (p = 0.035) compared to subjects who highly responded to pravastatin treatment. Moreover, excluding non-responders from pharmacogenetic studies yielded more robust results, as standard errors decreased. CONCLUSION: Our results suggest that non-responders to statin therapy are more likely to actually be non-adherers, since they have more characteristics that are viewed as indicators of high self-perceived health and low disease awareness, possibly making the subjects less adherent to study medication. We suggest that in pharmacogenetic research, extreme non-responders should be excluded to overcome the problem that non-adherence is investigated instead of non-responsiveness.

Drug-gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the QT interval.

Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the 'missing heritability' of complex traits. Here, we describe four independent analyses in 33 781 participants of European ancestry from 10 cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use=13.0%), tri/tetracyclic antidepressants (2.6%), sulfonylurea hypoglycemic agents (2.9%) and QT-prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4%). Drug-gene interactions were estimated using covariable-adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug-single-nucleotide polymorphism (SNP) interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (Pinteraction>5.0 × 10(-8)). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects.

Circulating interleukin-6 concentration and cognitive decline in old age: the PROSPER study.

BACKGROUND: Inflammation is involved in the pathogenesis of cardiovascular disease and cognitive decline. Interleukin-6 (IL-6) has a role in cardiovascular disease, but the association of IL-6 concentration and the functional IL-6 -174 polymorphism with cognitive decline has not been demonstrated unequivocally. The objective of this study was to investigate the associations between both high concentration of IL-6 and the -174 promoter polymorphism, and increased cognitive decline in old age. METHODS: Over 5000 participants of the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) with a mean age of 75 years and a history of cardiovascular disease or its risk factors were included in this study. We determined baseline concentrations of IL-6 and genotype of the IL-6 -174 polymorphism, of which the C allele was previously shown to be associated with higher circulating concentrations of IL-6. A cognitive test battery was administered at baseline and repeatedly during follow-up (mean 39 months). RESULTS: In the cross-sectional analysis of 5653 participants, higher IL-6 concentration was associated with worse executive cognitive function (P < 0.001), independent of cardiovascular disease status and risk factors. No association was found between IL-6 concentration and memory function (P > 0.14). In the prospective analysis, higher IL-6 concentration was associated with an increased rate of cognitive decline in both executive function (P = 0.002) and memory function (P = 0.002), again independent of cardiovascular disease status and risk factors. Although not associated with IL-6 concentrations, the IL-6 -174 CC genotype was associated with worse performance on the Stroop test (P = 0.045). CONCLUSIONS: Higher circulating levels of IL-6 were associated with worse cognitive function and steeper cognitive decline and provide preliminary genetic evidence for a potential causal association. The findings support the importance of the need for further investigation of the IL-6 pathway in cognitive decline.

The estimation of body height from ulna length in healthy adults from different ethnic groups.

BACKGROUND: Assessments of nutritional status frequently incorporate a measure of height to evaluate a person's relative thinness or fatness. Because height is often difficult to quantify, it may be predicted from alternative anthropometric measurements, including ulna length. Little information is available about the accuracy of these predictions in an ethnically diverse population. The present study aimed to evaluate published equations for predicting height from ulna length in adults from different ethnic groups. METHODS: Ulna length and standing height were measured in a gender-stratified sample of 60 Asian, 69 Black and 65 White healthy volunteers, aged 21-65 years. Height was predicted from ulna length using the Malnutrition Universal Screening Tool (MUST) equations and compared against the measured values. Linear regression analysis was used to develop equations to estimate height from ulna length and to explore the relationship between height and ulna length in subgroups. RESULTS: The mean (SD) age for Asian, Black and White in men was 31.7 (11.0), 32.0 (10.3) and 38.6 (12.5) years and in women was 26.2 (5.4), 32.6 (8.9) and 35.7 (11.7); the mean (SD) height in men was 170.9 (5.2), 178.1 (7.3) and 176.3 (7.7) cm and in women was 157.7 (4.7), 164.0 (5.9) and 163.7 (6.2) cm. Ulna length and measured height were significantly correlated among all subgroups, except Asian women (r=0.11, P=0.57). The mean (SD) difference between predicted and measured height showed significant overestimates for Asian and Black men [4.0 (4.8) and 6.7 (5.3) cm] and Asian and Black women [6.4 (4.9) and 4.4 (4.9) cm] but not for White men and women. CONCLUSIONS: The MUST equations for predicting height from ulna length in healthy adults should be used with some caution among ethnically diverse populations, particularly in Asian women.

The role of interleukin 12 and nitric oxide in the development of spontaneous autoimmune disease in MRL/MP-lpr/lpr mice.

MRL/MP-lpr/lpr (MRL/lpr) mice develop a spontaneous autoimmune disease. Serum from these mice contained significantly higher concentrations of nitrite/nitrate than serum from age-matched control MRL/MP-+/+ (MRL/+), BALB/c or CBA/6J mice. Spleen and peritoneal cells from MRL/lpr mice also produced significantly more nitric oxide (NO) than those from the control mice when cultured with interferon (IFN) gamma and lipopolysaccharide (LPS) in vitro. It is interesting to note that peritoneal cells from MRL/lpr mice also produced markedly higher concentrations of interleukin (IL) 12 than those from MRL/+ or BALB/c mice when cultured with same stimuli. It is striking that cells from MRL/lpr mice produced high concentrations of NO when cultured cells from MRL/+ or BALB/c mice. The enhanced NO synthesis induced by IFN-gamma/LPS was substantially inhibited by anti-IL-12 antibody. In addition, IL-12-induced NO production can also be markedly inhibited by anti-IFN-gamma antibody, but only weakly inhibited by anti-tumor necrosis factor alpha antibody. The effect of IL-12 on NO production was dependent on the presence of natural killer and possibly T cells. Serum from MRL/lpr mice contained significantly higher concentrations of IL-12 compared with those of MRL/+ or BALB/c control mice. Daily injection of recombinant IL-12 led to increased serum levels of IFN-gamma and NO metabolites, and accelerated glomerulonephritis in the young MRL/lpr mice (but not in the MRL/+ mice) compared with controls injected with phosphate-buffered saline alone. These data, together with previous finding that NO synthase inhibitors can ameliorate autoimmune disease in MRL/lpr mice, suggest that high capacity of such mice to produce IL-12 and their greater responsiveness to IL-12, leading to the production of high concentrations of NO, are important factors in this spontaneous model of autoimmune disease.

IgM-producing tumors in the BALB-c mouse: a model for B-cell maturation.

Five adjuvant induced BALB/c tumors producing IgM-McPc 1748, W 3469, TEPC 183, McPc 774, and Y 5781-were characterized morphologically by electron microscopy, analysis of the distribution of surface-bound and intracytoplasmic IgM using immunofluorescence, and by biochemical study of IgM synthesis, turnover, and secretion. The cells of different tumors appear to represent different stages in B-cell maturation when compared to normal, lipopolysaccharide-stimulated B cells. Thus, McPc 1748 tumor cells resemble 10-25-h stimulated normal B cells, 3469 cells resemble 20-35-h stimulated B cells, TEPC 183 cells resemble 45-65-h stimulated B cells, Y 5781 cells resemble 80-110-h stimulated B cells, and McPc 774 cells resemble 100-130-h stimulated B cells.

The kidney, subclinical thyroid disease and cardiovascular outcomes in older patients.

OBJECTIVE: Thyroid hormones have been implicated to play a role in cardiovascular disease, along with studies linking thyroid hormone to kidney function. The aim of this study is to investigate whether kidney function modifies the association of subclinical thyroid dysfunction and the risk of cardiovascular outcomes. METHODS: In total, 5804 patients were included in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). For the current analysis, 426 were excluded because of overt thyroid disease at baseline or 6 months, 266 because of inconsistent thyroid function at baseline and 6 months, 294 because of medication use that could influence thyroid function, and 16 because of missing kidney or thyroid values. Participants with normal fT4 were classified, based on TSH both at inclusion and 6 months, into three groups: subclinical hypothyroidism (TSH >4.5 mIU/L); euthyroidism (TSH = 0.45-4.5 mIU/L); and subclinical hyperthyroidism (TSH <0.45 mIU/L). Strata of kidney function were made based on estimated glomerular filtration rate into three clinically relevant groups: <45, 45-60, and >60 mL/min/1.73 m2. The primary endpoint consists of death from coronary heart disease, non-fatal myocardial infarction and (non)fatal stroke. RESULTS: Mean age was 75.3 years, and 49.0% patients were male. Mean follow-up was 3.2 years. Of all participants, 109 subjects (2.2%) had subclinical hypothyroidism, 4573 (94.0%) had euthyroidism, and 182 (3.7%) subclinical hyperthyroidism. For patients with subclinical hypothyroidism, euthyroidism, and subclinical hyperthyroidism, primary outcome occurred in 9 (8.3%), 712 (15.6%), and 23 (12.6%) patients, respectively. No statistically significant relationship was found between subclinical thyroid dysfunction and primary endpoint with adjusted hazard ratios of 0.51 (0.24-1.07) comparing subclinical hyperthyroidism and 0.90 (0.58-1.39) comparing subclinical hypothyroidism with euthyroidism. Neither was this relationship present in any of the strata of kidney function, nor did kidney function interact with subclinical thyroid dysfunction in the association with primary endpoint (P interaction = 0.602 for subclinical hyperthyroidism and 0.388 for subclinical hypothyroidism). CONCLUSIONS: In this secondary analysis from PROSPER, we found no evidence that the potential association between thyroid hormones and cardiovascular disease is modified by kidney function in older patients with subclinical thyroid dysfunction.

Are elevated circulating intercellular adhesion molecule 1 levels more strongly predictive of diabetes than vascular risk? Outcome of a prospective study in the elderly.

AIMS/HYPOTHESIS: The aim of this prospective study was to determine whether circulating intercellular adhesion molecule (ICAM) 1, as a potential surrogate of 'endothelial activation', is more strongly associated with risk of vascular events than with incident diabetes. METHODS: We related baseline ICAM-1 levels to vascular events (866 CHD and stroke events in 5,685 participants) and incident diabetes (292 in 4,945 without baseline diabetes) in the elderly over 3.2 years of follow-up. RESULTS: ICAM-1 levels correlated positively with triacylglycerol but negatively with LDL- and HDL-cholesterol. ICAM-1 levels were higher in those who developed diabetes (388.6 +/- 1.42 vs 369.4 +/- 1.39 ng/ml [mean+/-SD], p = 0.011) and remained independently associated with new-onset diabetes (HR 1.84, 95% CI 1.26-2.69, p = 0.0015 per unit increase in log[ICAM-1] after adjusting for classical risk factors and C-reactive protein). By contrast, ICAM-1 levels were not significantly (p = 0.40) elevated in those who had an incident vascular event compared with those who remained event-free, and corresponding adjusted risk associations were null (HR 0.98, 95% CI 0.80-1.22, p = 0.89) in analyses adjusted for other risk factors. CONCLUSIONS/INTERPRETATION: We show that elevated ICAM-1 levels are associated with risk of incident diabetes in the elderly at risk, despite no association with incident cardiovascular disease risk. We suggest that perturbations in circulating ICAM-1 levels are aligned more towards diabetes risk.

Haemostatic changes in the puerperium '6 weeks postpartum' (HIP Study) - implication for maternal thromboembolism.

OBJECTIVE: We aim to measure the thrombotic changes during the postnatal period up to 6 weeks after delivery and assess the extent of the risk period. DESIGN: Prospective observational study. SETTING: Queen Elizabeth II, an acute District General Hospital, Hertfordshire. POPULATION: Women booked at the antenatal clinic and prepared to deliver at the hospital. METHODS: We assessed the haemoglobin, platelet count and function, fibrinogen, prothrombin time, activated partial thromboplastin time, protein C, S and antithrombin level and as well as rotational thromboelastometry (ROTEM) from predelivery till 6 weeks postpartum. RESULTS: A total 50 women were recruited of which four dropped out. Results compared against the finding at 6 weeks after delivery. Platelet was significantly elevated on day 19 compared to day 42 (P < 0.001). Fibrinogen was elevated from predelivery till day 15 after delivery (P < 0.01). Prothrombin time (PT) was low till day 15 (P < 0.05) and activated partial thromboplastin time (APTT) was significantly lower till day 3 after delivery (P < 0.001). ROTEM revealed low clotting time (CT) at predelivery and continued to be low till day 7. Clot formation time (CFT) significantly low till day 25 (P < 0.05). Maximum clot firmness, alpha angle and amplitude at 20 minutes were raised till day 19 (P < 0.001, P < 0.01 and P < 0.001 respectively). While, comparing vaginal delivery against caesarean section there were nonsignificant increase in thrombotic parameters in caesarean section. CONCLUSION: Coagulation screens as well as thomboelastometry suggest a persistent hypercoagulation during the first 3 weeks after delivery.

Genetic variation in the interleukin-1 beta-converting enzyme associates with cognitive function. The PROSPER study.

Inflammation is thought to play an important role in the development of cognitive decline and dementia in old age. The interleukin-1 signalling pathway may play a prominent role in this process. The gene encoding for interleukin-1 beta-converting enzyme (ICE) is likely to influence IL-1 beta levels. Inhibition of ICE decreases the age-related increase in IL-1 beta levels and may therefore improve memory function. We assessed whether genetic variation in the ICE gene associates with cognitive function in an elderly population. All 5804 participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) were genotyped for the 10643GC, 9323GA, 8996AG and 5352GA polymorphisms in the ICE gene. Cross-sectional associations between the polymorphisms and cognitive function were assessed with linear regression. Longitudinal associations between polymorphisms, haplotypes and cognitive function were assessed with linear mixed models. All associations were adjusted for sex, age, education, country, treatment with pravastatin and version of test where appropriate. Subjects carrying the variants 10643C and 5352A allele had significantly lower IL-1 beta production levels (P < 0.01). Furthermore, we demonstrated that homozygous carriers of the 10643C and the 5352A allele performed better on all executive function tests at baseline and during follow-up compared to homozygous carriers of the wild-type allele (all P < 0.02). The haplotype with two variants present (10643C and 5352A) was associated with better executive function (all P < 0.02) compared to the reference haplotype without variants. For memory function the same trend was observed, although not significant. Genetic variation in the ICE gene is associated with better performance on cognitive function and lower IL-1 beta production levels. This suggests that low levels of IL-1 beta are protective for memory and learning deficits. Inhibition of ICE may therefore be an important therapeutic target for maintaining cognitive function in old age.

An 8- to 10-year review of the Rotaglide total knee replacement.

Mobile-bearing knee arthroplasty (MBKA) is an alternative to fixed-bearing knee arthroplasty. This was a retrospective study of the Rotaglide Total Knee System. We present the results of the monitoring of 77 patients (85 knees) with a median duration to failure or end of follow up of 8.5 years (range 0.4 to 10.1 years). Patients were clinically and radiologically assessed at dedicated follow up clinics. The Hospital for Special Surgery (HSS) and Knee Society Score (KSS) systems were used to describe the clinical and radiological findings. The prosthesis had an estimated survival probability of 93.5% (standard error 3.4%) at 9 years. It is associated with good rates of patient satisfaction and high scores on the HSS and KSS systems. No knees were revised for aseptic loosening. This knee replacement has a survival rate equivalent to other prostheses. It is a safe and reliable prosthesis associated with good clinical outcome.

Lymphotoxin-alpha C804A polymorphism is a risk factor for stroke. The PROSPER study.

Inflammation plays a prominent role in the development of atherosclerosis, which is the most important risk factor for vascular events. Lymphotoxin-alpha (LTA) is a pro-inflammatory cytokine and is found to be expressed in atherosclerotic lesions. We investigated the association between the C804A polymorphism within the LTA gene and coronary and cerebrovascular events in 5804 participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). The primary endpoint was the combined endpoint of death from coronary heart disease, non-fatal myocardial infarction, and clinical stroke. Secondary endpoints were the coronary and cerebrovascular components separately. All associations were assessed with a Cox-proportional hazards model adjusted for sex, age, pravastatin use, and country. Our overall analysis showed a significant association between the C804A polymorphism and the primary endpoint (p = 0.03). After stratification for gender, this association was found only in males. Furthermore, we found that the association between the C804A polymorphism and the primary endpoint was mainly attributable to clinical strokes (p = 0.02). The C804A polymorphism in the LTA gene associates with clinical stroke, especially in men. But further research is warranted to confirm our results.