Plasma Branched-Chain Amino Acid Concentrations and Glucose Homeostasis in Kidney Transplant Recipients and Candidates.

Background: Post-transplant diabetes mellitus (PTDM) encompasses new-onset and previously unrecognized type 2 diabetes. Kidney failure masks type 2 diabetes. Branched-chain amino acids (BCAA) are closely associated with glucose metabolism. Therefore, understanding BCAA metabolism both in kidney failure and after kidney transplantation may inform PTDM mechanisms. Objective: To understand the impact of present or absent kidney function on plasma BCAA concentrations. Design: Cross-sectional study of kidney transplant recipients and kidney transplant candidates. Setting: Large kidney transplant center in Toronto, Canada. Measurements: We measured plasma BCAA and aromatic amino acid (AAA) concentrations in 45 pre-kidney transplant candidates (15 with type 2 diabetes, 30 without type 2 diabetes) and 45 post-kidney transplant recipients (15 PTDM, 30 non-PTDM), along with insulin resistance and sensitivity by 75 g oral glucose loading for those in each group without type 2 diabetes. Methods: Plasma AA concentrations were analyzed using MassChrom AA Analysis and compared between groups. The insulin sensitivity for oral glucose tolerance tests or Matsuda index (a measure of whole-body insulin resistance), Homeostatic Model Assessment for Insulin Resistance (a measure of hepatic insulin resistance), and Insulin Secretion-Sensitivity Index-2 (ISSI-2, a measure of pancreatic ß-cell response) was calculated from fasting insulin and glucose concentrations, and compared with BCAA concentrations. Results: Each BCAA concentration was higher in post-transplant subjects than pre-transplant subjects (P < .001 for leucine, isoleucine, valine). In post-transplant subjects, each BCAA concentration was higher in PTDM versus non-PTDM (odds ratio for PTDM 3-4 per 1 SD increase in BCAA concentration, P < .001 for each). Tyrosine concentrations were also higher in post-transplant subjects than pre-transplant subjects, but tyrosine did not differ by PTDM status. By contrast, neither BCAA nor AAA concentrations were different in pre-transplant subjects with or without type 2 diabetes. Whole-body insulin resistance, hepatic insulin resistance, and pancreatic ß-cell response did not differ between nondiabetic post-transplant and pre-transplant subjects. Branched-chain amino acid concentrations correlated with the Matsuda index and Homeostatic Model Assessment for Insulin Resistance (P < .05 for each) only in nondiabetic post-transplant subjects-not in nondiabetic pre-transplant subjects. Branched-chain amino acid concentrations did not correlate with ISSI-2 in either pre-transplant or post-transplant subjects. Limitations: The sample size was small, and subjects were not studied prospectively for the development of type 2 diabetes. Conclusions: Plasma BCAA concentrations are higher post-transplant in type 2 diabetic states, but do not differ by diabetes status in the presence of kidney failure. The association of BCAA with measures of hepatic insulin resistance among nondiabetic post-transplant patients is consistent with impaired BCAA metabolism as a characteristic of kidney transplantation.

Contexte: Le diabète post-transplantation (DPT) englobe les nouvelles manifestations du diabète de type 2 nouveau et le diabète précédemment non reconnu. L'insuffisance rénale masque le diabète de type 2. Les acides aminés à chaîne ramifiée (AACR) sont étroitement liés au métabolisme du glucose. Par conséquent, la compréhension du métabolisme des acides aminés à chaîne ramifiée (AACR) à la fois dans l'insuffisance rénale et après la transplantation rénale peut informer les mécanismes de DPT. Objectifs: Comprendre l'impact de la présence ou de l'absence de fonction rénale sur les concentrations plasmatiques d'AACR. Type d'étude: Étude transversale portant sur des receveurs d'une greffe rénale et des candidats à une transplantation de rein. Cadre: Un grand centre de transplantation rénale de Toronto (Canada). Mesures: Nous avons mesuré les concentrations plasmatiques d'AACR et d'AA aromatiques (AAA) chez 45 candidats pré-transplantation rénale (15 atteints de diabète de type 2; 30 non-diabétiques) et 45 patients ayant reçu une greffe rénale (15 DPT, 30 non-DPT). Les patients des groupes non-diabétiques ont en outre subi un test de résistance et de sensibilité à l'insuline à la suite de l'administration orale de 75 g de glucose. Méthodologie: Les concentrations plasmatiques d'AA ont été analysées à l'aide de l'appareil Mass Chrom AA Analysis et comparées entre les groupes. La sensibilité à l'insuline pour les tests oraux de tolérance au glucose ou l'indice Matsuda (mesure de la résistance à l'insuline dans tout l'organisme), l'évaluation du modèle homéostatique de la résistance à l'insuline (mesure de la résistance hépatique à l'insuline) et l'indice de sensibilité à la sécrétion d'insuline-2 (mesure de la réponse des cellules ß pancréatiques) ont été calculés à partir des concentrations d'insuline et de glucose à jeun, et comparés aux concentrations d'AACR. Résultats: Chacune des concentrations en AACR était plus élevée chez les sujets post-transplantation que chez les sujets pré-transplantation (p < 0,001 pour la leucine, l'isoleucine, la valine). Chez les sujets post-transplantation, chaque concentration d'AACR était plus élevée chez les sujets DPT que chez le cas des sujets non-DPT (RC pour DPT: entre 3 et 4 pour chaque augmentation de l'écart-type; p < 0,001 pour chacun). Les concentrations de tyrosine étaient également plus élevées chez les sujets post-transplantation que chez les sujets pré-transplantation, mais ne différaient pas selon le statut du DPT. En revanche, ni les concentrations d'AACR ni les concentrations d'AAA n'étaient différentes chez les sujets pré-transplantation qu'ils soient ou non atteints de diabète de type 2. La résistance de tout l'organisme à l'insuline, la résistance hépatique à l'insuline et la réponse des cellules ß pancréatiques ne différaient pas entre les sujets non-diabétiques avant ou après la transplantation. Les concentrations d'AACR étaient corrélées avec l'indice Matsuda et l'évaluation du modèle homéostatique de la résistance à l'insuline (p<0,05 pour chacun) uniquement chez les sujets non-diabétiques après la transplantation, et non chez les sujets non-diabétiques avant la transplantation. Les concentrations d'AACR n'étaient pas en corrélation avec l'ISSI-2, que ce soit chez les sujets avant ou après la transplantation. Limites: L'échantillon était de petite taille et les sujets n'ont pas été étudiés prospectivement pour le développement du diabète de type 2. Conclusion: Les concentrations plasmatiques d'AACR sont plus élevées après la transplantation chez les sujets diabétiques de type 2, mais ne diffèrent pas selon le statut du diabète en présence d'une insuffisance rénale. Les associations entre les AACR et les mesures de la résistance hépatique à l'insuline chez les patients non-diabétiques post-transplantation sont cohérentes avec une altération du métabolisme des AACR comme caractéristique de la transplantation rénale.

Numerical solution of DGLAP equations using Laguerre polynomials expansion and Monte Carlo method.

We investigate the numerical solutions of the DGLAP evolution equations at the LO and NLO approximations, using the Laguerre polynomials expansion. The theoretical framework is based on Furmanski et al.'s articles. What makes the content of this paper different from other works, is that all calculations in the whole stages to extract the evolved parton distributions, are done numerically. The employed techniques to do the numerical solutions, based on Monte Carlo method, has this feature that all the results are obtained in a proper wall clock time by computer. The algorithms are implemented in FORTRAN and the employed coding ideas can be used in other numerical computations as well. Our results for the evolved parton densities are in good agreement with some phenomenological models. They also indicate better behavior with respect to the results of similar numerical calculations.

Strongly Metallic Electron and Hole 2D Transport in an Ambipolar Si-Vacuum Field Effect Transistor.

We report experiment and theory on an ambipolar gate-controlled Si(111)-vacuum field effect transistor where we study electron and hole (low-temperature 2D) transport in the same device simply by changing the external gate voltage to tune the system from being a 2D electron system at positive gate voltage to a 2D hole system at negative gate voltage. The electron (hole) conductivity manifests strong (moderate) metallic temperature dependence with the conductivity decreasing by a factor of 8 (2) between 0.3 K and 4.2 K with the peak electron mobility (∼18 m2/V s) being roughly 20 times larger than the peak hole mobility (in the same sample). Our theory explains the data well using random phase approximation screening of background Coulomb disorder, establishing that the observed metallicity is a direct consequence of the strong temperature dependence of the effective screened disorder.

The validity and reliability of the functional rating index for evaluating low back pain in athletes.

The purpose of the present study was to determine the reliability and validity of the Functional Rating Index (FRI) for athletes with low back pain (LBP). In this cross-sectional and prospective cohort study, the validated Persian FRI (PFRI) was tested in 100 athletes with LBP and 50 healthy athletes. From the athletes with LBP, data were recollected among 50 athletes with a 7-day interval to examine test-retest reliability. The content validity was excellent, and the athletes with LBP responded to all items with no floor or ceiling effects. The discriminative validity was supported by a statistically significant difference in PFRI total scores between the athletes with LBP and healthy athletes. The concurrent criterion validity was good (rho = 0.72). The construct, convergent validity was good (r = 0.83). The internal consistency reliability estimate was high (Cronbach's α = 0.90). Factor analysis demonstrated a single-factor structure with an explained variance of 52.22%. The test-retest reliability was excellent, indicated by an ICC(agreement) of 0.97, and the agreement observed in the Bland and Altman plot demonstrated no systematic bias. It is concluded that the PFRI has excellent psychometric properties for assessing athletes with LBP.

A new class of multi-stable neural networks: stability analysis and learning process.

Recently, multi-stable Neural Networks (NN) with exponential number of attractors have been presented and analyzed theoretically; however, the learning process of the parameters of these systems while considering stability conditions and specifications of real world problems has not been studied. In this paper, a new class of multi-stable NNs using sinusoidal dynamics with exponential number of attractors is introduced. The sufficient conditions for multi-stability of the proposed system are posed using Lyapunov theorem. In comparison to the other methods in this class of multi-stable NNs, the proposed method is used as a classifier by applying a learning process with respect to the topological information of data and conditions of Lyapunov multi-stability. The proposed NN is applied on both synthetic and real world datasets with an accuracy comparable to classical classifiers.

Common variants in PCSK1 influence blood pressure and body mass index.

Proprotein convertase subtilisin/kexin-type 1 (PCSK1) activates precursors pro-opiomelanocortin (POMC), proinsulin and prorenin. We investigated if common variants in the PCSK1 gene influence blood pressure and risk of hypertension. Additionally, we investigated the risk of obesity and type 2 diabetes (T2D). In the Rotterdam Study (RS1), a prospective, population-based cohort (n=5974), four single-nucleotide polymorphisms (rs10515237, rs6232, rs436321 and rs3792747) in PCSK1 were studied. Linear and Cox regression models served to analyze associations between variants and end points. Replication was performed in the Rotterdam Study Plus1 (RSPlus1, n=1895). Rs436321 was significantly associated with systolic and diastolic blood pressure and risk of hypertension (odds ratio (OR): 1.1-1.3; P<0.05 in both populations). Rs6232 was associated with body mass index (BMI) (P=0.007 and P=0.04 in RS1 and RSPlus1, respectively). In RSPlus1, heterozygotes for rs6232 had 1.5 times higher risk of obesity (OR: 1.46; 95% confidence interval: 1.04-2.03; P=0.03). We did not find significant associations of PCSK1 with fasting insulin levels and T2D. We found an association of genetic variation in the PCSK1 gene with blood pressure and hypertension. Furthermore, we replicated the association of PCSK1 with BMI and obesity. No relationship was found between PCSK1 variants and fasting insulin levels and T2D. Our findings suggest that genetic variation in PCSK1 may contribute to, at least, some of these interrelated disorders.

Stable isotope dilution microquantification of creatine metabolites in plasma, whole blood and dried blood spots for pharmacological studies in mouse models of creatine deficiency.

BACKGROUND: To develop an accurate stable isotope dilution assay for simultaneous quantification of creatine metabolites ornithine, arginine, creatine, creatinine, and guanidinoacetate in very small blood sample volumes to study creatine metabolism in mice. METHODS: Liquid-chromatography (C18) tandem mass spectrometry with butylation was performed in positive ionization mode. Stable isotope dilution assay with external calibration was applied to three different specimen types, plasma, whole blood and dried blood spot (DBS). RESULTS: Analytical separation, sensitivity, accuracy, and linearity of the assay were adequate. The stable isotope dilution assay in plasma revealed no significant bias to gold standard methods for the respective analytes. Compared to plasma, we observed an overestimate of creatine and creatinine (2- to 5-fold and 1.2- to 2-fold, respectively) in whole-blood and DBS, and an underestimate of arginine (2.5-fold) in DBS. Validation of the assay in mouse models of creatine deficiency revealed plasma creatine metabolite pattern in good accordance with those observed in human GAMT and AGAT deficiency. Single dose intraperitoneal application of ornithine in wild-type mice lead to fast ornithine uptake (Tmax ≤ 10 min) and elimination (T1/2=24 min), and a decline of guanidinoacetate. CONCLUSION: The assay is fast and reliable to study creatine metabolism and pharmacokinetics in mouse models of creatine deficiency.

Replication of TPMT and ABCC3 genetic variants highly associated with cisplatin-induced hearing loss in children.

Cisplatin is a widely used chemotherapeutic agent for the treatment of solid tumors. A serious complication of cisplatin treatment is permanent hearing loss. The aim of this study was to replicate previous genetic findings in an independent cohort of 155 pediatric patients. Associations were replicated for genetic variants in TPMT (rs12201199, P = 0.0013, odds ratio (OR) 6.1) and ABCC3 (rs1051640, P = 0.036, OR 1.8). A predictive model combining variants in TPMT, ABCC3, and COMT with clinical variables (patient age, vincristine treatment, germ-cell tumor, and cranial irradiation) significantly improved the prediction of hearing-loss development as compared with using clinical risk factors alone (area under the curve (AUC) 0.786 vs. 0.708, P = 0.00048). The novel combination of genetic and clinical factors predicted the risk of hearing loss with a sensitivity of 50.3% and a specificity of 92.7%. These findings provide evidence to support the importance of TPMT, COMT, and ABCC3 in the prediction of cisplatin-induced hearing loss in children.

A sensitive and rapid mass spectrometric method for the simultaneous measurement of eight steroid hormones and CALIPER pediatric reference intervals.

OBJECTIVES: To develop an accurate assay and establish the normal reference intervals for serum cortisol, corticosterone, 11-deoxycortisol, androstenedione, 21-hydroxyprogesterone, testosterone, 17-hydroxyprogesterone, and progesterone. These steroids are commonly used as biomarkers for the diagnosis and monitoring of endocrine diseases such as congenital adrenal hyperplasia. Appropriate age- and gender-stratified reference intervals are essential in accurate interpretation of steroid hormone levels. DESIGN AND METHODS: The samples analyzed in this study were collected from healthy, ethnically diverse children in the Greater Toronto Area as part of the CALIPER program. A total of 337 serum samples from children between the ages of 0 and 18years were analyzed. The concentrations were measured by using an LC-MS/MS method. The data were analyzed for outliers and age- and gender-specific partitions were established prior to establishing the 2.5th and 97.5th percentiles for the reference intervals. RESULTS: Reference intervals for all hormones required significant age-dependent stratification while testosterone and progesterone required additional sex-dependent stratification. CONCLUSIONS: We report a sensitive, accurate and relatively fast LC-MS/MS method for the simultaneous measurement of eight steroid hormones. Detailed reference intervals partitioned based on both age and gender were also established for all eight steroid hormones.

Prediction of codeine toxicity in infants and their mothers using a novel combination of maternal genetic markers.

Substantial variation exists in response to standard doses of codeine ranging from poor analgesia to life-threatening central nervous system (CNS) depression. We aimed to discover the genetic markers predictive of codeine toxicity by evaluating the associations between polymorphisms in cytochrome P450 2D6 (CYP2D6), UDP-glucuronosyltransferase 2B7 (UGT2B7), P-glycoprotein (ABCB1), mu-opioid receptor (OPRM1), and catechol O-methyltransferase (COMT) genes, which are involved in the codeine pathway, and the symptoms of CNS depression in 111 breastfeeding mothers using codeine and their infants. A genetic model combining the maternal risk genotypes in CYP2D6 and ABCB1 was significantly associated with the adverse outcomes in infants (odds ratio (OR) 2.68; 95% confidence interval (CI) 1.61-4.48; P(trend) = 0.0002) and their mothers (OR 2.74; 95% CI 1.55-4.84; P(trend) = 0.0005). A novel combination of the genetic and clinical factors predicted 87% of the infant and maternal CNS depression cases with a sensitivity of 80% and a specificity of 87%. Genetic markers can be used to improve the outcome of codeine therapy and are also probably important for other opioids sharing common biotransformation pathways.

Partial stabilization of uncertain nonlinear systems.

In this paper, the problem of robust partial stabilization is considered and two approaches for partial stabilization of uncertain nonlinear systems are presented. In these approaches, the nonlinear dynamical system is divided into two subsystems, which are called the first and the second subsystems. This division is done based on the required stability properties of the system's states. The reduced input vector (the vector that includes components of the input vector appearing in the first subsystem) is designed to asymptotically stabilize the first subsystem. In the first approach, a new partial stabilization technique, based on the first order sliding mode control idea is proposed. In the proposed method, hereafter called the partial sliding mode, a sliding surface is designed such that restricting the motion on this surface guarantees the stability of only the first part of the system's state. In the second approach, a Lyapunov-based controller is proposed for partial stabilization and then an additional feedback control is designed so that the overall feedback law guarantees a robust manner in the presence of uncertainties.

Mass and stiffness calibration of nanowires using thermally driven vibration.

Cantilevered or suspended nanowires show promise for force or mass sensing applications due to their small mass, high force sensitivity and high frequency bandwidth. To use these as quantitative sensors, their bending stiffness or mass must be calibrated experimentally, often using thermally driven vibration. However, this can be difficult because nanowires are slightly asymmetric, which results in two spatially orthogonal bending eigenmodes with closely spaced frequencies. This asymmetry presents problems for traditional stiffness calibration methods, which equate the measured thermal vibration spectrum near a resonance to that of a single eigenmode. Moreover, the principal axes may be arbitrarily rotated with respect to the measurement direction. In this work, the authors propose a method for calibrating the bending stiffness and mass of such nanowires' eigenmodes using a single measurement taken at an arbitrary orientation with respect to the principal axes.

Using PCA and LVQ neural network for automatic recognition of five types of white blood cells.

Designing an effective classifier has been a challenging task in the previous methods proposed in the literature. In this paper, we apply a combination of feature selection algorithm and neural network classifier in order to recognize five types of white blood cells in the peripheral blood. For this purpose, first nucleus and cytoplasm are segmented using Gram-Schmidt method and snake algorithm, respectively; second, three kinds of features are extracted from the segmented areas. Then the best features are selected using Principal Component Analysis (PCA). Finally, five types of white blood cells are classified using Learning Vector Quantization (LVQ) neural network. The performance analysis of the proposed algorithm is validated by an expert's classification results. The efficiency of the proposed algorithm is highlighted by comparing our results with those reported in a recent article which proposed a method based on the combination of Sequential Forward Selection (SFS) as the feature selection algorithm and Support Vector Machines (SVM) as the classifier.

Stabilization of nonlinear systems with a slowly varying parameter by a control Lyapunov function.

Based on a control Lyapunov function (CLF) strategy, a novel approach for designing a controller for a slowly varying nonlinear system is proposed. The approach may be thought of as being in between the time-invariant and time-varying CLF techniques. If the time-invariant technique is used to control a slowly varying system, stability will not be guaranteed. On the other hand, the time-varying CLF technique, due to the control law, has complexity and needs to measure or estimate the derivative of system parameters. The advantage of the proposed method is its independence from the measurement or estimation of the derivatives of the system parameters. It is shown that the proposed control law can even be independent of the parameters of the system. In this paper, the conditions are derived that allow using the simple CLF formula that guarantees the stability of a slowly varying system. The efficiency of the approach is shown through some simulations.

Sex-specific genetic effects influence variation in body composition.

AIMS/HYPOTHESIS: Despite well-known sex differences in body composition it is not known whether sex-specific genetic or environmental effects contribute to these differences. METHODS: We assessed body composition in 2,506 individuals, from a young Dutch genetic isolate participating in the Erasmus Rucphen Family study, by dual-energy X-ray absorptiometry and anthropometry. We used variance decomposition procedures to partition variation of body composition into genetic and environmental components common to both sexes and to men and women separately and calculated the correlation between genetic components in men and women. RESULTS: After accounting for age, sex and inbreeding, heritability ranged from 0.39 for fat mass index to 0.84 for height. We found sex-specific genetic effects for fat percentage (fat%), lean mass, lean mass index (LMI) and fat distribution, but not for BMI and height. Genetic correlations between sexes were significantly different from 1 for fat%, lean mass, LMI, android fat, android:gynoid fat ratio and WHR, indicating that there are sex-specific genes contributing to variation of these traits. Genetic variance was significantly higher in women for the waist, hip and thigh circumference and WHR, implying that genes account for more variance of fat distribution in women than in men. Environmental variance was significantly higher in men for the android:gynoid fat ratio. CONCLUSIONS/INTERPRETATION: Sex-specific genetic effects underlie sexual dimorphism in several body composition traits. The findings are relevant for studies on the relationship of body composition with common diseases like cardiovascular disease and type 2 diabetes and for genetic association studies.

Oral poliovirus vaccine in management of recurrent aphthous stomatitis.

Oral poliovirus vaccine (OPV) is reported to be effective in treatment of recurrent herpes simplex (RHS). According to our observation during recent years, OPV was not only effective in management of RHS but also in some patients with concomitant recurrent aphthous stomatitis (RAS) reducing its severity and frequency. The purpose of this study was to evaluate the efficacy of OPV in the management of RAS. In a longitudinal, case--control study 48 patients with RAS were recruited. Twenty patients received OPV and 28 patients received placebo. OPV was administered in a dose of 4 drops at monthly intervals for 3 months to the study group while the control group received placebo. The results were registered in 3 months after the last dose. Eight cases (40%) in the OPV group showed significant reduction in the duration of the ulcers, while no change was seen in the control group (P = 0.048). The frequency of recurrence of RAS was reduced in 13 cases (65%) in the OPV group, and in 6 cases (21.4%) of the placebo group (P = 0.006). The severity of attacks was reduced in 12 cases (60%) in the OPV group and in 4 cases (14.3%) in the placebo group (P = 0.008). In conclusion OPV appeared to be effective in the management of RAS.

Efficacy of 80% phenol solution in comparison with cryotherapy in the treatment of common warts of hands.

INTRODUCTION: The common wart is a common infectious disease caused by human papilloma virus. A variety of therapeutic modalities are available. Cryotherapy (liquid nitrogen) is one of the most common treatment forms. It freezes the tissue and destroys warts. Phenol is a caustic agent. Our purpose was to evaluate and compare the efficacy of cryotherapy and 80 percent phenol solution on common warts of hands. METHODS: This single-blinded clinical trial study was performed on 60 patients with common warts referred to the dermatology clinic of Ghaem Hospital Mashhad, Iran, in 2002. Patients were randomly divided into two groups; 30 patients were treated with cryotherapy and 30 patients were treated with 80 percent phenol, on a once-weekly basis until complete clearance of the lesions or a maximum duration of six weeks. RESULTS: Complete clearance of warts after six weeks was observed in 70 percent of patients who were treated with cryotherapy, and 82.6 percent of patients in the 80 percent phenol group; there was no statistically significant difference between the two methods (p-value is 0.014). CONCLUSION: Our data indicates that 80 percent phenol and cryotherapy are effective and simple treatments for common warts of hands, and patients do not experience any pain during the treatment.

Polymorphisms of the renin-angiotensin system are associated with blood pressure, atherosclerosis and cerebral white matter pathology.

BACKGROUND: The renin-angiotensin system is involved in the development of hypertension, atherosclerosis and cardiovascular disease. We studied the association between the M235T polymorphism of the angiotensinogen gene (AGT) and the C573T polymorphism of the angiotensin II type 1 receptor (AT1R) and blood pressure, carotid atherosclerosis and cerebrovascular disease. METHODS: We genotyped over 6000 subjects from the Rotterdam Study and more than 1000 subjects from the Rotterdam Scan Study. We used logistic regression and univariate analyses, adjusting for age and sex with, for AGT, the MM and, for AT1R, the TT genotype as reference. RESULTS: We found that AGT-235T increased systolic (p for trend = 0.03) and diastolic blood pressure (p for trend = 0.04). The prevalence of carotid plaques was increased 1.25-fold (95% CI 1.02-1.52) in AGT-TT carriers. There was a significant increase in mean volume deep subcortical white matter lesions (WML) for AGT-TT carriers (1.78 ml vs 1.09 ml in the reference group; p = 0.008). A significant interaction was found between AGT and AT1R, further increasing the effect on periventricular and subtotal WML (p for interaction = 0.02). We found a non-significant increased risk of silent brain infarction for AGT-TT carriers and AT1R-CC carriers, but no effect on stroke. CONCLUSION: We found an association between AGT and blood pressure, atherosclerosis and WML. Also, we found synergistic effects between AGT and AT1R on the development of WML. These findings raise the question of whether the renin-angiotensin system may be a therapeutic target for the prevention of cerebral white matter pathology.