Background-Elevated asymmetrical dimethylarginine (ADMA) is a novel risk factor for atherosclerosis that may impair endothelial function by interfering with endothelial nitric oxide synthesis. To gain insight into the effects of ADMA on systemic endothelial function, we examined the association between ADMA and brachial artery flow-mediated dilation (FMD) in a large population of young adults. Methods and Results-Plasma ADMA and brachial FMD, as well as conventional cardiovascular risk factors, were measured in 2096 white adults aged 24 to 39 years. In univariate analysis, ADMA was inversely correlated with FMD (rϭϪ0.07, Pϭ0.003). The inverse association between ADMA and FMD remained significant in a multivariable regression model adjusted for age, sex, conventional cardiovascular risk factors, estimated glomerular filtration rate, and brachial artery baseline diameter (␤ϮSE Ϫ1.56Ϯ0.62%, Pϭ0.01). Conclusions-We conclude that elevated plasma ADMA concentrations are associated with decreased brachial FMD responses in healthy adults. These data provide evidence at the population level that ADMA levels are associated with endothelial function.

Traumatic brain injury (TBI) is a major cause of disability and death in people of all ages worldwide. An initial brain injury caused by external mechanical forces triggers a cascade of tissue changes that lead to a wide spectrum of symptoms and disabilities, such as cognitive deficits, mood or anxiety disorders, motor impairments, chronic pain, and epilepsy. We investigated the detectability of secondary injury at a chronic time-point using ex vivo diffusion tensor imaging (DTI) in a rat model of TBI, lateral fluid percussion (LFP) injury. Our analysis of ex vivo DTI data revealed persistent microstructural tissue changes in white matter tracts, such as the splenium of the corpus callosum, angular bundle, and internal capsule. Histologic examination revealed mainly loss of myelinated axons and/or iron accumulation. Gray matter areas in the thalamus exhibited an increase in fractional anisotropy associated with neurodegeneration, myelinated fiber loss, and/or calcifications at the chronic phase. In addition, we examined whether these changes could also be detected with in vivo settings at the same chronic time-point. Our results provide insight into DTI detection of microstructural changes in the chronic phase of TBI, and elucidate how these changes correlate with cellular level alterations.

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BackgroundThe purpose of the present study was to investigate pregnancy-related changes in the maternal serum lipid profile and endothelial function. Methods and ResultsAs part of the population-based, prospective cohort Cardiovascular Risk in Young Finns study conducted in Finland, 57 pregnant Finnish women and 62 control women matched for age and smoking were examined throughout gestation. Serum triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were determined and concomitantly endothelium-dependent brachial artery flow mediated dilation (FMD) was measured by ultrasound. During pregnancy serum TC, LDL-C, HDL-C, TG and very-low-density lipoprotein cholesterol increased significantly when compared with the non-pregnant state (p<0.001 for each) and towards the end of pregnancy (p<0.001, p<0.001, p=0.007, p<0.001, p<0.001). FMD increased towards the end of pregnancy and there was a statistically significant direct correlation between gestational age and FMD% (r=0.345, p=0.010). Brachial artery diameter at rest and FMD% were negatively correlated in pregnant (r=-0.280, p=0.035) and non-pregnant women (r=-0.360, p<0.004). The univariate correlation analysis showed a direct correlation between maternal serum TC (r=0.333, p=0.012) and TG (r=0.366, p=0.006) and FMD%, whereas a negative non-significant correlation was found in non-pregnant women. In a multivariate model, vessel size ( =-0.436, p=0.001) and TG ( =0.502, p<0.001) were the most powerful predictors for FMD% in pregnancy, the influence of other lipids was non-significant. Conclusions In healthy pregnant women increased gestational age is associated with improved endothelium-dependent vasodilation responses regardless of concurrently appearing lipid changes. (Circ J 2006; 70: 768 -772)

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Diffusion tensor imaging (DTI) has become a valuable tool to investigate white matter integrity in the brain. DTI also gives contrast in gray matter, which has been relatively little explored in studies assessing post-injury structural abnormalities. The present study was designed to compare white and gray matter reorganization in the rat hippocampus after two epileptogenic brain injuries, status epilepticus (SE) and traumatic brain injury (TBI), using ex vivo high-resolution DTI. Imaging was performed at 6-12 months post-injury and findings were compared to histological analyses of Nissl, myelin, and Timm-stained preparations from the same animals. In agreement with the severity of histological damage, fractional anisotropy (FA), axial (D ||) and radial (D ⊥) diffusivities, and mean diffusivity (MD) measurements were altered in the order SE > TBI ipsilaterally > TBI contralaterally. After SE, the most severe abnormalities were found in the dentate gyrus and CA3b-c subfields, in which the mean FA was increased to 125 % (p < 0.001) and 143 % (p < 0.001) of that in controls, respectively. In both subfields, the change in FA was associated with an increase in D || (p < 0.01). In the stratum radiatum of the CA1, FA was decreased to 81 % of that in controls (p < 0.05) which was associated with an increase in D ⊥ (p < 0.01). After TBI, DTI did not reveal any major abnormalities in the dentate gyrus. In the ipsilateral CA3b-c, however, FA was increased to 126 % of that in controls (p < 0.01) and associated with a mild decrease in D ⊥ (p < 0.05). In the stratum radiatum of the ipsilateral CA1, FA was decreased to 88 % of that in controls (p < 0.05). Our data demonstrate that DTI reveals subfield-specific abnormalities in the hippocampus with remarkable qualitative and quantitative differences between the two epileptogenic etiologies, suggesting that DTI could be a valuable tool for follow-up of focal circuitry reorganization during the post-injury aftermath.

Understanding the pathophysiological mechanisms underlying Alzheimer disease (AD) relies on knowledge of disease onset and the sequence of development of brain pathologies. We present a comprehensive analysis of early and progressive changes in a mouse model that demonstrates a full spectrum of characteristic AD-like pathologies. This model demonstrates an altered immune redox state reminiscent of the human disease and capitalizes on data indicating critical differences between human and mouse immune responses, particularly in nitric oxide (NO) levels produced by immune activation of the NOS2 gene. Using the APPSwDI+/+/mNos2−/− (CVN-AD) mouse strain, we show a sequence of pathological events leading to neurodegeneration that include pathologically hyperphosphorylated tau in the perforant pathway at 6 weeks of age progressing to insoluble tau, the early appearance of β-amyloid peptides in perivascular deposits around blood vessels in brain regions known to be vulnerable in AD and progression to damage and overt loss in select vulnerable neuronal populations in these regions. The role of species differences between hNOS2 and mNos2 was supported by generating mice in which the human NOS2 gene replaced mNos2. When crossed to CVN-AD mice, pathological characteristics of this new strain (APPSwDI+/−/huNOS2t +/+g/mNos2−/−) mimicked the pathological phenotypes found in the CVN-AD strain.