Association between carotid plaque characteristics and cerebral white matter lesions: one-year follow-up study by MRI

Objective

To prospectively assess the relation between carotid plaque characteristics and the development of new cerebral white matter lesions (WMLs) at MRI.

Methods

Fifty TIA/stroke patients with ipsilateral 30–69% carotid stenosis underwent MRI of the plaque at baseline. Total plaque volume and markers of vulnerability to thromboembolism (lipid-rich necrotic core [LRNC] volume, fibrous cap [FC] status, and presence of intraplaque hemorrhage [IPH]) were assessed. All patients also underwent brain MRI at baseline and after one year. Ipsilateral cerebral WMLs were quantified with a semiautomatic method.

Results

Mean WML volume significantly increased over a one-year period (6.52 vs. 6.97 mm³, P = 0.005). WML volume at baseline and WML progression did not significantly differ (P>0.05) between patients with 30–49% and patients with 50–69% stenosis. There was a significant correlation between total plaque volume and baseline ipsilateral WML volume (Spearman ρ = 0.393, P = 0.005). There was no significant correlation between total plaque volume and ipsilateral WML progression. There were no significant associations between LRNC volume and WML volume at baseline and WML progression. WML volume at baseline and WML progression did not significantly differ between patients with a thick and intact FC and patients with a thin and/or ruptured FC. WML volume at baseline and WML progression also did not significantly differ between patients with and without IPH.

Conclusion

The results of this study indicate that carotid plaque burden is significantly associated with WML severity, but that there is no causal relationship between carotid plaque vulnerability and the occurrence of WMLs.     

In vivo gene transfer to cerebral white matter lesions with a recombinant adenovirus vector

Ischemic white matter lesions have been reported in rats after bilateral common carotid ligation (BCAL). Previously, comparing normotensive rats (WKY) with spontaneously hypertensive rats (SHR), we too found that sustained moderate ischemia with spontaneous hypertension accelerated the formation of ischemic white matter lesions. In this study, we explored the feasibility of gene therapy for lesioned white matter by means of an adenovirus vector expressing a reporter gene, LacZ. Using sham-operated and hypoperfused SHR as well as sham-operated and hypoperfused WKY, we demonstrated that (i) adenovirus vectors could deliver a foreign gene into oligodendrocytes and astrocytes in the cerebral white matter; (ii) the transduction efficiency was most effective in SHR after BCAL; and (iii) the level of alpha(V)-integrin was significantly correlated with adenoviral transduction efficiency.     

Severe deep white matter lesions and outcome in elderly patients with major depressive disorder: follow up study

Objective To determine the difference in outcome among elderly people with major depression who do and do not have severe white matter lesions on magnetic resonance imaging.Design Follow up study.Setting Two psychiatric and two general hospitals in Melbourne, Australia.Subjects 60 depressed subjects aged over 55 referred to hospital psychiatric services with major depressive disorder meeting American Psychiatric Association (DSM-IIIR) criteria.Main outcome measure Proportion with good outcome as determined by full recovery from initial illness and no evidence of depressive relapse or cognitive decline during follow up among those with and without lesions.Results Mean (SD) follow up was 31.9 (9.9) months. Survival analysis showed a significant effect of severe lesions on time to poor outcome (P=0.04), with median survival 136 days in those with severe lesions compared with 315 days in those without.Conclusion Severe white matter change on magnetic resonance imaging is associated with poor outcome in elderly depressed subjects.

Key messages

• Severe deep white matter lesions on magnetic resonance imaging are common in elderly patients with depression
• Patients with these lesions are at greater risk of poor long term outcome (chronicity and relapse) than those without lesions
• The neuropathogical and neurochemical correlates of these white matter changes need investigation

     

Shortened bleeding time in acute myocardial infarction and its relation to platelet mass.

The bleeding time, using the Simplate method, horizontal incision, and venostasis, was measured in a study of 51 patients admitted to a coronary care unit within 12 hours of the onset of chest pain. The bleeding time was significantly shorter in the 28 patients who were found to have definite myocardial infarction compared with the 23 others with chest pain but no definite infarction (p less than 0.0005). A bleeding time of less than 212 seconds correctly classified 84% of patients (sensitivity for definite myocardial infarction 89%) presenting to the coronary care unit with chest pain. Multiple regression analysis showed the bleeding time in all patients to be determined independently (and with high significance) by the following variables in order of importance: diagnostic group, platelet mass (platelet count X mean volume), and age. Packed cell volume was not a significant determinant. In the group with definite myocardial infarction considered alone the same order of variables was observed in predicting bleeding time, but none of them was significant. A major variable reducing bleeding time in acute myocardial infarction remains to be determined. There was no association between bleeding time and creatine phosphokinase activity or infarct size in the group with definite myocardial infarction.     

Common carotid wall shear stress and carotid atherosclerosis in end-stage renal disease patients

Decrease of arterial wall shear stress (WSS) is associated with higher probability of atherosclerotic plaque development in many disease conditions. End-stage renal diseases (ESRD) patients suffer from vascular disease frequently, but its nature differs from general population. This study was aimed at proving an association between common carotid wall shear stress and the presence of carotid bifurcation plaques in a group of ESRD patients. ESRD subjects, planned for the creation of a dialysis access and therapy were included. Wall shear rate (WSR) was used as a surrogate of WSS and was analyzed in the common carotid arteries by duplex ultrasonography. Intima media thickness (IMT) was measured at the same site. The presence/absence of carotid bifurcation plaques was recorded. The endothelial function was estimated by the levels of von Willebrand factor (vWf). 35 ESRD patients were included (19 females, 17 diabetics). Atherosclerotic plaque was present in 53 % of bifurcations. Wall shear rate was lower in arteries with plaques (349+/-148 vs. 506+/-206 s(-1), p=0.005) and was directly related to the height of IMT and inversely to the activity of vWf (r= -0.65, p=0.016). Lower wall shear rate in the common carotid arteries is linked to the endothelial dysfunction and to the presence of atherosclerotic plaques in carotid bifurcations in ESRD subjects. Faster arterial dilatation may facilitate this process in ESRD subjects.     

Improved sensitivity to cerebral white matter abnormalities in Alzheimer's disease with spherical deconvolution based tractography

Diffusion tensor imaging (DTI) based fiber tractography (FT) is the most popular approach for investigating white matter tracts in vivo, despite its inability to reconstruct fiber pathways in regions with "crossing fibers." Recently, constrained spherical deconvolution (CSD) has been developed to mitigate the adverse effects of "crossing fibers" on DTI based FT. Notwithstanding the methodological benefit, the clinical relevance of CSD based FT for the assessment of white matter abnormalities remains unclear. In this work, we evaluated the applicability of a hybrid framework, in which CSD based FT is combined with conventional DTI metrics to assess white matter abnormalities in 25 patients with early Alzheimer's disease. Both CSD and DTI based FT were used to reconstruct two white matter tracts: one with regions of "crossing fibers," i.e., the superior longitudinal fasciculus (SLF) and one which contains only one fiber orientation, i.e. the midsagittal section of the corpus callosum (CC). The DTI metrics, fractional anisotropy (FA) and mean diffusivity (MD), obtained from these tracts were related to memory function. Our results show that in the tract with "crossing fibers" the relation between FA/MD and memory was stronger with CSD than with DTI based FT. By contrast, in the fiber bundle where one fiber population predominates, the relation between FA/MD and memory was comparable between both tractography methods. Importantly, these associations were most pronounced after adjustment for the planar diffusion coefficient, a measure reflecting the degree of fiber organization complexity. These findings indicate that compared to conventionally applied DTI based FT, CSD based FT combined with DTI metrics can increase the sensitivity to detect functionally significant white matter abnormalities in tracts with complex white matter architecture.     

Alterations in serum selenium levels and their relation to troponin I in acute myocardial infarction

Selenium (Se) is an essential trace element with antioxidant function. The aim of the present study was to estimate the alterations of Se serum level during the acute phase of myocardial infarction and its relation to biomarkers of myocardial necrosis. Serum Se levels were measured at admission and after 24 h in 60 consecutive patients with acute coronary syndrome (both with and without ST elevation). Troponin I (TnI) was assessed at admission and then twice daily for 3 days; patients with normal levels were excluded. Fifty-five patients with acute MI (positive TnI) were included into the analysis. During the first day of hospitalization, patients received standard therapy, including acetylsalicylic acid, clopidogrel, and heparin or enoxaparin; all underwent urgent coronary angiography and percutaneous intervention, when appropriate. Mean Se levels at baseline and 24 h later were comparable (67.1 ± 2.1 vs. 67.2 ± 1.8 μg/L, ns). Linear regression has shown significant correlation between baseline Se levels and peak TnI (y = 3.4x ? 116, r ² = 0.13, P = 0.008). Positive correlation was found also between the peak TnI and the difference from baseline to 24 h (y = 2.2x + 115, r ² = 0.08, P = 0.04). Moreover, close negative correlation was observed between baseline Se levels and the difference from baseline to 24 h (y = ?0.9x + 62.7, r ² = 0.55, P<0.001). Our results have shown marked individual changes in Se levels during the acute phase of MI as well as correlation between Se levels and peak TnI. These results suggest that alterations in serum Se may be related to the extent of myocardial infarction.     

Sepiapterin enhances angiogenesis and functional recovery in mice after myocardial infarction

Uncoupling of nitric oxide synthase (NOS) has been implicated in left ventricular (LV) remodeling and dysfunction after myocardial infarction (MI). We hypothesized that inducible NOS (iNOS) plays a crucial role in LV remodeling after MI, depending on its coupling status. MI was created in wild-type, iNOS-knockout (iNOS(-/-)), endothelial NOS-knockout (eNOS(-/-)), and neuronal NOS-knockout (nNOS(-/-)) mice. iNOS and nNOS expressions were increased after MI associated with an increase in nitrotyrosine formation. The area of myocardial fibrosis and LV end-diastolic volume and ejection fraction were more deteriorated in eNOS(-/-) mice compared with other genotypes of mice 4 wk after MI. The expression of GTP cyclohydrolase was reduced, and tetrahydrobiopterin (BH(4)) was depleted in the heart after MI. Oral administration of sepiapterin after MI increased dihydrobiopterin (BH(2)), BH(4), and BH(4)-to-BH(2) ratio in the infarcted but not sham-operated heart. The increase in BH(4)-to-BH(2) ratio was associated with inhibition of nitrotyrosine formation and an increase in nitrite plus nitrate. However, this inhibition of NOS uncoupling was blunted in iNOS(-/-) mice. Sepiapterin increased capillary density and prevented LV remodeling and dysfunction after MI in wild-type, eNOS(-/-), and nNOS(-/-) but not iNOS(-/-) mice. N(ω)-nitro-L-arginine methyl ester abrogated sepiapterin-induced increase in nitrite plus nitrate and angiogenesis and blocked the beneficial effects of sepiapterin on LV remodeling and function. These results suggest that sepiapterin enhances angiogenesis and functional recovery after MI by activating the salvage pathway for BH(4) synthesis and increasing bioavailable nitric oxide predominantly derived from iNOS.     

Comparison of case fatality in south Asian and white patients after acute myocardial infarction: observational study.

OBJECTIVE--To compare mortality in south Asian (Indian, Pakistani, and Bangladeshi) and white patients in the six months after hospital admission for acute myocardial infarction. DESIGN--Observational study. SETTING--District general hospital in east London. PATIENTS--149 south Asian and 313 white patients aged < 65 years admitted to the coronary care unit with acute myocardial infarction from 1 December 1988 to 31 December 1992. MAIN OUTCOME MEASURE--All cause mortality in the first six months after myocardial infarction. RESULTS--The admission rate in the south Asians was estimated to be 2.04 times that in the white patients. Most aspects of treatment were similar in the two groups, except that a higher proportion of the south Asians received thrombolytic drugs (81.2% v 73.8%). After adjustment for age, sex, previous myocardial infarction, and treatment with thrombolysis or aspirin, or both, the south Asians had a poorer survival over the six months from myocardial infarction (hazard ratio 2.02 (95% confidence interval 1.14 to 3.56), P = 0.018), but a substantially higher proportion were diabetic (38% v 11%, P < 0.001), and additional adjustment for diabetes removed much of their excess risk (adjusted hazard ratio 1.26 (0.68 to 2.33), P = 0.47). CONCLUSION--South Asian patients had a higher risk of admission with myocardial infarction and a higher risk of death over the ensuing six months than the white patients. The higher case fatality among the south Asians, largely attributable to diabetes, may contribute to the increased risk of death from coronary heart disease in south Asians living in Britain.     

Disturbances of insulin in British Asian and white men surviving myocardial infarction.

OBJECTIVE--To examine the role of insulin as a cardiovascular risk factor in British Asian and white men. DESIGN--Case-controlled study of survivors of first myocardial infarction. SETTING--District general hospital. PATIENTS--Consecutive series of 76 white and 74 Asian men who survived first myocardial infarction compared with 58 white and 61 Asian male controls without coronary artery disease who were randomly sampled from the community. RESULTS--More Asians than white subjects had impaired glucose tolerance or overt diabetes as measured by the two hour glucose tolerance test (23/74 (32%) v 11/76 (15%) (p less than 0.001) among patients; 17/61 (28%) v 3/58 (6%) (p less than 0.001) among controls). Insulin and C peptide concentrations were higher in both patient groups than in respective controls (p less than 0.001) and higher in Asian than in white subjects, irrespective of their glucose tolerance. Triglyceride concentrations were higher in patients than in controls (1.92 (SD 1.05) v 1.43 (0.82) mmol/l among Asian men; 1.65 (0.83) v 1.3 (0.61) mmol/l among white subjects; p less than 0.001). Total cholesterol concentrations were lower in both groups of Asians than in respective white subjects (5.78 (0.99) v 6.22 (1.04) mmol/l (p less than 0.01) among patients; 5.54 (1.01) v 5.65 (1.11) mmol/l (p less than 0.6) among controls). High density lipoprotein cholesterol concentrations were lower in Asian than in white subjects. The ratio of total cholesterol to high density lipoprotein cholesterol was significantly higher (p less than 0.001) in both patient groups (6.69 (1.81) in Asian patients and 6.31 (1.91) in white patients) than in respective controls (5.24 (1.19) and 4.77 (1.43)). Regression analysis identified C peptide concentration and the ratio of total to high density lipoprotein cholesterol as powerful independent predictors of myocardial infarction in Asian and white men. Total cholesterol concentration predicted infarction in white but not in Asian men. CONCLUSIONS--Secretion and hepatic extraction of insulin are high in survivors of myocardial infarction and especially high in British Asians. Tissue resistance to the action of insulin, giving rise to increased pancreatic secretion, may be an important risk factor for coronary artery disease in both ethnic groups and may be partly responsible for the high incidence of diabetes and coronary artery disease in Asian populations.     

Light/dark patterns of interleukin-6 in relation to the pineal hormone melatonin in patients with acute myocardial infarction

AIMS: Atherosclerosis is a chronic disease that, from its origin to its ultimate complications, involves inflammatory cells, inflammatory proteins, and inflammatory responses from vascular cells. It has been demonstrated that cytokine activities are under neuroendocrine control, in part exerted by the pineal gland through the circadian secretion of its main product melatonin. Melatonin is mainly released during the night, but the precise relationship between melatonin and the light/dark rhythm of interleukin-6 in patients with acute myocardial infarction is still unclear. METHODS AND RESULTS: The study included 60 patients diagnosed with acute myocardial infarction and 60 healthy volunteers whose venous blood samples were collected at 09:00 h (light period) and 02:00 h (dark period). Our results demonstrate that interleukin-6 concentrations presented a light/dark pattern with mean serum concentrations being higher in the acute myocardial infarction group than in the control group (101.26 +/- 13.43 and 52.67 +/- 7.73 pg/ml at 02:00 h, 41.93 +/- 5.90 and 22.98 +/- 4.49 pg/ml at 09:00 h, respectively, p < 0.05). Differences in the day/night changes in melatonin levels in control subjects (48.19 +/- 7.82 at 02:00 h, 14.51+/- 2.36 at 09:00 h, pg/ml) and acute myocardial infarction patients (25.97 +/- 3.90 at 02:00 h, 12.29 +/- 4.01 at 09:00 h, pg/ml) (p < 0.05) were a result of a reduced nocturnal elevation of melatonin in the acute myocardial infarction group. CONCLUSIONS: The current findings suggest that the circadian secretion of melatonin may be responsible at least in part for light/dark variations of endogenous interleukin-6 production in patients with acute myocardial infarction. In this study, the melatonin seems to have an anti-inflammatory effect.     

Hypoxia during pregnancy in rats leads to the changes of the cerebral white matter in adult offspring

The aim of the present study is to evaluate the effect of reduced fetal oxygen supply on cerebral white matter in the adult offspring and further assess its susceptibility to postnatal hypoxia and high-fat diet. Based on a 3 × 2 full factorial design consisting of three factors of maternal hypoxia, postnatal high-fat diet, and postnatal hypoxia, the ultrastructure of myelin, axon and capillaries were observed, and the expression of myelin basic protein (MBP), neurofilament-H+L(NF-H+L), and glial fibrillary acidic protein (GFAP) was analyzed in periventricular white matter of 16-month-old offspring. Demyelination, injured axon and damaged microvasculars were observed in maternal hypoxia offspring. The main effect of maternal hypoxia lead to decreased expression of MBP or NF-H+L, and increased expression of GFAP (all P < 0.05). Moreover, there was positive three-way interaction among maternal hypoxia, high-fat diet and postnatal hypoxia on MBP, NF-H+L or GFAP expression (all P < 0.05). In summary, our results indicated that maternal hypoxia during pregnancy in rats lead to changes of periventricular white matter in adult offspring, including demyelination, damaged axon and proliferated astroglia. This effect was amplified by high-fat diet and postnatal hypoxia.     

Different processing of Alzheimer's beta-protein precursor in the vessel wall of patients with hereditary cerebral hemorrhage with amyloidosis-Dutch type

Hereditary cerebral hemorrhage with amyloidosis in patients of Dutch origin is an autosomal-dominant type of amyloidosis restricted to the small vasculature of the brain and clinically characterized by recurrent strokes. Amyloid fibrils from the leptomeninges of two patients were isolated and the primary structure determined. The complete sequence of the amyloid protein shows homology to the vascular (beta-protein) and plaque amyloid (A4-protein) obtained from Alzheimer's Disease. However, it is three residues shorter (39 instead of 42) than that reported for the plaque amyloid. The difference at the carboxy terminal may reflect specific degradation that occurs in the vessel wall and not in the brain parenchyma.     

Soil microbial activity in relation to dissolved organic matter properties under different tree species

Background and aims

The total concentration of dissolved organic carbon (DOC) has often been observed to correlate positively with soil microbial respiration. The aim was to explain the correlation with the properties of dissolved organic matter (DOM).

Methods

A dataset from previously published papers was gathered together and subjected to multivariate analyses. Samples were collected from five tree species experiments in Finland. The degradability of DOM was assessed by measuring bacterial and fungal growth in DOM. The chemical properties of DOM were assessed by XAD resin fractionation and molecular weight. Soil microbial activity was assessed as C and N mineralization and microbial biomass.

Results

Both low and high molecular weight compounds, as well as hydrophilic neutral compounds, seemed to be relatively easily degradable. In contrast to our presupposition, easily degradable DOM seemed to be less abundant in soil where variables describing microbial activity were higher. Birch soil with higher microbial biomass N seemed to contain less easily degradable DOM than spruce soil.

Conclusion

We suggest that DOM collected and characterized at a certain point reflects more the accumulation of refractory compounds following high microbial activity than the easily degradable compounds that microbes would be using when measured.