Neural development in the marsupial frog Gastrotheca riobambae

Hypertriglyceridemia may contribute to the development of atherosclerosis by increasing expression of cell adhesion molecules (CAMs). Although the cellular expression of CAMs is difficult to assess clinically, soluble forms of CAMs (sCAMs) are present in the circulation and may serve as markers for CAMs. In this study, we examined the association between sCAMs and other risk factors occurring with hypertriglyceridemia, the effect of triglyceride reduction on sCAM levels, and the role of soluble vascular cell adhesion molecule-1 (sVCAM-1) in monocyte adhesion in vitro. Compared with normal control subjects (n=20), patients with hypertriglyceridemia and low HDL (n=39) had significantly increased levels of soluble intercellular adhesion molecule-1 (sICAM-1) (316+/-28.8 versus 225+/-16.6 ng/mL), sVCAM-1 (743+/-52.2 versus 522+/-43.6 ng/mL), and soluble E-selectin (83+/-5.9 versus 49+/-3.6 ng/mL). ANCOVA showed that the higher sCAM levels in patients occurred independently of diabetes mellitus and other risk factors. In 27 patients who received purified n-3 fatty acid (Omacor) 4 g/d for > or =7 months, triglyceride level was reduced by 47+/-4.6%, sICAM-1 level was reduced by 9+/-3.4% (P=.02), and soluble E-selectin level was reduced by 16+/-3.2% (P<.0001), with the greatest reduction in diabetic patients. These results support previous in vitro data showing that disorders in triglyceride and HDL metabolism influence CAM expression and treatment with fish oils may alter vascular cell activation. In a parallel-plate flow chamber, recombinant sVCAM-1 at the concentration seen in patients significantly inhibited adhesion of monocytes to interleukin-1-stimulated cultured endothelial cells under conditions of flow by 27.5+/-7.2%. Thus, elevated sCAMs may negatively regulate monocyte adhesion.     

Circulating vascular cell adhesion molecule-1 (VCAM-1) in atherosclerotic NIDDM patients

Vascular cell adhesion molecule-1 (VCAM-1) has been shown to be highly expressed in atherosclerotic lesions. Although the soluble form of VCAM-1 (sVCAM-1) is detected in human sera, the relation between the degree of atherosclerosis and serum sVCAM-1 level has not been defined. In the present study, sVCAM-1 concentrations were measured in sera from 101 Japanese NIDDM patients. The mean +/- SD serum sVCAM-1 concentration in 26 patients with symptomatic atherosclerotic vascular diseases (789 +/- 187 ng/ml) was higher than that in 75 patients without the disease (664 +/- 175 ng/ml). Among the 101 NIDDM patients, 56 had atherosclerotic change of the carotid arteries, based on the evaluation by high-resolution B-mode ultrasonography. Their sVCAM-1 level was 759 +/- 201 ng/ml, higher than that in 45 patients without any detectable atherosclerosis of the carotid arteries (619 +/- 130 ng/ml). In addition, there was a positive correlation between sVCAM-1 concentration and thickness of the intimal plus medial complex (IMT) of the carotid arteries in the NIDDM patients (r = 0.41, P < 0.0001). Multivariate regression analysis revealed significant predictors of mean IMT value to be sVCAM-1 concentration (F = 62.88, P = 0.0001) and age (F = 9.59, P = 0.0026). By contrast, sVCAM-1 concentration was not increased in nondiabetic patients with atherosclerotic change of the carotid arteries (668 +/- 191 ng/ml; n = 36) compared with those without the atherosclerotic change (632 +/- 177 ng/ml; n = 28), and there was no correlation between sVCAM-1 level and IMT of the carotid arteries in the nondiabetic subjects. These results indicate that circulating sVCAM-1 may be a marker of atherosclerotic lesions in NIDDM patients with symptomatic and asymptomatic atherosclerosis.     

Left ventricular concentric remodelling and carotid structural changes in essential hypertension

AIM: Left ventricular concentric remodelling defines a modified left ventricular geometry in the presence of a normal left ventricular mass; it is an early and frequent adaptation in arterial hypertension. The present study was designed to evaluate the extent of carotid structural changes in essential hypertensives with left ventricular remodelling. PATIENTS AND METHODS: Two groups of hypertensive patients, who had never previously received anti-hypertensive treatment, 14 with left ventricular concentric remodelling (group I, relative wall thickness 0.48 +/- 0.02) and 48 with normal left ventricular geometry (group II, relative wall thickness 0.37 +/- 0.04) underwent clinical and laboratory examination, echocardiography, carotid artery ultrasonography and 24 h ambulatory blood pressure monitoring (ABPM). The left ventricular dimensions and mass were obtained according to the Penn convention. The intima-media thickness (IMT) of the posterior wall of both common carotid arteries was measured 5, 10 and 20 mm caudally to the bulb and the average value was used for analysis. RESULTS: In both groups age (group I 44 +/- 9 years; group II 40 +/- 9 years), body surface area (group I 1.85 +/- 0.2 m2; group II 1.80 +/- 0.2 m2), duration of hypertension (group I 4.4 +/- 4; group II 3.8 +/- 3.9 years), metabolic parameters and smoking habits were similar. Both clinic and 24 h ABPM values were higher in group I (clinic 157 +/- 12/102 +/- 5; 24 h ABPM 145 +/- 10/95 +/- 7 mmHg) than they were in group II (clinic 146 +/- 11/97 +/- 5; 24 h ABPM = 134 +/- 10/87 +/- 8 mmHg, P < 0.01). The left ventricular mass index (LVMI) and IMT were found to be slightly but significantly greater in group I than they were in group II (LVMI 106 +/- 7 versus 98 +/- 12 g/m2, P < 0.05; IMT 0.68 +/- 0.13 versus 0.61 +/- 0.10 mm, P < 0.05). A significant correlation was found between LVMI and common carotid IMT in the whole group of hypertensive patients (r = 0.43, P < 0.01). CONCLUSIONS: Our results indicate that left ventricular concentric remodelling does not represent the only early cardiovascular change in arterial hypertension but rather is associated often with carotid intima-media thickening.     

Age-related deterioration in arterial structure and function in postmenopausal women: impact of hormone replacement therapy

Epidemiological evidence suggests that hormone replacement therapy (HRT) reduces morbidity and mortality from cardiovascular diseases in postmenopausal women. In this study, indices of arterial function [total systemic arterial compliance (SAC) and carotid arterial distensibility coefficient (DC)], structure [carotid intima-media thickness (IMT)], and lipid profiles were compared in postmenopausal women on long-term HRT and aged-matched controls. One hundred nine women aged 44 to 77 years taking HRT and an age-matched group of 108 female controls were entered into the study. The two groups were similar for body mass index, smoking status, exercise level, alcohol intake, and blood pressure. Fasting cholesterol, low density lipoprotein, and lipoprotein(a) were reduced and high density lipoprotein increased in the HRT group. IMT increased with age; SAC and DC were reduced with age in both groups. The HRT group had a higher mean SAC (0.42+/-0.02 versus 0.34+/-0.02 U/mm Hg, P=0.0001) and a lower mean IMT (0.67+/-0.01 versus 0.74+/-0.02 mm, P=0.006) than did controls. Subgroup analysis for estrogen versus estrogen plus progestin revealed no differences for SAC and IMT; DC, however, was greater in estrogen-only users. Smokers on HRT had a higher mean SAC (0.41+/-0.02 versus 0.31+/-0.01 U/mm Hg, P=0.008) and a lower IMT (0.65+/-0.02 versus 0.75+/-0.03 mm, P=0.002) than did smokers not taking such therapy. A protective effect of long-term estrogen therapy on age-related changes in arterial structure and function in postmenopausal women was evident in smokers and nonsmokers alike. Progestin appeared to counteract the effects of estrogen on carotid compliance only. Long-term controlled trials are needed to determine the significance of these findings.     

Opposite effects of plasma homocysteine and the methylenetetrahydrofolate reductase C677T mutation on carotid artery geometry in asymptomatic adults

Studies of symptomatic patients have identified hyperhomocysteinemia as an independent risk factor for vascular disease. In case-control studies, a point mutation (C677T) in the gene encoding 5,10-methylenetetrahydrofolate reductase (MTHFR) has also been linked to an increased risk of vascular disease through its effect on homocysteinemia. Our aim was to extend these observations to asymptomatic subjects by studying the influence of both homocysteinemia and its mutation on carotid artery geometry. We examined 144 subjects free of atherosclerotic lesions. Fasting homocysteinemia was measured by high-performance liquid chromatography with fluorometric detection. MTHFR genotype was analyzed by polymerase chain reaction followed by HinfI digestion. Carotid artery geometry was characterized by internal diameter and intima-media thickness, as assessed by a high-resolution echo-tracking system. Subjects in the upper homocysteine tertile had a greater carotid internal diameter than did subjects in the middle and lower tertiles (6516+/-770 versus 6206+/-641 and 5985+/-558 microm, respectively; P<0.001). Subjects homozygous for the mutation had a smaller carotid artery internal diameter than did subjects heterozygous or homozygous for the wild-type allele (5846+/-785 versus 6345+/-673 and 6199+/-671 microm, respectively; P<0.05). Homocysteinemia was not significantly increased in subjects homozygous for the mutation. In multivariate regression analysis, homocysteinemia was independently and positively associated with lumen diameter (P=0.0008) and wall thickness (P=0.020). Conversely, homozygosity for the mutation was negatively associated with internal diameter (P=0.009). These preliminary data suggest that mildly elevated homocysteinemia and homozygosity for the MTHFR C677T mutation are associated with opposite preclinical modifications of carotid artery geometry. If confirmed, these results may have important implications for new treatment strategies for vascular disease before the onset of clinical manifestations.     

Repeat consultations in pediatric hospital emergencies

OBJECTIVE: To assess the extent of early atherosclerotic changes of the carotid arteries in young patients with familial hypercholesterolaemia (FH) detected as increased intima-media thickness (IMT), and to determine the relations between IMT and some clinical and blood variables such as lipid and lipoprotein(a) (Lp(a)) concentration and haemostatic factors. DESIGN: The IMT of the carotid bifurcation, the proximal 1 cm of the internal carotid artery, and the distal 1 cm of the common carotid artery was determined in all subjects using B mode ultrasonography. Blood lipids, fasting glucose, and several haemostatic variables were also analysed. SUBJECTS: 28 patients with FH (12 males and 16 females aged 11 to 27 years, one homozygote, 27 heterozygotes) and 28 sex and age matched normolipidaemic healthy subjects. RESULTS: The mean carotid IMT (the average of six measurements of the maximum far wall IMT in the three carotid segments on each side) was significantly greater in patients with FH than in controls (mean (SD) 0.71 (0.15) v 0.49 (0.08) mm, P < 0.001). In all subjects, the mean IMT was significantly correlated with total cholesterol (r = 0.59), low density lipoprotein (LDL) cholesterol (r = 0.60), triglycerides (r = 0.27), and systolic blood pressure (r = 0.47). No correlation was found between the mean IMT and Lp(a), fibrinogen, tissue plasminogen activator, and plasminogen activator inhibitor 1. CONCLUSIONS: The majority of young patients with FH have a greater intima-media thickness of the carotid arteries than healthy subjects. Since the individual susceptibility of patients with FH to increased LDL cholesterol is different, B mode ultrasonography could provide a useful tool to identify those who are more likely to develop premature atherosclerotic disease.     

Soluble adhesion molecules reflect endothelial cell activation in ischemic stroke and in carotid atherosclerosis

BACKGROUND AND PURPOSE: Activation of endothelial cells and platelets plays an important role in the development of atherosclerosis and thrombotic disorders. Soluble adhesion molecules originating from these cells can be demonstrated in plasma. We hypothesized that elevated plasma concentrations of soluble P-selectin (sP-selectin), soluble intercellular adhesion mole-cule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), and soluble E-selectin (sE-selectin) can reflect activation of endothelial cells and/or platelets in acute ischemic stroke and in previously symptomatic internal carotid artery stenosis. METHODS: Plasma was sampled from patients within 2 days of acute ischemic stroke (n = 28), from patients with a previous (> 1 week) transient or persistent ischemic neurological deficit associated with stenosis of the internal carotid artery (n = 34), and from control patients without a history of vascular disease (n = 34). Concentrations of sP-selectin, sICAM-1, sVCAM-1, and sE-selectin were measured by means of an enzyme-linked immunosorbent assay. RESULTS: Compared with control subjects, sP-selectin and sE-selectin were significantly elevated in the acute stage of ischemic stroke (P < .0001 and P = .001, respectively) as well as in previously symptomatic carotid stenosis (P < .0001 and P = .0007). sICAM-1 and sVCAM-1 were not increased. CONCLUSIONS: The elevated levels of sE-selectin indicate that endothelial cell activation occurs both in the acute stage of ischemic stroke and in previously symptomatic carotid atherosclerosis. Increased sP-selectin concentrations reflect endothelial cell activation as well but may also be caused by platelet activation.     

Effect of ibudilast on microcirculation thrombosis in rat inner ear

Arterial wall thickening may be quantitatively assessed by measuring the intima-media thickness (IMT) with high resolution ultrasound. Previous studies have shown a good inter/intraobserver variability of IMT measurements in the common carotid. In this study we evaluated the inter/intraobserver variability of IMT measurements in 10 randomly selected asymptomatic subjects (age 55.4 +/- 6). Two carotids and two femorals were studied in each subject. IMT for each patient was the average of five IMT measurements at the artery bifurcation. Three observers repeated the scanning and the measurements twice with no knowledge of the previous readings. The between observer coefficient of variation (CV) was 8.45%; the intraobserver CV (mean of carotids and femorals) varied from 4.4 to 5.1% for the three observers who measured IMT three times. The mean absolute difference between the first and the third measurement was 0.0738 mm. In conclusion IMT measurement variability is mostly due to differences between observers. The intraobserver variability is very small. IMT measurements at the carotid and femoral bifurcations have a low variability and are a good expression of atherosclerosis as they consider early lesions at the bifurcation level which may not be observed in the common carotid.     

Circulating ICAM-1 and VCAM-1 in peripheral artery disease and hypercholesterolaemia: relationship to the location of atherosclerotic disease, smoking, and in the prediction of adverse events

We examined the relationship of soluble intercellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1) with smoking and hypercholesterolaemia in peripheral artery disease (PAD). Serum samples were obtained from 119 patients with objectively-proven PAD, 39 patients with hypercholesterolaemia but asymptomatic for PAD, and 132 age and sex matched asymptomatic controls. Using ELISAs, we found increased sICAM-1 and sVCAM-1 (both p <0.01) in the patients with PAD relative to the controls, but no significant change in patients with hypercholesterolaemia. However, the effect for sVCAM-1 was lost when smoking was entered as a covariate. Only sICAM-1 was higher in patients with PAD in the femoral/iliac arteries compared to the carotid arteries (p <0.05). In a 39-month follow-up of 112 patients with PAD, increased ICAM-1 weakly (univariate p <0.05) predicted those 57 whose disease progressed (i.e. to end points such as myocardial infarction and arterial surgery). However, high fibrinogen was a much better (univariate p = 0.001, multivariate p <0.05) predictor of disease progression. We suggest (i) that increased levels of sVCAM-1 in atherosclerosis are due to smoking, (ii) that increased sICAM-1 is independent of this risk factor, (iii) that both these changes are independent of hypercholesterolaemia, and (iv) that increased sICAM-1 is a weak predictor of disease progression in peripheral atherosclerosis.     

Stress-induced pulse pressure change predicts women's carotid atherosclerosis

BACKGROUND AND PURPOSE: Individuals who exhibit large increases in blood pressure and heart rate during mental stress may be at risk for accelerated atherosclerosis. This report evaluates the association between stress-induced hemodynamic responses and carotid atherosclerosis in 254 healthy postmenopausal women. METHODS: The magnitude of change in blood pressure and heart rate from rest to public speaking and mirror image tracing, two stressful tasks, was measured. Average intima-media thickness (IMT) and focal plaque in the common carotid artery, bulb, and internal carotid artery were measured with the use of duplex ultrasonography on average 2.3 years later. RESULTS: The average IMT was 0.77 mm, with a range of 0.60 to 1.37; 52.5% had at least one plaque. Correlational analysis showed that greater IMT was associated with greater pulse pressure change during mental stress (r = 0.17, P < 0.01). Statistical adjustments for possible confounders (age, hormone replacement therapy use, resting pulse pressure, smoking status, and triglyceride levels) did not alter the results. The plaque index was associated with greater pulse pressure change during the mirror image tracing task (odds ratio = 1.47, P = 0.01) for women with a plaque score of > or = 2 versus 1 or 0, adjusted for possible confounders. CONCLUSIONS: Mental stress-induced pulse pressure changes may influence the development of early atherosclerosis in the carotid artery of women. Widening of pulse pressure during stress, as well as at rest, may be a marker of compromised compliance in the vessel wall.     

Carotid atherosclerosis in adolescents and young adults with IDDM. Relation to urinary endothelin, albumin, free cortisol, and other factors

OBJECTIVE: To investigate 1) alterations of carotid intimal-plus-medial thickness (IMT) in subjects with IDDM and 2) the relation of IMT to indexes of diabetic angiopathy and to risk factors of atherosclerosis. RESEARCH DESIGN AND METHODS: IMT was assessed by ultrasound B-mode imaging in 39 subjects with IDDM (23 male, 16 female young adults aged 17.5 +/- 5.2 years, diabetes duration 8.8 +/- 5.9) and in 22 control subjects (healthy siblings of the IDDM subjects) of comparable age. Urinary endothelin (UET1) and urinary free cortisol (UFC) were determined by radioammunoassay (RIA), urinary albumin by nephelometry, HbA1c by high-performance liquid chromatography (HPLC), and plasma renin by immunoradiometric assay (IRMA). RESULTS: The IMT values were greater in IDDM subjects than in control subjects (0.49 +/- 0.1 mm, 0.44 +/- 0.09 mm, respectively; P = 0.048) and greater in IDDM male subjects than in control male subjects (0.52 +/- 0.09 and 0.44 +/- 0.06 mm, respectively; P = 0.015), with no difference between IDDM and control female subjects. The IMT values were greater in diabetic male subjects than in female subjects (0.52 +/- 0.09 and 0.45 +/- 0.1 mm, respectively; P = 0.017). In IDDM subjects, but not in control subjects, there was a positive correlation of IMT to urinary albumin (P = 0.008), systolic blood pressure (P = 0.023), UET1 (P = 0.016), UFC (P = 0.002), and BMI (P = 0.021). Multiple regression analysis demonstrated that in IDDM subjects the variable that interacts independently with IMT was the BMI (P = 0.001). CONCLUSIONS: IMT, an index of atherosclerosis (macroangiopathy), is increased in IDDM subjects quite early (already in adolescence), and it is positively related to urinary albumin, UET1, blood pressure, and UFC.     

Association between mitral annulus calcification and carotid atherosclerotic disease

BACKGROUND AND PURPOSE: It has been established that mitral annulus calcification (MAC) is an independent predictor of stroke, though a causative relationship was not proved, and that carotid artery atherosclerotic disease is also associated with stroke. The aim of this study was to determine whether there is an association between the presence of MAC and carotid artery atherosclerotic disease. METHODS: Of the 805 patients in whom the diagnosis of MAC was made by transthoracic echocardiography between 1995 and 1997, 133 patients (60 men and 73 women; mean age, 74.3+/-8 years; range, 47 to 89 years) underwent carotid artery duplex ultrasound for various indications; the study group comprised these patients. They were compared with 129 age- and sex-matched patients without MAC (57 men and 72 women; mean age, 73.6+/-7 years; range, 61 to 96 years) who underwent carotid artery duplex ultrasound during the same period for the same indications. MAC was defined as a dense, localized, highly reflective area at the base of the posterior mitral leaflet. MAC was considered severe when the thickness of the localized, highly reflective area was > or =5 mm on 2-dimensional echocardiography in the 4-chamber view. Carotid artery stenosis was graded as follows: 0%, 20%, 40%, 60%, 80%, and 100%. RESULTS: Compared with the control group, the MAC group showed a significantly higher prevalence of carotid stenosis of > or =40% (45% versus 29%, P=0.006), which was associated with > or =2-vessel disease (23% versus 10%, P=0.006) and bilateral carotid artery atherosclerotic disease (21% versus 10%, P=0.011). Severe MAC was found in 48 patients. More significant differences were found for the severe MAC subgroup (for carotid stenosis of > or =40%) in rates of carotid artery atherosclerotic disease (58% versus 29%, P=0.001), and > or =2-vessel disease (31% versus 10%, P=0.001), in addition to bilateral carotid artery stenosis (27% versus 10%, P=0.004) and even bilateral proximal internal carotid artery stenosis (21% versus 8%, P=0.015). Furthermore, significant carotid artery atherosclerotic disease (stenosis of > or =60%) was significantly more common in the severe MAC subgroup than in the controls (42% versus 26%, P<0.05) and was associated with higher rates of > or =2-vessel disease (19% versus 7%, P=0.02) and bilateral carotid artery stenosis (17% versus 7%, P=0.05). On multivariate analysis, MAC and age but not traditional risk factors were the only independent predictors of carotid atherosclerotic disease (P=0.007 and P=0.04, respectively). CONCLUSIONS: There is a significant association between the presence of MAC and carotid artery atherosclerotic disease. MAC may be an important marker for atherosclerotic disease of the carotid arteries. This association may explain the high prevalence of stroke in patients with MAC.     

Plasma endothelin and early coronary endothelial dysfunction in recipients of a cardiac transplant

Serotonin constricts coronary arteries with endothelial dysfunction, possibly through reduced endothelial release of nitric oxide or enhanced production of constricting factors such as endothelin. Because the plasma levels of this peptide are increased in the early months after cardiac transplantation, we assessed whether a coronary hypersensitivity to the vasoconstrictor effect of serotonin is associated with high plasma endothelin levels. One to 3 months after cardiac transplantation, serotonin (1, 10, or 20 micrograms/min for 2.5 min each) was infused into the coronary circulation in 32 patients. Changes in coronary diameters were determined by quantitative angiography. A > or = 40% reduction in coronary diameter for a dose of serotonin < or = 10 micrograms/min was observed in group A (n = 14) whereas in group B (n = 18), this diameter reduction was never reached even for a 20 micrograms/min infusion of serotonin. Plasma endothelin levels were significantly higher (p < 0.01) in the coronary ostium and coronary sinus in group A, at 23.4 +/- 1.3 pg/ml and 24.9 +/- 0.9 pg/ml versus 12.6 +/- 0.9 pg/ml and 13.8 +/- 1.1 pg/ml, respectively, in group B. These endothelin levels did not significantly change after intracoronary infusion of serotonin. A significant correlation was found between plasma endothelin levels in the coronary ostium and peak coronary constriction (percentage diameter reduction) in both groups (r = 0.77 for group A and r = 0.92 for group B). Thus, early after cardiac transplantation, serotonin-induced coronary constriction is a common finding, and the severity of this abnormality seems to be influenced by plasma endothelin levels.     

Proinsulin and insulin concentrations in relation to carotid wall thickness: Insulin Resistance Atherosclerosis Study

BACKGROUND AND PURPOSE: Insulin resistance and hyperinsulinemia have been associated with atherosclerosis. Recent attention has focused on the possible role of proinsulin because most radioimmunoassays for insulin cross-react with proinsulin. Therefore, it is not known which of the two, insulin per se or proinsulin, is more strongly related to atherosclerosis. METHODS: We examined the relation between fasting proinsulin, fasting split proinsulin, fasting and 2-hour insulin (after oral glucose load), and intima-media wall thickness (IMT) in the common carotid artery (CCA) and internal carotid artery (ICA) in 985 nondiabetic subjects from the Insulin Resistance Atherosclerosis Study, a multiethnic study of insulin resistance and atherosclerosis. RESULTS: In the overall population, a weak but significant relation between proinsulin and CCA IMT was observed (r=0.07, P=0.029). However, the relation between proinsulin and IMT was stronger in Hispanics and non-Hispanic whites than in African Americans. In non-Hispanic whites and Hispanics, significant correlations between CCA and proinsulin (r=0.087) and between ICA and proinsulin (r=0.101), split proinsulin (r = 0.092), and fasting insulin (r = 0.087) were observed. The significant correlations became more attenuated (and nonsignificant) after adjustment for cardiovascular risk factors, especially plasminogen activator inhibitor-1 (PAI-1). CONCLUSIONS: The association between proinsulin and IMT, while weak, appears to be stronger than the association between insulin and IMT. Adjustment for PAI-1 markedly attenuated the association between proinsulin and IMT, suggesting a possible mediating role for PAI-1 in this association. It is possible that proinsulin may represent a marker of atherosclerosis rather than a causal factor for atherosclerosis. Studies of the insulin resistance syndrome and atherosclerosis that use insulin as a surrogate for insulin resistance should consider the use of specific insulin assays as well as determination of proinsulin concentrations.     

Genetic basis of variation in carotid artery wall thickness

BACKGROUND AND PURPOSE: Other than the documented associations of risk factors and carotid artery wall thickness, the genetic basis of variation in carotid artery intimal-medial thickness (IMT) is unknown. The purpose of this study was to examine the extent to which variation in common carotid artery (CCA) IMT and internal carotid artery (ICA) IMT are under genetic control. METHODS: The sibship data used for this analysis were part of an epidemiological survey in Mexico City. The CCA and ICA analyses were based on 46 and 44 sibships of various sizes, respectively. The CCA and ICA IMTs were measured with carotid ultrasonography. Using a robust variance decomposition method, we performed genetic analyses of CCA IMT and ICA IMT measurements with models incorporating several cardiovascular risk factors (eg, lipids, diabetes, blood pressure, and smoking) as covariates. RESULTS: After accounting for the effects of covariates, we detected high heritabilities for CCA IMT (h2 = 0.92 +/- 0.05, P = .001) and ICA IMT (h2 = 0.86 +/- 0.13, P = .029). Genes accounted for 66.0% of the total variation in CCA IMT, whereas 27.7% of variation was attributable to covariates. For ICA IMT, genes explained a high proportion (74.9%) of total phenotypic variation. The covariates accounted for 11.5% of variation in ICA IMT. CONCLUSIONS: Our results suggest that substantial proportions of phenotypic variance in CCA IMT and ICA IMT are attributable to shared genetic factors.     

Estimation of the pulmonary capillary wedge pressure from transesophageal pulsed Doppler echocardiography of pulmonary venous flow: influence of the respiratory cycle during mechanical ventilation

AIM: Endothelial Dysfunction (ED) is an early functional marker and Intima-Media-Thickness (IMT) an early morphological parameter of atherogenesis. Is there a simple, non-invasive routine method for the identification of atherosclerosis including the detection of the early functional endothelial impairment seen for example in Type 2 diabetic patients? METHODS: Using high resolution ultrasound we studied peripheral endothelial function expressed as flow-associated dilation (FAD %) and endothelial independent vasodilation after administration of 400 micrograms glycerol trinitrate (postnitro %) of the brachial artery as well as IMT of the common carotid artery in 25 Type 2 diabetic patients and their matched controls. RESULTS: (mean +/- SD): The diabetic patients showed a remarkable ED (FAD%: 3.8 +/- 3.3 vs. 6.9 +/- 4.4%, p = 0.01) and an already increased IMT (0.72 +/- 0.14 vs. 0.62 +/- 0.10 mm, p < 0.01). The similar postnitro % in diabetic patients and controls suggests normal dilating capacity of the studied vessels in the diabetic patients (postnitro %: 14.3 +/- 9.4 vs. 14.9 +/- 8.5%, p = ns). CONCLUSION: With a combination of these three sonomorphological parameters it is possible to document the stage of atherosclerosis including endothelial dysfunction in Type 2 diabetic patients.     

Clinical, haematological and molecular studies in patients with chromosome translocation t(7;11): a study of four Chinese patients in Taiwan

We examined the association between the polymorphism of the apolipoprotein E (apoE) and the ACE genes and the intima-media thickness (IMT) of the carotid and femoral arteries measured using ultrasonography. The values of IMT of each artery were significantly higher in NIDDM patients (n = 356) than in control subjects (n = 235). The E4 allele or the D allele did not affect clinical characteristics, including age, fasting plasma glucose, total cholesterol, HDL cholesterol, LDL cholesterol, or blood pressure, in NIDDM or control subjects. No difference in the carotid IMT value was noted among the apoE genotypes in control or diabetic subjects. The carotid IMT was significantly higher in diabetic patients with the DD genotype (1.200 +/- 0.586 mm) than in those with the II genotypes (0.990 +/- 0.364 mm). Neither the E4 allele nor the D allele affected the femoral IMT in control or diabetic subjects. Multiple regression analysis demonstrated that the carotid IMT of NIDDM patients was associated with age, the D allele, and LDL cholesterol but not with the E4 allele, whereas that of control subjects was associated with age, sex, systolic blood pressure, LDL cholesterol, and HDL cholesterol, inversely. These results suggested that the E4 allele was not associated with the carotid or femoral IMTs, but that the D allele was statistically associated with carotid IMT in NIDDM patients but not control subjects. However, since the association was weak (2.3% explanatory power), its biological significance remains to be determined.     

Anorexigen (TNF-alpha, cholecystokinin) and orexigen (neuropeptide Y) plasma levels in peritoneal dialysis (PD) patients: their relationship with nutritional parameters

BACKGROUND: Malnutrition has definitely been related to mortality among dialysis patients. Persistent loss of appetite is one of the major symptoms found in these patients. It is also well recognized that several substances produce anorexia or disorders of the hunger-satiety cycle in several diseases. The aim of this study was to identify the role of anorexigen substances (TNF-alpha and cholecystokinin or CCK) and an orexigen substance (neuropeptide Y or NPY) in anorexia and malnutrition among 55 clinically stable peritoneal dialysis (PD) patients. RESULTS: High TNF-alpha plasma levels were found in 41 of 42 patients (97.6%) with a mean of 70.5+/-32.3 pg/ml. Patients with anorexia (n=11) or anorexia with nausea or vomiting (n=5) had higher TNF-alpha values than patients without these symptoms (75.9+/-34 vs 52.1 +/-24.5 pg/ml, P<0.05). Eight patients with a prior diagnosis of acid pylori disease showed higher TNF-alpha values (87.2+/-24.3) than 30 unaffected patients (63.6+/-30.5, P<0.05). TNF-alpha showed a significant negative linear correlation with retinol binding protein (RBP) (r=-0.37, n=34, P<0.05), and venous pH (r=-0.4, n=42, P<0.01); also, TNF-alpha values higher than 65 pg/ml were inversely associated with transferrin, cholesterol, blood urea nitrogen (BUN) and CCK. Patients with prealbumin levels lower than 30 mg/dl, a BMI lower than 30 kg/m2, nPCR lower than 1.1 g/kg/day and urea KT/V lower than 2.2 showed higher serum TNF-alpha levels. Patients who had been on CAPD treatment for longer periods showed higher TNF-alpha values. High plasma CCK levels were found in 38 of 45 patients (84%), mean 45.9+/-32.3 pg/ml. Patients with anorexia had no difference in CCK values compared with those without. A direct association was found between CCK levels and some nutritional markers (albumin, fibronectin, triglycerides, folic acid and nPCR in non diabetic patients). Although CCK has a recognized anorectic effect, this direct association might be because of an abnormal stimulation of CCK glucose feedback (trypsin) due to continuous peritoneal glucose absorption. This suggests that CCK could be an immediate food intake marker in PD patients. The NPY plasma levels were normal in 33 patients, high in 6 and low in 11. Patients with anorexia showed lower NPY levels than those without. NPY values greater than 50 pg/ml were directly associated with higher transferrin, prealbumin, RBP, nPCR and urea KT/V values. Importantly, a negative linear correlation between NPY and TNF-alpha was found (r=-0.42, n= 41, P<0.01). There was no significant relationship between residual renal clearance and the serum levels of the three peptides. CONCLUSION: In conclusion, our data suggest that high TNF-alpha and low NPY serum levels are associated with anorexia. High TNF-alpha, low CCK and low NPY serum levels are also related to a poor nutritional status. Further research on these circulating substances is required.     

Changes in cerebrospinal fluid and cerebrovascular endothelin concentrations during hypotension and hypertension in newborn piglets with induced sterile meningitis

The effects of sterile meningitis on endothelin-1 (ET-1) and big ET-1 concentrations during hypotension and hypertension were studied in the cerebrospinal fluid and plasma of newborn piglets. Cerebrospinal fluid was obtained via cisterna magna puncture, and blood was obtained from the sagittal sinus vein and left subclavian artery. The study group consisted of 14 newborn piglets injected with 0.5 mL heat-killed group B streptococcus (GBS) (10(9) colony forming unit (cfu) equivalents), into the right cerebral lateral ventricle; the control group consisted of 10 newborn piglets injected with sterile normal saline, in a similar fashion. Hypotension (mean arterial blood pressure (MABP) 20-59 mmHg; 1 mmHg = 133.3 Pa) and hypertension (MABP 110-140 mmHg) were induced 1.5-2 h apart in random sequence in each animal, by inflating balloon-tipped catheters placed at the aortic root and descending aorta, respectively. Cerebral blood flow (CBF) was measured using radiolabeled microspheres, 15 min before and after injection of GBS or saline (normotension), during the hypotension and hypertension episodes, and during recovery normotension, immediately prior to cerebrospinal fluid and blood sampling. ET-1 and big ET-1 concentrations (pg/mL) were measured using radioimmunoassay kits. The combined effect of induced sterile meningitis and induced hypotension resulted in a significant rise in the concentration of cerebrospinal fluid ET-1 (control, 5.1 +/- 0.1; GBS, 9.3 +/- 0.2 pg/mL; p < 0.01), cerebrospinal fluid big ET-1 (control, 0; GBS, 18.1 +/- 2.7 pg/mL; p < 0.01), and sagittal sinus (cerebrovascular) big ET-1 (control, 15.5 +/- 4.2; GBS, 47.5 +/- 9.6 pg/mL; p < 0.01). In contrast, the combined effect of induced sterile meningitis and induced hypertension resulted in a marked elevation in cerebrovascular ET-1 concentrations (control, 9.5 +/- 0.9; GBS, 28.5 +/- 6.1 pg/mL; p < 0.01), with no significant change in cerebrospinal fluid concentrations. In addition, cerebrovascular production of ET-1 increased dramatically during hypertension in the GBS group (control, 0; GBS, 161.7 +/- 13.2 pg.min-1.100 g-1; p < 0.001), and was maintained during the recovery period (133.7 +/- 10.8 pg.min-1.100 g-1). Cerebrovascular ET-1 concentrations correlated significantly with total CBF and MABP in both groups of animals (control, r = 0.49, p < 0.002; GBS, r = 0.64, p < 0.0001), but the response was of a much greater magnitude in the GBS group. There was an inverse relationship between cerebrovascular big ET-1 concentrations and total CBF (r = -0.53, p < 0.0001) and MABP (r = -0.71, p < 0.0001) in the GBS group. In the MABP range of 60-110 mmHg a positive relationship was observed between cerebrovascular ET-1 concentrations and cerebral vascular resistance, in the control group only (r = 0.59, p < 0.002). The combined insult of induced sterile meningitis and induced hypotension or hypertension may be associated with increased cerebrovascular ET-1 and (or) big ET-1 concentrations. Changes in these vasoactive agents may contribute to pressure passivity of CBF in the newborn with meningitis.     

Increased formation of distinct F2 isoprostanes in hypercholesterolemia

BACKGROUND: F2 isoprostanes are stable, free radical-catalyzed products of arachidonic acid that reflect lipid peroxidation in vivo. METHODS AND RESULTS: Specific assays were developed by use of mass spectrometry for the F2 isoprostanes iPF2alpha-III and iPF2alpha-VI and arachidonic acid (AA). Urinary excretion of the 2 F2 isoprostanes was significantly increased in hypercholesterolemic patients, whereas substrate AA in urine did not differ between the groups. iPF2alpha-III (pmol/mmol creatinine) was elevated (P<0.0005) in homozygous familial hypercholesterolemic (HFH) patients (85+/-5. 5; n=38) compared with age- and sex-matched normocholesterolemic control subjects (58+/-4.2; n=38), as were levels of iPF2alpha-VI (281+/-22 versus 175+/-13; P<0.0005). Serum cholesterol correlated with urinary iPF2alpha-III (r=0.41; P<0.02) and iPF2alpha-VI (r=0. 39; P<0.03) in HFH patients. Urinary excretion of iPF2alpha-III (81+/-10 versus 59+/-4; P<0.05) and iPF2alpha-VI (195+/-18 versus 149+/-20; P<0.05) was also increased in moderately hypercholesterolemic subjects (n=24) compared with their controls. Urinary excretion of iPF2alpha-III and iPF2alpha-VI was correlated (r=0.57; P<0.0001; n=106). LDL iPF2alpha-III levels (ng/mg arachidonate) were elevated (P<0.01) in HFH patients (0.32+/-0.08) compared with controls (0.09+/-0.02). The concentrations of iPF2-III in LDL and urine were significantly correlated (r=0.42; P<0.05) in HFH patients. CONCLUSIONS: Asymptomatic patients with moderate and severe hypercholesterolemia have evidence of oxidant stress in vivo.