Biomedical subjects

J Levenson

Publications and source records attributed to J Levenson.

At least 19 recordsLinked to original sources

PubMed2026

Age-stratified mutation patterns in early-onset colorectal cancer reveal distinct molecular features and therapeutic implications.

BACKGROUND: Colorectal cancer (CRC) is increasingly diagnosed in younger adults, with evidence that early-onset cases (age <50 years) differ in the spectrum of prevalent gene mutations compared with older individuals. To evaluate how these age-related differences may inform testing guidelines and therapeutic development, we examined mutation rates of the most prevalent gene mutations across four age-stratified cohorts. PATIENTS AND METHODS: Clinicogenomic data were obtained from Memorial Sloan Kettering Center for Harmonized Onco-genomic Research Dataset and China Pan-Cancer cohorts available in cBioPortal. A total of 6762 samples were analyzed. Mutation frequencies for a comprehensive panel of the 100 most prevalent CRC genes were compared across four age groups: 18-29 (n = 79), 30-39 (n = 402), 40-49 (n = 1064), and ≥50 (n = 5217) using chi-square analysis. False discovery rate (FDR) correction for multiple comparisons was carried out using Benjamini-Hochberg procedure. RESULTS: Statistically significant variation in mutation frequency across age groups was seen in 22 key genes. APC mutations increased with age and were seen in 49.4% of patients in the 18-29 group, 69.7% in 30-39, 73.3% in 40-49, and 75.25% of patients ≥50 (P < 0.001, FDR < 0.001). The oldest cohort was more than three times more likely to have an APC mutation than the youngest [odds ratio (OR) = 3.74, 95% confidence interval (CI) 2.44-5.74, P < 0.001]. In contrast, SMAD4 mutations were twice as common in the youngest age group at 31.6% compared with those over 40, with a prevalence of 17.29% in patients 40-49, and 18.84% in patients over 50 (OR = 2.03, 95% CI 1.26-3.27, P < 0.001, FDR < 0.001). POLE mutations peaked in the 30-39 age group with a prevalence of 10.7% compared with 6.3% in patients aged 18-29, 4.9% in patients aged 40-49, and 5.9% in patients aged ≥50 (P < 0.001, FDR < 0.001). Individuals in the 30-39 group were nearly twice as likely to carry a POLE mutation compared with those over 40 (OR = 1.96, 95% CI 1.41-2.74, P < 0.001). CONCLUSIONS: Differences in mutations of key genes including a lower prevalence of APC mutations and increased SMAD4 mutations in younger individuals provides further supporting evidence that early-onset CRC may represent a distinct biological subtype of CRC. Enrichment of POLE mutations in younger patients highlights the importance of expanded molecular profiling in early-onset CRC, which could help identify patients most likely to benefit from immunotherapy and advance personalized treatment strategies in CRC. Together, these findings reinforce the need to approach early-onset CRC as a distinct biological entity and ensure that appropriate molecular assays are incorporated to guide care.

APC↗

PubMed2004

Smooth muscle role on pulmonary arterial function during acute pulmonary hypertension in sheep.

AIM: We determined the wall mechanical response of the pulmonary artery (PA) to acute pulmonary hypertension induced pharmacologically and by an occlusion maneuver, to study the vascular response of the local segment and its influence in the whole pulmonary circulation. METHODS: Pulmonary pressure and diameter were measured in six anaesthetized sheep under steady-state conditions. Transient hypertension in the PA was induced by phenylephrine (PHE) and a high pressure (HP) mechanical occlusion aimed at producing the same pulse and mean pressure responses. A viscoelastic arterial wall model was applied and the elastic (E(pd)) and viscous (micro) indexes were obtained. The micro/E(pd) ratio was adopted to quantify the damping performance of the arterial wall segment. The diastolic time constant was used as an indicator of the whole pulmonary buffering function. The systemic pressure was always measured. RESULTS: The pulmonary mean, systolic and pulse pressure increases (P < 0.05) were similar during PHE and HP, with respect to control. PHE also induced a systemic pressure rise (P < 0.05). The E(pd) elastic index increased during HP (P < 0.05) and tended to increase during PHE with respect to control. The viscous index micro only increased with PHE (P < 0.05) with respect to control and occlusion. The diastolic time constant increased with PHE with respect to control (P < 0.05). CONCLUSIONS: A pressure rise in the PA, induced by an occlusion maneuver, increased local stiffness. Similar pressure rises with smooth muscle activation (PHE), produced both a stiffness and viscous index increase. In PHE resistance increases more than compliance decreases so that the global net effect is a longer decay time. Smooth-muscle activation enhances the local damping effect (micro/E(pd)), concomitant with the buffering function improvement.

Acute Disease↗

PubMed2001

Gender differences in wall shear-mediated brachial artery vasoconstriction and vasodilation.

OBJECTIVES: We sought to investigate wall shear rate (WSR) and brachial artery diameter (BAD) changes simultaneously and to determine whether any gender differences exist in arterial reactivity. BACKGROUND: Wall shear rate/stress and arterial reactivity are rarely assessed at the same time. Furthermore, flow-mediated vasoconstriction has received less attention than flow-mediated vasodilation in humans. METHODS: A new noninvasive evaluation of WSR in the brachial artery, using multigated, pulsed Doppler velocimeter and a double-transducer probe moved and fixed by a robotic system, was developed. RESULTS: The validity of the system was tested in vitro with calibrated tubes and showed a high correlation (r = 0.98, p < 0.001). In 10 men and 10 women of similar age, induction of low and high shear rates by forearm occlusion produced significant vasoconstriction and vasodilation, respectively. The time lag for maximal BAD changes was 3 min for vasoconstriction and 1 min for vasodilation. A greater half-time for vasodilation (96 +/- 6 for men and 86 +/- 12 s for women) than for shear rate (31 +/- 5 s for men and 34 +/- 4 s for women) was observed after discontinuation of occlusion. Relative BAD was correlated with WSR changes, showing a significantly higher slope in women than in men (p < 0.01). Moreover, a larger normalized arterial diameter per shear rate was observed for vasoconstriction (p < 0.01) and vasodilation (p < 0.01) in women than in men. CONCLUSIONS: Shear-mediated arterial vasodilation and vasoconstriction were more pronounced in women than in men, suggesting different gender-related sensitivity in the regulation of large-artery vascular tone.

Adult↗

PubMed2001

Differential effects of nifedipine and co-amilozide on the progression of early carotid wall changes.

BACKGROUND: Common carotid artery intima-media thickness (IMT) progression was compared between 4 years of treatment with nifedipine and diuretic. METHODS AND RESULTS: This study, ancillary to the International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment (INSIGHT), involved nifedipine 30 mg or co-amilozide (hydrochlorothiazide 25 mg and amiloride 2.5 mg) with optional subsequent titration. Among 439 randomized hypertensive patients, 324 had >/=1 year of follow-up (intent-to-treat group), and 242 completed follow-up (until-end-of-study group). Ultrasonography was performed at baseline, 4 months later, and then every year. Central computerized reading provided far-wall IMT, diameter, and cross-sectional area IMT (CSA-IMT). The primary outcome was IMT progression rate (slope of IMT-time regression). Secondary outcomes were changes from baseline (Delta) in IMT, diameter, and CSA-IMT. In the until-end-of-study population, between-treatment differences existed in IMT progression rate (P=0.002), Delta IMT (P=0.001), and Delta CSA-IMT (P=0.006), because IMT progressed on co-amilozide but not on nifedipine. In the intent-to-treat population, treatment differences existed in Delta IMT (P=0.004) and Delta CSA-IMT (P=0.04) but not in IMT progression rate (P=0.09). Patients with >/=2, 3, or 4 years of follow-up showed treatment differences in IMT progression rate (P=0.04, 0.004, 0.007, respectively), Delta IMT (P=0.005, 0.001, 0.005), and Delta CSA-IMT (P=0.025, 0.013, 0.015). Diameter decreased more on co-amilozide than on nifedipine in the intent-to-treat population (P<0.05), whereas blood pressure decreased similarly on both treatments. CONCLUSIONS: A difference in early carotid wall changes is shown between 2 equally effective antihypertensive treatments.

Aged↗

PubMed2001

Effect of hypertension on viscoelasticity of large arteries in humans.

Two traditional methodologic approaches, the analysis of the arterial pressure waveform in the time domain and the measurement of pulse wave velocity along the arterial tree, have been extensively used to determine the distensibility of large arteries in humans. They have shown that large artery walls are stiffened in the presence of hypertension. However, several methodologic limitations, especially the incapability of these methods to take into account the physiologic pressure-dependence of arterial distensibility, have led to the development of new approaches for characterizing more in depth the elastic and viscous properties of large arteries. The noninvasive recording of instantaneous pressure and diameter waveforms in superficial arteries (carotid or femoral) by means of tonometry and ultrasonography allows, via appropriate model of the arterial wall, determination of the pure elastic properties as well as the wall viscosity of the vessel. Using case (hypertensive)-control (normotensive) studies it has been found that elastic alteration (stiffening) was preferential in the femoral artery rather than in the carotid artery and that viscous alteration (increased wall viscosity) was relatively uniform in both arteries. This topographic dissociation between elastic and viscous responses of the arterial wall to hypertension suggests that the elastic alteration might be a local phenomena dependent on the singularities of the arterial system, whereas abnormal wall viscosity may reflect a more general influence of hypertension on large artery smooth muscle, the likely determinant factor of viscosity. Therefore, the elastic and viscous components of the arterial walls should be considered independently when assessing the development of hypertensive vascular change and its response to antihypertensive treatment.

Arteries↗

PubMed2001

Do arterial effects of antihypertensive drugs depend on subject's serum cholesterol?

Effects of antihypertensive treatment on large arteries may be influenced by the type of drug and concomitant risk factors such as blood cholesterol. To explore these possibilities we investigated the common carotid artery of 20 subjects with low cholesterol and 19 subjects with high cholesterol, all with essential hypertension, randomly allocated to 3 months of treatment with nitrendipine (20 mg/d) or trandolapril (2 mg/d). Carotid parameters were determined by recording instantaneous pressure (applanation tonometry) and diameter (echotracking device) and by modeling the pressure-diameter loop to obtain the Peterson modulus, stiffness index, measured and isobaric compliances, and wall viscosity. Effects of drugs on carotid parameters did not differ, except on systolic and diastolic diameters (p < 0.01), which increased insignificantly under nitrendipine but decreased (p < 0.01) under trandolapril. Blood cholesterol status did not influence carotid effects of trandolapril, whereas patients with low and high cholesterol treated with nitrendipine exhibited significant differences in drug effects on (a) systolic and pulse pressures (p < 0.05), which decreased in patients with low cholesterol (p < 0.01, p < 0.05) but not in those with high cholesterol; (b) diastolic diameter (p = 0.05), which increased insignificantly in patients with low cholesterol but was unchanged in those with high cholesterol; and (c) wall viscosity (p < 0.01), which decreased in patients with low cholesterol (p < 0.05) but increased insignificantly in those with high cholesterol. Also, wall viscosity change under nitrendipine was positively related to the baseline blood cholesterol ( r = 0.64, p < 0.01). Thus, nitrendipine and trandolapril show noteworthy differences in their effects on the carotid artery, in particular with respect to the status of blood cholesterol, but these differences should be confirmed by larger studies.

Adult↗

PubMed2001

Identification of arterial wall dynamics in conscious dogs.

Viscoelastic properties determine the dynamic behaviour of the arterial wall under pulsatile pressure and flow, suggesting time- or frequency-dependent responses to changes in wall stress and strain. The objectives of the present study were: (i) to develop a simplified model to derive simultaneously the elastic, viscous and inertial wall moduli; (ii) to assess Young's modulus as a function of frequency, in conscious, chronically instrumented dogs. Parametric discrete time models were used to characterise the dynamics of the arterial system based on thoracic aortic pressure (microtransducer) and diameter (sonomicrometry) measurements in control steady state and during activation of smooth muscle with the alpha-adrenoceptor agonist phenylephrine (5 microg kg(-1) min(-1), I.V.), in eight conscious dogs. The linear autoregressive model and a physically motivated non-linear model were fitted to the input-output (stress-strain) relationship. The aortic buffering function (complex Young's modulus) was obtained in vivo from the identified linear model. Elastic, viscous and inertial moduli were significantly increased from control state ((44.5 +/- 7.7) x 10(4) Pa; (12.3 +/- 4.7) x 10(4) Pa s; (0.048 +/- 0.028) x 10(4) Pa s(2) ) to active state ((85.3 +/- 29.5) x 10(4) Pa, P < 0.001; (22.4 +/- 8.3) x 10(4) Pa s, P < 0.05; (0.148 +/- 0.060) x 10(4) Pa s(2), P < 0.05). These moduli, obtained using the linear model, did not present significant differences compared with those derived using the non-linear model. In control conditions, the magnitude of the normalised complex Young's modulus was found to be similar to that reported in previous animal studies ranging from 1 to 10 Hz. During vascular smooth muscle activation, this modulus was found to be increased with regard to control conditions (P < 0.01) in the frequency range used in this study. The frequency-dependent Young's modulus of the aortic wall was obtained for the first time in conscious, unsedated dogs. The parametric modelling approach allows us to verify that vascular smooth muscle activation increases the elastic, viscous and inertial moduli with the advantage of being able to track their time evolution. Furthermore, under activation, the aortic wall remains stiff in the physiological frequency range, suggesting the impairment of the arterial buffering function. Experimental Physiology (2001) 86.4, 519-528.

Animals↗

PubMed2001

Difference in carotid artery wall structure between Swedish and French men at low and high coronary risk.

BACKGROUND AND PURPOSE: We attempted to detect a group-specific north-south difference in carotid artery intima-media thickness (IMT), a marker of subsequent cardiovascular complication, by means of a case (high risk)-control (low risk) study in French and Swedish men. METHODS: The selection of high-risk and low-risk subjects was performed within the lower and upper percentiles of the Framingham risk distribution of 2 samples of 1000 white, male auto workers (45 to 50 years of age) in France (Renault) and Sweden (Volvo). In total, 299 men at low risk (79 French, 76 Swedish) and high risk (61 French, 83 Swedish), free from sustained hypertension, definite hypercholesterolemia, and cardiovascular disease, were included. Both common carotid arteries, by ultrasonography and central off-line computerized analysis, provided measurements of far wall media thickness, lumen diameter, and cross-sectional area IMT (CSA-IMT). RESULTS: As compared with low-risk status, high-risk status was associated with higher IMT (P<0.001), diameter (P<0.01), and CSA-IMT (P<0.001) in French men and higher CSA-IMT (P<0.05) in Swedish men. IMT, diameter, and CSA-IMT were higher in Swedish than in French men in the low-risk group (P<0.001) and in the high-risk group (P<0.01, P<0.001, P<0.001). The multivariate analysis of the whole population showed that IMT, diameter, and CSA-IMT were associated with risk status (P<0.01, P<0.01, P<0.001) and geographic status (P<0.001). CONCLUSIONS: These findings show that the geographic status influences carotid artery structure independent of traditional cardiovascular risk factors and that this may affect the mortality and morbidity gradient between Northern and Southern Europe.

Age Distribution↗

PubMed2000

Long-term regulation of neuronal high-affinity glutamate and glutamine uptake in Aplysia.

An increase in transmitter release accompanying long-term sensitization and facilitation occurs at the glutamatergic sensorimotor synapse of Aplysia. We report that a long-term increase in neuronal Glu uptake also accompanies long-term sensitization. Synaptosomes from pleural-pedal ganglia exhibited sodium-dependent, high-affinity Glu transport. Different treatments that induce long-term enhancement of the siphon-withdrawal reflex, or long-term synaptic facilitation increased Glu uptake. Moreover, 5-hydroxytryptamine, a treatment that induces long-term facilitation, also produced a long-term increase in Glu uptake in cultures of sensory neurons. The mechanism for the increase in uptake is an increase in the V(max) of transport. The long-term increase in Glu uptake appeared to be dependent on mRNA and protein synthesis, and transport through the Golgi, because 5,6-dichlorobenzimidazole riboside, emetine, and brefeldin A inhibited the increase in Glu uptake. Also, injection of emetine and 5,6-dichlorobenzimidazole into Aplysia prevented long-term sensitization. Synthesis of Glu itself may be regulated during long-term sensitization because the same treatments that produced an increase in Glu uptake also produced a parallel increase in Gln uptake. These results suggest that coordinated regulation of a number of different processes may be required to establish or maintain long-term synaptic facilitation.

Animals↗

PubMed2000

Localization of glutamate and glutamate transporters in the sensory neurons of Aplysia.

The sensorimotor synapse of Aplysia has been used extensively to study the cellular and molecular basis for learning and memory. Recent physiologic studies suggest that glutamate may be the excitatory neurotransmitter used by the sensory neurons (Dale and Kandel [1993] Proc Natl Acad Sci USA. 90:7163-7167; Armitage and Siegelbaum [1998] J Neurosci. 18:8770-8779). We further investigated the hypothesis that glutamate is the excitatory neurotransmitter at this synapse. The somata of sensory neurons in the pleural ganglia showed strong glutamate immunoreactivity. Very intense glutamate immunoreactivity was present in fibers within the neuropil and pleural-pedal connective. Localization of amino acids metabolically related to glutamate was also investigated. Moderate aspartate and glutamine immunoreactivity was present in somata of sensory neurons, but only weak labeling for aspartate and glutamine was present in the neuropil or pleural-pedal connective. In cultured sensory neurons, glutamate immunoreactivity was strong in the somata and processes and was very intense in varicosities; consistent with localization of glutamate in sensory neurons in the intact pleural-pedal ganglion. Cultured sensory neurons showed only weak labeling for aspartate and glutamine. Little or no gamma-aminobutyric acid or glycine immunoreactivity was observed in the pleural-pedal ganglia or in cultured sensory neurons. To further test the hypothesis that the sensory neurons use glutamate as a transmitter, in situ hybridization was performed by using a partial cDNA clone of a putative Aplysia high-affinity glutamate transporter. The sensory neurons, as well as a subset of glia, expressed this mRNA. Known glutamatergic motor neurons B3 and B6 of the buccal ganglion also appeared to express this mRNA. These results, in addition to previous physiological studies (Dale and Kandel [1993] Proc Natl Acad Sci USA. 90:7163-7167; Trudeau and Castellucci [1993] J Neurophysiol. 70:1221-1230; Armitage and Siegelbaum [1998] J Neurosci. 18:8770-8779)) establish glutamate as an excitatory neurotransmitter of the sensorimotor synapse.

ATP-Binding Cassette Transporters↗

PubMed2000

Gender difference in the influence of smoking on arterial wall thickness.

BACKGROUND: We hypothesized that arterial wall thickening, an early atherogenic alteration, might be associated with smoking differently according to gender, considering the cardiovascular protection of female sex hormones. METHODS AND RESULTS: We measured ultrasonographically carotid and femoral intima-media thickness (IMT) in 194 men and 330 women without risk factors other than smoking. In men: (i) current smokers had greater carotid and femoral IMT (P<0.01, P<0.001) and former smokers had greater femoral IMT (P<0.01) than never smokers; (ii) in pooled never, current and former smokers carotid and femoral IMT correlated to current daily smoking (P<0.01) and lifelong smoking (P<0.001); and (iii) carotid and femoral IMT correlated to age in never smokers (P<0.001), current smokers (P<0.01, P<0.001) and former smokers (P<0.01), with greater slopes in current than in former smokers at carotid site (P<0.05) and in current than in never smokers at femoral site (P<0.05). In women: (i) IMT did not differ by smoking status; (ii) in pooled smokers and non smokers femoral IMT correlated to current daily smoking (P=0.01) and to lifelong smoking (P<0.01) with a lower slope than in men (P<0.001), while carotid IMT did not; and (iii) carotid and femoral IMT correlated to age in never smokers (P<0.001), current smokers (P<0.001, P<0.05) and former smokers (P<0.001, P<0.01) with no different slopes. CONCLUSION: Smoking-related increase in IMT existed in men but not in women, suggesting a possible protection of female gender from early structural arterial alteration of smoking.

Adolescent↗

PubMed2000

Distribution of ultrasonographically-assessed dimensions of common carotid arteries in healthy adults of both sexes.

Our objective was to provide a description of 'normal' carotid artery dimensions which are increasingly used for detecting early atherosclerosis and predicting clinical complications. Far wall intima-media thickness (IMT), lumen diameter and cross-sectional area intima-media thickness (CSA-IMT) were measured on 1 cm-distal common carotid artery segments on both sides by B-mode ultrasound, using an automated computerized edge-detection program, in 133 men and 216 women aged 17-65 years and free from cardiovascular disease and traditional risk factors. IMT and CSA-IMT increased with age in both sexes and on both sides, while diameter did not, except on the right side in men. Women had lower diameter than men except on the left side at 30 years or below, while IMT did not differ between sexes except on the left side from 31 to 50 years where IMT was higher in men; as a result of their lower diameter, women had lower CSA-IMT than men except on the right side above 50 years. IMT was lower on the right side than on the left side in both sexes, except in 30-year old or younger men and 31- to 40-year old women, while diameter was higher on the right side than on the left side in men and women aged 31-40 years and in women aged 41-50 years; also CSA-IMT was lower on the right side than on the left side in both sexes above 40 years. These data provide reference values of carotid artery dimensions and show that age, sex and side of measurement should be taken into account in the interpretation of 'normal' values of IMT and diameter in clinical practice and trials.

Adolescent↗

PubMed2000

Association of plasma viscosity and carotid thickening in a French working cohort.

Plasma viscosity and intima-media thickness (IMT) are frequently associated with cardiovascular disease and its risk factors. We evaluated the association of rheologic and vascular factors in asymptomatic subjects. Plasma viscosity (coaxial cylinder viscometry) and both preintrusive and intrusive atherosclerosis in the carotid arteries (ultrasonography) were investigated in 246 men and 337 women aged 17 to 65 years from the AXA study, a prospective cohort of healthy workers. Plasma viscosity was positively related to age-adjusted mean bifurcation carotid artery IMT (P < .01 for men; P < .04 for women) and maximum carotid artery IMT (P < .01 for men; P < .02 for women), but not to mean common carotid artery IMT. Multivariate adjustment affected these relations to a greater extent in men than in women. The odds ratio (range) of having intrusive atherosclerosis in relation to 1 SD greater plasma viscosity was 2.27 (1.52 -3.38) in men and 1.63 (1.17-2.26) in women. Adjustment of age, waist-to-hip ratio, smoking, hypercholesterolemia, hypertension, diabetes, and fibrinogen had very little effect on the magnitude of these odds ratios. Thus, plasma viscosity was associated with carotid thickening, suggesting that rheologic factors are involved in the subclinical phase of atherosclerosis.

Adolescent↗

PubMed2000

Feasibility and reliability of ankle/arm blood pressure index in preventive medicine.

Despite its potential usefulness for assessing preclinical atherosclerosis and cardiovascular risk, the ankle/arm blood pressure index (AAI) has not yet been the matter of study evaluating its feasibility and reliability by nonspecialist doctors in a general population. This study was planned for two steps. In step 1, the measurement of AAI, (ratio between Doppler systolic pressure at the ankle for each lower limb and the highest value of Doppler systolic pressure of the two upper limbs), should be performed by 50 general practitioners (GPs), 50 social security center physicians, and 50 occupational health physicians in 3,000 male smokers, 40 to 59 years, without clinical cardiovascular disease. In step 2, AAI measurement, coupled with echography-Doppler of iliofemoral arteries, should be repeated by a specialist in all subjects with decreased AAI (<0.90) and the first two subjects with normal AAI recruited in step 1 by each nonspecialist. The number of physicians and subjects participating in step 1 was lower than planned (80 physicians and 962 subjects) with the greatest defect for GPs (six physicians and 35 subjects) and the prevalence of decreased AAI was low (28 subjects). AAI measurement was repeated in step 2 in only 12 subjects with decreased AAI in step 1 and in 124 subjects with normal AAI in step 1. Five of the six subjects with decreased AAI in step 2 also had decreased AAI in step 1 and 123 of the 130 subjects with normal AAI in step 2 also had normal AAI in step 1. As regards echographic stenosis, decreased AAI had a sensitivity of 44% and a specificity of 98%. AAI seems more feasible for occupational health physicians and social security center physicians and AAI is also reliable for nonspecialists previously trained, but its predictive value as regards echographic stenosis is poor in asymptomatic subjects, which may limit its usefulness for detecting preclinical atherosclerosis.

Adult↗

PubMed2000

[Blood and arterial wall rheology and cardiovascular risk factors].

The vascular endothelium and circulating blood cells are exposed to a hemodynamic environment related to the pulsatile nature of the pressure and blood flow which influence the morphology, the physical properties and the metabolism of the cells. Among these mechanical forces, shear stresses, related to the speed gradients and to the blood viscosity, control vascular vasomotor tone and thrombogenecity, stimulating the production of the endothelial factors of relaxation or contraction, of the coagulation factors or activating erythrocyte and platelet aggregation or disaggregation phenomena. Low shear stress is considered to be a critical factor in the causation of thickening of the arterial wall and in the formation of atheromatous plaques. These plaques develop predominantly in specific parts of the arterial tree where asymmetries in the velocity profiles occur. A close relationship has been found in a large general population between plasma viscosity and thickening of the carotid bifurcation. The blood cells share the same environment as the endothelial cells. Thus, the shear stresses to which the erythrocytes are submitted is a major determinant of the blood viscosity. Shear is also an important physiological parameter regulating platelet aggregation in flowing suspensions. However, in vivo, the response of platelets depends on the balance between activation of the platelets by shear and the same rheological forces acting on the endothelial cells which produce mediators which inhibit this activation in order to maintain blood fluidity.

Arteries↗

PubMed1999

Levels of serotonin in the hemolymph of Aplysia are modulated by light/dark cycles and sensitization training.

Serotonin (5-hydroxytryptamine, 5-HT) modulates the behavior and physiology of both vertebrate and invertebrate animals. Effects of injections of 5-HT and the morphology of the serotonergic system of Aplysia indicate that 5-HT may have a humoral, in addition to a neurotransmitter, role. To study possible humoral roles of 5-HT, we measured 5-HT in the hemolymph. The concentration of 5-HT in the hemolymph was approximately 18 nM, a value close to previously reported thresholds for eliciting physiological responses. The concentration of 5-HT in the hemolymph expressed a diurnal rhythm. In addition, electrical stimulation that leads to long-term sensitization significantly increased levels of 5-HT in the hemolymph during training, 1.5 hr after training, and 24 hr after training. Moreover, levels of 5-HT in the hemolymph were significantly correlated with the magnitude of sensitization. The half-life of an increase in 5-HT in the hemolymph was approximately 0.5 hr. Therefore, the persistent increase of 5-HT in the hemolymph 24 hr after sensitization training indicates that training caused a long-lasting increase in the release of 5-HT. This long-lasting increase in 5-HT in the hemolymph was blocked by treatment with an inhibitor of protein synthesis during training. Based on the levels of 5-HT in the hemolymph and its regulation by environmental events, we propose that 5-HT has a humoral role in regulation of the behavioral state of Aplysia. In support of this hypothesis, we found that increasing levels of 5-HT in the hemolymph led to significant alterations in feeding behavior. Increasing levels of 5-HT during the daytime when they were normally low increased the latency to assume feeding posture from daytime to nighttime values.

Animals↗

PubMed1999

Influence of hypercholesterolemia and endothelin-3 pre-treatment on the effects of shear forces on platelet aggregation and cyclic GMP content.

Shear forces induce platelet aggregation and stimulate the endothelial production of anti-aggregatory factors. Among them, endothelin-3 (ET-3) has been reported to reduce aggregation and to increase platelet cyclic GMP (cGMP) content. Since hypercholesterolemia modifies both platelet aggregability and endothelial function, we compared in 14 hypercholesterolemic and 15 normocholesterolemic subjects the influences of shear forces (240 and 650 s(-1)) on platelet aggregation and cGMP content, and their modulation by ET-3. Spontaneous maximal aggregation occurred earlier and at a greater extent in hypercholesterolemic than in normocholesterolemic subjects (63+/-2 vs 46+/-6% P < 0.01). Pre-treatment with ET-3 abolished the shear-induced facilitation of maximal aggregation in platelets of normocholesterolemic (from 70+/-2 to 52+2% at 240 s(-1) and from 73+/-1 to 59+/-2S at 650s(-1); P < 0.05) and hypercholesterolemic (from 78+/-3 to 64+/-2 at 240 s(-1) and from 78+/-2 to 66+/-3 at 650 s(-1); P < 0.05) subjects. cGMP content did not significantly differ between normocholesterolemic and hypercholesterolemic subjects (6.1+/-0.5 vs 6.9+/-0.7 pmol/10(9) platelets). It was reduced in platelets submitted to shear forces (P < 0.05). This shear-dependent reduction was suppressed by ET-3 pre-treatment. These results demonstrate that shear forces enhance platelet aggregation and diminish their cGMP content. ET-3 reduces the pro-aggregating effects of shear, suggesting a rise in cGMP content as a dynamic associated mechanism.

Blood Platelets↗

PubMed1999

Experimental and clinical validation of arterial diameter waveform and intimal media thickness obtained from B-mode ultrasound image processing.

A new automated computerized system (IôTEC) that assesses concomitantly the instantaneous temporal arterial diameter and intimal media thickness (IMT) obtained from B-mode ultrasound (US) images was validated by sonomicrometry in sheep, by an echo-tracking system in humans, and by a Lucite phantom in vitro. Differences between methods for diameter measurements did not vary in any systematic way, with no significant differences in the lower frequency range. Ultrasonic measurements of the true phantom gap sizes showed high correlation (r2 = 0.98,p < 0.001) with no systematic errors. Carotid and femoral arteries in humans were strongly related between IôTEC and echo-tracking device (r2 = 0.94 carotid; R2 = 0.88 femoral, p < 0.001), with a Gaussian distribution of the errors. This new method showed high intra- and interobserver repeatability of arterial diameter and IMT, allowing consistent characterization of arterial dynamics in humans.

Animals↗