Observation of Rayleigh-Lamb waves generated by the 2022 Hunga-Tonga volcanic eruption with the POLA detectors at Ny-Ålesund.

The eruption of the Hunga-Tonga volcano in the South Pacific Ocean on January 15, 2022, at about 4:15 UTC, generated a violent explosion, which created atmospheric pressure disturbances in the form of Rayleigh-Lamb waves detected all over the globe. Here we discuss the observation of the Hunga-Tonga shock-wave performed at the Ny-Ålesund Research Station on the Spitsbergen island, by the detectors of the PolarquEEEst experiment and their ancillary sensors. Online pressure data as well as the results of dedicated offline analysis are presented and discussed in details. Results include wave arrival times, wave amplitude measurements and wave velocity calculation. We observed five passages of the shock wave with a significance larger than 3 [Formula: see text] and an amplitude up to 1 hPa. The average propagation velocity resulted to be (308 ± 0.6) m/s. Possible effects of the atmospheric pressure variation associated with the shock-wave multiple passages on the cosmic-ray rate at ground level are also investigated. We did not find any significant evidence of this effect.

Large-Area SiPM Pixels (LASiPs): A cost-effective solution towards compact large SPECT cameras.

Single Photon Emission Computed Tomography (SPECT) scanners based on photomultiplier tubes (PMTs) are still largely employed in the clinical environment. A standard camera for full-body SPECT employs ~50-100 PMTs of 4-8 cm diameter and is shielded by a thick layer of lead, becoming a heavy and bulky system that can weight a few hundred kilograms. The volume, weight and cost of a camera can be significantly reduced if the PMTs are replaced by silicon photomultipliers (SiPMs). The main obstacle to use SiPMs in full-body SPECT is the limited size of their sensitive area. A few thousand channels would be needed to fill a camera if using the largest commercially-available SiPMs of 6 × 6 mm2. As a solution, we propose to use Large-Area SiPM Pixels (LASiPs), built by summing individual currents of several SiPMs into a single output. We developed a LASiP prototype that has a sensitive area 8 times larger than a 6 × 6 mm2 SiPM. We built a proof-of-concept micro-camera consisting of a 40 × 40 × 8 mm3 NaI(Tl) crystal coupled to 4 LASiPs. We evaluated its performance in a central region of 15×15 mm2, where we were able to reconstruct images of a 99mTc capillary with an intrinsic spatial resolution of ~2 mm and an energy resolution of ~11.6% at 140 keV. We used these measurements to validate Geant4 simulations of the system. This can be extended to simulate a larger camera with more and larger pixels, which could be used to optimize the implementation of LASiPs in large SPECT cameras. We provide some guidelines towards this implementation.

Bisperoxovanadium, a phospho-tyrosine phosphatase inhibitor, reprograms myogenic cells to acquire a pluripotent, circulating phenotype.

Satellite cells are the main source of myogenic progenitors in postnatal skeletal muscle, but their use in cell therapy for muscle disorders is limited because these cells cannot be delivered through circulation and they are rapidly exhausted in severe myopathies. The search for alternative donor cells is ongoing, but none of the candidates so far show all the features required for successful colonization and repair of diseased muscle. In this study, we show that bisperoxovanadium, a phospho-tyrosine phosphatase inhibitor, induces myogenic cells to acquire a gene expression profile and a differentiation potential consistent with the phenotype of a circulating precursors, while maintaining their myogenic potential. These effects are mediated, at least in part, by NF-kappaB activation through the Tyr42-IkappaB-alpha phosphorylation, as shown by the expression of the dominant negative mutant form of the p50 NF-kappaB subunit. Moreover, when bisperoxovanadium-treated cells are injected into the femoral artery of alpha-sarcoglican null dystrophic mice, they are able to circulate and to reach muscle tissue; importantly, they contribute to muscle regeneration, as shown by the expression of alpha-sarcoglican in some fibers. Our observations indicate that bisperoxovanadium, or similar compounds, may prove very valuable to obtain and to expand, from committed cells, multipotent cell populations suitable for gene-cell therapy applications and may help to understand the molecular basis of genome reprogramming and "stem-ness."

Practical guidelines for familial combined hyperlipidemia diagnosis: an up-date.

Familial combined hyperlidemia (FCH) is a common metabolic disorder characterized by: (a) increase in cholesterolemia and/or triglyceridemia in at least two members of the same family, (b) intra-individual and intrafamilial variability of the lipid phenotype, and (c) increased risk of premature coronary heart disease (CHD). FCH is very frequent and is one of the most common genetic hyperlipidemias in the general population (prevalence estimated: 0.5%-2.0%), being the most frequent in patients affected by CHD (10%) and among acute myocardial infarction survivors aged less than 60 (11.3%). This percentage increases to 40% when all the myocardial infarction survivors are considered without age limits. However, because of the peculiar variability of laboratory parameters, and because of the frequent overlapping with the features of metabolic syndrome, this serious disease is often not recognized and treated. The aim of this review is to define the main characteristics of the disease in order to simplify its detection and early treatment by all physicians by mean of practical guidelines.

The role of anchoring protein RACK1 in PKC activation in the ageing rat brain.

High levels of expression of Ca2+/phospholipid-dependent protein kinase C (PKC) occur in neuronal tissues and play a strategic role in the modulation of short- and long-term functions (ion channels, receptor desensitization, neurotransmitter release and synaptic efficiency) that become modified during the brain ageing process. Recent studies have clarified the key role played by the anchoring proteins in mediating subcellular PKC location, that is, in driving the enzyme to specific sites of action. The protein, receptor for activated C-kinase 1 (RACK1) is involved in PKC-mediated signal transduction. A postnatal developmental increase in RACK1 levels indicates their significance in the outgrowth of neuronal processes. In a physiological model of impairment in PKC translocation-the aged rat brain cortex-RACK1 levels are reduced and the PKC isoenzymes known to interact with it do not translocate to membrane compartments upon stimulation. Anchoring proteins might represent new targets for compounds that modulate PKC signal transduction processes.

Simvastatin, an inhibitor of cholesterol biosynthesis, shows a synergistic effect with N,N'-bis(2-chloroethyl)-N-nitrosourea and beta-interferon on human glioma cells.

The effect of simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on human glioma cell growth was investigated. When incubated with simvastatin, cell proliferation decreased in a concentration-dependent fashion, as measured by cell number and [3H]-thymidine incorporation into DNA (concentration producing 50% inhibition, 60 nM). The effect was detectable 12 h after cells were exposed to the drug and persisted for 2 days. Addition of mevalonate to cells exposed effect of simvastatin in combination with beta-interferon and N,N'-bis(2-chloroethyl)-N-nitrosourea, both antitumoral drugs, was also evaluated by cell growth inhibition assay. The concentration producing 50% inhibition for each of these drugs was 650 units/ml and 50 nM, respectively. Subliminal concentrations of beta-interferon or N,N'-bis(2-chloroethyl)-N-nitrosourea were incubated together with 1 nM simvastatin. The data were analyzed with the aid of an isobologram using the concept of an envelope of additivity. Simultaneous cell exposure to simvastatin with either N,N'-bis(2-chloroethyl)-N-nitrosourea or beta-interferon produced a strong synergistic inhibitory effect on cell proliferation. These data provide in vitro support for the possibility that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, utilized as plasma cholesterol-lowering agents, could potentiate the effect of antiblastic drugs on tumor growth.

In vivo enhanced antitumor activity of carmustine [N,N'-bis(2-chloroethyl)-N-nitrosourea] by simvastatin.

The effects of a combination of simvastatin, a cholesterol-lowering agent, and carmustine (BCNU; N,N'-bis(2-chloroethyl)-N-nitrosourea) on experimental C6 glioma were studied in vitro and in vivo. In vitro simvastatin and BCNU alone inhibited cell proliferation in a dose-dependent fashion. A subliminal concentration of simvastatin (0.1 microM) markedly and synergistically increased the BCNU toxicity to C6 glioma cells. The cytofluorimetric analysis of DNA from simvastatin-treated C6 glioma cells showed, besides the already described arrest in G1, an arrest/retardation in G2-M. Mitotic index from C6 cells incubated with simvastatin (10 microM) decreased by about 90%, indicating a specific C6 arrest/retardation in G2. The drug effects could be completely reversed by simvastatin withdrawal or mevalonate addition to the cultured cells. The combination of simvastatin and BCNU resulted predominantly from the profound retardation of cells in the G2-M compartment of the cell cycle. In vivo simvastatin (administered daily mixed with food) and BCNU (single i.p. injection), when given separately, caused a dose-dependent inhibition of labeling index in C6 glioma homografts (ID50, 61 mg/kg/day and 8.7 mg/kg, respectively). The combination of the lowest doses tested (simvastatin, 25 mg/kg/day and BCNU 0.3 mg/kg) resulted in a significant growth delay (compared to either drug alone) in C6 glioma (P < 0.05). There was no significant increase in toxicity as assessed by myelosuppression (WBC counts and bone marrow labeling index) and body weight. The results provide in vivo support for the combined use of simvastatin, a cholesterol-lowering agent, and BCNU in brain tumor treatment.

New insights into the pharmacodynamic and pharmacokinetic properties of statins.

The beneficial effects of statins are assumed to result from their ability to reduce cholesterol biosynthesis. However, because mevalonic acid is the precursor not only of cholesterol, but also of many nonsteroidal isoprenoid compounds, inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase may result in pleiotropic effects. It has been shown that several statins decrease smooth muscle cell migration and proliferation and that sera from fluvastatin-treated patients interfere with its proliferation. Cholesterol accumulation in macrophages can be inhibited by different statins, while both fluvastatin and simvastatin inhibit secretion of metalloproteinases by human monocyte-derived macrophages. The antiatherosclerotic effects of statins may be achieved by modifying hypercholesterolemia and the arterial wall environment as well. Although statins rarely have severe adverse effects, interactions with other drugs deserve attention. Simvastatin, lovastatin, cerivastatin, and atorvastatin are biotransformed in the liver primarily by cytochrome P450-3A4, and are susceptible to drug interactions when co-administered with potential inhibitors of this enzyme. Indeed, pharmacokinetic interactions (e.g., increased bioavailability), myositis, and rhabdomyolysis have been reported following concurrent use of simvastatin or lovastatin and cyclosporine A, mibefradil, or nefazodone. In contrast, fluvastatin (mainly metabolized by cytochrome P450-2C9) and pravastatin (eliminated by other metabolic routes) are less subject to this interaction. Nevertheless, a 5- to 23-fold increase in pravastatin bioavailability has been reported in the presence of cyclosporine A. In summary, statins may have direct effects on the arterial wall, which may contribute to their antiatherosclerotic actions. Furthermore, some statins may have lower adverse drug interaction potential than others, which is an important determinant of safety during long-term therapy.

Lipid and non-lipid effects of statins.

Long- and short-term trials with the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have demonstrated significant reductions in cardiovascular events in patients with and without history of coronary heart disease. Statins are well-established low-density lipoprotein (LDL)-lowering agents, but their clinical benefit is believed to result from a number of lipid and non-lipid effects beyond LDL lowering, including a rise in plasma high-density lipoprotein levels. Beyond improving the lipid profile, statins have additional non-lipid effects including benefit on endothelial function, inflammatory mediators, intima-media thickening, prothombotic factors that ultimately result in plaque stabilization. These effects arise through the inhibition of several mevalonate-derived metabolites other than cholesterol itself, which are involved in the control of different cellular functions. Although statins represent the gold standard in the prevention and treatment of coronary heart disease, combination therapy with other lipid-lowering drugs, as well as novel therapeutic indications, may increase their therapeutic potential.

The lowering of lipoprotein[a] induced by estrogen plus progesterone replacement therapy in postmenopausal women.

OBJECTIVE: To evaluate whether estrogen plus progesterone replacement therapy influences the plasma lipoprotein[a] (Lp[a]) levels in postmenopausal women. DESIGN: Fifty-five women who had been menopausal for at least 1 year were followed up for 12 months. Twenty-four subjects served as the control group and 31 subjects served as the therapy group. The therapy consisted of conjugated estrogen (1.25 mg/d) and medroxyprogesterone acetate (10 mg/d for 10 days a month). Blood samples were obtained before the start of therapy and at 6 months and 12 months after therapy. Nine subjects in the therapy group were followed up for an additional year after the treatment was suspended (washout group). SETTINGS: All subjects were healthy women (mean age, 52 years) who had natural menopause at least 1 year before the beginning of recruitment. None of the women had received exogenous sex steroids or drugs known to influence lipid and lipoprotein metabolism in the previous 12 months. MAIN RESULTS: In the control group, no change was noted in the plasma Lp[a] concentrations during the study. In the treatment group, the mean plasma Lp[a] concentrations decreased 50% after 6 months (P < .01) and remained at this level 12 months after treatment was started. In the washout group, mean plasma Lp[a] levels tended to return to pretherapy values. In addition, estrogen plus progesterone treatment significantly lowered total cholesterol levels by 15% and low-density lipoprotein cholesterol levels by 30%; it increased high-density lipoprotein cholesterol levels by 19%. CONCLUSION: The results suggest that in estrogen plus progesterone-treated postmenopausal women, the lipid profile is improved not only by lowering low-density lipoprotein cholesterol levels and raising high-density lipoprotein levels, but also by lowering plasma Lp[a] concentrations.

Pleiotropic effects of statins in atherosclerosis and diabetes.

OBJECTIVE: To investigate the direct anti-atherosclerotic properties of statins. RESEARCH DESIGN AND METHODS: Using in vitro and ex vivo models, the effect of different statins on key events involved in atherogenesis has been investigated. We studied the ability of statins to modulate modified LDL-induced cholesterol esterification, metalloproteinase secretion by macrophages, and arterial myocyte migration and proliferation. The mechanisms underlying the inhibitory effect of statins have also been explored. Finally, the antiproliferative effect of sera from statin-treated patients has been confirmed in a cell culture system. RESULTS: Fluvastatin, simvastatin, lovastatin, atorvastatin, and cerivastatin, but not pravastatin, dose-dependently decrease smooth muscle cell (SMC) migration and proliferation. Moreover, statins are able to reduce cholesterol accumulation in macrophages in vitro by blocking cholesterol esterification and endocytosis of modified lipoproteins and matrix-degrading enzyme secretion. This in vitro inhibition was completely prevented by mevalonate and partially by all-trans farnesol and all-trans geranylgeraniol, confirming the specific role of isoprenoid metabolites (probably through prenylated protein[s]) in regulating these cellular events. The inhibitory effect of statins on SMC proliferation has been shown in different models of proliferating cells, such as cultured arterial myocytes and rapidly proliferating carotid and femoral intimal lesions in rabbits, independently of their ability to reduce plasma cholesterol. Finally, ex vivo studies showed that sera from fluvastatin-treated patients interfere with SMC proliferation. CONCLUSIONS: These results suggest that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors exert a direct anti-atherosclerotic effect in the arterial wall, beyond their effects on plasma lipids that could translate into a more significant prevention of cardiovascular disease. These findings provide a basis for the beneficial effect of statins in clinical trials also involving diabetic patients--a population with a higher absolute risk of recurrent cardiovascular events.

Acute-phase proteins before cerebral ischemia in stroke-prone rats: identification by proteomics.

BACKGROUND AND PURPOSE: A high degree of proteinuria has been reported in stroke-prone spontaneously hypertensive rats (SHRSP). We studied the effect of salt loading on the detailed protein pattern of serum and urine in 3 rat strains: Wistar-Kyoto, spontaneously hypertensive rats, and SHRSP, an inbred animal model for a complex form of cerebrovascular disorder resembling the human disease. METHODS: Rats were given a permissive diet and received 1% NaCl in drinking water. The protein pattern in body fluids was assessed over time by 2-dimensional electrophoretic analysis. Brain alterations were monitored by MRI and histology. RESULTS: Several proteins were excreted in urine after weeks of treatment and in advance of stroke: transferrin, hemopexin, albumin, alpha(2)-HS-glycoprotein, kallikrein-binding protein, alpha(1)-antitrypsin, Gc-globulin, and transthyretin. Markers of an inflammatory response, including very high levels of thiostatin, were detected in the serum of SHRSP at least 4 weeks before a stroke occurred. CONCLUSIONS: In SHRSP subjected to salt loading, an atypical inflammatory condition and widespread alterations of vascular permeability developed before the appearance of anomalous features in the brain detected by MRI. Urinary concentrations of each of the excreted serum proteins correlated positively with time before stroke occurred.

State-of-the-Art lecture. Statins and blockers of the renin-angiotensin system: vascular protection beyond their primary mode of action.

In addition to their primary mode of action, statins and blockers of the renin-angiotensin system possess common additional properties that are under active investigation. The inhibition of cellular proliferation, the restoration of endothelial activity, the inhibition of platelet reactivity, and an antioxidant potential are only a few examples of shared effects that target the arterial wall. These and other properties may eventually become exploited for the improved treatment of cardiovascular diseases and of other diseases apparently unrelated to the cardiovascular field, including inflammation and cancer. This review analyzes the current knowledge on the pleiotropic properties of these classes of drugs. Direct comparison indicates that study of the associations among these drugs may eventually disclose additive or synergistic effects that, perhaps even at lower dosages, may provide improved vascular protection and a strong alliance against several atherogenic mechanisms.

Preferential utilization of endogenous arachidonate by cyclo-oxygenase in incubations of human platelets.

Thromboxane B2 (TXB2) and 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE) formed from the endogenous and exogenous arachidonate during human platelet incubation, was evaluated by selected ion monitoring (SIM). TXB2 formed from endogenous substrate accounted for about one third of the total, whereas the great part of 12-HETE derived from exogenous arachidonate. These data indicate that under the tested conditions the pool of arachidonate that acts as substrate for cyclo-oxygenase is different from the pool that acts as substrate for lipoxygenase and that the arachidonate released from phospholipids is preferentially utilized by cyclo-oxygenase.

N-3 fatty acids do not lead to an increased diabetic risk in patients with hyperlipidemia and abnormal glucose tolerance. Italian Fish Oil Multicenter Study.

A multicenter, randomized, double-blind, place-bo-controlled study evaluated the possible worsening of glycemic control after a moderate daily intake of n-3 fatty acid ethyl esters in patients with hypertriglyceridemia with and without glucose intolerance or diabetes. A total of 935 patients of both sexes in 63 Italian clinical centers were selected; 55% had either impaired glucose tolerance or non-insulin-dependent diabetes mellitus (NIDDM). They received for 2 mo either 1 g n-3 ethyl esters three times a day or a corresponding placebo, followed by 4 mo of either 1 g n-3 ethyl esters twice a day or placebo. In addition to the complete lipid and lipoprotein evaluation, patients with impaired glucose tolerance also underwent an oral-glucose-tolerance test; in patients with NIDDM, serum insulin and glycated hemoglobin (Hb A1c) concentrations were determined. Plasma triacylglycerol concentrations decreased significantly, up to 21.53% at 6 mo compared with baseline (decreased 15% compared with placebo), with a tendency toward a progressive reduction with time. There was no evidence for a different response in patients with either NIDDM or impaired glucose tolerance. Among NIDDM patients, the triacylglycerol reduction was greater in those with high-density-lipoprotein cholesterol < or = 0.91 mmol/L. There was no alteration in the major glycemic indexes: fasting glucose, Hb A1c, insulinemia, and oral glucose tolerance in patients with impaired glucose tolerance or NIDDM after treatment with n-3 ethyl esters. Treatment with a moderate daily dose of n-3 ethyl esters over a prolonged period of time significantly reduced triacylglycerol concentrations without any worsening of glucose tolerance in patients with hypertriglyceridemia with and without impaired glycemic regulation.

Best practice--ongoing polemics.

Current treatment strategies and disease management programs for hyperlipidemia employ a range of lipid-lowering drugs. Results from early lipid-lowering trials using diet, fibrates, niacin and other classes of drug showed that lowering plasma cholesterol can significantly reduce the risk of developing ischemic cardiovascular events. The landmark statin trials have clearly demonstrated the benefits of lipid-lowering therapy in coronary heart disease (CHD) prevention and unlike early lipid-lowering studies, a reduction in mortality may become evident with statin therapy during the first year of treatment. The number of successful lipid-intervention trials continues to increase and evidence is accumulating that lipid modification can also reduce the risk of cardiovascular events among individuals with only modest degrees of blood-lipid abnormalities. With increasingly powerful drugs to modify blood lipids, the potential levels at which to initiate treatment and the appropriate target levels are rapidly changing and debate surrounds the question of where the line to initiate treatment should be drawn. The relative lack of major adverse events with statin therapy means that the level of CHD risk at which clinical benefit occurs cannot be determined by the degree of risk at which benefit exceeds adverse events. Therefore, patients with only moderately raised cholesterol levels can be treated because statin treatment is well tolerated. One of the most important aspects of the statin trials is the finding that clinical events, such as death and disability due to coronary artery disease, may be preventable or limited in a significant number of patients if they receive aggressive therapy. Current goals for cholesterol levels in patients with established CHD are rarely achieved with non-aggressive treatment; however, with aggressive lipid lowering statins can achieve these goals in a safe and effective manner.

Efficacy and safety of a combination of fluvastatin and bezafibrate in patients with mixed hyperlipidaemia (FACT study).

Preliminary data suggest that fluvastatin may be safely combined with fibrates. The Fluvastatin Alone and in Combination Treatment Study examined the effects on plasma lipids and safety of a combination of fluvastatin and bezafibrate in patients with coronary artery disease and mixed hyperlipidaemia. A total of 333 patients were randomly allocated in this multicentre double-blind trial to receive 40 mg fluvastatin alone (n=80), 400 mg bezafibrate (n=86), 20 mg fluvastatin+400 mg bezafibrate (n=85) or 40 mg fluvastatin+400 mg bezafibrate (n=82) for 24 weeks. Low-density lipoprotein (LDL)-cholesterol decreased >20% in all fluvastatin-containing regimens, with significantly greater decreases compared with bezafibrate alone (P<0.001). Bezafibrate alone and fluvastatin+bezafibrate combinations resulted in greater increases in high-density lipoprotein (HDL)-cholesterol and decreases in triglycerides compared with fluvastatin alone (P<0.001). Fluvastatin (40 mg)+bezafibrate was the most effective for all lipid parameters with a decrease from baseline at endpoint in LDL-cholesterol of 24%, a decrease in triglycerides of 38% and an increase in HDL-cholesterol of 22%. All treatments were well tolerated with no increase in adverse events for combination therapy versus monotherapy, or between combination regimens. No clinically relevant liver (aspartate aminotransferase [ASAT] or alanine aminotransferase [ALAT]) greater than three times the upper limit of normal) or muscular (creatine phosphokinase (CPK) greater than four times the upper limit of normal) laboratory abnormalities were reported. This large study shows 40 mg fluvastatin in combination with 400 mg bezafibrate to be highly effective and superior to either drug given as monotherapy in mixed hyperlipidaemia, and to be safe and well tolerated.

Treatment of hypertriglyceridemia with metformin. Effectiveness and analysis of results.

The triglyceride-lowering effect of metformin (N,N-dimethylbiguanide) was tested in a series of patients with stable hypertriglyceridemia (types IIB, III and IV) and with variable degrees of glucose intolerance. Metformin caused a 38% mean decrease of plasma triglycerides. A selective decrease of very low density lipoprotein cholesterol was observed without reciprocal increase of low density lipoproteins. Thirty patients completed the study. Eighteen, who showed a hypotriglyceridemic effect exceeding 30%, were considered as "Responders"; the other 12, where the effect was negligible, were considered as "Non-Responder". Analysis of the pre-and post-treatment glucose tolerance tests of Responders and Non-Responders showed that the former had, on the average, a normal glucose tolerance and insulin secretion, whereas the latter had an impaired glucose tolerance with increased insulin secretion. These parameters were only slightly modified by metformin. The conclusions of this study support the hypothesis that biguanides exert a triglyceride-lowering effect by decreasing lipoprotein secretion, independent of changes in glucose tolerance and/or insulin secretion.

Relationship between mevalonate pathway and arterial myocyte proliferation: in vitro studies with inhibitors of HMG-CoA reductase.

The role of mevalonate and its products (isoprenoids) in the control of cellular proliferation was examined by investigating the effect of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (vastatins) on growth and on cholesterol biosynthesis of cultured arterial myocytes (SMC). Simvastatin (S) and fluvastatin (F), but not pravastatin (P), decreased the rate of growth of rat vascular SMC. The inhibition, evaluated as cell number, was dose-dependent with IC50 values of 2.8 and 2.2 microM for S and F, respectively; P (1-500 microM) was inactive. The inhibition of cell growth induced by 3.5 microM S (70% decrease) was prevented completely by the addition of 100 microM mevalonate, partially (70-85%) by the addition of 10 microM geraniol, 10 microM farnesol and 5 microM geranylgeraniol, but not by the addition of squalene, confirming the specific role of isoprenoid metabolites in regulating cell proliferation. All the tested vastatins inhibited the incorporation of [14C]acetate into cholesterol but P had 800 times lower potency than S and F. Similar results were obtained in SMC from human femoral artery. At least 80% inhibition of cholesterol synthesis was necessary to induce a decrease in SMC proliferation. To further investigate the relationship between cholesterol synthesis and cell growth, two enantiomers of F were investigated. The enantiomer more active on HMG-CoA reductase was 70- and 1.6-fold more potent on arterial myocyte proliferation than its antipode and the racemic mixture, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Ultrasonographic measurement of the common carotid artery wall thickness in hypercholesterolemic patients. A new model for the quantitation and follow-up of preclinical atherosclerosis in living human subjects.

Ultrasound high resolution B-mode imaging of human arteries allows in vivo an accurate and non-invasive determination of the thickness of the intimal-medial complex. A computer assisted procedure to measure this parameter at the level of common carotid arteries was developed. The average difference between duplicate thickness determinations was 4.6%. The thickness of the intimal medial complex of common carotid arteries was then measured in a group of hypercholesterolemic patients. This parameter was significantly greater in these patients as compared to controls (P less than 0.001). The prevalence of small plaques in the carotid arterial tree was also significantly increased in patients. Analysis of data showed that in controls, but not in patients, the thickness of the intimal medial complex increases with age (r = 0.46, P less than 0.05). Within the hypercholesterolemic group, intimal-medial complex values were greater in male patients and in smokers. It is concluded that the common carotid arteries of hypercholesterolemic patients show thickening of the intimal-medial complex. Cigarette smoking, male sex and age increase the extent of this modification. The determination of this parameter using a non-invasive technique may represent an important tool to monitor in vivo the progression and/or the regression of early atherosclerosis in man.