Ultra-short antibiotic prophylaxis guided by preoperative microbiological nasal swabs in endoscopic endonasal skull base surgery.

PURPOSE: Endoscopic endonasal skull base surgery (EESBS) is a clean-contaminated procedure. Guidelines regarding the antibiotic prophylaxis in EESBS have not been developed yet, and today, there are no universally accepted protocols. In this article, we investigated the efficacy of our new ultra-short antibiotic prophylaxis protocol for EESBS guided by the cultural results of preoperative microbiological nasal swabs. METHODS: We defined as "nasal swab-related antibiotic protocol" the administration of a first-generation cephalosporin (cefazolin 2 g) in patients whose nasal swabs revealed the presence of normal nasal flora or methicillin-sensitive Staphylococcus aureus (MSSA), and the administration of vancomycin 1 g intravenously in patients whose nasal swabs revealed the presence of methicillin-resistant Staphylococcus aureus (MRSA) or with reported cephalosporin/penicillin allergy. This case-control study included 120 patients who underwent EESBS. The case group included 60 cases who received the "nasal swab-related antibiotic protocol," while the control group included 60 cases who received the "standard hospital antibiotic protocol" used in neurosurgery (cefazolin 2 g plus metronidazole 500 mg at induction, and 2 g of cefazolin repeated after 180 min). RESULTS: The preoperative microbiological nasal swabs showed normal nasal flora in 42 patients (70%), MSSA in 17 patients (28.3%), and MRSA in 1 patient (1.6%). During the study period, no cases of meningitis or sinusitis occurred in the case group ("nasal swab-related antibiotic protocol"), while two infections (3.3%, 1 sinusitis and 1 meningitis) were reported in the control group ("standard hospital antibiotic protocol"). Mean length of hospitalization was 6.5 days for the case group and 8.5 days in the control group. "Standard hospital antibiotic protocol" is less expensive (range, 2.88-5.42 euros) compared with our new "nasal swab-related antibiotic protocol" (range, 10.02-32.56 euros), but in line with other antibiotic prophylaxis protocols reported in literature. DISCUSSION: The low complication rates of our case series (0%) is comparable to complication rates reported in literature (1.6% for meningitis and 8% for sinusitis). Compared with other perioperative antibiotic regimens reported in literature, the "nasal swab-related antibiotic protocol" is cheap and at least equally effective. We discuss the rationale on which we based the choice of chemoprophylaxis, the timing, and the length of our regimen. CONCLUSIONS: Our study confirmed the safety and efficacy of our easily applicable and low-cost antibiotic prophylaxis protocol.

Perfil metabólico de vacas Holandês e mestiças Holandês x Jersey no periparto / Metabolic profile of Holstein and crossbred Holstein x Jersey cows in the peripartum

O objetivo do presente trabalho foi determinar e comparar o perfil metabólico de vacas Holandês (H) e mestiças Holandês x Jersey (HxJ) no periparto. Avaliaram-se 24 vacas, sendo 11 vacas Holandês e 13 mestiças Holandês x Jersey. Semanalmente, coletou-se sangue para a determinação das concentrações séricas de glicose, beta-hidroxibutirato (BHB), proteína total, albumina, aspartato aminotransferase (AST), creatinoquinase (CK), cálcio total, cálcio iônico, magnésio, fósforo inorgânico e colesterol. Avaliou-se também o peso vivo e o escore de condição corporal (ECC). Os dados foram submetidos à análise de variância com medidas repetidas no tempo. As vacas Holandês apresentaram maior peso vivo. Não houve diferença entre os grupamentos genéticos para ECC. Foi observada tendência de maiores concentrações séricas de BHB, AST e maior concentração de cálcio iônico em vacas mestiças Holandês x Jersey. Vacas mestiças Holandês x Jersey e Holandês apresentaram perfil energético similar durante o período de transição pré e pós-parto na maioria dos indicadores, com exceção do cálcio, que foi maior nas vacas mestiças, e do fósforo, que foi superior nas vacas Holandês.(AU)

The aim of this study was to determine and compare the metabolic profile of Holstein (H) and crossbred Holstein x Jersey (HxJ) on peripartum. For this, 24 cows were evaluated, 11 Holstein and 13 crossbreeds Holstein x Jersey. Weekly, venous blood sample were collected to determine concentration of glucose, beta-hydroxybutyrate (BHBA), total protein, albumin, aspartate aminotransferase (AST), creatine kinase (CK), total calcium, ionic calcium, magnesium, inorganic phosphorus and cholesterol. Body weight (BW) and body condition score (BCS) were also evaluated. The data were submitted to analysis of variance with repeated measures in time. Holstein cows presented higher BW, however, there was no difference for BCS in compare to crossbreed Holstein x Jersey cows. Tendency for higher serum concentrations of BHBA, AST and higher concentration of ionic calcium was observed in crossbreed cows in comparison to the Holstein. The energetic profile during the pre and postpartum transition period is similar for both genetic groups with higher concentrations of BHBA on the first week of lactation, however, with a tendency of higher serum concentrations of BHBA for crossbreed cows. Higher concentrations of ionic calcium were observed in crossbreed cows and higher concentrations of phosphorus in Holstein cows on peripartum. Holstein and Holtein x Jersey crossbreed cows have a similar energy profile during the pre and postpartum transition period in most of the indicators, except for calcium that was higher in crossbred cows and higher phosphorus in Holstein cows.(AU)

On-pump Cardiac Surgery Enhances Platelet Renewal and Impairs Aspirin Pharmacodynamics: Effects of Improved Dosing Regimens.

On-pump cardiac surgery may trigger inflammation and accelerate platelet cyclooxygenase-1 renewal, thereby modifying low-dose aspirin pharmacodynamics. Thirty-seven patients on standard aspirin 100 mg once-daily were studied before surgery and randomized within 36 hours postsurgery to 100 mg once-daily, 100 mg twice-daily, or 200 mg once-daily for 90 days. On day 7 postsurgery, immature and mature platelets, platelet mass, thrombopoietin, glycocalicin, leukocytes, C-reactive protein, and interleukin-6 significantly increased. Interleukin-6 significantly correlated with immature platelets. At day 7, patients randomized to 100 mg once-daily showed a significant increase in serum thromboxane (TX)B2 within the 24-hour dosing interval and urinary TXA2 metabolite (TXM) excretion. Aspirin 100 mg twice-daily lowered serum TXB2 and prevented postsurgery TXM increase (P < 0.01), without affecting prostacyclin metabolite excretion. After cardiac surgery, shortening the dosing interval, but not doubling the once-daily dose, rescues the impaired antiplatelet effect of low-dose aspirin and prevents platelet activation associated with acute inflammation and enhanced platelet turnover.

Markers of inflammation, thrombosis and endothelial activation correlate with carotid IMT regression in stable coronary disease after atorvastatin treatment.

BACKGROUND AND AIMS: MIAMI is a prospective multicenter clinical study designed to investigate the relationship between changes in carotid intima-media thickness (C-IMT) and changes in circulating markers of inflammation, thrombosis and endothelial activation in stable coronary patients treated for 20+/-3.7 months with 20mg/day atorvastatin. METHODS AND RESULTS: Eighty-five subjects had their C-IMT, blood lipids and soluble markers measured at baseline, at the 12th month and at the end of the study. Almost all soluble markers decreased upon treatment except for high-sensitivity C-reactive protein (hs-CRP), interleukin-18 (IL-18), tissue factor pathway inhibitor-free (TFPI-free) and soluble vascular cell adhesion molecules-1 (sVCAM-1) which did not change significantly, and interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and soluble CD40 ligand (sCD40L) which increased. sCD40L, fibrinogen, tissue factor pathway inhibitor-total (TFPI-total), soluble intercellular adhesion molecules-1 (sICAM-1), sE-selectin, interleukin-8 (IL-8) and von Willebrand factor (vWF) changed significantly even after application of the Bonferroni correction for multiple comparisons. Changes in lipids did not correlate with C-IMT regression either when considered singly or when combined in a lipid score. Changes in soluble markers correlated poorly with C-IMT regression when analyzed singly, but strongly when combined in relevant composite scores (inflammation/coagulation score, endothelial activation score, soluble markers score and total score). CONCLUSION: In patients with stable coronary artery disease treated with moderate doses of atorvastatin, carotid IMT regression correlated with changes of inflammation, thrombosis and endothelial activation profiles.

E-selectin and TFPI are associated with carotid intima-media thickness in stable IHD patients: the baseline findings of the MIAMI study.

OBJECTIVE: MIAMI was a prospective multicenter clinical study designed to investigate the relationship between changes in carotid intima-media thickness (C-IMT) and those in the levels of circulating markers of inflammation, thrombosis and endothelial dysfunction. The study was performed in a group of stable coronary patients treated for two years with a moderate dosage of atorvastatin (20mg/day). In this paper the cross-sectional relationship between C-IMT and the same circulating markers of inflammation, thrombosis and endothelial dysfunction measured at baseline was investigated. METHODS: Eighty-five subjects that had not used statins for at least two months were enrolled in the study. At time of enrollment, the levels of vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1), E-selectin, interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-alpha, high-sensitivity C-reactive protein (hs-CRP), tissue factor (TF), tissue factor pathway inhibitor (TFPI), von Willebrand factor (vWF), fibrinogen, total cholesterol (TC), high-density lipoprotein (HDL) and low-density lipoprotein (LDL), and triglycerides were measured, in parallel with C-IMT assessment. RESULTS: In cross-sectional analyses, markers of endothelial perturbation (i.e. E-selectin) and TFPI were more strongly correlated with arherosclerotic burden than markers of inflammation. The baseline picture in this study indicates that E-selectin and TFPI are linked with atherosclerotic burden.

Rosuvastatin displays anti-atherothrombotic and anti-inflammatory properties in apoE-deficient mice.

Inflammation contributes importantly to all stages of atherosclerosis, including the onset of acute thrombotic complications. In clinical trials, statins are beneficial in the primary and secondary prevention of coronary heart disease. Moreover, statins have been shown to possess several pleiotropic properties independent of cholesterol lowering in experimental settings. Based on these premises, we investigated the anti-inflammatory and anti-atherothrombotic properties of rosuvastatin in vivo, testing its effect on cholesterol and monocyte accumulation, and on adhesion molecules and tissue factor (TF) expression. ApoE-deficient female mice were fed a cholesterol-rich diet containing rosuvastatin (0, 1, 2 or 10 mg kg(-1)d(-1)) for 12 weeks. Treatment with rosuvastatin did not significantly affect either body weight gain or plasma total cholesterol (C) and triglyceride levels. However, rosuvastatin treatment dose-dependently reduced ICAM-1 expression in the aortic valves (V) (up to 40% inhibition, p<0.05) and in the proximal segment of the ascending aorta (AA) (-50%, p<0.001). Similarly, rosuvastatin inhibited VCAM-1 expression in the V (-40%) and in the AA (-35%, p<0.05). Moreover, there was a reduced accumulation of macrophages in the V in a dose-dependent and statistically significant manner (-45%, p<0.01). These anti-inflammatory effects were reflected in a reduction of cholesterol deposition in the entire aorta, both in the free and in the esterified form. Finally, the expression of tissue factor, the most potent pro-thrombogenic agent, was consistently reduced in AA by rosuvastatin treatment (-71%, p<0.001). Altogether, these data demonstrate that rosuvastatin has anti-inflammatory and anti-atherothrombotic activities in apoE-deficient mice that could translate in a beneficial effect on atherogenesis.

Distinct roles for PAR1- and PAR2-mediated vasomotor modulation in human arterial and venous conduits.

BACKGROUND: Patency rates after coronary artery bypass grafting (CABG) are better if the internal mammary artery (IMA) is used rather than the greater saphenous vein (GSV), and may be related to the endothelial release of vasodilators antagonizing vascular contraction. It has recently been shown that a family of protease-activated receptors (PARs) modulate endothelium-dependent vasodilatation. OBJECTIVE AND METHODS: The aim of this study was to evaluate the presence and functional role of protease-activated receptor 1 (PAR1) and protease-activated receptor 2 (PAR2) in mediating vascular tone in IMAs and GSVs from patients undergoing CABG by means of real time-PCR and isometric tension measurements. RESULTS: PAR1 mRNA levels were higher than those of PAR2 mRNA in both vessels. A selective PAR2-activating peptide (PAR2-AP), SLIGKV-NH(2) (0.01-100 micromol L(-1)), failed to induce vasorelaxation in precontracted IMA and GSV rings, whereas the selective PAR1-AP, TFLLR-NH(2) (0.001 to 10 micromol L(-1)), caused greater endothelium-dependent relaxation in the IMAs (pD(2) values 7.25 +/- 0.6 vs. 7.86 +/- 0.42, P < 0.05; E(max) values 56.2 +/- 17.3% vs. 29.7 +/- 13.4%, P < 0.001). Preincubation with TNFalpha (3 nmol L(-1)) induced vasorelaxation in IMAs in response to PAR2-AP (P < 0.05 vs. non-stimulated vessels); the response to PAR1-AP was unchanged. The relaxation induced by both PAR-APs was NO- and endothelium-dependent. CONCLUSION: These data show that functionally active PAR1 and PAR2 are present in IMAs and GSVs, and that inflammatory stimuli selectively enhance endothelium-dependent relaxation to PAR2-AP in IMAs.

15-deoxy-delta12,14-Prostaglandin J2 inhibits tissue factor expression in human macrophages and endothelial cells: evidence for ERK1/2 signaling pathway blockade.

Basic and clinical evidence has provided insight into the molecular events that link inflammation and coagulation. Increased expression of tissue factor (TF) by circulating and vascular cells has been indicated as responsible for the thrombotic complications associated with acute and chronic inflammation. TF is indeed inducible in circulating and vascular cells by cytokines and bacterial lipopolysaccharide (LPS) and its expression triggers the coagulation. The cyclopentenone prostaglandins are naturally occurring prostaglandin D2 (PGD2) derivatives that comprises prostaglandin J2 (PGJ2) and its metabolites delta12-PGJ2 and 15-deoxy- delta12,14-prostaglandin J2 (15d-PGJ2). These compounds, detected in vivo in a later phase of the inflammatory response, are characterized by anti-inflammatory activity and participate to the resolution of inflammation. We have here investigated the effect of 15d-PGJ2 on TF expression in human macrophages and endothelial cells (HUVEC). Our results indicate that 15d-PGJ2 down-regulates LPS- and TNFalpha-induced TF activity, protein and mRNA through inhibition of TF gene transcription. The effect of 15d-PGJ2 is targeted to the NF-kappaB/I-kappaB pathway and to the mitogen activated protein kinase ERK1/2. A role of PPAR-gamma activation in TF inhibition by 15d-PGJ2 was excluded. We conclude that 15d-PGJ2 negatively affects TF expression in macrophages and endothelial cells through a PPARgamma-independent mechanism. This down-regulation may be crucial to limit excessive blood clotting activation in immuno-inflammatory diseases.

Statins prevent endothelial cell activation induced by antiphospholipid (anti-beta2-glycoprotein I) antibodies: effect on the proadhesive and proinflammatory phenotype.

OBJECTIVE: To investigate the ability of statins, the inhibitors of the hydroxymethylglutaryl-coenzyme A reductase enzyme, to affect endothelial cell activation induced by anti-beta2-glycoprotein I (anti-beta2GPI) antibodies in vitro. METHODS: Human umbilical vein endothelial cell (HUVEC) activation was evaluated as U937 monocyte adhesion, E-selectin, and intercellular adhesion molecule I (ICAM-1) expression by cell enzyme-linked immunosorbent assay and as interleukin-6 (IL-6) messenger RNA (mRNA) expression by RNA protection assay. E-selectin-specific nuclear factor kappaB (NF-kappaB) DNA-binding activity was evaluated by the gel-shift assay. HUVECs were activated by polyclonal affinity-purified IgG, human monoclonal IgM anti-beta2GPI antibodies, human recombinant IL-1beta, tumor necrosis factor alpha, or lipopolysaccharide (LPS). RESULTS: Fluvastatin reduced, in a concentration-dependent manner (1-10 microM), the adhesion of U937 to HUVECs and the expression of E-selectin and ICAM-1 induced by anti-beta2GPI antibodies as well as by cytokines or LPS. Another lipophilic statin, simvastatin, displayed similar effects but to a lesser extent than fluvastatin. The inhibition of E-selectin expression exerted by fluvastatin was related to the impairment of NF-kappaB binding to DNA. Moreover, the drug attenuated the expression of IL-6 mRNA in HUVEC exposed to anti-beta2GPI antibodies or cytokines. Incubation of HUVECs with mevalonate (100 microM), concomitantly with fluvastatin, greatly prevented the inhibitory effect of statin. CONCLUSION: Endothelial activation mediated by anti-beta2GPI antibody can be inhibited by statins. Because of the suggested role of endothelial cell activation in the pathogenesis of antiphospholipid syndrome (APS), our data provide, for the first time, a rationale for using statins as an additional therapeutic tool in APS.

Angiotensin-converting enzyme inhibitors downregulate tissue factor synthesis in monocytes.

Angiotensin-converting enzyme (ACE) inhibitors reduce the risk of recurrent myocardial infarction in patients with left ventricular dysfunction. Tissue factor (TF), the initiator of blood coagulation, plays a pivotal role in arterial thrombosis that occurs after atherosclerotic plaque fissuring. Because monocytes synthesize TF and contain several components of the renin-angiotensin system, we investigated the possibility that ACE inhibitors could modulate monocyte TF expression. Mononuclear leukocytes from healthy volunteers were incubated with endotoxin in the presence or absence of different ACE inhibitors. Captopril reduced TF expression in endotoxin-stimulated mononuclear leukocytes, as measured by a 1-stage clotting assay and ELISA analysis, by approximately 60%. The effect was dose-dependent and was attributable to ACE inhibition, given that other ACE inhibitors, such as idrapril or fosinopril, and losartan, an antagonist of the angiotensin II AT(1) receptor, caused a comparable reduction in TF activity. Reverse transcriptase-polymerase chain reaction indicated that endotoxin-mediated increased levels of TF mRNA were inhibited by ACE inhibitors. Moreover, endotoxin-induced nuclear factor-kappaB translocation to the promoter region of the gene encoding for TF was markedly inhibited by captopril. The finding that ACE inhibitors and angiotensin II AT(1) antagonists can potentially modulate TF expression by mononuclear cells has important biological and therapeutic implications for the evolution of thrombi. Our results suggest that the anti-ischemic effect of these drugs might be explained, at least in part, by their ability to reduce TF expression in monocytes.

Tissue factor in atherosclerosis.

Thrombosis is a key feature of the initiation and progression of atherosclerosis and its clinical sequelae. Acute thrombosis can lead to arterial occlusion and consequently provoke myocardial infarction, unstable angina, stroke and sudden death. Acute thrombosis can also be a complication of arterial bypass surgery, balloon angioplasty, atherectomy, or coronary artery stenting. The thrombotic response is influenced by several factors, among them the thrombogenicity of the vessel wall and of certain blood components as well as their interaction with the lipid pool. Tissue factor (TF) is considered to be the primary cofactor of cellular origin that is involved in activation of the coagulation pathway. The active form of TF has been shown to be present in specimens of human coronary artery in association both with acellular lipid areas and with macrophages and smooth muscle cells, which suggests that TF plays a major role in determining plaque thrombogenicity. We discuss here what is currently known about the role of tissue factor in atherogenesis, and focus attention on pharmacological approaches in this area.

Cooperation between VEGF and TNF-alpha is necessary for exposure of active tissue factor on the surface of human endothelial cells.

This study was undertaken to characterize tissue factor (TF) induction, localization, and functional activity in cultured human umbilical vein endothelial cells (HUVECs) exposed to recombinant vascular endothelial growth factor (rVEGF) and recombinant tumor necrosis factor-alpha (rTNF-alpha). rVEGF (1 nmol/L) and rTNF-alpha (500 U/mL) synergistically increased TF mRNA, protein, and total activity, as measured in cell lysates. To examine surface TF expression, living cells were treated with antibody to TF and examined microscopically. Almost no staining was seen in control cells or cells treated with a single agent. In contrast, cells treated with both agonists showed intense membrane staining with surface patches, appearing as buds by confocal microscopy. To determine surface TF activity, studies were performed using a parallel-plate flow chamber, which allows detection of factor Xa generation on living cells. rVEGF and rTNF-alpha induced little surface TF activity (0.032+/-0.008 and 0.014+/-0.008 fmol/cm2, respectively). In combination, they significantly increased TF expression on the cell surface (0.429+/-0.094 fmol/cm2, P<0.05). These data indicate that the synergistic effect of rVEGF and rTNF-alpha is necessary to generate functional TF on the surface of endothelial cells. The requirement for multiple agonists to expose active TF may serve to protect endothelial cells from acting as a procoagulant surface, even under conditions of cell perturbation.

Profibrinolytic properties characterize a stably transformed human endothelial cell line.

A stable immortalized venous endothelial cell (IVEC) line, obtained by transfection of human umbilical vein endothelial cells (HUVEC), retains many normal differentiated endothelial characteristics. We compared the fibrinolytic activities of IVEC and HUVEC, and observed that IVEC express a more profibrinolytic phenotype than HUVEC, since they bind and activate plasminogen more efficiently, produce more tissue plasminogen activator and urokinase-type plasminogen activator antigens, and secrete less plasminogen activator inhibitor-1 antigen both under basal conditions and after stimulation with lipopolysaccharide, phorbol ester and tumor necrosis factor. Moreover, immunostaining and Western blotting of IVEC for the plasminogen/tissue plasminogen activator receptor annexin II, as well as Northern blotting of annexin II mRNA, revealed similar patterns of surface expression in IVEC and HUVEC. Plasminogen activator inhibitor-2 is expressed similarly in both cell types. IVEC may be a useful human model for functional and pharmacological explorations and modulations of fibrinolytic system components.

Hemodynamic effects of transdermal estradiol alone and combined with norethisterone acetate.

A 24 weeks, randomized, two-period, placebo controlled study was conducted to compare the effects of continuous transdermal 17 beta-estradiol replacement therapy (0.05 mg/day once a week) with placebo on systemic hemodynamics and blood pressure in postmenopausal women. Twenty-nine postmenopausal women (47-62 years) free of hormone replacement therapy were randomized in two groups; group 1 received estradiol patches for the first 12 weeks and placebo patches for the second, and group 2 received the same treatments in the reverse order. The effect of combined estradiol plus oral norethisterone acetate (NETA) 1 mg was also evaluated in the subset of women with intact uteri (n = 24). Crossover analysis showed that stroke volume and cardiac output were significantly higher (P < 0.05) and blood pressure was significantly lower (P < 0.05) with estradiol, irrespective of the order in which the treatments were administered. Although correlations between plasma estradiol levels during active treatment and hemodynamic changes were not significant, hemodynamic changes were significantly greater above 63 pg/ml than below this level (P < 0.05). Oral norethisterone acetate administration either during transdermal placebo or estradiol arms tended to modify systemic hemodynamics in the same direction than estradiol but the changes did not attained statistical significance. In summary compared with placebo, transdermal 17 beta-estradiol, replacement to postmenopausal women, increased cardiac output and decreased blood pressure. Although the average magnitude of changes was small, the results suggest that plasma estradiol levels could be a source of individual variability in the hemodynamic response. Oral NETA administration tended to enhance rather than reverse the estradiol-induced changes.

Vastatins inhibit tissue factor in cultured human macrophages. A novel mechanism of protection against atherothrombosis.

We examined the effect of fluvastatin, the first entirely synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor that is structurally different from other vastatins, on tissue factor (TF) expression in human macrophages spontaneously differentiated in culture from blood monocytes. Fluvastatin decreased TF activity in a dose-dependent manner (1 to 5 mumol/L) in both unstimulated and lipopolysaccharide-stimulated macrophages, and this reduction paralleled the decrease in immunologically recognized TF protein. The same results were obtained with another lipophilic vastatin, simvastatin, but not with hydrophilic pravastatin. The reduction in TF expression was also observed in macrophages enriched in cholesterol after exposure to 50 micrograms/mL acetylated low density lipoprotein. The inhibitory effect of fluvastatin on TF activity and antigen was fully reversible by coincubation with 100 mumol/L mevalonate or 10 mumol/L all-trans-geranylgeraniol but not with dolichol, farnesol, or geraniol. Suppression of TF antigen and activity was accompanied by a diminution in TF mRNA levels, which was completely prevented by mevalonate. Furthermore, fluvastatin impaired bacterial lipopolysaccharide-induced binding of c-Rel/p65 heterodimers to a kappa B site in the TF promoter, indicating that this drug influences induction of the TF gene. We conclude that lipophilic vastatins inhibit TF expression in macrophages, and because this effect is prevented by mevalonate and geranylgeraniol, a geranylgeranylated protein plays a crucial role in the regulation of TF biosynthesis. The suppression of TF in macrophages by vastatins indicates a potential mechanism by which these drugs interfere with the formation and progression of atherosclerotic plaque as well as thrombotic events in hyperlipidemic patients.

Plasminogen activator inhibitor type-1 synthesis and mRNA expression in HepG2 cells are regulated by VLDL.

The effect of VLDL on plasminogen activator inhibitor type 1 biosynthesis in HepG2 cells was investigated. Exposure of HepG2 cells to VLDL (range, 10 to 100 micrograms protein per milliliter) for 16 hours resulted in an enhanced release of PAI-1 antigen and PAI activity into conditioned medium, accompanied by the accumulation of intracellular triglycerides. By using a monoclonal antibody (IgG C7) specific to the LDL receptor, we showed that the effect of VLDL is mediated by its interaction with the LDL receptor. Enhanced PAI-1 release was due to increased biosynthesis: PAI-1 mRNA was doubled, mainly because of the effect on the 2.2-kb PAI-1 mRNA rather than the 3.2-kb transcript. Addition of insulin with the VLDL further enhanced PAI-1 antigen release and PAI-1 mRNA accumulation. The effect of VLDL on steady state levels of PAI-1 mRNA was apparently not due to an increase of gene transcription but to stabilization of both PAI-1 mRNA transcripts. The enhancing effect of VLDL on PAI-1 biosynthesis in HepG2 cells may raise PAI-1 antigen levels not only in hypertriglyceridemic states but also in those conditions in which both insulin and VLDL are elevated.

Influencia de la siesta sobre la presión arterial en pacientes hipertensos esenciales / Afternoon nap influence on blood pressure in essential hypertensives

Hay suficientes evidencias que demuestran que el descenso nocturno de la presión arterial es consecuencia de la inactividad y no depende de una hora determinada, ya que la presión arterial desciende cuando los individuos duermen durante el día. Comparamos la presión arterial sistólica, diastólica y la frecuencia cardíaca durante la siesta, el período nocturno de actividad y el sueño nocturno en 59 pacientes (32 mujeres, 27 hombres) hipertensos sin medicación (edad promedio: 53 ñ 14 años, rango: 26-84 años). La presión arterial y la frecuencia cardíaca fueron registradas utilizando un Pressurometer Del Mar IV 1990. Veintidós pacientes durmieron dos horas por lo menos luego de almorzar, 17 descansaron sin dormir y 20 permanecieron activos en el período posprandial. Evaluamos la media, el área bajo la curva y el desvío estándar de la presión arterial sistólica, diastólica y frecuencia cardíaca durante el período posprandial, el sueño nocturno y el resto del día. Tanto el sueño nocturno como el sueño posprandial disminuyeron la presión arterial sistólica, diastólica y la frecuencia cardíaca. Durante el descanso posprandial la presión arterial diastólica fue similar a la presión arterial diastólica nocturna y durante la siesta disminuyó más que durante el sueño nocturno

Functionally abnormal monocytes in hypercholesterolemia.

We investigated some functions of monocytes from 20 type IIa hypercholesterolemic (HC) and five homozygous familial hypercholesterolemic (FH) patients. Monocytes from the HC patients contained as much cholesterol and formed as much thromboxane B2 in response to N-formyl-methionyl-leucyl-phenylalanine (fMLP) or calcium ionophore A23187 as those from normal individuals. In contrast, the generation of prostaglandin E2 and 6-ketoprostaglandin F1 alpha in response to these agonists was 1.5-3 times normal, and that of leukotriene B4 was 40-60% of the normal value (p < 0.05 for all). Studies in which the combination of fMLP or A23187 with sodium arachidonate were employed suggested that these abnormalities were independent of the availability of the endogenous substrate for the lipoxygenase or cyclooxygenase enzymes. Quantitatively and qualitatively comparable abnormalities were found in monocytes from the five FH patients, and these were little affected when the patients' plasma cholesterol levels were almost normalized by low density lipoprotein apheresis. In keeping with the abnormalities in the eicosanoid metabolism, monocytes from HC patients exhibited a defective ability (p < 0.05) to generate O2-, the extent of which was correlated with the impaired formation of leukotriene B4. On the other hand, adhesion studies indicated that patients' cells exhibited an abnormally high ability to adhere to glass (p < 0.01). These data indicate the presence of functionally abnormal monocytes in hypercholesterolemia and suggest a direction to be followed to understand the importance of such cells in the premature atherosclerosis that occurs in these patients.