917-97 Decreased Resistance Against Oxidation of LDL from Patients with Homozigous Familial Hypercholesterolemia

Familial hypercholesterolemia (FH) was the first genetic disorder recognized to cause myocardial infarction. Homozigotes (H) inherit two mutant genes at the low density lipoprotein (LDL) receptor locus, and as a result of the increased levels and prolonged residence time of LDL in plasma, there is a strong tendency toward accumulation of LDL in the arterial wall, causing early atherogenesis. It has been shown that LDL might undergo oxidation before it can be taken up by macrophages and it become foam cells. Thus, one additional explanation for atherogenesis in FH may be the extent to which LDL is susceptible to oxidation. We selected 8 homozigous FH pts (mean total-cholesterol 825±70mg/dl) matched with 8 healthy subjects to investigate the LDL oxidizability. Skin fibroblast cultures showed that one patient was receptor negative, while others were receptor-defective. LDL were isolated from serum by ultracentrifugations in KBr. Purified LDL was exposed to oxygen radicals generated by the xanthine/xanthine oxidase reaction (2mM and 100mU, respectively for 18hs at 37°C). Malonildihaldehyde (MDAI content was evaluated by the thiobarbiturate method. LDL analysis was carried on polyacrylamide (PAGE; 5 to 16% gradient) and agarose gel electrophoresis (0.8% in Tris-HCL buffer). No significant increase was observed in the basal concentration of MDA between LDL from H and controls (0.8±0.12 and 0.9±0.15nmoles of MDAlmg of protein, respectively). Instead, afteroxidation MDAwas 35.1±4.5* nmoles/mg of protein LDL from H, and 23.5±4.1 in controls (*p<0.05). PAGE confirmed the purity of LDL, present as an intact apolipoprotein B100(apo-B100). When oxidized LDL was run on PAGE an extensive apo-B100fragmentation, replaced by lower fragments ranging from 97.400 to 205.000 m.w., was only observed in LDL from H but not in controls in our experimental conditions. MDA content after oxidation of LDL correlated well with the loss of intact apo-B100. Finally, the relative LDL mobility on agarose gel was evaluated. This assay allows to detect changes in electric charge induced by oxidation. Basal LDL from H and controls migrated as homogeneous bands to 1.2±0.2 and 1.1±0.2cm from the origin. In contrast, oxidized LDL from H migrated to 2.1±0.3*cm from the origin while those of controls migrated to 1.5±0.2 (*p<0.05). Thus, in FH LDL appear to be more susceptible to oxidationin vitro; the indices for LDL oxidizability were all significantly different from those of controls. This phenomenon may be an important additional mechanism of atherogenesis in homozigous FH

24-hour blood pressure recording in patients with orthostatic hypotension.

Continuous intra-arterial blood pressure measurement and electrocardiograms were obtained in two ambulatory patients with orthostatic hypotension due to autonomic dysfunction. Systolic and diastolic arterial pressure presented marked variations which took place mainly during the day and were related to several physical activities; however, marked falls in blood pressure were also observed during sleep and at the moment of arousal. A peak incidence of hypotensive events was found in the afternoon, mainly in the hours following the afternoon meal. Recording was repeated after 3 weeks of treatment with propranolol, 40 mg t.i.d. In patient 1, beta blockade drastically reduced the number and severity of hypotensive episodes, while propranolol failed to control blood pressure in patient 2, who experienced a higher number of hypotensive events during treatment. Findings of this study may be relevant to the management of patients with orthostatic hypotension and should contribute to a more accurate characterization of blood pressure profile in autonomic dysfunction

Heart rate, pr, and qt intervals in normal children: A 24‐hour holter monitoring study

A dynamic electrocardiographic Holter monitoring study was performed in 32 healthy children (20 males and 12 females, age range 6-11 years old), without heart disease, according to clinical and noninvasive instrumental examination. We evaluated atrioventricular conduction time (PR), heart rate (HR), and QT interval patterns defining the range of normality of these electrocardiographic parameters. The PR interval ranged from 154 +/- 10 ms (mean +/- SD) for HR less than or equal to 60 to 102 +/- 12 ms for HR greater than or equal to 120 (range 85-180). The absolute mean HR was 87 +/- 10 beats/min (range 72-104), the minimum observed HR being 61 +/- 10 (range 51-79), the maximum 160 +/- 20 beats/min (range 129-186). Daytime mean HR gave a mean value of 93 +/- 10 (range 71-148), while during night hours it was 74 +/- 11 (range 54-98). The minimum QT interval averaged 261 +/- 10 ms for HR greater than 120 and the maximum 389 +/- 9 ms for HR less than or equal to 60; the corresponding mean value of QTc (i.e., QT corrected for HR) ranged from 388 +/- 8 for HR less than or equal to 60 beats/min to 403 +/- 14 ms for HR greater than 120 beats/min. The results of the present study provide data of normal children which can be readily compared against those of subjects in whom cardiac abnormalities are suspect or patient.(ABSTRACT TRUNCATED AT 250 WORDS

Akt Regulates Drug-Induced Cell Death through Bcl-w Downregulation

Akt is a serine threonine kinase with a major role in transducing survival signals and regulating proteins involved in apoptosis. To find new interactors of Akt involved in cell survival, we performed a two-hybrid screening in yeast using human full-length Akt c-DNA as bait and a murine c-DNA library as prey. Among the 80 clones obtained, two were identified as Bcl-w. Bcl-w is a member of the Bcl-2 family that is essential for the regulation of cellular survival, and that is up-regulated in different human tumors, such as gastric and colorectal carcinomas. Direct interaction of Bcl-w with Akt was confirmed by immunoprecipitation assays. Subsequently, we addressed the function of this interaction: by interfering with the activity or amount of Akt, we have demonstrated that Akt modulates the amount of Bcl-w protein. We have found that inhibition of Akt activity may promote apoptosis through the downregulation of Bcl-w protein and the consequential reduction in interaction of Bcl-w with pro-apoptotic members of the Bcl-2 family. Our data provide evidence that Bcl-w is a new member of the Akt pathway and that Akt may induce anti-apoptotic signals at least in part through the regulation of the amount and activity of Bcl-w

IPO-V2: A prospective, multicenter, randomized, comparative clinical investigation of the effects of sulodexide in preventing cardiovascular accidents in the first year after acute myocardial infarction

AbstractObjectives. This study was conducted to assess the efficacy of sulodexide, a glycosaminoglycan compound with antithrombotic properties, in preventing death and thromboembotic events after acute myocardial infarction.Background. Antithrombotic therapy has been found to play an important role in the prevention of cardiovascular events and death after acute myocardial infarction. Glycosaminoglycan-containing compounds, including sulodexide, show profibrinolytic and antithrombotic properties that render them suitable for use in patients after infarction.Methods. A total of 3,986 patients who had recovered from acute myocardial infarction were randomized to receive either the standard therapy routinely administered at each study center, excluding antiplatelet and anticoagulant drugs (control group, 1,970 patients), or the standard therapy plus sulodexide (treated group, 2,016 patients). Between 7 and 10 days after the episode of acute myocardial infarction, sulodexide was administered as a single daily 600-lipoprotein-lipase-releasing unit (LRU) intramuscular injection for the 1st month, followed by oral capsules of 500 LRU twice daily. Patients were evaluated for ≥12 months.Results. At the end of the study, 140 (7.1%) were recorded in the control group and 97 (4.8%) in the sulodexide group (32% risk reduction, p = 0.0022, chi-square test). A total of 90 patients (4.6%) in the control group had a further infarction, compared with 66 (33%) in the sulodexide group (28% risk reduction, p = 0.035). Furthermore, a reduction in left ventricular thrombus formation (evaluated by echocardiography) was observed in the sulodeside group (n = 12; 0.6%), compared with values in the control group (n = 25; 1.3%) (53% risk reduction, p = 0.027). Sulodexide was well tolerated and devoid of significant adverse events. All significant results were confirmed by “actual treatment” analyses.Conclusions. The study provides evidence that long-term therapy with sulodexide started early after an episode of acute myocardial infarction is associated with reductions in total mortality, rate of reinfarction and mural thrombus formation

Combined fit to the spectrum and composition data measured by the Pierre Auger Observatory including magnetic horizon effects

The measurements by the Pierre Auger Observatory of the energy spectrum and mass composition of cosmic rays can be interpreted assuming the presence of two extragalactic source populations, one dominating the flux at energies above a few EeV and the other below. To fit the data ignoring magnetic field effects, the high-energy population needs to accelerate a mixture of nuclei with very hard spectra, at odds with the approximate E$^{-2}$ shape expected from diffusive shock acceleration. The presence of turbulent extragalactic magnetic fields in the region between the closest sources and the Earth can significantly modify the observed CR spectrum with respect to that emitted by the sources, reducing the flux of low-rigidity particles that reach the Earth. We here take into account this magnetic horizon effect in the combined fit of the spectrum and shower depth distributions, exploring the possibility that a spectrum for the high-energy population sources with a shape closer to E$^{-2}$ be able to explain the observations