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Background The 24-week randomized, double-blind ODYSSEY ALTERNATIVE trial (NCT01709513) demonstrated significant low-density lipoprotein cholesterol (LDL-C) reductions with the PCSK9 inhibitor alirocumab vs ezetimibe in statin-intolerant patients, with significantly fewer skeletal muscle events (SMEs; 32.5%) vs atorvastatin (46.0%; hazard ratio: 0.61, 95% confidence interval: 0.38 to 0.99, P = .042). Objective ALTERNATIVE participants could enter an open-label treatment period (OLTP) for assessment of long-term safety. Methods Two hundred and eighty one patients entered the OLTP; 93.7%, 84.0%, and 92.9% of patients who received atorvastatin, ezetimibe, and alirocumab, respectively, during double-blind treatment, including 216 patients (76.9%) who completed double-blind treatment, as well as patients who either prematurely discontinued treatment due to SME (n = 51 [18.1%]) or other reasons (n = 14 [5.0%]) but completed week 24 assessments. All patients in the OLTP received alirocumab (75 or 150 mg every 2 weeks based on investigator decision) for ∼3 years or until commercial availability, whichever came first. Results SMEs were reported by 38.4% of patients in the OLTP. Safety results from the OLTP were similar to those of the alirocumab group in the double-blind period, except for a lower rate of discontinuations due to SMEs observed with alirocumab in the OLTP (3.2% vs 15.9% in the double-blind period). At OLTP week 8, mean LDL-C reduction from baseline (=week 0 of double-blind period) was 52.0%, with reductions sustained through to the end-of-treatment visits (55.4% and 53.7% reduction at weeks 100 and 148, respectively). Conclusions In this population of statin-intolerant patients, alirocumab was well tolerated and produced durable LDL-C reductions over 3 years.

Background Little is known regarding relationships between high-sensitivity C-reactive protein (hsCRP) and lipoproteins other than low-density lipoprotein cholesterol (LDL-C). High-density lipoprotein (HDL), with both anti-inflammatory and cholesterol-mediating effects, is of particular interest. This exploratory analysis assessed associations between hsCRP and lipids in older (>65 years) patients with moderate and/or high cardiovascular disease risk, before and after treatment with ezetimibe/simvastatin (E/S) or atorvastatin (ATV). Methods An analysis of a multicenter, randomized, double-blind, 12-week study. Correlations were assessed in 1054 patients with both baseline and 12-week hsCRP ≤10 mg/L, pooled across doses of E/S (10/20 and 10/40 mg) and ATV (10, 20, and 40 mg), and combined E/S + ATV treatments. Because of multiple comparisons, observed relationships were considered significant only if P values were Results Correlations between baseline levels of hsCRP and either LDL-C, non–HDL-C, or apolipoprotein B were weak and nonsignificant in the E/S, ATV, and E/S + ATV groups. After 12 weeks of treatment, these correlations increased slightly and significantly in all groups, except for LDL-C in the ATV group. HDL-C was significantly but inversely correlated with hsCRP in the ATV and E/S + ATV groups at baseline, and in all groups at 12 weeks. Only with HDL-C did change correlate with change in hsCRP in both the E/S and combined groups. Conclusions Relationships between hsCRP and lipid factors in older patients were weak at baseline and somewhat stronger after treatment. HDL-C was inversely and consistently correlated with baseline and 12-week on-treatment hsCRP and with therapy-induced changes in HDL-C and hsCRP.

The goal of the VA Diabetes Trial (VADT) was to determine the effect of intensive glucose control on macrovascular events in subjects with difficult-to-control diabetes. No significant benefit was found. This report examines predictors of the effect of intensive therapy on the primary outcome in this population.This trial included 1791 subjects. Baseline cardiovascular risk factors were collected by interview and the VA record. The analyses were done by intention to treat.Univariate analysis at baseline of predictors of a primary cardiovascular (CV) event included a prior CV event, age, insulin use at baseline, and duration of diagnosed diabetes (all P.0001). Multivariable modeling revealed a U-shaped relationship between duration of diabetes and treatment. Modeled estimates for the hazard ratios (HRs) for treatment show that subjects with a short duration (3 years or less) of diagnosed diabetes have a nonsignificant increase in risk (HR1.0) after which the HR is below 1.0. From 7 to 15 years' duration at entry, subjects have HRs favoring intensive treatment. Thereafter the HR approaches 1.0 and over-21-years' duration approaches 2.0. Duration over 21 years resulted in a HR of 1.977 (CI 1.77-3.320, P.01). Baseline c-peptide levels progressively declined up to 15 years and were stable subsequently.In difficult-to-control older subjects with type 2 DM, duration of diabetes altered the response to intensive glucose control. Intensive therapy may reduce CV events in subjects with a duration of 15 years or less and may increase risks in those with longer duration.

Background Coronary heart disease (CHD) risk increases with age; yet lipid-lowering therapies are significantly under-utilized in patients > 65 years. The objective was to evaluate the safety and efficacy of lipid-lowering therapies in older patients treated with atorvastatin 10 mg + ezetimibe 10 mg (EZ/Atorva) vs. increasing the atorvastatin dose to 40 mg. Methods Patients ≥ 65 years with atherosclerotic vascular disease (LDL-C ≥ 1.81 mmol/L) or at high risk for coronary heart disease (LDL-C ≥ 2.59 mmol/L) were randomized to EZ/Atorva for 12 wk vs. uptitration to atorvastatin 20 mg for 6 wk followed by atorvastatin 40 mg for 6 wk. The percent change in LDL-C and other lipid parameters and percent patients achieving prespecified LDL-C levels were assessed after 12 wk. Results EZ/Atorva produced greater reductions in most lipid parameters vs. uptitration of atorvastatin in patients ≥ 75 years (n = 228), generally consistent with patients 65–74 years (n = 812). More patients achieved LDL-C targets with combination therapy vs. monotherapy in both age groups at 6 wk and in patients ≥ 75 years at 12 wk. At 12 wk, more patients ≥ 75 years achieved LDL-C targets with monotherapy vs. combination therapy. EZ/Atorva produced more favorable improvements in most lipids vs. doubling or quadrupling the atorvastatin dose in patients ≥ 75 years, generally consistent with the findings in patients 65–74 years. Conclusions Our results extended previous findings demonstrating that ezetimibe added to a statin provided a generally well-tolerated therapeutic option for improving the lipid profile in patients 65 to 74 years and ≥ 75 years of age.

The effects of intensive glucose control on cardiovascular events in patients with long-standing type 2 diabetes mellitus remain uncertain.We randomly assigned 1791 military veterans (mean age, 60.4 years) who had a suboptimal response to therapy for type 2 diabetes to receive either intensive or standard glucose control. Other cardiovascular risk factors were treated uniformly. The mean number of years since the diagnosis of diabetes was 11.5, and 40% of the patients had already had a cardiovascular event. The goal in the intensive-therapy group was an absolute reduction of 1.5 percentage points in the glycated hemoglobin level, as compared with the standard-therapy group. The primary outcome was the time from randomization to the first occurrence of a major cardiovascular event, a composite of myocardial infarction, stroke, death from cardiovascular causes, congestive heart failure, surgery for vascular disease, inoperable coronary disease, and amputation for ischemic gangrene.The median follow-up was 5.6 years. Median glycated hemoglobin levels were 8.4% in the standard-therapy group and 6.9% in the intensive-therapy group. The primary outcome occurred in 264 patients in the standard-therapy group and 235 patients in the intensive-therapy group (hazard ratio in the intensive-therapy group, 0.88; 95% confidence interval [CI], 0.74 to 1.05; P=0.14). There was no significant difference between the two groups in any component of the primary outcome or in the rate of death from any cause (hazard ratio, 1.07; 95% CI, 0.81 to 1.42; P=0.62). No differences between the two groups were observed for microvascular complications. The rates of adverse events, predominantly hypoglycemia, were 17.6% in the standard-therapy group and 24.1% in the intensive-therapy group.Intensive glucose control in patients with poorly controlled type 2 diabetes had no significant effect on the rates of major cardiovascular events, death, or microvascular complications with the exception of progression of albuminuria (P = 0.01) [added]. (ClinicalTrials.gov number, NCT00032487.)

Objective: This study evaluated the glycosylated hemoglobin (HbA 1c -lowering effect of colesevelam hydrochloride, a bile acid sequestrant, in subjects with type 2 diabetes that was inadequately controlled by existing antihyperglycemic therapy. Methods: After a 4-week placebo run-in period, subjects with type 2 diabetes and an HbA 1c value of 7.0% to 10.0% were randomized to receive colesevelam 3.75 g/d or matching placebo for 12 weeks. Subjects' previous oral anti hyperglycemic medication (sulfonylurea and/or metformin) was continued throughout the study. Fasting blood samples were obtained at weeks −5, −1, 0, 1, 4, 8, and 12. The primary efficacy end point was the change in HbA 1c from baseline to week 12. Secondary end points included changes in fructosamine levels, fasting plasma glucose levels, postprandial glucose level, and meal glucose response (ie, difference between preprandial and postprandial levels), and percent changes in lipid parameters from baseline to week 12. Results: The 65 randomized subjects (31 colesevelam, 34 placebo) had a mean age of 56.2 years and a mean body mass index of 32.4 kg/m 2 ; 55.4% were male and 53.8% were white. The difference in least squares (LS) mean (SE) change in HbA 1c between the colesevelam group and the placebo group was −0.5% (0.18) ( P = 0.007). In subjects with a baseline HbAIc ≥ 8.0%, the difference in LS mean change in HbA 1c was −1.0% (0.27) ( P = 0.002). Relative to placebo, colesevelam treatment was associated with reductions in levels of fructosamine (−29.0 [10.9] pmol/L; P = 0.011) and postprandial glucose (−31.5 [13.6] mg/dL; P = 0.026). The mean percent change in low-density lipoprotein cholesterol was -9.6% in the colesevelam group, compared with 2.1% in the placebo group (treatment difference, −11.7% [4.2]; P = 0.007); the respective mean percent changes in total cholesterol were −4.0% and 3.4% (treatment difference, −7.3% [3.0]; P = 0.019). Colesevelam also was associated with significant decreases in the percent change in apolipoprotein B (P = 0.003) and low-density lipoprotein particle concentration ( P = 0.037). The incidence of treatment-emergent adverse events (TEAEs) was similar in both groups, although treatment-related adverse events were more frequent in the colesevelam group than in the placebo group (29.0% vs 8.8%, respectively). The most frequent TEAEs in the colesevelam group were gastrointestinal disorders (22.6%), primarily constipation (19.4%), compared with an 8.8% incidence of gastrointestinal disorders (0% constipation) in the placebo group. There were no significant changes in body weight or the occurrence of hypoglycemia between treatment groups. Conclusions: In these subjects with type 2 diabetes, 12 weeks of colesevelam treatment were associated with significant reductions in HbA 1c and in fructosamine and postprandial glucose levels compared with placebo. The 2 groups had a similar adverse-event profile, with the exception of an increased incidence of constipation in the colesevelam group. These results suggest that colesevelam may improve both lipid control and glycemic control in patients with type 2 diabetes receiving oral antihyperglycemic medications.

The lipid-modifying effects of statin therapy in hypercholesterolemic African-Americans have not been well characterized. This study compared the efficacy and safety of rosuvastatin and atorvastatin treatment for 6 weeks in hypercholesterolemic African-American adults. In the African American Rosuvastatin Investigation of Efficacy and Safety (ARIES) trial (4522US/0002), 774 adult African-Americans with low-density lipoprotein cholesterolor = 160 andor = 300 mg/dl and triglycerides400 mg/dl were randomized to receive open-label rosuvastatin 10 or 20 mg or atorvastatin 10 or 20 mg for 6 weeks. At week 6, significantly greater reductions in low-density lipoprotein cholesterol, total cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B concentrations, as well as lipoprotein and apolipoprotein ratios, were seen with rosuvastatin versus milligram-equivalent atorvastatin doses (analysis of variance with Bonferroni-adjusted critical p0.017 for all comparisons). Rosuvastatin 10 mg also increased high-density lipoprotein cholesterol significantly more than atorvastatin 20 mg (p0.017). Although statistical comparisons were not performed, larger proportions of rosuvastatin-treated patients than atorvastatin-treated patients achieved National Cholesterol Education Program Adult Treatment Panel III low-density lipoprotein cholesterol goals. The median high-sensitivity C-reactive protein levels were significantly reduced statistically from baseline with rosuvastatin 20 mg and atorvastatin 20 mg among all patients and with rosuvastatin 10 and 20 mg and atorvastatin 20 mg in those patients with a baseline C-reactive protein level2.0 mg/L. The 2 study medications were well tolerated during the 6-week study period. In conclusion, rosuvastatin 10 and 20 mg improved the overall lipid profile of hypercholesterolemic African-Americans better than did milligram-equivalent doses of atorvastatin.

The 6-week efficacy and safety of atorvastatin versus simvastatin was determined during a 54-week, open-label, multicenter, parallel-arm, treat-to-target study. In all, 1,424 patients with mixed dyslipidemia (triglyceride 200 to 600 mg/dl [2.26 to 6.77 mmol/L]) were stratified to 1 of 2 groups (diabetes or no diabetes). Patients were then randomized to receive either atorvastatin 10 mg/ day (n = 730) or simvastatin 10 mg/day (n = 694). Efficacy was determined by measuring changes from baseline in lipid parameters including low-density lipoprotein (LDL) cholesterol, total cholesterol, triglycerides, and apolipoprotein B. Compared with simvastatin, atorvastatin produced significantly greater (p < 0.0001) reductions from baseline in LDL cholesterol (37.2% vs 29.6%), total cholesterol (27.6% vs 21.5%), triglycerides (22.1% vs 16.0%), the ratio of LDL cholesterol to high-density lipoprotein (HDL) cholesterol (41.1% vs 33.7%), and apolipoprotein B (28.3% vs 21.2%), and a comparable increase from baseline in HDL cholesterol (7.4% vs 6.9%). Atorvastatin was also significantly (p < 0.0001) more effective than simvastatin at treating the overall patient population to LDL cholesterol goals (55.6% vs 38.4%). Fewer than 6% of patients in either treatment group experienced drug-attributable adverse events, which were mostly mild to moderate in nature. Diabetic patients treated with either statin had safety characteristics similar to nondiabetics, with atorvastatin exhibiting superior efficacy to simvastatin. In conclusion, atorvastatin, at a dose of 10 mg/day, is more effective than simvastatin 10 mg/day at lowering lipids and reaching LDL cholesterol goals in patients with mixed dyslipidemia. Both statins are well tolerated with safety profiles similar to other members of the statin class.

The Adult Treatment Panel III guidelines established non-high-density lipoprotein cholesterol (non-HDL-C) as a secondary treatment target. However, non-HDL-C levels are not reported on standard lipid panels by many hospital-based and/or commercial biochemical laboratories.We determined whether reporting non-HDL-C was associated with improved non-HDL-C goal attainment.We identified patients with cardiovascular disease (CVD) and/or diabetes receiving care within the Veterans Health Administration. We matched a facility that reported non-HDL-C levels on lipid panels (3994 CVD and 5108 diabetes patients) to a facility with similar size, patient complexity, and academic mission that did not report non-HDL-C (4269 CVD and 6591 diabetes patients). We performed patient-level analysis to assess differences in non-HDL-C from baseline to the most recent lipid panel at these facilities.Baseline non-HDL-C levels for CVD patients were 114 mg/dL and 107 mg/dL at the reporting and nonreporting facilities, respectively. At 2.3-year follow-up, non-HDL-C levels decreased at both facilities but by a greater amount at the reporting facility (-11 mg/dL vs -3 mg/dL at the nonreporting facility, P.001). Results remained significant (P.001) after we adjusted for patient's age, race, gender, illness burden, history of diabetes, hypertension, medication adherence, statin use, number of lipid panels, and number of primary care visits between baseline and follow-up. Reductions were greater among CVD patients with triglycerides ≥200 mg/dL (-25 mg/dL vs -16 mg/dL at the respective facilities, P = .004). Results were similar in diabetes patients. Reporting was also associated with greater proportions of patients meeting non-HDL-C treatment goal of130 mg/dL.Non-HDL-C reporting could improve non-HDL-C goal attainment.

Few clinical studies have focused on the efficacy of lipid-lowering therapies in patientsor = 65 years of age. The percentage of change from baseline in low-density lipoprotein (LDL) cholesterol and the percentage of patients achieving prespecified LDL cholesterol levels after 12 weeks of ezetimibe 10 mg plus atorvastatin versus up titration of atorvastatin were assessed in subjectsor = 65 years old with hyperlipidemia and at high risk of coronary heart disease. After stabilization of atorvastatin 10-mg therapy, 1,053 patients,or = 65 years old, at high risk of coronary heart disease, with and without atherosclerotic vascular disease and a LDL cholesterol level that was not70 or100 mg/dl, respectively, were randomized to receive ezetimibe added to atorvastatin 10 mg for 12 weeks versus up titration to atorvastatin 20 mg for 6 weeks followed by up titration to atorvastatin 40 mg for an additional 6 weeks. Ezetimibe added to atorvastatin 10 mg resulted in significantly greater changes at week 6 in LDL cholesterol (p0.001), significantly more patients with atherosclerotic vascular disease achieving a LDL cholesterol level of70 mg/dl (p0.001), and significantly more patients without atherosclerotic vascular disease achieving a LDL cholesterol level of100 mg/dl (p0.001) at weeks 6 and 12 compared to atorvastatin 20 mg or atorvastatin 40 mg. In addition, ezetimibe plus atorvastatin 10 mg resulted in significantly greater changes at week 6 in total cholesterol, triglycerides, non-high-density lipoprotein (HDL) cholesterol, apolipoprotein B (all p0.001), and HDL cholesterol (p = 0.021) compared with atorvastatin 20 mg and significantly greater changes at week 12 in LDL cholesterol, non-HDL cholesterol, apolipoprotein A-I (p = 0.001), total cholesterol, apolipoprotein B (p0.030), and HDL cholesterol (p0.001) compared with atorvastatin 40 mg. Both treatments were generally well tolerated, with comparable safety profiles. In conclusion, adding ezetimibe to atorvastatin 10 mg produced significantly greater favorable changes in most lipids at 6 and 12 weeks and significantly greater attainment of prespecified LDL cholesterol levels than doubling or quadrupling the atorvastatin dose in patientsor =65 years old at high risk for coronary heart disease.

Combination therapy to improve the total lipid profile may achieve greater coronary risk reductions than lowering low-density lipoprotein cholesterol (LDL-C) alone. A new extended-release niacin (niacin ER)/lovastatin tablet substantially lowers LDL-C, triglyceride, and lipoprotein(a) levels and raises high-density lipoprotein cholesterol (HDL-C) level. We evaluated these serum lipid responses to niacin ER/lovastatin at all clinically reasonable doses.Men (n = 85) and women (n = 79) with type IIa or IIb primary hyperlipidemia after diet were randomized among 5 parallel treatment arms. Each arm had 5 sequential 4-week treatment periods: niacin ER (starting at 500 mg/d, increasing in 500-mg increments to 2500 mg/d); lovastatin (starting at 10 mg, increasing to 20 mg, then 40 mg/d); and 3 combinations arms, each with a constant lovastatin dose and escalating niacin ER doses.For primary comparisons, mean LDL-C level reductions from baseline were greater with niacin ER/lovastatin (1500/20 mg) than with lovastatin (20 mg) (35% vs 22%, P.001) and with niacin ER/lovastatin (2000/40 mg) than with lovastatin (40 mg) (46% vs 24%, P.001). Each 500-mg increase in niacin ER, on average, decreased LDL-C levels an additional 4% and increased HDL-C levels 8%. The maximum recommended dose (2000/40 mg/d) increased HDL-C levels 29% and decreased LDL-C levels 46%, triglyceride levels 38%, and lipoprotein(a) levels 14%. All lipid responses were dose dependent and generally additive. Graphs of the dose-response relationships as 3-dimensional surfaces documented the strength and consistency of these responses.Niacin ER/lovastatin combination therapy substantially improves 4 major lipoprotein levels associated with atherosclerotic disease. Dose-response surfaces provide a practical guide for dose selection.

When ribosomes are incubated with G factor and GTP, a ribosome-G factor-GDP complex is formed. Fusidic acid does not inhibit the formation of this complex; in fact, more complex is isolated in the presence of the antibiotic (10−3 M) than in its absence. No complex containing GTP is detectable in the presence or absence of the antibiotic.

The conditions necessary for the formation and detection of a ribosome-G factor (the soluble translocation protein)-GDP complex in the presence of fusidic acid have been examined. Complex detection has been accomplished by sucrose density gradient sedimentation and both gel and Millipore filtration. The latter two methods reveal a good correlation, as a function of fusidic acid concentration, between the amount of isolatable complex and the inhibition of the GTPase activity of the G factor-ribosome system by the antibiotic. Complex formation requires Mg2+ (10 to 20 mm) but apparently does not require a monovalent cation. The binding of nucleotide requires and is limited by both ribosomes and G factor. An examination of the stoichiometry of complex formation was carried out by varying ribosomes and G factor. The results of these experiments, on the basis of certain assumptions, are interpreted to indicate the formation, in the presence of fusidic acid, of a relatively stable ternary complex involving ribosomes, G factor, and GDP in a molar ratio of 1:1:1.

The rate and extent of GTP hydrolysis by a molar excess of ribosomes and G factor (the soluble translocation protein) are unaffected by fusidic acid. When the nucleotide substrate level is increased to exceed the macromolecular components, there is a burst of fusidic acid-resistant hydrolysis approximately equivalent to the molar amount of G factor when ribosomes are present in excess. Neither ribosomes nor G factor alone is capable of catalyzing even 1 eq of GTP hydrolysis. Several methods were used to show that at initial GTP concentrations as low as 10-8 m (the lowest level of discrimination) essentially all of the nucleotide, as GDP, is in the form of a ternary complex with ribosomes and G factor in the presence of fusidic acid. The binding of the reaction product, GDP, is also stabilized by the antibiotic. Furthermore, the preliminary binding of unlabeled GDP prevents the subsequent binding of labeled GTP. This is in contrast to the case with equimolar amounts of GMP and the GTP analogue, guanylyl methylene diphosphonate, neither of which under these conditions prevents the subsequent binding of GTP despite the fact that the analogue is a competitive inhibitor of GTP in translocation. The following mechanism is proposed for the uncoupled hydrolysis of GTP by the ribosome and G factor to account for these and previous observations: [see PDF for equation] [see PDF for equation] [see PDF for equation]

A single intraperitoneal injection of the carcinogenic arylhydroxamic acid N-hydroxy-2-fluorenylacetamide given to male rats inhibited the two RNA polymerase activities of isolated liver nuclei by as much as 80%. Low doses of the carcinogen inhibited the Mg2+-dependent polymerase activity preferentially; high doses inhibited the Mn2+ + (NH4)2SO4-dependent activity to a greater extent. Inhibition was detectable 15 min after injection of the compound and was maximal in 1 hour. Several related noncarcinogenic compounds and carcinogenic arylhydroxamic acids which were inactive toward the liver completely lacked the inhibitory effect shown by N-hydroxy-2-fluorenylacetamide. Female rats, which develop few liver tumors on administration of N-hydroxy-2-fluorenylacetamide, were refractory to the inhibition of liver RNA polymerase by this compound. The depression of RNA synthesis by N-hydroxy-2-fluorenylacetamide was not due to decreased permeability of the nuclear membrane to substrates, nor to increased hydrolysis of newly synthesized RNA. Similar types of RNA were made in the control and treated rats, and the template capacities of liver chromatin and DNA were not affected by the carcinogen. These data suggest that the inhibition of RNA synthesis by N-hydroxy-2-fluorenylacetamide is due to inactivation of the RNA polymerases and not to decreased availability of DNA for transcription.

The effects of magnesium deficiency on the in vivo incorporation of labeled precursors into tissue macromolecules were studied. In severe Mg deficiency developing over 4 months, total protein synthesis in spleen and thymus was depressed by 40% to 50%, while DNA synthesis was increased by as much as 350%. RNA synthesis was not significantly altered. Protein synthesis in kidney was also reduced. In the intact liver, DNA synthesis was increased and RNA synthesis reduced, but protein synthesis was unchanged. The regeneration of the liver after partial hepatectomy was impaired, however, which suggested that the capacity of the liver protein synthetic system was reduced. The effects of magnesium deficiency were unaltered by the ingestion of ethanol that comprised approximately 25% of total energy. Each of the organs enlarged in Mg deficiency, and the spleen was strikingly hyperplastic. The increase in splenic DNA synthesis in the presence of depressed protein synthesis may be an early stage in a lymphoproliferative process leading ultimately to neoplasia.

This study demonstrated that the phospholipase A1 purified from human post-heparin plasma catalyzes the same reactions (hydrolysis and transacylation) and utilizes the same substrates as the phospholipase A1 obtained by heparin treatment of the plasmalemma of rat liver (Waite, M. and Sisson, P. (1973) J. Biol. Chem. 248, 7985). 1-acylglycerol was the preferred acyl donor and transacylation was the predominate reaction. The results strongly support our earlier conclusions that the phospholipase in plasma originates from the liver and that this enzyme is capable of using a variety of acyl acceptors, including water.

To investigate the basis for the depressed protein synthesis in vivo in magnesium deficient spleens, the activities of splenic subcellular fractions in polypeptide synthesis were studied in vitro. Splenic ribosomes from Mg deficient animals were normal structurally and functionally. In contrast, supernatant fractions from the deficient spleens had a reduced ability to incorporate labeled amino acids into protein, both in the presence of endogenous mRNA and in the presence of added polyuridylic acid. The specific defects observed in the Mg deficient supernatants were twofold: There was a modest reduction in the rate of acylation of tRNA and a more marked reduction in the activity of the elongation factors, EF-I and EF-II. The reduction in elongation factor activity was quantitatively sufficient to account for the inhibition of protein synthesis in vivo.

A procedure has been developed for the separation of labeled fatty acids from tri-, di-, and monoglycerides using small disposable columns of TEAE-cellulose. This procedure is used as the basis of a lipase assay which is rapid, sensitive and unaffected by wide variations in the composition of the reaction mixtures. 0.5 nmole [14C]oleic acid can be detected, and the entire procedure requires less than 3 min.

The erroneous binding of isoleucyl-tRNA to ribosomes in response to poly U shows the same pattern of inhibition by tetracycline as the correct binding of phenylalanyl-tRNA, while the poly U directed binding of leucyl-tRNA is largely sensitive to tetracycline. It is concluded that the coding specificity of the peptidyl site on the ribosome is at least equivalent to that of the aminoacyl site.

Post-heparin phospholipase activity is reduced by 80% in the hepatectomized rat. In contrast, post-heparin lipase activity is unaffected by hepatectomy. Since the phospholipase originates mainly in the liver and the lipase originates entirely in extrahepatic tissues, these two activities must be different enzymes.

Few clinical studies have focused on the efficacy of lipid-lowering therapies in patients ≥65 years. After stabilization on atorvastatin 10 mg, hypercholesterolemic subjects ≥65 years at high/very high risk for CHD and not at LDL-C