Guar gum and gemfibrozil--an effective combination in the treatment of hypercholesterolaemia

Twenty-nine hypercholesterolaemic patients, treated for one year with gemfibrozil but being still hypercholesterolaemic (serum total cholesterol greater than or equal to 6.25 mmol/l) were included in a double-blind trial to evaluate the hypocholesterolaemic effects of gemfibrozil-guar gum combination (GE + GU) vs. gemfibrozil-placebo combination (GE + PL) using a cross-over study design. The patients were treated with gemfibrozil on a constant dosage (range 900-1200 mg/day) during the entire trial. After a 4-week run-in period on GE + PL treatment the patients were randomly allocated to 2 groups: one received GE + GU 15 g/day, and the other GE + PL for 3 months and after that groups were crossed over. Guar gum and placebo were administered as granules taken 3 times a day during meals. Serum total cholesterol was 8.61 +/- 0.17 mmol/l before gemfibrozil therapy, and 7.29 +/- 0.15 mmol/l at the end of the run-in period on GE + PL (P less than 0.01). During the double-blind phase serum total cholesterol values were 6.28 +/- 0.19 mmol/l at the end of the GE + GU treatment period and 7.21 +/- 0.16 mmol/l at the end of the GE + PL treatment period (P less than 0.01). At the end of the GE + GU treatment period serum total cholesterol was 27% lower and LDL-cholesterol 39% lower than before gemfibrozil treatment. A marked improvement (23%) was found in HDL/LDL ratio during GE + GU treatment compared with GE + PL treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Relation between baseline lipid and lipoprotein values and the incidence of coronary heart disease in the Helsinki Heart Study

A 34% reduction in the incidence of definite coronary heart disease events was observed in dyslipidemic men treated with gemfibrozil in the Helsinki Heart Study, a controlled 5-year, double-blind primary prevention trial for coronary heart disease. Over the entire study period, gemfibrozil therapy induced mean decreases of 10% in serum total cholesterol levels, 11% in low-density lipoprotein (LDL) cholesterol, 35% in triglyceride levels, and a mean increase of 11% in high-density lipoprotein (HDL) cholesterol level, compared with placebo. The differences in percentage changes in LDL cholesterol between gemfibrozil- and placebo-treated men varied among Fredrickson hyperlipoproteinemia types; after 1 year of treatment the difference was greatest for type IIA hyperlipoproteinemia (14 percentage units) and smallest for IIB hyperlipoproteinemia (3 percentage units). The treatment-associated changes in HDL cholesterol and triglycerides did not differ materially between the 3 hyperlipoproteinemia types, when calculated in the same way. The gemfibrozil-associated reduction in incidence of definite coronary events varied among Fredrickson types and among tertiles of baseline HDL cholesterol and triglycerides. The greatest rate reductions were seen in subjects with type IIB hyperlipoproteinemia, low initial HDL level or high initial triglycerides. These results suggest that subjects with low HDL cholesterol and type IIB hyperlipoproteinemia (and possibly type IV hyperlipoproteinemia) would benefit from treatment with gemfibrozil.     

Spectrum of mutations in aspartylglucosaminuria.

Aspartylglucosaminuria (AGU) is an inherited lysosomal storage disorder caused by the deficiency of aspartylglucosaminidase. We have earlier reported a single missense mutation (Cys163----Ser) to be responsible for 98% of the AGU alleles in the isolated Finnish population, which contains about 90% of the reported AGU patients. Here we describe the spectrum of 10 AGU mutations found in unrelated patients of non-Finnish origin. Since 11 out of 12 AGU patients were homozygotes, consanguinity has to be a common denominator in most AGU families. The mutations were distributed over the entire coding region of the aspartylglucosaminidase cDNA, except in the carboxyl-terminal 17-kDa subunit in which they were clustered within a 46-amino acid region. Based on the character of the mutations, most of them are prone to affect the folding and stability and not to directly affect the active site of the aspartylglucosaminidase enzyme.     

Predictive value for coronary heart disease of baseline high-density and low-density lipoprotein cholesterol among Fredrickson type IIa subjects in the Helsinki Heart Study

In the Helsinki Heart Study 2,590 subjects (63.5% of total) had a type IIa hyperlipoproteinemia at screening. Baseline low-density lipoprotein (LDL) cholesterol (mean 193 mg/dl; 5 mmol/liter) and high-density lipoprotein (HDL) cholesterol (mean 50.2 mg/dl; 1.3 mmol/liter) showed no statistical correlation (r = 0.046). Both the placebo (1,293 patients) and gemfibrozil groups (1,297 patients) were divided into tertiles by baseline HDL and LDL cholesterol to determine the relative predictive risk of developing coronary artery disease. In a population with elevated LDL cholesterol, it is significant that the lipoprotein fraction with the greatest predictive value was HDL cholesterol. The severity of LDL cholesterol elevation did not provide any differential predictive value for coronary artery disease.     

Progestin and G protein-coupled receptor 30 inhibit mitogen-activated protein kinase activity in MCF-7 breast cancer cells

We have previously shown that the G protein-coupled receptor (GPR)30 is critical for progestin-induced growth inhibition. In this study, we addressed signal transduction pathways involved in progestin-mediated signaling. Progestin could not provide any additional growth inhibitory effect to MCF-7 cells treated with specific MAPK kinase inhibitors, PD98059 and U0126. Medroxyprogesteroneacetate (MPA) induced a late (22-23 h) decrease in ERK-1 and -2 activities verified by immunoblotting and kinase assay. The inactivation was abrogated by antiprogestin. Transient expression of GPR30 decreased ERK-1 and -2 activity; and in the cells in which GPR30 expression was decreased by the antisense, ERK activities were increased. The antisense-expressing cells were able to significantly resist the growth-inhibitory effect of the MAPK kinase inhibitors PD98059 and U0126 but not that of other factors tested. Interestingly, the decrease of ERK activity induced by MPA was abrogated by GPR30 antisense. Collectively, these results show that MAPK activity is inhibited by progestin and GPR30 and suggest that progestin-induced ERK inactivation is mediated through GPR30. Coupled with our previous findings, the data imply that up-regulation of GPR30 by progestin leads to ERK-1 and -2 inactivation associated with MPA-induced growth inhibition.     

Effect of gemfibrozil on the concentration and composition of serum lipoproteins. A controlled study with special reference to initial triglyceride levels

We investigated the modulating effect of serum total triglycerides on the lipid composition of various lipoproteins, and on the response to gemfibrozil treatment. This placebo controlled study was conducted blind in 60 participants of the Helsinki Heart Study. An inverse relationship was observed between cholesterol content in all lipoprotein fractions and serum total triglyceride level. Gemfibrozil, in addition to changing the absolute amounts of lipoprotein lipids, also normalized the qualitative abnormalities associated with hypertriglyceridemia. Gemfibrozil increased the level of HDL-cholesterol with the main effect on HDL3-subfraction. The observed reduction in LDL-cholesterol was dependent on the initial triglyceride level.     

A novel mutation, Ser143Pro, in the lamin A/C gene is common in finnish patients with familial dilated cardiomyopathy.

AIMS: The mutations most frequently associated with dilated cardiomyopathy (DCM) have been reported in the lamin A/C gene. The role of variants of the lamin A/C gene was investigated in patients with DCM from eastern and southern Finland. METHODS AND RESULTS: All 12 exons of the lamin A/C gene were screened in 18 well-characterised familial DCM patients from eastern and southern Finland and in 72 sporadic DCM patients from eastern Finland using the PCR-SSCP method. A novel mutation, Ser143Pro (S143P), was detected in the lamin A/C gene in 24 subjects from 5 unrelated families and in one sporadic case of DCM. Sinus or atrioventricular nodal dysfunction occurred in the majority of the affected subjects, many of which required pacemaker implantation. Seven patients (28%) with the S143P mutation died suddenly or from progressive heart failure, or underwent heart transplantation. The haplotypes 5-5-5-3, 5-5-5-2, and 5-5-5-1 co-segregated with the Ser143Pro mutation, suggesting a founder effect of this mutation. CONCLUSIONS: A novel mutation S143P in the lamin A/C gene was found to be common among Finnish DCM patients. Haplotype analysis strongly suggests a founder effect of this mutation. The phenotype is characterised by severe heart failure, progressive atrioventricular conduction defects, and sudden death. Screening for the lamin A/C gene and, particularly, the S143P mutation seems warranted when patients with DCM have conduction system disturbances.     

Carnitine Intake and Serum Levels Associate Positively with Postnatal Growth and Brain Size at Term in Very Preterm Infants

Carnitine has an essential role in energy metabolism with possible neuroprotective effects. Very preterm (VPT, <32 gestation weeks) infants may be predisposed to carnitine deficiency during hospitalization. We studied the associations of carnitine intake and serum carnitine levels with growth and brain size at term equivalent age (TEA) in VPT infants. This prospective cohort study included 35 VTP infants admitted to Kuopio University Hospital, Finland. Daily nutrient intakes were registered at postnatal weeks (W) 1 and 5, and serum carnitine levels were determined at W1, W5, and TEA. The primary outcomes were weight, length, and head circumference Z-score change from birth to TEA, as well as brain size at TEA in magnetic resonance imaging. Carnitine intake at W1 and W5, obtained from enteral milk, correlated positively with serum carnitine levels. Both carnitine intake and serum levels at W1, W5, and TEA showed a positive correlation with weight, length, and head circumference Z-score change and with brain size at TEA. In linear models, independent positive associations of carnitine intake and serum carnitine levels with length and head circumference Z-score change and brain size at TEA were seen. In VPT infants, sufficient carnitine intake during hospitalization is necessary since it is associated with better postnatal growth and larger brain size at term age.     

Onyx,a New Liquid Embolic Material for Peripheral Interventions: Preliminary Experience in Aneurysm,Pseudoaneurysm, and Pulmonary Arteriovenous Malformation Embolization

Purpose To describe our preliminary experience with a new liquid embolization agent, Onyx, in peripheral interventions. Methods and results We successfully treated two peripheral aneurysms (one in an internal iliac artery, one in a thoracic collateral artery of an aortic coarctation), two peripheral pseudoaneurysms (one in a lumbar artery, one in a renal artery), and one pulmonary arteriovenous malformation. Conclusion Onyx is a promising alternative embolic material for peripheral interventions. It can be combined with coils in selected cases, and balloon catheters can be effectively used during slow injection of embolic material to control flow and protect the aneurysm neck.