Genetic polymorphisms affecting the phenotypic expression of familial hypercholesterolemia.

The clinical expression of heterozygous familial hypercholesterolemia (FH) is highly variable even in patients carrying the same LDL receptor (LDL-R) gene mutation. This variability might be due to environmental factors as well as to modifying genes affecting lipoprotein metabolism. We investigated Apo E (2, 3, 4), MTP (-493G/T), Apo B (-516C/T), Apo A-V (-1131T/C), HL (-514C/T and -250G/A), FABP-2 (A54T), LPL (D9N, N291S, S447X) and ABCA1 (R219K) polymorphisms in 221 unrelated FH index cases and 349 FH relatives with defined LDL-R gene mutations.

Physical activity modulates effects of some genetic polymorphisms affecting cardiovascular risk in men aged over 40 years.

Background And Aim: Several genetic polymorphisms have been found to be involved in cardiovascular risk, and many studies have documented the beneficial effect of systematic physical activity (PA) on the cardiovascular system. Our aim was to investigate the interactive effects of PA and genetic background on plasma lipids and homocysteine (tHcy) levels.

Methods And Results: Clinical and metabolic parameters, dietary intakes and some polymorphisms of the genes involved in cardiovascular risk (Apo E, fatty acid binding protein-2, Apo AII, hepatic lipase and methylene tetrahydrofolate reductase) were determined in 100 men aged over 40 years who cycle 120-150 Km/week and 100 age-matched sedentary controls.

Pseudodominance of lipoprotein lipase (LPL) deficiency due to a nonsense mutation (Tyr302>Term) in exon 6 of LPL gene in an Italian family from Sardinia (LPL(Olbia)).

We analyzed the molecular defect in the lipoprotein lipase (LPL) gene of a young boy from Sardinia who had primary hyperchylomicronemia, pancreatitis, and a complete LPL deficiency in post-heparin plasma. Analysis of LPL gene was performed by using single strand conformation polymorphism (SSCP) and direct sequencing of SSCP-positive region. The proband was homozygous for a C > A transversion in exon 6, which converts the codon for tyrosine at position 302 into a termination codon and eliminates an RsaI restriction site; this allowed the rapid screening of the proband's family members, among whom nine heterozygotes and one additional homozygote were identified.

Influence of beta(0)-thalassemia on the phenotypic expression of heterozygous familial hypercholesterolemia : a study of patients with familial hypercholesterolemia from Sardinia.

One of the genetic features of the Sardinian population is the high prevalence of hemoglobin disorders. It has been estimated that 13% to 33% of Sardinians carry a mutant allele of the alpha-globin gene (alpha-thalassemia trait) and that 6% to 17% are beta-thalassemia carriers. In this population, a single mutation of beta-globin gene (Q39X, beta(0) 39) accounts for >95% of beta-thalassemia cases.

Analysis of LDL receptor gene mutations in Italian patients with homozygous familial hypercholesterolemia.

The aim of this study was the characterization of mutations of the LDL receptor gene in 39 Italian patients with homozygous familial hypercholesterolemia, who were examined during the period 1994 to 1996. The age of the patients ranged from 1 to 64 years; one third of them were older than 30. Plasma LDL cholesterol level ranged from 10.

Apolipoprotein E epsilon 4 allele frequency is not increased in progressive supranuclear palsy.

We examined apolipoprotein E (ApoE) immunoreactivity and allele frequency in 12 autopsied cases of progressive supranuclear palsy (PSP), a neurodegenerative disease characterized by diffuse neurofibrillary tangle (NFT) formation without beta-amyloid deposits. In spite of the ApoE immunoreactivity associated with NFTs, in PSP the ApoE allele frequency was comparable with that of age-matched normal controls. This suggests that in Alzheimer's disease the increased frequency of ApoE epsilon 4 does not influence neurofibrillary degeneration, but is probably linked to beta-amyloid deposition.

Lipoprotein (a) is increased in acute coronary syndromes (unstable angina pectoris and myocardial infarction), but it is not predictive of the severity of coronary lesions.

Lipoprotein (a) [Lp(a)] concentrations were determined in 365 patients undergoing coronary angiography for stable angina (n = 159), unstable angina (n = 99), recent myocardial infarction (n = 45), and nonischemic heart disease (cardiomyopathy or valvular disease, n = 62, non-IHD). Mean +/- SD and median Lp(a) concentrations in stable angina (29.9 +/- 29.

Serum lipid levels during interferon therapy in patients with chronic hepatitis C.

Interferon-alpha (IFN-alpha) may affect lipid metabolism by stimulating hepatic fatty acid synthesis. The aim of this study was to evaluate serum lipid levels during IFN-alpha therapy in patients with biopsy-proven chronic active hepatitis C. A total of 22 patients (18 males and 4 females; age 25-55 years) received 3 MU of recombinant IFN-alpha 2b 3 times a week for 6 months.

Four novel partial deletions of LDL-receptor gene in Italian patients with familial hypercholesterolemia.

In this study, we report four new partial deletions of the LDL-receptor (LDL-R) gene discovered during a survey of 326 Italian patients with familial hypercholesterolemia (FH). All deletions were found in FH heterozygotes whose LDL-R activity in skin fibroblasts ranged from 52% to 43% of the values found in control cells. The size and boundaries of the deletions were defined by Southern blotting and, in some cases, by polymerase chain reaction (PCR) amplification of genomic DNA.

Partial duplication of the EGF precursor homology domain of the LDL-receptor protein causing familial hypercholesterolemia (FH-Salerno).

A novel mutation of low density lipoprotein (LDL)-receptor gene was found in an Italian family hypercholesterolemia (FH) patient during a screening of 300 FH patients. The proband as well as her daughter were found to be heterozygotes for the mutation. Binding, internalization, and degradation of 125I-labeled LDL by the proband's fibroblasts were reduced to approximately 50% compared to values found in control cells.

Regional cerebral blood flow in familial hypercholesterolemia.

Background And Purpose: Although epidemiologic investigations are trying to clarify the role of plasma lipid concentrations (primarily cholesterol and its subfractions) as risk factors for both ischemic and hemorrhagic stroke, little information is available regarding the effect of sustained hypercholesterolemia on cerebral perfusion.

Methods: Regional cerebral blood flow (CBF) was measured by the 133Xe inhalation method in 25 heterozygous patients (four untreated) affected with familial hypercholesterolemia. In 15 patients regional CBF was repeated 20 minutes after intravenous administration of acetazolamide (10 mg/kg body wt) to evaluate cerebrovascular reactivity.

Chorionic DNA analysis for the prenatal diagnosis of familial hypercholesterolaemia.

Prenatal diagnosis for familial hypercholesterolaemia (FH) was performed by using restriction fragment length polymorphisms (RFLPs) of the LDL receptor gene on chorionic villi DNA taken during the 10th week of pregnancy. Both parents were FH heterozygotes and had previously had a healthy son and an FH homozygous son. Two RFLPs were informative in this family and revealed that the fetus was unaffected by FH.

The SCH9 protein kinase mRNA contains a long 5' leader with a small open reading frame.

The SCH9 yeast gene, that was previously identified as a suppressor of cdc25 and ras1- ras2-ts temperature-sensitive mutants, encodes a putative protein kinase that positively regulates the progression of yeast cells through the G1 phase of the cell cycle. We have determined the structure of the SCH9 transcription unit, using primer extension and S1 mapping techniques. The corresponding mRNA included an unusually long 5' region of more than 600 nucleotides preceding the major open reading frame (ORF).

A large deletion in the LDL receptor gene--the cause of familial hypercholesterolemia in three Italian families: a study that dates back to the 17th century (FH-Pavia).

In the LDL-receptor gene, a large rearrangement causing hypercholesterolemia was detected in three apparently unrelated families living in northern Italy. In all probands, binding, internalization, and degradation of 125I-LDL measured in skin fibroblasts were found to be 40%-50% of control values, indicative of heterozygous familial hypercholesterolemia (FH). Southern blot analysis revealed that the probands were heterozygous for a large (25-kb) deletion of the LDL-receptor gene eliminating exons 2-12.

RFLPs of the LDL-receptor gene: their use in the diagnosis of FH and in evaluation of different levels of gene expression on normal subjects.

The usefulness of the RFLPs of the LDL-receptor gene in early diagnosis of Familial Hypercholesterolemia (FH) was investigated in 122 FH-families. Four RFLPs, produced by digestion with the enzymes PvuII, ApaLI and AvaII/XbaI were able to detect the affected gene and to follow the inheritance of the disease in 72 out of 97 families (74%). In the remaining 25 families, unambiguous diagnosis was possible in 66% of the cases by use of PvuII, ApaLI and BstEII/EcoRI RFLPs.

Variation in the low density lipoprotein receptor gene is associated with differences in plasma low density lipoprotein cholesterol levels in young and old normal individuals from Italy.

We have used four restriction fragment length polymorphisms (RFLPs) of the human low density lipoprotein receptor (LDL-R) gene, detected by the restriction enzymes Ava II, Pvu II, and ApaLI (5' and 3'), to study the effect of variation at this gene locus in determining plasma cholesterol and LDL cholesterol levels. Two hundred eighty-nine normolipidemic individuals were studied from the Liguria region of Italy. The Pvu II RFLP was significantly associated with differences in plasma total and LDL cholesterol levels, explaining 9.

Identification of regulatory residues of the yeast adenylyl cyclase.

We have attempted to identify amino acid residues of the yeast adenylyl cyclase that are involved in the regulation of its activity, by isolating adenylyl cyclase-linked spontaneous mutations capable of suppressing the temperature-sensitive phenotype of ras1- ras2-ts1 strains. We previously identified a mutated adenylyl cyclase in which a single point mutation, called CR14, led to the replacement of threonine 1651 with isoleucine. We have now investigated the biological effects of CR14, and of other mutations that cause the replacement of threonine 1651 by distinct amino acids.

TSH circadian secretions in aged men and effect of phosphatidylserine treatment.

In 20 euthyroid aged men (from 65 to 85 years of age) no significant circadian periodicity of thyrotropin (TSH) secretion has been shown by the population mean cosinor method. At the end of a period of 30 days of hospitalization the cosinor evaluation of TSH secretion showed a restored highly significant (p less than 0.001) circadian rhythmicity in phosphatidylserine (PS) (400 mg/daily) treated group (10 aged subjects).

Thyrotropin and prolactin responses to different doses of thyrotropin-releasing hormone in depression.

The effects of low doses of thyrotropin-releasing hormone (TRH, 50 and 200 micrograms) on thyrotropin (TSH) and prolactin levels have been studied in depressed women and compared with the depressive condition and with the results of the dexamethasone suppression test (DST). TRH administration elicited blunted hormonal responses that were not correlated either with the age of the patients or with DST results. Different effects were observed in subgroups of depressive patients classified according to DSM III and ICD.

A rapid electrochemical assay of lecithin in amniotic fluid using a fluoride ion-sensitive electrode.

An electrochemical method is described for the determination of lecithin in rat and human amniotic fluid. Choline is released from lecithin enzymatically by phospholipase D and the hydrogen peroxide released by the action of choline oxidase is quantitatively determined by peroxidase-catalyzed rupture of the covalent C-F bond of 4-fluorophenol. The concentration of F- ions in solutions is determined by a fluoride sensitive electrode from the resulting cell potential difference recorded before and 10 min after addition of a solution containing phospholipase D, choline oxidase and horseradish peroxidase.

Thyroid-stimulating hormone and prolactin responses to thyrotropin-releasing hormone in common migraine.

Intravenous administration of 50 micrograms or 200 micrograms thyrotropin-releasing hormone (TRH) to men with common migraine elicited blunted prolactin (PRL) responses, when compared with healthy controls. The thyroid-stimulating hormone (TSH) response was enhanced after 50 micrograms TRH in the migraineurs, but not after 200 micrograms. The physiologic TSH dose-response relationship was abolished in migraine sufferers.

Measurement of fetal surfactant production by fluorescence polarization of amniotic fluid in complicated pregnancies.

The results are presented of fluorescence polarization as a method for measurement of surfactant production in 159 specimens of amniotic fluid collected from pregnant women with diabetes, hypertension, Rh immunization, premature rupture of membranes (for more than 48 h prior to delivery) and intrauterine growth retardation (IUGR). The predictability of the development of respiratory distress syndrome has been assessed by this assay. Its specificity, sensitivity and overall accuracy were similar to the lecithin/sphingomyelin (L/S) ratio.