Early diagnosis is important in familial hypercholesterolemia (FH), a highly atherogenic condition, but internationally agreed clinical diagnostic criteria are lacking. Genetic testing for ...low-density lipoprotein (LDL) receptor (LDLR) and apolipoprotein B (APOB) gene defects is the preferable diagnostic method, but the best phenotype indication to proceed with genetic diagnosis has not been established. The aim of this study was to assess the predictive and accuracy values of standard diagnostic criteria for detecting disease-causing mutations in 825 subjects with clinical FH aged ≥14 years from 3 lipid clinics in Spain. All subjects underwent thorough genetic testing for the detection of LDLR and APOB defects using the Lipochip platform. FH-causing mutations were detected in 459 subjects (55.6%). By logistic regression analysis, familial or personal history of tendon xanthoma (TX) and LDL cholesterol were strongly associated with genetic diagnosis (p <0.005, R 2 = 0.41). In subjects without familial or personal histories of TX, the diagnostic criteria for FH of the Make Early Diagnosis to Prevent Early Deaths (MEDPED) project, based on age-specific LDL cholesterol thresholds, showed sensitivity of 72.4%, specificity of 71.1%, and accuracy of 71.6%. LDL cholesterol ≥190 mg/dl in subjects with familial or personal histories of TX and ≥220, ≥225, and ≥235 mg/dl in those without such histories aged <30, 30 to 39, and ≥40 years, respectively, showed sensitivity of 91.1%, specificity of 71.1%, and accuracy of 74.2% for a positive genetic diagnosis. This new set of diagnostic criteria for FH was validated in an independent group of 440 subjects from 6 additional Spanish lipid clinics. In conclusion, TX and age-adjusted LDL cholesterol cut-off values have the highest value for clinical diagnosis and indication of genetic testing in FH.
Secondary hypertriglyceridemia Viñals, Clara; Zambón, Daniel; Yago, Gema ...
Clinica e investigacion en arteriosclerosis : publicacion oficial de la Sociedad Espanola de Arteriosclerosis
33 Suppl 2
Journal Article
Recenzirano
Secondary hypertriglyceridemia (HTG) are the most common cause of excess triglyceride rich particles in plasma. Faced with HTG, the first thing to do is rule out if there is a secondary cause since ...it can interact with genetic susceptibility and further aggravate the HTG. The most common causes are diet with high fat and high glycemic index, obesity, diabetes mellitus, alcohol consumption, renal disease like nephrotic syndrome, hepatic disorders and medications. The most important medications that can influence in HTG are oestrogen, isotretinoin, immunosuppressant therapy, L-asparaginase and with less effect thiazides, beta blockers, atypical antipsychotics and glucocorticoids. Other causes less frequent are endocrinological diseases such as Cushing's syndrome, acromegaly, hypothyroidism; pregnancy, lipodystrophies and autoimmune diseases. Lastly, the identifications and treatment or correction of secondary causes is a corner stone in the treatment of this disease.
High-resolution B-mode ultrasound measurements of intima-media thickness (IMT) and plaque presence are useful to assess preclinical atherosclerosis. Normal carotid IMT values, but not normal femoral ...IMT values, have been reported in Spanish subjects. Our aim was to define the normality data of femoral ultrasound by sex and age.
We studied 192 healthy subjects from a community cohort, 85 men and 107 women (mean age: 49 years; range: 20-81 years). We sonographically determined mean and maximum IMT in the far wall of the common femoral artery, plaque occurrence, and maximum plaque height.
Reference values for femoral IMT, expressed as 25th, 50th, and 75th percentiles by sex and 5 age groups, were obtained. The 50th percentiles of mean IMT ranged from 0.50 to 1.04 mm in men in the age groups < or = 35 years and > or = 65 years, respectively. For women, corresponding IMT values ranged from 0.40 to 0.53 mm. IMT was positively related to age in both men (r = 0.44; p < 0.001) and women (r = 0.23; p = 0.019). From the regression equations of IMT versus age, the estimated yearly increase in IMT was 0.016 mm in men and 0.008 mm in women. More than 50% of men aged > or = 55 years and women aged > or = 65 years had plaques.
Both IMT and plaque frequency are associated with age in men and women. Femoral IMT values in a Spanish community cohort are lower than those reported for geographical areas with higher cardiovascular risk, such as the Northern European countries and the US.
The genetic origin of familial combined hyperlipidemia (FCH) is not well understood. We used microarray profiling of peripheral blood monocytes to search novel genes and pathways involved in FCH.
...Fasting plasma for determination of lipid profiles, inflammatory molecules and adipokines was obtained and peripheral blood monocytes were isolated from male FCH patients basally and after 4 weeks of atorvastatin treatment. Sex-, age- and adiposity-matched controls were also studied. Gene-expression profiles were analyzed using Affymetrix Human Genome U133A 2.0 GeneChip arrays.
Analysis of gene expression by cDNA microarrays showed that 82 genes were differentially expressed in FCH monocytes compared with controls. Atorvastatin treatment modified the expression of 86 genes. Pathway analysis revealed the over-representation of the complement and coagulation cascades, the hematopoietic cell lineage and the arachidonic acid metabolism pathways. Changes in the expression of some genes, confirmed by real-time RT-PCR, (CD36, leucine-rich repeats and immunoglobulin-like domains-1, tissue factor pathway inhibitor 2, myeloid cell nuclear differentiation antigen, tumor necrosis factor receptor superfamily, member 25, CD96 and lipoprotein lipase), may be related to a proinflammatory environment in FCH monocytes, which is partially reversed by atorvastatin. Higher plasma levels of triglycerides and free fatty acids and lower levels of adiponectin in FCH patients could also trigger changes in gene expression that atorvastatin cannot modify.
Our results show clear differences in gene expression in FCH monocytes compared with those of matched healthy controls, some of which are influenced by atorvastatin treatment.
Transition to circular economy requires the production of sustainable and eco-designed materials that help to reduce environmental impacts of metallic components. The development of sensing layers ...providing luminescent tracking functionalities is a potential method for extending the service life of metallic parts. In this study, incorporation of luminescent Ce3+ doped yttrium aluminum garnet (YAG:Ce) within a stainless steel 316L (SS316L) matrix has been achieved for the first time by laser powder bed fusion (L-PBF). Embedding of phosphor particles was successfully carried out on a selected area of the 3D printed sample. Despite harsh processing conditions of L-PBF, luminescent emission was detected by optical spectroscopy. Microstructure and chemical composition of the incorporation zone were investigated in order to better understand optical properties. The precipitated particles exhibit new optical features, arising from the modification of the luminescent host lattice and the intricate interactions with the metal matrix.
Background and Objectives
Fibrates induce hepatic peroxisome proliferation and carcinogenesis in rodents by activating peroxisome proliferator‐activated receptor α (PPARα). There is no conclusive ...evidence that humans are unresponsive to peroxisome proliferation, and concern exists about the long‐term safety of fibrate treatment.
Methods
In a university hospital setting, 48 patients with uncomplicated gallstones and a serum level of low‐density lipoprotein cholesterol greater than 130 mg/dL were randomly assigned to open‐label treatment with bezafibrate (400 mg/d), fenofibrate (200 mg/d), gemfibrozil (900 mg/d), or placebo for 8 weeks before elective cholecystectomy. Serum samples for lipid determinations were obtained at baseline and before surgery. A liver specimen was obtained at operation, and the relative levels of messenger ribonucleic acid (mRNA) for the wild and truncated forms of PPARα, acyl coenzyme A oxidase, liver carnitine palmitoyltransferase I, apolipoprotein A‐I, and stearoyl coenzyme A desaturase were determined.
Results
Fenofibrate, bezafibrate, and gemfibrozil reduced plasma low‐density lipoprotein cholesterol levels by 22% (P = .009), 14% (P = .042), and 11% (not significant), respectively. Plasma triglyceride levels decreased significantly (24%‐36%; P < .05), whereas high‐density lipoprotein cholesterol levels rose nonsignificantly after treatment with the 3 fibrates. Except for a 35% increase of apolipoprotein A‐I mRNA after fenofibrate administration (P < .05), none of the individual fibrates induced significant changes in the mRNAs tested, although as a group they increased the mRNA for liver carnitine palmitoyltransferase I by 40%(P = .08; marginally significant).
Conclusions
Fibrate administration to humans at pharmacologic doses able to activate PPARα and to induce a hypolipidemic effect does not increase the hepatic expression of acyl coenzyme A oxidase, a well‐known marker of peroxisome proliferation in rodents.
Clinical Pharmacology & Therapeutics (2002) 72, 692–701; doi: 10.1067/mcp.2002.128605
New polymorphs of EuP5O14 and GdP5O14 ultraphosphates have been discovered and their crystal structures have been determined. The luminescence properties of the Eu3+ ion incorporated as a local ...structural probe for GdP5O14 have been investigated at room temperature.
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•The crystal structures of new polymorphs of EuP5O14 and GdP5O14 have been determined from single crystals X-ray diffraction.•Structural properties of GdP5O14 polycrystalline thoroughly discussed by using XRD, FT-IR and Raman spectroscopy.•Photoluminescence excitation and emission spectra of GdP5O14:Eu3+ were measured.
New polymorphs of EuP5O14 and GdP5O14 ultraphosphates have been discovered and their crystal structures have been determined from single-crystal X-ray diffraction. These two polymorphs crystallize with monoclinic symmetry in the space group C2/c (no. 15). They complement the series of type II ultraphosphates with the formula LnP5O14 known for heavier rare earths from Tb to Lu inclusively and including the homologous Y and Bi members. The structural properties of polycrystalline GdP5O14 have been thoroughly discussed with reference to X-ray diffraction results, Fourier-infrared and Raman spectroscopy. Under ultraviolet excitation, Gd1−xP5O14:xEu3+ (x = 5%, 10%) samples show a characteristic red emission originating from the 5D0 → 7F2 transition of the Eu3+ ion.Photoluminescence excitation and emission spectra of GdP5O14:Eu3+ were measured. The results show that it can be considered as a promising red phosphor for solid-state lighting and as such may have potential applications in atomic-like all-optical devices. The luminescence properties of the Eu3+ ion incorporated in the monoclinic C2/c polymorph as local structural probe show that in GdP5O14:Eu3+ powders, the Eu3+ ions are distributed over the two Gd3+ crystallographic sites of C2 symmetry of this structure.
Whether metabolic control in type 2 diabetes mellitus (DM) is best achieved with the traditional high-carbohydrate (CHO), low-fat diet or a low-CHO, high-fat diet is still controversial. In a ...randomized crossover study, we compared the effects of a low-fat (30% of daily energy) diet and a high-fat (40% of daily energy), high-monounsaturated-fat diet for 6 weeks each on fasting and postprandial glucose, insulin, and lipoprotein concentrations in 12 patients with well-controlled type 2 DM (fasting blood glucose, 176 ± 54 mg/dL; hemoglobin A
1c, 6.4% ± 0.7%) and no overt dyslipidemia (serum total cholesterol, 235 ± 43 mg/dL; triglycerides, 180 ± 63 mg/dL). Home-prepared foods were used and olive oil was the main edible fat, accounting for 8% and 25% of daily energy requirements in the low-fat and high-fat diets, respectively. For postprandial studies, the same mixed meal containing 36% fat was used in both dietary periods. Body weight and fasting and 6-hour postprandial blood glucose, insulin, and lipoprotein levels were similar after the two diets. The mean incremental area under the curve of serum triglycerides 0 to 6 hours after the challenge meal, adjusted for baseline levels, did not change significantly after the high-fat diet compared with the low-fat diet (1,484 ± 546
v 1,714 ± 709 mg · 6 h/dL, respectively,
P = .099). Mean postprandial triglyceride levels at 6 hours were increased about 2 times over fasting levels and were still greater than 300 mg/dL after either diet. A diet high in total and monounsaturated fat at the expense of olive oil is a good alternative diet to the traditional low-fat diet for patients with type 2 DM. However, ongoing postprandial hypertriglyceridemia with either diet points to the need for other therapies to decrease triglyceride-rich lipoproteins (TRL) and the inherent atherogenic risk in type 2 diabetics.
The adipocyte-derived cytokine, resistin, has been proposed as the link between obesity and type 2 diabetes mellitus in murine models. In humans, resistin is identical to FIZZ3 (found in inflammatory ...zone 3), which belongs to a family of proteins that appears to be involved in inflammatory processes. To study the mechanisms by which fibrates improve glucose homeostasis, we determined resistin mRNA levels by using relative quantitative reverse-transcriptase-polymerase chain reaction (RT-PCR) in omental white adipose tissue samples obtained from patients treated with placebo or fenofibrate (200 mg/d) for 8 weeks before elective cholecystectomy. Fenofibrate treatment reduced total plasma cholesterol and low-density lipoprotein (LDL)-cholesterol levels by 24% and 35%, respectively. Compared with placebo values, a 2.4-fold induction in resistin mRNA levels was observed in white adipose tissue of fenofibrate-treated patients, whereas no changes were observed in the mRNA levels of the well-known perosixome proliferator-activated receptor (PPAR) target genes CD36, acyl-CoA oxidase, and carnitine palmitoyltransferase. These findings indicate that resistin changes were not related to PPAR activation by fenofibrate. Interestingly, resistin mRNA levels showed a negative correlation with plasma cholesterol levels (r2 =.53, P =.039, n = 8), but not with triglyceride levels (r2 =.02, P =.73, n = 8). These results suggest that cholesterol regulates resistin expression in human white adipose tissue. Copyright 2003, Elsevier Science (USA). All rights reserved.
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