Association between non-HDL-C/HDL-C ratio and carotid atherosclerosis in postmenopausal middle-aged women.

Background: A novel lipid relation, the non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol (non-HDL-C/HDL-C) ratio gathers information on all atherogenic and antiatherogenic particles on a single date. The relationship between this lipid marker and the presence of carotid atherosclerotic plaque (CAP) in postmenopausal women is unknown. Methods: Postmenopausal women in primary prevention up to 70 years of age were recruited. Association between the non-HDL-C/HDL-C ratio and presence of CAP, assessed by ultrasonography, was analyzed. Receiver operating characteristic (ROC) curve analysis was performed. Results: A total of 440 females with a mean age of 58.1 ± 5.3 years were recruited. The mean non-HDL-C/HDL ratio was 3.1 ± 1.2 and 28.2% of woman had CAP. A positive relationship was seen between quintiles of the non-HDL-C/HDL-C ratio and prevalence of CAP (p < 0.001). Regardless of other risk factors, women with higher non-HDL-C/HDL-C ratios had a greater chance of having CAP (odds ratio 1.30, 95% confidence interval: 1.07-1.58, p = 0.009). In the ROC curve analysis, the area under the curve of the non-HDL-C/HDL ratio for detecting CAP was 0.703 (95% confidence interval: 0.640-0.765) and the optimal cut-off point was 3.0 (Youden index 0.395). Conclusion: The present study suggests that the non-HDL-C/HDL-C ratio might be a strong marker for predicting the risk of CAP in postmenopausal women.

Inhibidores de la proproteína convertasa plasmática subtilisina kexina tipo 9 y riesgo de cataratas: revisión sistemática y metaanálisis / Plasma proprotein convertase subtilisin/kexin type 9 inhibitors and cataract risk: A systematic review and meta-analysis

Antecedentes: El marcado descenso en los niveles de C-LDL producidos por los inhibidores de la proproteína convertasa plasmática subtilisina kexina tipo 9 (iPCSK9) podría asociarse con un mayor riesgo de cataratas. Métodos: Realizamos un metaanálisis que incluyó ensayos clínicos aleatorizados y controlados con iPCSK9, solos o combinados con otros fármacos hipolipidemiantes, que reportaron nuevos casos de cataratas, buscando en PubMed/Medline, bases de datos de EMBASE y Cochrane Clinical Trials. Se utilizó un modelo de efectos fijos y se realizó una metarregresión evaluando la relación entre el C-LDL intratratamiento y el riesgo de desarrollar cataratas. Resultados: Se tomaron en cuenta 5 estudios elegibles con iPCSK9 que incluyeron 83.492 pacientes para el análisis, refiriendo 531 nuevos casos de cataratas en el grupo con iPCSK9 frente a 532 en el grupo placebo. La terapia con iPCSK9 no se asoció con un mayor riesgo de presentar cataratas (OR: 0,96; IC 95%: 0,85-1,08; p = 0,86, I2: 0%]. Asimismo, no se encontró una asociación significativa entre la diferencia de C-LDL intratratamiento entre las ramas de los estudios y el riesgo de cataratas. Conclusión. En nuestro análisis, la utilización de iPCSK9 no se asoció con un mayor riesgo de cataratas

Background: The marked decrease in LDL-C levels produced by the inhibitors of the plasma proprotein convertase subtilisin/kexin type 9 (iPCSK9) could be associated with an increased risk of cataracts. Methods: A meta-analysis was performed that included randomised clinical trials controlled with iPCSK9, alone, or in combination with other lipid-lowering drugs, which reported new cases of cataracts, by searching PubMed/Medline, databases of EMBASE and Cochrane Clinical Trials. A fixed-effect model was used, and a meta-regression was carried out evaluating the relationship between intra-treatment LDL-C and the risk of developing cataracts. Results: Five eligible studies of iPCSK9 including 83,492 patients were taken into account for the analysis, and 531 new cases of cataracts in iPCSK9 group vs. 532 in placebo group were diagnosed. The iPCSK9 therapy was not associated with an increased risk of cataracts [OR: 0.96, 95% CI: 0.85-1.08; P = .86, I2: 0%]. Likewise, no significant association was found between on-treatment LDL-C levels, differences between study arms, and new cases of cataracts. Conclusion: In this analysis, the use of iPCSK9 was not associated with an increased risk of cataracts

Plasma proprotein convertase subtilisin/kexin type 9 inhibitors and cataract risk: A systematic review and meta-analysis. / Inhibidores de la proproteína convertasa plasmática subtilisina kexina tipo 9 y riesgo de cataratas: revisión sistemática y metaanálisis.

BACKGROUND: The marked decrease in LDL-C levels produced by the inhibitors of the plasma proprotein convertase subtilisin/kexin type 9 (iPCSK9) could be associated with an increased risk of cataracts. METHODS: A meta-analysis was performed that included randomised clinical trials controlled with iPCSK9, alone, or in combination with other lipid-lowering drugs, which reported new cases of cataracts, by searching PubMed/Medline, databases of EMBASE and Cochrane Clinical Trials. A fixed-effect model was used, and a meta-regression was carried out evaluating the relationship between intra-treatment LDL-C and the risk of developing cataracts. RESULTS: Five eligible studies of iPCSK9 including 83,492 patients were taken into account for the analysis, and 531 new cases of cataracts in iPCSK9 group vs. 532 in placebo group were diagnosed. The iPCSK9 therapy was not associated with an increased risk of cataracts [OR: 0.96, 95% CI: 0.85-1.08; P=.86, I2: 0%]. Likewise, no significant association was found between on-treatment LDL-C levels, differences between study arms, and new cases of cataracts. CONCLUSION: In this analysis, the use of iPCSK9 was not associated with an increased risk of cataracts.

Therapy with cholesteryl ester transfer protein (CETP) inhibitors and diabetes risk.

BACKGROUND: Cholesteryl ester transfer protein (CETP) inhibitors are a class of drugs that targets the CETP enzyme to significantly increase serum high-density lipoprotein cholesterol (HDL-C) and decrease low-density lipoprotein cholesterol (LDL-C) levels. As HDL-C has potential antidiabetic properties, and the beneficial effects of CETP drugs on glucose homoeostasis have not been sufficiently studied, the aims of this study were: (1) to evaluate the effect of CETP inhibitors on the incidence of diabetes; and (2) to assess the association between CETP inhibitor-induced changes in HDL-C levels and incidence of diabetes. METHODS: A meta-analysis was performed of randomized controlled clinical trials of CETP inhibitor therapy, either alone or combined with other lipid-lowering drugs, reporting data from new cases of diabetes with a minimum of 6 months of follow-up, after searching the PubMed/MEDLINE, Embase and Cochrane Controlled Trials databases. A fixed-effects meta-regression model was then applied. RESULTS: Four eligible trials of CETP inhibitors, involving a total of 73,479 patients, were considered for the analyses, including 960 newly diagnosed cases of diabetes in the CTEP inhibitor group vs 1086 in the placebo group. CETP inhibitor therapy was associated with a significant 12% reduction in incidence of diabetes (OR: 0.88, 95% CI: 0.81-0.96; P=0.005). Assessment of the relationship between on-treatment HDL-C and the effect of CETP inhibitors showed a statistically non-significant trend (Z=-1.13, P=0.26). CONCLUSION: CETP inhibitors reduced the incidence of diabetes. The improvement in glucose metabolism may have been related, at least in part, to the increase in HDL-C concentration.

Riesgo cardiovascular a lo largo de la vida en pacientes con bajo riesgo en el corto plazo. Asociación con la ateromatosis carotídea / Cardiovascular lifetime risk in patients with low risk in the short term. Association with carotid atheromatosis

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Características y actitudes del tabaquismo en médicos de la Argentina en relación a la especialidad / Smoking characteristics and attitudes in physicians in Argentine in regards to the specialty

Objetivos. Analizar la epidemiología del tabaquismo en médicos de Argentina y la actitud que estos toman frente a sus pacientes fumadores, en relación con la especialidad ejercida. Métodos y pacientes. Estudio transversal, analítico-observacional. Se evaluaron médicos de ambos géneros, clasificándolos en categorías según la especialidad: cardiólogos, neumólogos, psiquiatras, clínicos (resto de las especialidades clínicas), tocoginecólogos y cirujanos (otras especialidades quirúrgicas). Se analizaron las características del consumo, la capacitación y el consejo médico en relación a la especialidad. Resultados. Se incluyeron 6.150 médicos, 63% varones, edad 41,5 ± 10 años, fumadores 29,7%, 28% comenzaron a fumar antes de los 15 años, consumo promedio 14 cigarrillos/día, 30% fumaban al despertar, y otro tanto tenían capacitación en tabaquismo. Los psiquiatras mostraron mayor prevalencia (40,8%), el mayor consumo (16 ± 9,7/día) y la mayor proporción de fumadores en la primera hora del despertar (42,9%) o en el hospital (54,8%). Dichas características se observaron menos frecuentemente en las otras especialidades. Los cardiólogos y neumólogos mostraron un mayor entrenamiento y fueron los que más frecuentemente brindaban consejo de cesación tabáquica (>90%). Conclusión. En este estudio, la prevalencia de tabaquismo en médicos fue elevada. Las características del consumo de cigarrillos, el grado de entrenamiento y la frecuencia de brindar el consejo de cesación tabáquica mostraron diferencias según la especialidad analizada (AU)

Objective. To analyze the epidemiology of smoking in Argentinian physicians and their attitude towards their patients who smoke, in relation to medical specialty. Methods and patients. A cross-sectional, observational-analytical study was performed. Physicians of both sexes were evaluated, classifying them into categories by specialty: cardiologists, pneumonologists, psychiatrists, clinical (other clinical specialties), gynecologists and surgeons (other surgical specialties). Characteristics of cigarette consumption, medical training and advice to quit smoking among physicians by specialty were analyzed. Results. 6,150 physicians were included (male 63%, mean age 41.5 ± 10 years, smokers 29.7%). 28% of the doctors started smoking before age 15, and the average consumption was 14 cigarettes/day. Thirty percent of the physicians smoke at the time of awakening. Other thirty percent had training in tobacco. Psychiatrists showed the higher prevalence of smoking (40.8%), daily consumption of cigarettes (16 ± 9.7) and proportion of smokers that smoked at the first hour of awakening (42.9%) or in the hospital (54.8%). These characteristics were observed less frequently in other specialties. Cardiologists and pneumonologists showed further training and were the most frequently provided advice to quit smoking (>90%). Conclusion. The prevalence of smoking was high in this study. The characteristics of smoking consumption, the degree of medical training and the frequency that physicians gave advice to quit smoking, showed differences according to specialty (AU)

Tratamiento con insulina y heparina en la hipertrigliceridemia severa / Treatment with Insulin and Heparin in Severe Hypertriglyceridemia

La hipertrigliceridemia severa se asocia con pancreatitis aguda y suele producirse por una deficiencia genética o adquirida en la actividad de la lipoproteín lipasa (LPL). El tratamiento habitual en pacientes ambulatorios se basa en una alimentación saludable, ejercicio físico, control del peso, complementos de omega 3 y fármacos como los fibratos y la niacina. Ante situaciones de hipertrigliceridemia severa asociados o no a pancreatitis, se recomienda el tratamiento con insulina y/o heparina para disminuir rápidamente el nivel de triglicéridos aumentando la actividad de la LPL, tanto en pacientes diabéticos como en no diabéticos. En esta presentación se describe el caso de una mujer joven, tabaquista y obesa, sin antecedentes de dislipemia previa que en un análisis de control se detecta una hipertrigliceridemia severa (12214 mg/dL) en contexto de una diabetes de reciente diagnóstico. Durante la internación se administró insulina endovenosa, heparina sódica y gemfibrozil, disminuyendo rápidamente los niveles de triglicéridos y evolucionando favorablemente sin desarrollar pancreatitis. Los autores declaran no poseer conflictos de interés.

Severe hypertriglyceridemia is associated with acute pancreatitis and it is usually caused by a genetic or acquired deficiency in the activity of lipoprotein lipase (LPL). The usual treatment in outpatients is based on healthy eating, exercise, weight control, omega-3 supplements and drugs such as fibrates and niacin. In situations of severe hypertriglyceridemia, whether or not associated with pancreatitis, treatment with insulin and/or heparin is recommended to rapidly decrease triglyceride levels by increasing LPL activity, in diabetic and non-diabetic patients. We report the case of a young, obese smoker woman with no prior history of dyslipidemia, who had severe hypertriglyceridemia (12214 mg/dL) detected in a control test in the context of new onset diabetes. During hospitalization, intravenous insulin, sodium heparin and gemfibrozil were administered, with a rapid decrease in triglyceride levels and good progress with no development of pancreatitis. No financial conflicts of interest exist.

Tratamiento con insulina y heparina en la hipertrigliceridemia severa / Treatment with Insulin and Heparin in Severe Hypertriglyceridemia

La hipertrigliceridemia severa se asocia con pancreatitis aguda y suele producirse por una deficiencia genética o adquirida en la actividad de la lipoproteín lipasa (LPL). El tratamiento habitual en pacientes ambulatorios se basa en una alimentación saludable, ejercicio físico, control del peso, complementos de omega 3 y fármacos como los fibratos y la niacina. Ante situaciones de hipertrigliceridemia severa asociados o no a pancreatitis, se recomienda el tratamiento con insulina y/o heparina para disminuir rápidamente el nivel de triglicéridos aumentando la actividad de la LPL, tanto en pacientes diabéticos como en no diabéticos. En esta presentación se describe el caso de una mujer joven, tabaquista y obesa, sin antecedentes de dislipemia previa que en un análisis de control se detecta una hipertrigliceridemia severa (12214 mg/dL) en contexto de una diabetes de reciente diagnóstico. Durante la internación se administró insulina endovenosa, heparina sódica y gemfibrozil, disminuyendo rápidamente los niveles de triglicéridos y evolucionando favorablemente sin desarrollar pancreatitis. Los autores declaran no poseer conflictos de interés.(AU)

Severe hypertriglyceridemia is associated with acute pancreatitis and it is usually caused by a genetic or acquired deficiency in the activity of lipoprotein lipase (LPL). The usual treatment in outpatients is based on healthy eating, exercise, weight control, omega-3 supplements and drugs such as fibrates and niacin. In situations of severe hypertriglyceridemia, whether or not associated with pancreatitis, treatment with insulin and/or heparin is recommended to rapidly decrease triglyceride levels by increasing LPL activity, in diabetic and non-diabetic patients. We report the case of a young, obese smoker woman with no prior history of dyslipidemia, who had severe hypertriglyceridemia (12214 mg/dL) detected in a control test in the context of new onset diabetes. During hospitalization, intravenous insulin, sodium heparin and gemfibrozil were administered, with a rapid decrease in triglyceride levels and good progress with no development of pancreatitis. No financial conflicts of interest exist.(AU)

A phenotype map of the mouse X chromosome: models for human X-linked disease.

The identification of many of the transcribed genes in man and mouse is being achieved by large scale sequencing of expressed sequence tags (ESTs). Attention is now being turned to elucidating gene function and many laboratories are looking to the mouse as a model system for this phase of the genome project. Mouse mutants have long been used as a means of investigating gene function and disease pathogenesis, and recently, several large mutagenesis programs have been initiated to fulfill the burgeoning demand of functional genomics research. Nevertheless, there is a substantial existing mouse mutant resource that can be used immediately. This review summarizes the available information about the loci encoding X-linked phenotypic mutants and variants, including 40 classical mutants and 40 that have arisen from gene targeting.

The sex-linked fidget mutation abolishes Brn4/Pou3f4 gene expression in the embryonic inner ear.

We have demonstrated that the phenotype of the mouse mutant sex-linked fidget ( slf ) is caused by developmental malformations of the inner ear that result in hearing loss and vestibular dysfunction. Recently, pilot mapping experiments suggested that the mouse Brn4 / Pou3f4 gene co-segregated with the slf locus on the mouse X chromosome. These mapping data, in conjunction with the observation that the vertical head-shaking phenotype of slf mutants is identical to that observed in mice with a targeted deletion of the Brn4 gene, suggested that slf is a mutant allele of the Brn4 gene. In this paper, we have identified the nature of the slf mutation, and demonstrated that it is an X chromosomal inversion with one breakpoint close to Brn4. This inversion selectively eliminates the expression of the Brn4 gene in the developing inner ear, but not the neural tube. Finally, these results demonstrate that the slf mutation is a good mouse model for the most prevalent form of X-linked congenital deafness in man, which is associated with mutations in the human Brn4 ortholog, POU3F4.

Abnormalities of copper accumulation in cell lines established from nine different alleles of mottled are the same as those found in Menkes disease.

Menkes disease (MD) is caused by a defect in copper homeostasis and has a recognised mouse model, mottled (Atp7aMo). Copper uptake and retention assays performed on fibroblast cultures have been used successfully for pre- and postnatal diagnosis of Menkes disease. We report here the results of these assays applied to primary fibroblast cultures established from nine independent mottled alleles associated with phenotypes of varying severity maintained on identical genetic backgrounds. No significant differences were found between the different alleles, or between the mottled cultures and fibroblasts established from MD patients. Thus, in the mouse, the data obtained for copper retention/uptake at the cellular level do not correlate with the severity of the phenotype.

The use of compound heterozygotes and Hprt selection to analyze X-linked mottled alleles associated with prenatal lethality.

X-linked mutant alleles associated with prenatal male lethality are difficult to analyze because only heterozygous females are readily available for study. Genomic analysis of the mutant allele is facilitated by the construction of somatic cell hybrids because this enables the segregation of the X Chromosomes (Chrs) that carry the mutant and wild-type alleles. We describe here a method that ensures that the X Chr carrying the mutant allele is retained in somatic cell hybrids in an active selectable state. This is achieved by mating heterozygous females to males that carry a mutation at the hypoxanthine phosphoribosyl transferase (Hprt) locus. The resultant F1 females are compound heterozygotes, and when cells from these females are fused to HPRT- Chinese hamster cells and subjected to selection in HAT medium, the only survivors are those hybrid cells that retain an active X Chr carrying the mutant allele together with the wild-type Hprt allele. We use hybrids constructed by this method to demonstrate that there are no gross deletions or genomic rearrangements present in three mottled alleles associated with prenatal male lethality.

The effectiveness of restriction endonucleases in cell killing and mutation.

The use of restriction endonucleases (RE) to study the importance of DNA break end structures in differential cellular response has proved controversial. The number of DNA cut sites and the accessibility of RE are recognized examples of confounding factors. We have eliminated these factors by comparing the effectiveness of isoschizomers. Additionally, we considered for the first time the tolerance of the enzymes to cellular conditions. Cell killing and mutation were compared to the overall cutting ability of the enzymes in an "intracellular" buffer. We found that the activity of each RE combined with its lifetime, under simulated cellular conditions, were the overriding factors in determining effectiveness.

Analysis of large deletions in the HPRT gene of primary human fibroblasts using the polymerase chain reaction.

Spontaneous and X-ray-induced mutants of the HPRT gene were isolated from two primary human fibroblast lines. The limited life-span of the mutants restricted the use of methods requiring large quantities of DNA, and the polymerase chain reaction (PCR) was used in particular to check for the presence of multiple genomic sites in mutant analysis. Robust PCR primers were designed to amplify sites of up to 1 kb, mostly with 1-kb spacings between sites, over the entire 56-kb HPRT gene region. Using PCR, large deletions were found in 43% of independent X-ray-induced mutants, and their breakpoints were localized where these fell within the gene. Anonymous DNA sites in the Xq26 chromosomal region containing HPRT (covering > or = 1.5 Mb) were also amplified by PCR to assess codeletion with HPRT; sites up to 1 Mb distal to the gene (DXS86, DXS10) were codeleted in some mutants, but no mutant was found with loss of a proximal site (DXS79).

DNA methylation changes in the IL-1 (2F) chromosomal region of some radiation-induced acute myeloid leukaemias carrying chromosome 2 rearrangements.

Acute myeloid leukaemias (AML) arising in irradiated CBA/H mice frequently have breakpoints in the F region of chromosome 2. The closely linked cytokine genes interleukin (IL)-1 alpha and beta map to this region, and the beta gene is deregulated in some AMLs. Using pulsed-field gel electrophoresis techniques, we show here that an 800 kb 2F region encoding IL-1 alpha and beta is not obviously rearranged in six leukaemias carrying chromosome 2 abnormalities. However, changes in IL-1 region DNA methylation in three leukaemias may be consistent with loss of hypermethylated sequences from one chromosome copy. These possible 2F region losses are discussed in relation to genomic imprinting and its potential role in murine myeloid leukaemogenesis.