Perfil lipoproteico por espectroscopia nuclear magnética en pacientes con insuficiencia cardiaca crónica comparado con controles emparejados / 1H-magnetic resonance spectroscopy lipoprotein profile in patients with chronic heart failure versus matched controls

Introducción y objetivos El fenotipado avanzado de lipoproteínas es mejor predictor del riesgo aterosclerótico que el colesterol. El perfil de lipoproteínas en la insuficiencia cardiaca (IC) no está completamente caracterizado. Nuestro objetivo fue describir el perfil de lipoproteínas en IC crónica en comparación con una población de control emparejada. Métodos Estudio transversal entre mayo 2006 y abril 2014, que incluyó pacientes ambulatorios con IC crónica. Las concentraciones de lípidos y el tamaño de las principales fracciones de lipoproteínas (lipoproteínas de alta densidad [HDL], lipoproteínas de baja densidad [LDL] y lipoproteínas de muy alta densidad) y concentración de sus subfracciones (grandes, medianas y pequeñas) se evaluaron mediante espectroscopia de resonancia magnética. Resultados 429 pacientes con IC crónica se compararon con 428 controles. Los pacientes con IC crónica presentaron menor colesterol total y menor concentración de partículas de LDL (1.115 frente a 1.352 nmol/L; p <0,001) y HDL (25,7 frente a 27,9μmol/L; p <0,001), esta última mediada principalmente por la reducción de la subfracción pequeña de HDL (15,2 frente a 18,6μmol/L; p <0,001). El tamaño medio de las partículas lipoproteínas de muy alta densidad, LDL y HDL fue significativamente mayor en los pacientes con IC. Todas las diferencias relacionadas con la partícula HDL persistieron después del ajuste por clase funcional o índice de masa corporal. Encontramos fuertes correlaciones negativas entre biomarcadores cardiacos (fracción aminoterminal del propéptido natriurético cerebral y interleucina-1 tipo de receptor 1) con concentraciones de LDL y HDL, sus subfracciones pequeñas y el tamaño de la partícula HDL. Conclusione Los pacientes con IC crónica difieren significativamente en su perfil de lipoproteínas en comparación con controles emparejados. Se necesitan más investigaciones para comprender mejor la relevancia patogénica de esta diferencia (AU)

Introduction and objectives Advanced lipoprotein phenotyping is a better predictor of atherosclerotic cardiovascular risk than cholesterol concentration alone. Lipoprotein profiling in heart failure (HF) is incompletely characterized. We aimed to describe the lipoprotein profile in patients with chronic HF compared with a matched control population. Methods This cross-sectional study was performed from May 2006 to April 2014 and included ambulatory patients with chronic HF. Lipid concentrations and the size of main lipoprotein fractions (high-density lipoprotein [HDL], low-density lipoprotein [LDL], and very low-density lipoprotein) and the particle concentration of their 3 subfractions (large, medium and small) were assessed using 1H magnetic resonance spectroscopy. Results The 429 included patients with chronic HF were compared with 428 matched controls. Patients with chronic HF had lower total cholesterol and lower mean LDL (1115 vs 1352 nmol/L; P<.001) and HDL (25.7 vs 27.9μmol/L; P <.001) particle concentrations, with this last difference being mediated by a significantly lower concentration of the small subfraction of HDL (15.2 vs 18.6μmol/L; P <.001). Mean very low-density lipoprotein, LDL, and HDL particle size was significantly higher in patients with HF vs controls. All HDL-related differences from controls persisted after adjustment for New York Heart Association functional class or body mass index. We found strong negative correlations of known cardiac biomarkers (N-terminal pro-brain natriuretic peptide and interleukin-1 receptor-like 1) with total and small LDL and HDL fractions and HDL particle size. Conclusions Patients with chronic HF significantly differ in their lipoprotein profile compared with unaffected controls. Further research is needed to better understand the pathogenic relevance of this difference (AU)

Genetics: Is LADA just late onset type 1 diabetes?

Background: There is a controversy regarding Latent Autoimmune Diabetes in Adults (LADA) classification and whether it should be considered a slowly progressing form of type 1 (T1) diabetes (DM) or a distinct type of DM altogether. Methods: This cross-sectional study assessed major genes associated with T1DM (class II HLA, PTPN22 [rs2476601] and INS [rs689]) in patients with LADA, as compared with participants with T1DM (stratified according to age of diagnosis before or after 30) and T2DM. HLA genotyping of the DRB1, DQA1 and DQB1 loci was performed by reverse PCR sequence-specific oligonucleotides. HLA haplotypes were assigned according to those most frequently described in the European population. INS and PTPN22 SNPs were genotyped by real-time PCR. Results: A total of 578 participants were included: 248 with T1DM (70 diagnosed after the age of 30), 256 with T2DM and 74 with LADA. High risk HLA alleles were significantly more frequent in LADA than in T2DM, whereas the opposite was true for protective alleles. We found a lower frequency of the high-risk DRB1*04-DQB1*03:02-DQA1*03:01 haplotype in LADA (21.1%) than in the overall T1DM (34.7%) (p<0.05), whereas no differences were found between these groups for DRB1*03-DQB1*02:01-DQA1*05:01 or for protective alleles. Only 12% the overall T1DM group had no risk alleles vs 30% of LADA (p<0.0005). However, HLA allele distribution was similar in LADA and T1DM diagnosed after the age of 30. A total of 506 individuals (195 with T1DM [21 diagnosed after age 30] 253 with T2DM and 58 with LADA) were genotyped for the PTPN22 and INS SNPs. The G/A genotype of the PTPN22 rs2476601 was more frequent and the T/T genotype of the INS SNP rs689 was less frequent in T1DM compared to LADA. We did not find any significant differences in the frequency of the mentioned SNPs between LADA and T2DM, or between LADA and T1DM diagnosed after the age of 30. Conclusion: In this relatively small cross-sectional study, the genetic profile of subjects with LADA showed a similar T1DM-related risk allele distribution as in participants with T1DM diagnosed after the age of 30, but fewer risk alleles than those diagnosed before 30. Differences were present for HLA, as well as PTPN22 and INS genes.

Particle size and cholesterol content of circulating HDL correlate with cardiovascular death in chronic heart failure.

Evidence regarding any association of HDL-particle (HDL-P) derangements and HDL-cholesterol content with cardiovascular (CV) death in chronic heart failure (HF) is lacking. To investigate the prognostic value of HDL-P size (HDL-Sz) and the number of cholesterol molecules per HDL-P for CV death in HF patients. Outpatient chronic HF patients were enrolled. Baseline HDL-P number, subfractions and HDL-Sz were measured using 1H-NMR spectroscopy. The HDL-C/P ratio was calculated as HDL-cholesterol over HDL-P. Endpoint was CV death, with non-CV death as the competing event. 422 patients were included and followed-up during a median of 4.1 (0-8) years. CV death occurred in 120 (30.5%) patients. Mean HDL-Sz was higher in CV dead as compared with survivors (8.39 nm vs. 8.31 nm, p < 0.001). This change in size was due to a reduction in the percentage of small HDL-P (54.6% vs. 60% for CV-death vs. alive; p < 0.001). HDL-C/P ratio was higher in the CV-death group (51.0 vs. 48.3, p < 0.001). HDL-Sz and HDL-C/P ratio were significantly associated with CV death after multivariable regression analysis (HR 1.22 [95% CI 1.01-1.47], p = 0.041 and HR 1.04 [95% CI 1.01-1.07], p = 0.008 respectively). HDL-Sz and HDL-C/P ratio are independent predictors of CV death in chronic HF patients.

Reliability and repeatability of pulp volume reconstruction through three different volume calculations.

OBJECTIVE: To test the variability of the volume measurements when different segmentation methods are applied in pulp volume reconstruction. MATERIALS AND METHODS: Osirix® and ITK-SNAP software were used. Different segmentation methods (Part A) and volume approaches (Part B) were tested in a sample of 21 dental CBCT's from upper canines. Different combinations of the data set were also tested on one lower molar and one upper canine (Part C) to determine the variability of the results when automatic segmentation is performed. RESULTS: Although the obtained results show correlation among them(r > 0.75), there is no evidence that these methods are sensitive enough to detect small volume changes in structures such as the dental pulp canal (Part A and Part B). Automatic segmentation is highly susceptible to be affected by small variations in the setting parameters (Part C). CONCLUSIONS: Although the volumetric reconstruction and pulp/tooth volume ratio has not shown better results than methods based on dental radiographs, it is worth to persevere with the research in this area with new development in imaging techniques.

Sprouty1 induces a senescence-associated secretory phenotype by regulating NFκB activity: implications for tumorigenesis.

Genes of the Sprouty family (Spry1-4) are feedback inhibitors of receptor tyrosine kinase (RTK) signaling. As such, they restrain proliferation of many cell types and have been proposed as tumor-suppressor genes. Although their most widely accepted target is the Extracellular-regulated kinases (ERK) pathway, the mechanisms by which Spry proteins inhibit RTK signaling are poorly understood. In the present work, we describe a novel mechanism by which Spry1 restricts proliferation, independently of the ERK pathway. In vivo analysis of thyroid glands from Spry1 knockout mice reveals that Spry1 induces a senescence-associated secretory phenotype via activation of the NFκB pathway. Consistently, thyroids from Spry1 knockout mice are bigger and exhibit decreased markers of senescence including Ki67 labeling and senescence-associated ß-galactosidase. Although such 'escape' from senescence is not sufficient to promote thyroid tumorigenesis in adult mice up to 5 months, the onset of Phosphatase and tensin homolog (Pten)-induced tumor formation is accelerated when Spry1 is concomitantly eliminated. Accordingly, we observe a reduction of SPRY1 levels in human thyroid malignancies when compared with non-tumoral tissue. We propose that Spry1 acts as a sensor of mitogenic activity that not only attenuates RTK signaling but also induces a cellular senescence response to avoid uncontrolled proliferation.

SIRT1 promotes thyroid carcinogenesis driven by PTEN deficiency.

Current genetic evidence in mice indicates that SIRT1 has potent tumor suppressor activity in a variety of cancer models, with no evidence yet for SIRT1 oncogenic activity in vivo. We report here that transgenic Sirt1 expression is oncogenic in murine thyroid and prostate carcinogenesis initiated by Pten-deficiency. Based on mRNA expression analyses of pre-tumoral murine thyroids, we find that SIRT1 increases c-MYC transcriptional programs. Moreover, we show higher c-MYC protein levels in murine thyroid cancers from Sirt1 transgenic mice. Similarly, SIRT1 is overexpressed in human thyroid cancers and it is positively correlated with c-MYC protein levels. Finally, we show in cultured thyroid cancer cells that SIRT1 stabilizes c-MYC protein. These results implicate SIRT1 as a new candidate target for the treatment of thyroid carcinomas.