Comparative Screening of the Liver Gene Expression Profiles from Type 1 and Type 2 Diabetes Rat Models.

Experimental animal models of diabetes can be useful for identifying novel targets related to disease, for understanding its physiopathology, and for evaluating emerging antidiabetic treatments. This study aimed to characterize two rat diabetes models: HFD + STZ, a high-fat diet (60% fat) combined with streptozotocin administration (STZ, 35 mg/kg BW), and a model with a single STZ dose (65 mg/kg BW) in comparison with healthy rats. HFD + STZ- induced animals demonstrated a stable hyperglycemia range (350-450 mg/dL), whereas in the STZ-induced rats, we found glucose concentration values with a greater dispersion, ranging from 270 to 510 mg/dL. Moreover, in the HFD + STZ group, the AUC value of the insulin tolerance test (ITT) was found to be remarkably augmented by 6.2-fold higher than in healthy animals (33,687.0 ± 1705.7 mg/dL/min vs. 5469.0 ± 267.6, respectively), indicating insulin resistance (IR). In contrast, a more moderate AUC value was observed in the STZ group (19,059.0 ± 3037.4 mg/dL/min) resulting in a value 2.5-fold higher than the average exhibited by the control group. After microarray experiments on liver tissue from all animals, we analyzed genes exhibiting a fold change value in gene expression <-2 or >2 (p-value <0.05). We found 27,686 differentially expressed genes (DEG), identified the top 10 DEGs and detected 849 coding genes that exhibited opposite expression patterns between both diabetes models (491 upregulated genes in the STZ model and 358 upregulated genes in HFD + STZ animals). Finally, we performed an enrichment analysis of the 849 selected genes. Whereas in the STZ model we found cellular pathways related to lipid biosynthesis and metabolism, in the HFD + STZ model we identified pathways related to immunometabolism. Some phenotypic differences observed in the models could be explained by transcriptomic results; however, further studies are needed to corroborate these findings. Our data confirm that the STZ and the HFD + STZ models are reliable experimental models for human T1D and T2D, respectively. These results also provide insight into alterations in the expression of specific liver genes and could be utilized in future studies focusing on diabetes complications associated with impaired liver function.

Combined Gamma Conglutin and Lupanine Treatment Exhibits In Vivo an Enhanced Antidiabetic Effect by Modulating the Liver Gene Expression Profile.

Previous studies have individually shown the antidiabetic potential of gamma conglutin (Cγ) and lupanine from lupins. Until now, the influence of combining both compounds and the effective dose of the combination have not been assessed. Moreover, the resulting gene expression profile from this novel combination remains to be explored. Therefore, we aimed to evaluate different dose combinations of Cγ and lupanine by the oral glucose tolerance test (OGTT) to identify the higher antidiabetic effect on a T2D rat model. Later, we administered the selected dose combination during a week. Lastly, we evaluated biochemical parameters and liver gene expression profile using DNA microarrays and bioinformatic analysis. We found that the combination of 28 mg/kg BW Cγ + 20 mg/kg BW lupanine significantly reduced glycemia and lipid levels. Moreover, this treatment positively influenced the expression of Pdk4, G6pc, Foxo1, Foxo3, Ppargc1a, Serpine1, Myc, Slc37a4, Irs2, and Igfbp1 genes. The biological processes associated with these genes are oxidative stress, apoptosis regulation, and glucose and fatty-acid homeostasis. For the first time, we report the beneficial in vivo effect of the combination of two functional lupin compounds. Nevertheless, further studies are needed to investigate the pharmacokinetics and pharmacodynamics of the Cγ + lupanine combined treatment.

Opioids for the management of dyspnea in patients with heart failure: a systematic review of the literature / Opioides para el manejo de la disnea en pacientes con insuficiencia cardiaca: Revisión sistemática de la literatura

Abstract Introduction: Heart failure is a chronic, progressive, prevalent disease, with a high impact on health systems and on the quality of life of patients and families. Dyspnea is a common symptom and management with opioids has been proposed. Objective: To conduct a systematic review of the literature pertaining to the use of opioids for the management of dyspnea in patients with stable chronic heart failure, functional class New York Heart Association (NYHA) II, III, or IV. Materials and methods: A systematic review was conducted in the MEDLINE, Embase, Cochrane, OVID, LILACS, and PROSPERO databases of articles published in 5 languages between January 1, 1995 and July 31, 2018. Studies describing the administration of any type of opioid for the management of dyspnea in patients with stable chronic heart failure NYHA II, III, or IV were included. Results: Four clinical trials were obtained for the final analysis with a total number of 70 patients, describing opioid administration for the management of dyspnea in patients with stable chronic heart failure, NYHA II, III, or IV. Conclusion: In adult patients with compensated chronic heart failure under optimum treatment, there is low-quality evidence that shows benefit with the use of opioids for the management of dyspnea. For a stronger recommendation, controlled, randomized studies with a larger number of subjects are required.

Resumen Introducción: La insuficiencia cardiaca es una enfermedad crónica, progresiva, prevalente, con un alto impacto en los sistemas de salud y en la calidad de vida de los pacientes y sus familias, la disnea es un síntoma común y se ha planteado el uso de opioides para su control. Objetivo: Revisión sistemática de la literatura sobre el uso de opioides en el manejo de la disnea en pacientes con insuficiencia cardiaca crónica estable con clase funcional NYHA II, III o IV. Materiales y métodos: Se realizó una revisión sistemática de los artículos encontrados en las bases de datos MEDLINE, Embase, Cochrane, OVID, LILACS, PROSPERO a partir del 1 de enero del 1995 hasta el 31 de julio del 2018, publicados en cinco idiomas. Se incluyeron aquellos estudios en los cuales se describe la administración de cualquier tipo de opioide para el manejo de la disnea en pacientes con insuficiencia cardiaca crónica estable, NYHA II, III o IV. Resultados: Se incluyeron cuatro ensayos clínicos para el análisis final, con un numero total de 70 pacientes, en los cuales se describe la administración de opioides para el manejo de la disnea en pacientes con insuficiencia cardiaca crónica estable, NYHA II, III, o IV. Conclusiones: En pacientes adultos con insuficiencia cardiaca crónica compensada en tratamiento óptimo, existe evidencia de baja calidad que muestra beneficio para el manejo de la disnea con opioides, deben realizarse estudios aleatorizados controlados con una cantidad de individuos mayor para poder generar una recomendación más fuerte.

Comparison of pharmacological treatment alone versus treatment combined with cardiac resynchronization therapy in patients over 75 years.

BACKGROUND: The role of cardiac resynchronization therapy (CRT) in patients aged ≥75 years is not well established. METHODS: We identified 607 patients aged ≥75 years with left ventricular ejection fraction (LVEF) of ≤35 %, of whom 78 met the guidelines for indication of CRT. Based on the decision of the patients or attending cardiologists, 34 patients received a CRT defibrillator (CRT-D). RESULTS: The age of patients with a CRT indication was 80 ± 4 years, and 73 % were males. As compared with patients on medical therapy, CRT-D patients were younger (79 ± 3 vs. 83 ± 4, P < 0.001), had lower LVEF (23 ± 7 vs. 27 ± 7 %, P = 0.008) and higher rate of decompensated heart failure episodes (77 vs. 55 %, P = 0.04), were more frequently New York Heart Association (NYHA) class III-IV (53 vs. 25 %, P = 0.01), and were more likely to be on beta-blockers (88 vs. 66 %, P = 0.023), anticoagulants (61 vs. 32 % P = 0.02), and anti-aldosterone drugs (82 vs. 50 %, P = 0.003). After a median follow-up of 26 months, seven patients in the CRT-D group (21 %) and 20 non-CRT patients (46 %) died (hazard ratio (HR) 0.16 [95 % confidence interval (CI) 0.06-0.46]). The end point of mortality or hospitalization was not reduced because of a similar rate of hospitalizations for heart failure of CRT-D patients. Four CRT-D patients (12 %) had received appropriate device therapy, and one had been inappropriately discharged. During follow-up, 44 % of CRT-D patients improved their LVEF by >40 %. CONCLUSION: CRT-D is potentially of benefit in terms of mortality in our population; this effect persists after correction for use of beta-blockers. In patients ≥75 years, CRT indications should be similar to those accepted for younger subjects.

Comparison of electrocardiographic criteria for the detection of cardiac abnormalities in elite black and white athletes.

BACKGROUND: Recent efforts have focused on improving the specificity of the European Society of Cardiology (ESC) criteria for ECG interpretation in athletes. These criteria are derived predominantly from white athletes (WAs) and do not account for the effect of Afro-Caribbean ethnicity or novel research questioning the relevance of several isolated ECG patterns. We assessed the impact of the ESC criteria, the newly published Seattle criteria, and a group of proposed refined criteria in a large cohort of black athletes (BAs) and WAs. METHODS AND RESULTS: Between 2000 and 2012, 1208 BAs were evaluated with history, examination, 12-lead ECG, and further investigations as appropriate. ECGs were retrospectively analyzed according to the ESC recommendations, Seattle criteria, and proposed refined criteria which exclude several specific ECG patterns when present in isolation. All 3 criteria were also applied to 4297 WAs and 103 young athletes with hypertrophic cardiomyopathy. The ESC recommendations raised suspicion of a cardiac abnormality in 40.4% of BAs and 16.2% of WAs. The Seattle criteria reduced abnormal ECGs to 18.4% in BAs and 7.1% in WAs. The refined criteria further reduced abnormal ECGs to 11.5% in BAs and 5.3% in WAs. All 3 criteria identified 98.1% of athletes with hypertrophic cardiomyopathy. Compared with ESC recommendations, the refined criteria improved specificity from 40.3% to 84.2% in BAs and from 73.8% to 94.1% in WAs without compromising the sensitivity of the ECG in detecting pathology. CONCLUSION: Refinement of current ECG screening criteria has the potential to significantly reduce the burden of false-positive ECGs in athletes, particularly BAs.