Summary
We describe here two novel DRB1 alleles, officially named *040405 and *1190. DRB1*040405 differs from DRB1*0404 for one point mutation at codon 72 with no coding changes. DRB1*1190 is ...identical to DRB1*110101 except for a nucleotide substitution at codon 24 which causes an aminoacidic mutation from valine to methionine. Over time we have been witnessing the identification of a great number of new HLA alleles. DRB1 allelic variability is mostly present in the second exon and more that 760 alleles have been so far identified. Here, we report the description of two novel DRB1 alleles, named *040405 and *1190, and identified in two Caucasoid subjects.
Sepsis remains a major cause of morbidity and mortality mainly because of sepsis-induced multiple organ dysfunction. In contrast to preclinical studies, most clinical trials of promising new ...treatment strategies for sepsis have failed to demonstrate efficacy. Although many reasons could account for this discrepancy, the misinterpretation of preclinical data obtained from experimental studies and especially the use of animal models that do not adequately mimic human sepsis may have been contributing factors. In this review, the potentials and limitations of various animal models of sepsis are discussed to clarify to which extent these findings are relevant to human sepsis. Such models include intravascular infusion of endotoxin or live bacteria, bacterial peritonitis, cecal ligation and perforation, soft tissue infection, pneumonia or meningitis models using different animal species including rats, mice, rabbits, dogs, pigs, sheep, and nonhuman primates. Despite several limitations, animal models remain essential in the development of all new therapies for sepsis and septic shock because they provide fundamental information about the pharmacokinetics, toxicity, and mechanism of drug action that cannot be replaced by other methods. New therapeutic agents should be studied in infection models, even after the initiation of the septic process. Furthermore, debility conditions need to be reproduced to avoid the exclusive use of healthy animals, which often do not represent the human septic patient.
Pentoxifylline (PTX) has been shown to have beneficial effects on microcirculatory blood flow. In this study we evaluate the potential hemodynamic and metabolic benefits of PTX during hepatic ...ischemia. We also test the hypothesis that portal PTX infusion can minimize the I/R injury when compared to systemic infusion. Methods. Twenty-four dogs (18.1±0.7 kg) were subjected to portal triad occlusion (PTO) for 45 min. The animals were assigned to 3 groups: CT (control, PTO, n=8), PTX-syst (PTO + 25 mg/Kg of PTX IV, n=8), and PTX-pv (PTO + 25 mg/Kg of PTX in the portal vein, n=8). Animals were followed for 120 min. Systemic hemodynamics, gastrointestinal tract perfusion, oxygen-derived variables, and liver enzymes were evaluated throughout the experiment. Results. Animals treated with PTX presented significantly higher CO in the first hour after reperfusion, when compared to the CT (~3.7 vs. 2.1 L/min, P<0.05). Alanine aminotransferase (ALT) was similar in the PTX groups two hours after reperfusion but significantly higher in the CT (227 vs. ~64 U/L, P<0.05). Conclusion. PTX infusion was associated with hemodynamic benefits and was able to minimize liver injury during normothermic hepatic I/R. However, local PTX infusion was not associated with any significant advantage over systemic route.
Background Acute kidney injury (AKI) following prolonged laparoscopy is a documented phenomenon. Carbon dioxide pneumoperitoneum induces oxidative stress. Previous experimental studies have shown ...that the antioxidant, N -acetylcysteine, protects the rat from AKI following ischemia-reperfusion. The aim of this study was to evaluate the effects of N -acetylcysteine (NAC) on rat renal function after prolonged pneumoperitoneum. Methods Normal rats treated or not with NAC were submitted to abdominal CO2 insufflation of 10 mmHg, at short and long periods of time of 1 and 3 h, respectively, and evaluated at 24, 72 h, and 1 wk after deinsufflation. Glomerular filtration rate (GFR) was measured by inulin clearance and oxidative stress was evaluated by serum thiobarbituric acid reactive substances (TBARS) Results No significant alterations in GFR were observed in normal animals submitted to the pneumoperitoneum of 1 h and evaluated after 24 h desufflation. With 3 h of pneumoperitoneum, a significant and progressive decrease in GFR occurred 24 and 72 h after desufflation with an increase in serum TBARS. GFR returned to normal levels a week later. In the NAC-treated rats, a complete protection against GFR drops was observed 24 and 72 h following 3 h of pneumoperitoneum associated with a decrease in TBARS. Conclusion These results suggest that NAC protects against acute kidney injury following prolonged pneumoperitoneum. These findings have significant clinical implications.
Abstract
Background
Recent insights have emphasized the importance of myocardial and systemic inflammation in Takotsubo Syndrome (TTS).
Objective
In a large registry of unselected patients, we sought ...to evaluate whether residual high inflammatory response (RHIR) could impact cardiovascular outcome after TTS.
Methods
Patients with TTS were retrospectively included between 2008 and 2018 in three general hospitals. 385 patients with TTS were split into three subgroups, according to tertiles of C-reactive protein (CRP) levels at discharge (CRP<5.2 mg/l, CRP range 5.2 to 19 mg/l, and CRP>19 mg/L). The primary endpoint was the impact of RHIR, defined as CRP>19 mg/L at discharge, on cardiac death or hospitalization for heart failure.
Results
Follow-up was obtained in 382 patients (99%) after a median of 747 days. RHIR patients were more likely to have a history of cancer or a physical trigger. Left ventricular ejection fraction (LVEF) at admission and at discharge were comparable between groups. By contrast, RHIR was associated with lower LVEF at follow-up (61.7 vs. 60.7 vs. 57.9%; p=0.004) and increased cardiac late mortality (0% vs. 0% vs. 10%; p=0.001). By multivariate Cox regression analysis, RHIR was an independent predictor of cardiac death or hospitalization for heart failure (hazard ratio: 1.97; 95% confidence interval: 1.11 to 3.49; p=0.02).
Conclusions
RHIR was associated with impaired LVEF recovery and was evidenced as an independent factor of cardiovascular events. All together these findings underline RHIR patients as a high-risk subgroup, to target in future clinical trials with specific therapies to attenuate RHIR.
Main results
Funding Acknowledgement
Type of funding source: Public grant(s) – National budget only. Main funding source(s): GERCA (Groupe pour l'Enseignement, la prévention et la Recherche Cardiovasculaire en Alsace)
Abstract
Introduction
Although there is an apparent rapid and spontaneous recovery of left ventricular ejection fraction (LVEF) in patients with takotsubo cardiomyopathy, recent studies have ...demonstrated the long-lasting functional impairment in those patients.
Purpose
We sought to evaluate the predictors of incomplete recovery in chronic phase and its impact on cardiovascular mortality after takotsubo cardiomyopathy.
Methods
Patients with takotsubo cardiomyopathy between 2008 and 2018 were retrospectively enrolled in three different institutions. Takotsubo cardiomyopathy was diagnosed according to the European Society of Cardiology Heart Failure Association criteria. After exclusion of in-hospital deaths, 407 patients were split into 2 subgroups according whether their LVEF were >50% (recovery group; n=333), or ≤50% (incomplete recovery group; n=74) at follow-up. The primary endpoint was the impact of incomplete recovery on cardiovascular mortality.
Results
Patients with incomplete recovery were more likely to be male, to have dementia, pacemaker, and supraventricular arrhythmia. C-reactive protein (CRP) levels on admission, at peak, and at discharge were significantly higher in patients with incomplete recovery. By multivariate logistic regression analysis, lower EF at discharge (odds ratio OR: 0.91; 95% confidence interval CI: 0.88 to 0.95; p<0.001) and higher CRP levels (OR: 5.56; 95% CI: 1.86 to 16.61; p<0.001) were independent predictors of incomplete recovery at follow-up. The cumulative event-free survival rate according to cardiovascular death was significantly lower in the incomplete recovery group (p<0.001; log-rank test).
Conclusions
We demonstrate that incomplete recovery after takotsubo cardiomyopathy is characterized by a residual systemic inflammation and an increased cardiac mortality at follow-up. Altogether, our findings underline patients with persistent inflammation as a high-risk subgroup, to target in future clinical trials with specific therapies to attenuate inflammation.
Funding Acknowledgement
Type of funding source: None
The aim of this study was to evaluate prospectively the clinical impact of routine transmission of CYP2C19 genotype in the management of acute ST-segment elevation myocardial infarction with primary ...percutaneous coronary intervention.
Response to clopidogrel differs widely among patients, notably because of CYP2C19 genetic polymorphisms.
CYP2C19 genotype (6 alleles) was determined centrally and communicated within 4.1 ± 1.9 days of primary percutaneous coronary intervention in 1,445 patients with ST-segment elevation myocardial infarction recruited at 57 centers in France. CYP2C19 metabolic status was predicted from genotype and served to adjust thienopyridine treatment. The primary endpoint was differences in 12-month outcomes (death, myocardial infarction, and stent thrombosis) between patients with the wild-type genotype or gain-of-function allele (class 1, n = 1,118) and those with loss-of-function (LOF) alleles (class 2, n = 272) who received optimized thienopyridine treatment.
Detection of LOF alleles resulted in adjustment of P2Y
inhibition in 85% of patients, with significantly higher use of prasugrel or double-dose clopidogrel. The primary endpoint did not differ between class 1 and class 2 patients (3.31% vs. 3.04%, respectively; p = 0.82). In contrast, carriers of LOF alleles without treatment adjustment had significantly worse outcomes (15.6%; p < 0.05). Bleeding rates were not different between groups.
In a real-world setting, a complete CYPC2C19 genotype can be mostly determined in <7 days using analysis of saliva deoxyribonucleic acid collected during the in-hospital phase among patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention. Genotype information led to stronger platelet inhibition treatment in the vast majority of LOF allele carriers and to similar clinical outcomes as in patients carrying the wild-type genotype or gain-of-function allele. (Genotyping Infarct Patients to Adjust and Normalize Thienopyridine Treatment GIANT; NCT01134380).
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