Profiles of urine and blood metabolomics in autism spectrum disorders

Early diagnosis and treatment for autism spectrum disorder (ASD) pose challenges. The current diagnostic approach for ASD is mainly clinical assessment of patient behaviors. Biomarkers-based identification of ASD would be useful for pediatricians. Currently, there is no specific treatment for ASD, and evidence for the efficacy of alternative treatments remains inconclusive. The prevalence of ASD is increasing, and it is becoming more urgent to find the pathogenesis of such disorder. Metabolomic studies have been used to deeply investigate the alteration of metabolic pathways, including those associated with ASD. Metabolomics is a promising tool for identifying potential biomarkers and possible pathogenesis of ASD. This review comprehensively summarizes and discusses the abnormal metabolic pathways in ASD children, as indicated by evidence from metabolomic studies in urine and blood. In addition, the targeted interventions that could correct the metabolomic profiles relating to the improvement of autistic behaviors in affected animals and humans have been included. The results revealed that the possible underlying pathophysiology of ASD were alterations of amino acids, reactive oxidative stress, neurotransmitters, and microbiota-gut-brain axis. The potential common pathways shared by animal and human studies related to the improvement of ASD symptoms after pharmacological interventions were mammalian-microbial co-metabolite, purine metabolism, and fatty acid oxidation. The content of this review may contribute to novel biomarkers for the early diagnosis of ASD and possible therapeutic paradigms.

     

Serial echocardiographic left ventricular ejection fraction measurements: A tool for detecting thalassemia major patients at risk of cardiac death

Cardiac damage remains a major cause of mortality among patients with thalassemia major. The detection of a lower cardiac magnetic resonance T2* (CMR-T2*) signal has been suggested as a powerful predictor of the subsequent development of heart failure. However, the lack of worldwide availability of CMR-T2* facilities prevents its widespread use for follow-up evaluations of cardiac function in thalassemia major patients, warranting the need to assess the utility of other possible procedures. In this setting, the determination of left ventricular ejection fraction (LVEF) offers an accurate and reproducible method for heart function evaluation. These findings suggest a reduction in LVEF ≥ 7%, over time, determined by 2-D echocardiography, may be considered a strong predictive tool for the detection of thalassemia major patients with increased risk of cardiac death. The reduction of LVEF ≥ 7% had higher (84.76%) predictive value. Finally, Kaplan–Meier survival curves of thalassemia major patients with LVEF ≥ 7% showed a statistically significant decreased probability of survival for heart disease (p = 0.0022).However, because of limitations related to the study design, such findings should be confirmed in a large long-term prospective clinical trial.     

Effect of rosiglitazone on cardiac electrophysiology, infarct size and mitochondrial function in ischaemia and reperfusion of swine and rat heart

Rosiglitazone, a peroxisome proliferator-activated receptor γ agonist, has been used to treat type 2 diabetes. Despite debates regarding its cardioprotection, the effects of rosiglitazone on cardiac electrophysiology are still unclear. This study determined the effect of rosiglitazone on ventricular fibrillation (VF) incidence, VF threshold (VFT), defibrillation threshold (DFT) and mitochondrial function during ischaemia and reperfusion. Twenty-six pigs were used. In each pig, either rosiglitazone (1 mg kg(-1)) or normal saline solution was administered intravenously for 60 min. Then, the left anterior descending coronary artery was ligated for 60 min and released to promote reperfusion for 120 min. The cardiac electrophysiological parameters were determined at the beginning of the study and during the ischaemia and reperfusion periods. The heart was removed, and the area at risk and infarct size in each heart were determined. Cardiac mitochondria were isolated for determination of mitochondrial function. Rosiglitazone did not improve the DFT and VFT during the ischaemia-reperfusion period. In the rosiglitazone group, the VF incidence was increased (58 versus 10%) and the time to the first occurrence of VF was decreased (3 ± 2 versus 19 ± 1 min) in comparison to the vehicle group (P < 0.05). However, the infarct size related to the area at risk in the rosiglitazone group was significantly decreased (P < 0.05). In the cardiac mitochondria, rosiglitazone did not alter the level of production of reactive oxygen species and could not prevent mitochondrial membrane potential changes. Rosiglitazone increased the propensity for VF, and could neither increase defibrillation efficacy nor improve cardiac mitochondrial function.     

Granulocyte colony-stimulating factor stabilizes cardiac electrophysiology and decreases infarct size during cardiac ischaemic/reperfusion in swine

Aim: Effects of granulocyte colony‐stimulating factor (G‐CSF) on cardiac electrophysiology during ischaemic/reperfusion (I/R) period are unclear. We hypothesized that G‐CSF stabilizes cardiac electrophysiology during I/R injury by prolonging the effective refractory period (ERP), increasing the ventricular fibrillation threshold (VFT) and decreasing the defibrillation threshold (DFT), and that the cardioprotection of G‐CSF is via preventing cardiac mitochondrial dysfunction. Methods: In intact‐heart protocol, pigs were infused with either G‐CSF or vehicle (n = 7 each group) without I/R induction. In I/R protocol, pigs were infused with G‐CSF (0.33 μg kg^?1 min^?1) or vehicle (n = 8 each group) for 30 min prior to a 45‐min left anterior descending artery occlusion and at reperfusion. Diastolic pacing threshold (DPT), ERP, VFT and DFT were determined in all pigs before and during I/R period. Rat’s isolated cardiac mitochondria were used to test the protective effect of G‐CSF (100 nm ) in H₂O₂‐induced mitochondrial oxidative damage. Results: Neither G‐CSF nor vehicle altered any parameter in intact‐heart pigs. During ischaemic period, G‐CSF significantly increased the DPT, ERP and VFT without altering the DFT. During reperfusion, G‐CSF continued to increase the DPT without altering other parameters. The infarct size was significantly decreased in the G‐CSF group, compared to the vehicle. G‐CSF could also prevent cardiac mitochondrial swelling, decrease ROS production, and prevent mitochondrial membrane depolarization. Conclusion: G‐CSF increases the DPT, ERP and VFT and reduces the infarct size, thus stabilizing the myocardial electrophysiology, and preventing fatal arrhythmia during I/R. The protective mechanism could be via its effect in preventing cardiac mitochondrial dysfunction.     

Effects of left ventricular function on the exercise capacity in patients with repaired tetralogy of Fallot

Background: Tissue Doppler imaging has been recently used to evaluate ventricular function. Peak oxygen uptake (V^?O₂peak) has been demonstrated as a predictor for death in adults with repaired tetralogy of Fallot (TOF). The aim of this study was to determine which Doppler parameters correlated with V^?O₂peak in patients with repaired TOF. Method and Results: Doppler echocardiography, tissue Doppler imaging, and exercise test were performed in 30 patients with TOF after surgical repair. In 30 patients with repaired TOF (median age 14 years, range 9–25 years), 11 patients (37%) were female. Seven patients (median age 12 years) had normal left ventricular diastolic function, whereas the rest of the patients were classified as diastolic dysfunction grade II (median age 15 years; n = 15) and III and IV (median age 18 years; n = 8). The oxygen uptake at anaerobic threshold (V^?O_2AT) and peak exercise in patients with left ventricular diastolic dysfunction was significantly lower than that in those with normal diastolic function. Also, V^?O_2AT and V^?O₂peak in patients with diastolic dysfunction grade III and IV were significantly lower than that in those with diastolic dysfunction grade II. Left ventricular early diastolic myocardial velocity was most closely correlated to V^?O₂peak (r = 0.51; P = 0.005). Peak early ventricular filling velocity to early diastolic myocardial velocity ratio was significantly correlated with V^?O₂peak (r =?0.50; P = 0.006). Conclusion: Left ventricular diastolic dysfunction is correlated with V^?O₂peak. Left ventricular diastolic function should be a routine echocardiographic assessment in patients with repaired TOF. (Echocardiography 2011;28:1019‐1024)     

Calcium channels and iron uptake into the heart

Iron overload can lead to iron deposits in many tissues,particularly in the heart.It has also been shown to be associated with elevated oxidative stress in tissues.Elevated cardiac iron deposits can lead to iron overload cardiomyopathy,a condition which provokes mortality due to heart failure in iron-overloaded patients.Currently,the mechanism of iron uptake into cardiomyocytes is still not clearly understood.Growing evidence suggests L-type Ca2+channels(LTCCs)as a possible pathway for ferrous iron(Fe2+)uptake into cardiomyocytes under iron overload conditions.Nevertheless,controversy still exists since some findings on pharmacological interventions and those using different cell types do not support LTCC’s role as a portal for iron uptake in cardiac cells.Recently,T-type Ca2+channels (TTCC)have been shown to play an important role in the diseased heart.Although TTCC and iron uptake in cardiomyocytes has not been investigated greatly,a recent finding indicated that TTCC could be an important portal in thalassemic hearts.In this review,comprehensive findings collected from previous studies as well as a discussion of the controversy regarding iron uptake mechanisms into cardiomyocytes via calcium channels are presented with the hope that understanding the cellular iron uptake mechanism in cardiomyocytes will lead to improved treatment and prevention strategies,particularly in iron-overloaded patients.     

Heart rate variability in beta‐thalassemia patients

Background: Cardiac failure remains the major cause of death in beta‐thalassemia major (TM). Reduced heart rate variability (HRV) is associated with a higher risk of arrhythmias after myocardial infarction and heart failure. We evaluated HRV in TM patients and its relationship with hemodynamics and echocardiographic parameters during a 6‐month follow‐up. Methods: Thirty‐four TM patients (19 ± 10 yr) and 20 healthy subjects (17 ± 6 yr) were evaluated. Hematologic, biochemical, echocardiographic and HRV parameters were determined at entry and at 6‐month follow‐up. Time and frequency domain HRV parameters were analyzed from 24‐h recorded electrocardiograms. All TM patients received blood transfusion and chelation therapy. Results: Both time and frequency domain HRV parameters were markedly reduced in TM patients, compared to the control. The significantly improved HRV was seen in correlation with higher hemoglobin (Hb) level when compared within TM group at different time point. No correlation was seen between HRV and serum ferritin, reactive oxygen species (ROS) and non‐transferrin bound iron (NTBI). Conclusion: HRV is depressed in TM patients. HRV was significantly correlated with Hb level, suggesting that anemia greatly influences the cardiac autonomic balance.