Microglial TLR4 Mediates White Matter Injury in a Combined Model of Diesel Exhaust Exposure and Cerebral Hypoperfusion.

BACKGROUND: Air pollution particulate matter exposure and chronic cerebral hypoperfusion (CCH) contribute to white matter toxicity through shared mechanisms of neuroinflammation, oxidative stress, and myelin breakdown. Prior studies showed that exposure of mice to joint particulate matter and CCH caused supra-additive injury to corpus callosum white matter. This study examines the role of TLR4 (toll-like receptor 4) signaling in mediating neurotoxicity and myelin damage observed in joint particulate matter and CCH exposures. METHODS: Experiments utilized a novel murine model of inducible monocyte/microglia-specific TLR4 knockout (i-mTLR4-ko). Bilateral carotid artery stenosis (BCAS) was induced surgically to model CCH. TLR4-intact (control) and i-mTLR4-ko mice were exposed to 8 weeks of either aerosolized diesel exhaust particulate (DEP) or filtered air (FA) in 8 experimental groups: (1) control/FA (n=10), (2) control/DEP (n=10), (3) control/FA+BCAS (n=9), (4) control/DEP+BCAS (n=10), (5) i-mTLR4-ko/FA (n=9), (6) i-mTLR4-ko/DEP (n=8), (7) i-mTLR4-ko/FA+BCAS (n=8), and (8) i-mTLR4-ko/DEP+BCAS (n=10). Corpus callosum levels of 4-hydroxynonenal, 8-Oxo-2'-deoxyguanosine, Iba-1 (ionized calcium-binding adapter molecule 1), and dMBP (degraded myelin basic protein) were assayed via immunofluorescence to measure oxidative stress, neuroinflammation, and myelin breakdown, respectively. RESULTS: Compared with control/FA mice, control/DEP+BCAS mice exhibited increased dMBP (41%; P<0.01), Iba-1 (51%; P<0.0001), 4-hydroxynonenal (100%; P<0.0001), and 8-Oxo-2'-deoxyguanosine (65%; P<0.05). I-mTLR4 knockout attenuated responses to DEP/BCAS for all markers. CONCLUSIONS: i-mTLR4-ko markedly reduced neuroinflammation and oxidative stress and attenuated white matter degradation following DEP and CCH exposures. This suggests a potential role for targeting TLR4 signaling in individuals with vascular cognitive impairment, particularly those exposed to substantial ambient air pollution.

Angiotensin II downregulates vascular endothelial cell hydrogen sulfide production by enhancing cystathionine γ-lyase degradation through ROS-activated ubiquitination pathway.

The interactions between vasoactive peptides and gasotransmitters have attracted considerable attention from scientists. However, the impact of angiotensin II (AngII) on the endogenous hydrogen sulfide/cystathionine γ-lyase (H2S/CSE) pathway in vascular endothelial cells remains unclear. In this study, we found, for the first time, that AngII downregulated the endogenous H2S/CSE pathway in a time-dependent manner. Mechanistically, AngII accelerated the degradation of the CSE protein and shortened its half-life in endothelial cells. AngII significantly induced Lys48 (K48)-linked CSE ubiquitination and subsequent CSE degradation but did not affect Lys63 (K63)-linked CSE ubiquitination in vascular endothelial cells. Treatment with the proteasome inhibitor MG132 and mutation of Lys48 to Arg in ubiquitin successfully blunted the inhibitory effects of AngII on the endogenous H2S/CSE pathway in vascular endothelial cells. Furthermore, we found that superoxide anion levels were significantly increased in AngII-treated endothelial cells compared with controls and that the ROS scavenger N-acetyl-l-cysteine (NAC) significantly abolished CSE ubiquitination. Taken together, our data suggested that AngII inhibited endogenous H2S generation through ubiquitination-mediated CSE degradation via the ROS pathway in vascular endothelial cells.

Frequency Domain Indices of Heart Rate Variability are Useful for Differentiating Vasovagal Syncope and Postural Tachycardia Syndrome in Children.

OBJECTIVE: To explore the value of frequency domain indices of heart rate variability (HRV) in the differential diagnosis between pediatric vasovagal syncope and postural tachycardia syndrome (POTS). STUDY DESIGN: Eighty-five patients aged 7-16 years with either vasovagal syncope or POTS were enrolled in the experimental group; 18 healthy children served as controls. Holter electrocardiography was used to detect HRV frequency-domain indices in patients with vasovagal syncope, patients with POTS, and control subjects. The differences in HRV indices were compared between the vasovagal syncope and POTS groups. The receiver operating characteristic (ROC) curve was calculated to analyze the predictive value of HRV for the differential diagnosis between vasovagal syncope and POTS in children. In addition, 37 children aged 7-17 years with either vasovagal syncope or POTS were recruited as an external validation group. RESULTS: The daytime ultra-low frequency (dULF), nighttime ULF (nULF), daytime very low frequency (dVLF), and nighttime VLF (nVLF) were higher in the vasovagal syncope group compared with the POTS group (P < .01 for dULF, dVLF, and nVLF; P < .05 for nULF). The dULF, nULF, dVLF, and nVLF yielded a sensitivity of 73.3%, 71.1%, 68.9%, and 62.2%, respectively, and a specificity of 72.5%, 62.5%, 60.0%, and 60.0%, respectively, to differentiate vasovagal syncope from POTS. The external validation with clinical diagnostic standard showed that a dULF cutoff value of 36.2 ms2 for differentiating POTS from vasovagal syncope yielded a sensitivity of 71.4%, a specificity of 75.0%, and an accuracy of 73.0%. CONCLUSION: dULF may be a useful measure for the differential diagnosis between vasovagal syncope and POTS in adolescents.

Endogenous hydrogen sulfide sulfhydrates IKKß at cysteine 179 to control pulmonary artery endothelial cell inflammation.

BACKGROUND: Pulmonary artery endothelial cell (PAEC) inflammation is a critical event in the development of pulmonary arterial hypertension (PAH). However, the pathogenesis of PAEC inflammation remains unclear. METHODS: Purified recombinant human inhibitor of κB kinase subunit ß (IKKß) protein, human PAECs and monocrotaline-induced pulmonary hypertensive rats were employed in the study. Site-directed mutagenesis, gene knockdown or overexpression were conducted to manipulate the expression or activity of a target protein. RESULTS: We showed that hydrogen sulfide (H2S) inhibited IKKß activation in the cell model of human PAEC inflammation induced by monocrotaline pyrrole-stimulation or knockdown of cystathionine γ-lyase (CSE), an H2S generating enzyme. Mechanistically, H2S was proved to inhibit IKKß activity directly via sulfhydrating IKKß at cysteinyl residue 179 (C179) in purified recombinant IKKß protein in vitro, whereas thiol reductant dithiothreitol (DTT) reversed H2S-induced IKKß inactivation. Furthermore, to demonstrate the significance of IKKß sulfhydration by H2S in the development of PAEC inflammation, we mutated C179 to serine (C179S) in IKKß. In purified IKKß protein, C179S mutation of IKKß abolished H2S-induced IKKß sulfhydration and the subsequent IKKß inactivation. In human PAECs, C179S mutation of IKKß blocked H2S-inhibited IKKß activation and PAEC inflammatory response. In pulmonary hypertensive rats, C179S mutation of IKKß abolished the inhibitory effect of H2S on IKKß activation and pulmonary vascular inflammation and remodeling. CONCLUSION: Collectively, our in vivo and in vitro findings demonstrated, for the first time, that endogenous H2S directly inactivated IKKß via sulfhydrating IKKß at Cys179 to inhibit nuclear factor-κB (NF-κB) pathway activation and thereby control PAEC inflammation in PAH.

Electrocardiography-Derived Predictors for Therapeutic Response to Treatment in Children with Postural Tachycardia Syndrome.

OBJECTIVE: To explore whether electrocardiography (ECG) variables could be used to predict responses to physical treatment in children with postural tachycardia syndrome (POTS). STUDY DESIGN: Forty children with POTS and 32 healthy controls were enrolled in this study. General information and hemodynamic and supine ECG variables, including QT interval dispersion (QTd), were collected. The children with POTS received physical treatment and 3 months of follow-up. A receiver-operating characteristic curve was used to evaluate the value of ECG variables for predicting the effectiveness of physical treatment. RESULTS: Compared with the healthy children, the children with POTS had longer baseline QTd and heart rate (HR)-corrected QTd (QTcd), but shorter minimum QT intervals (QTmin) and minimum HR-corrected QT intervals (P < .05). In children with POTS, responders to physical treatment had a longer baseline time between QRS complexes (RR) interval of minimum QT interval and a longer QTcd compared with nonresponders. A longer QTcd was a significant risk factor for the presence of POTS (OR, 1.022; P = .02) and for undesirable responses to physical treatment in children with POTS (OR, 1.044; P = .03). Baseline QTcd was positively correlated with the HR elevation from supine to upright seen in children with POTS (r = 0.348; P = .003). Receiver operating characteristic curve analysis demonstrated an area under the curve of 0.73, and using 43.0 msec as a cutoff of QTcd yielded a sensitivity of 90% and a specificity of 60%. CONCLUSION: QTcd might be useful for predicting the effectiveness of physical treatment for POTS in children.

Magnetic resonance imaging of white matter response to diesel exhaust particles.

Air pollution is associated with risks of dementia and accelerated cognitive decline. Rodent air pollution models have shown white matter vulnerability. This study uses diffusion tensor imaging (DTI) to quantify changes to white matter microstructure and tractography in multiple myelinated regions after exposure to diesel exhaust particulate (DEP). Adult C57BL/6 male mice were exposed to re-aerosolized DEP (NIST SRM 2975) at a concentration of 100 ug/m3 for 200 hours. Ex-vivo MRI analysis and fractional anisotropy (FA)-aided white matter tractography were conducted to study the effect of DEP exposure on the brain white matter tracts. Immunohistochemistry was used to assess myelin and axonal structure. DEP exposure for 8 weeks altered myelin composition in multiple regions. Diffusion tensor imaging (DTI) showed decreased FA in the corpus callosum (30%), external capsule (15%), internal capsule (15%), and cingulum (31 %). Separate immunohistochemistry analyses confirmed prior findings. Myelin basic protein (MBP) was decreased (corpus callosum: 28%, external capsule: 29%), and degraded MPB increased (corpus callosum: 32%, external capsule: 53%) in the DEP group. White matter is highly susceptible to chronic DEP exposure. This study demonstrates the utility of DTI as a neuroanatomical tool in the context of air pollution and white matter myelin vulnerability.

Hydrogen sulfide regulates insulin secretion and insulin resistance in diabetes mellitus, a new promising target for diabetes mellitus treatment? A review.

BACKGROUND: Insulin resistance and impaired insulin secretion lead to disorders of glucose metabolism, which contributes to the development of diabetes. Hydrogen sulfide (H2S), a novel gasotransmitter, is found to play important roles in regulation of glucose metabolism homeostasis. AIM OF REVIEW: This study aimed to summarize and discuss current data about the function of H2S in insulin secretion and insulin resistance regulation as well as the underlying mechanisms. KEY SCIENTIFIC CONCEPTS OF REVIEW: H2S could be endogenously produced in islet ß cells, liver, adipose, skeletal muscles, and the hypothalamus, and regulates local and systemic glucose metabolism. It is reported that H2S suppresses insulin secretion, promotes or reduces the apoptosis of islet ß cells. It plays important roles in the regulation of insulin sensitivity in insulin responsive tissues. H2S inhibits glucose uptake and glycogen storage, and promotes or inhibits gluconeogenesis, mitochondrial biogenesis and mitochondrial bioenergetics in the liver. In adipose tissue, several investigators indicated that H2S promoted glucose uptake in adipocytes, while other studies reported that H2S inhibits this process. H2S has also been shown to promote adipogenesis, inhibit lipolysis, and regulate adiponectin and MCP-1 secretion from adipocytes. In skeletal muscle, H2S increases glucose uptake and improves insulin sensitivity. It is also observed that H2S modulates circadian-clock genes in muscle. Hypothalamic CBS/H2S pathway reduces obesity and improves insulin sensitivity via the brain-adipose interaction. Most studies indicated plasma H2S levels decreased in diabetic patients. However, the mechanisms by which H2S regulates systemic glucose metabolism remain unclear. Whether H2S acts as a new promising target for diabetes mellitus treatment merits further studies.

Hydrogen sulfide and vascular regulation - An update.

BACKGROUND: Hydrogen sulfide (H2S) is considered to be the third gasotransmitter after carbon monoxide (CO) and nitric oxide (NO). It plays an important role in the regulation of vascular homeostasis. Vascular remodeling have has proved to be related to the impaired H2S generation. AIM OF REVIEW: This study aimed to summarize and discuss current data about the function of H2S in vascular physiology and pathophysiology as well as the underlying mechanisms. KEY SCIENTIFIC CONCEPTS OF REVIEW: Endogenous hydrogen sulfide (H2S) as a third gasotransmitter is primarily generated by the enzymatic pathways and regulated by several metabolic pathways. H2S as a physiologic vascular regulator, inhibits proliferation, regulates its apoptosis and autophagy of vascular cells and controls the vascular tone. Accumulating evidence shows that the downregulation of H2S pathway is involved in the pathogenesis of a variety of vascular diseases, such as hypertension, atherosclerosis and pulmonary hypertension. Alternatively, H2S supplementation may greatly help to prevent the progression of the vascular diseases by regulating vascular tone, inhibiting vascular inflammation, protecting against oxidative stress and proliferation, and modulating vascular cell apoptosis, which has been verified in animal and cell experiments and even in the clinical investigation. Besides, H2S system and angiotensin-converting enzyme (ACE) inhibitors play a vital role in alleviating ischemic heart disease and left ventricular dysfunction. Notably, sulfhydryl-containing ACEI inhibitor zofenopril is superior to other ACE inhibitors due to its capability of H2S releasing, in addition to ACE inhibition. The design and application of novel H2S donors have significant clinical implications in the treatment of vascular-related diseases. However, further research regarding the role of H2S in vascular physiology and pathophysiology is required.

Endogenous sulfur dioxide is a novel inhibitor of hypoxia-induced mast cell degranulation.

Introduction: Mast cell (MC) degranulation is an important step in the pathogenesis of inflammatory reactions and allergies; however, the mechanism of stabilizing MC membranes to reduce their degranulation is unclear. Methods: SO2 content in MC culture supernatant was measured by HPLC-FD. The protein and mRNA expressions of the key enzymes aspartate aminotransferase 1 (AAT1) and AAT2 and intracellular AAT activity were detected. The cAMP level in MCs was detected by immunofluorescence and ELISA. The release rate of MC degranulation marker ß-hexosaminidase was measured. The expression of AAT1 and cAMP, the MC accumulation and degranulation in lung tissues were detected. Objectives: To exam whether an endogenous sulfur dioxide (SO2) pathway exists in MCs and if it serves as a novel endogenous MC stabilizer. Results: We firstly show the existence of the endogenous SO2/AAT pathway in MCs. Moreover, when AAT1 was knocked down in MCs, MC degranulation was significantly increased, and could be rescued by a SO2 donor. Mechanistically, AAT1 knockdown decreased the cyclic adenosine monophosphate (cAMP) content in MCs, while SO2 prevented this reduction in a dose-independent manner. Pretreatment with the cAMP-synthesizing agonist forskolin or the cAMP degradation inhibitor IBMX significantly blocked the increase in AAT1 knockdown-induced MC degranulation. Furthermore, in hypoxia-stimulated MCs, AAT1 protein expression and SO2 production were markedly down regulated, and MC degranulation was activated, which were blunted by AAT1 overexpression. The cAMP synthesis inhibitor SQ22536 disrupted the suppressive effect of AAT1 overexpression on hypoxia-induced MC degranulation. In a hypoxic environment, mRNA and protein expression of AAT1 was significantly reduced in lung tissues of rats. Supplementation of SO2 elevated the cAMP level and reduced perivascular MC accumulation and degranulation in lung tissues of rats exposed to a hypoxic environment in vivo. Conclusion: SO2 serves as an endogenous MC stabilizer via upregulating the cAMP pathway under hypoxic circumstance.

Endogenous SO2-dependent Smad3 redox modification controls vascular remodeling.

Sulfur dioxide (SO2) has emerged as a physiological relevant signaling molecule that plays a prominent role in regulating vascular functions. However, molecular mechanisms whereby SO2 influences its upper-stream targets have been elusive. Here we show that SO2 may mediate conversion of hydrogen peroxide (H2O2) to a more potent oxidant, peroxymonosulfite, providing a pathway for activation of H2O2 to convert the thiol group of protein cysteine residues to a sulfenic acid group, aka cysteine sulfenylation. By using site-centric chemoproteomics, we quantified >1000 sulfenylation events in vascular smooth muscle cells in response to exogenous SO2. Notably, ~42% of these sulfenylated cysteines are dynamically regulated by SO2, among which is cysteine-64 of Smad3 (Mothers against decapentaplegic homolog 3), a key transcriptional modulator of transforming growth factor ß signaling. Sulfenylation of Smad3 at cysteine-64 inhibits its DNA binding activity, while mutation of this site attenuates the protective effects of SO2 on angiotensin II-induced vascular remodeling and hypertension. Taken together, our findings highlight the important role of SO2 in vascular pathophysiology through a redox-dependent mechanism.

Body mass index is a promising predictor of response to oral rehydration saline in children with vasovagal syncope.

BACKGROUND: Vasovagal syncope (VVS) greatly impairs quality of life. The therapeutic efficacy of oral rehydration saline (ORS) for unselected VVS patients is not satisfactory due to the diverse mechanisms of the disease. Body mass index (BMI) was demonstrated to reflect blood volume to a certain extent. Therefore, the present study explored the capability of BMI to predict the therapeutic response of children with VVS to ORS treatment. METHODS: Seventy-four children with VVS who visited the Syncope Unit of Pediatrics at Peking University First Hospital from November 2010 to June 2019 receiving ORS treatment were enrolled for this retrospective case-control study. A comparison of demographic, clinical, and hemodynamic characteristics was performed between responders and non-responders. The correlation between baseline BMI and response time was analyzed. To determine the value of baseline BMI in predicting the therapeutic efficacy of ORS in children with VVS, a receiver operating characteristic curve analysis was performed. RESULTS: Fifty-two children were identified as responders, and the remaining 22 children were identified as non-responders. The baseline BMI of the responders was much lower than that of the non-responders (16.4 [15.5, 17.8] kg/m2vs. 20.7 ±e6 kg/m2, P < 0.001), and baseline BMI was positively correlated with response time in the head-up tilt test after adjusting for sex (r = 0.256, 95% confidence interval [CI]: 0.067-0.439, P = 0.029). The area under the receiver operating characteristic curve of baseline BMI was 0.818 (95% CI: 0.704-0.932, P < 0.001), and an optimal cut-off value of 18.9 kg/m2 yielded a sensitivity of 83% and a specificity of 73% to predict the efficacy of ORS in VVS. CONCLUSION: Prior to treatment, baseline BMI is a promising predictor of response to ORS in children with VVS.

Reduced 24-h Sodium Excretion Is Associated With a Disturbed Plasma Acylcarnitine Profile in Vasovagal Syncope Children: A Pilot Study.

Objective: To investigate if the low sodium intake is associated with the plasma carnitine and acylcarnitine profile in children with vasovagal syncope (VVS). Materials and Methods: Twenty-six children suffering from VVS were recruited in the present study and divided into a group of low urinary sodium excretion or a group of normal urinary sodium excretion according to the excretion of 24-h urinary sodium <3 or 3-6 g, respectively. The excretion of 24-h urinary sodium was detected with ion-selective electrode approach. Plasma carnitine and acylcarnitine concentrations were measured with tandem mass spectrometry. Each participant completed the head-up tilt test. The demographics, clinical characteristics, hemodynamic parameters and plasma carnitine and acylcarnitine concentrations were compared between the two groups. A bivariate correlation between plasma acylcarnitine profiles and the excretion of 24-h urinary sodium was conducted with Spearman's correlation coefficients. Results: Of the enrolled VVS patients, 14 patients were assigned to the group of low urinary sodium excretion and the remaining 12 patients were assigned to the group of normal urinary sodium excretion. Symptoms of fatigue were more prevalent in the group of low urinary sodium excretion than in the group of normal urinary sodium excretion (p = 0.009). Aside from fatigue, no other differences in the demographics, clinical characteristics or hemodynamic parameters during the head-up tilt test were found between the two groups (p > 0.05). Concentrations of plasma tiglylcarnitine (C5:1), hydroxyhexadecanoylcarnitine (C16OH), hydroxyoctadecanoylcarnitine (C18OH), and carnitine C22 were significantly higher in the group of low urinary sodium excretion than in the group of normal urinary sodium excretion (all p-values = 0.048); moreover, they were all negatively correlated with 24-h urinary sodium levels (all p-values = 0.016). There were no differences between the two groups in other acylcarnitines or free carnitine. Conclusions: Reduced excretion of 24-h urinary sodium is associated with a disturbed plasma acylcarnitine profile in children with VVS. The findings suggest that restricted sodium intake-induced disturbance of plasma acylcarnitines and related cellular energy metabolism might be involved in the pathogenesis of VVS in children.

Endothelin-1 Downregulates Sulfur Dioxide/Aspartate Aminotransferase Pathway via Reactive Oxygen Species to Promote the Proliferation and Migration of Vascular Smooth Muscle Cells.

The regulatory mechanisms for proliferation and migration of vascular smooth muscle cells have not yet been clear. The present study was designed to investigate whether and how endothelin-1 (ET-1) impacted the generation of endogenous sulfur dioxide (SO2) in rat vascular smooth muscle cell (VSMC) proliferation and migration. Primary VSMCs and purified aspartate aminotransferase (AAT) protein were used in this study. We found that in the presence of ET-1, the expression of PCNA and Ki-67 was upregulated and the migration of VSMCs was promoted, while the AAT activity and SO2 levels in VSMCs were reduced without any changes in AAT1 and AAT2 expression. SO2 supplementation successfully prevented the ET-1-facilitated expression of PCNA and Ki-67 and the migration of VSMCs. Interestingly, ET-1 significantly increased reactive oxygen species (ROS) production in association with SO2/AAT pathway downregulation in VSMCs compared with controls, while the ROS scavenger N-acetyl-L-cysteine (NAC) and the antioxidant glutathione (GSH) significantly abolished the ET-1-stimulated downregulation of the SO2/AAT pathway. Moreover, the AAT activity was reduced in purified protein after the treatment for 2 h. However, NAC and GSH blocked the hydrogen peroxide-induced AAT activity reduction. In conclusion, our results suggest that ET-1 results in the downregulation of the endogenous SO2/AAT pathway via ROS generation to enhance the proliferation and migration of VSMCs.

Bosentan for Treatment of Pediatric Idiopathic Pulmonary Arterial Hypertension: State-of-the-Art.

Idiopathic pulmonary arterial hypertension (IPAH) is a complex disease associated with progressive deterioration. Targeted therapy for IPAH has improved in the last several decades. However, there remain many challenges to current treatment of children with IPAH, including poor prognosis and a median survival of 0.8 years. Endothelin-1 (ET-1) appears to be a key mediator in the pathogenesis of IPAH, with elevated concentrations in the plasma. Bosentan, an endothelin receptor antagonist, has been confirmed in Food and Drug Administration (FDA) to effectively treat IPAH when administered in recent studies. This review focuses on related studies and advance of bosentan in the treatment of IPAH in children.

Corticosteroids and Intravenous Immunoglobulin in Pediatric Myocarditis: A Meta-Analysis.

Background: The efficacy of corticosteroids and intravenous immunoglobulin (IVIG) in pediatric myocarditis remains controversial. Objectives: The authors performed a meta-analysis to assess the therapeutic efficacy of corticosteroids and IVIG in children with myocarditis. Methods: We retrieved the trials on corticosteroids and IVIG therapy, respectively, in pediatric myocarditis from nine databases up to December 2018. Statistical analysis was performed using Review Manager 5.3. Results: Our analysis included 8 studies and 334 pediatric patients. The data demonstrated that children receiving corticosteroids showed no significant improvement on left ventricular ejection fraction (LVEF) from 1 to 8 month-follow-up (MD = 5.17%, 95% CI = -0.26% to 10.60%, P = 0.06), and no significant improvement in death or heart transplantation incidence at the end of follow-up (OR = 1.33, 95% CI = 0.27-6.70, P = 0.73). However, children receiving IVIG revealed a statistically remarkable increase in LVEF at a follow-up over the course of 6 months to 1 year (MD = 18.91%, 95% CI = 11.74-26.08%, P < 0.00001), and a decrease in death or heart transplantation at the end of follow-up (OR = 0.31, 95% CI = 0.12-0.75, P = 0.01). Further comparisons showed that the mortality and heart transplantation rate of children with myocarditis treated with IVIG were significantly lower than those with corticosteroid therapy (t' = 11.336, P < 0.001). Conclusions: IVIG might be beneficial to improve LVEF and survival for myocarditis in children. However, the present evidence does not support corticosteroids as superior to conventional therapy in children with myocarditis. Further randomized controlled trials with a larger sample size are required.

Differential Diagnostic Models Between Vasovagal Syncope and Psychogenic Pseudosyncope in Children.

Objective: We aimed to establish useful models for the clinical differential diagnosis between vasovagal syncope (VVS) and psychogenic pseudosyncope (PPS). Methods: This bicentric study included 176 patients (150 VVS and 26 PPS cases) for model development. Based on the results of univariate and multivariate analyses, a logistic regression model and a scoring model were established and their abilities to differentiate VVS from PPS were tested. Another 78 patients (53 VVS and 25 PPS) were used for external validation. Results: In the logistic regression model, the outcome indicated that the QT-dispersion (QTd) (P < 0.001), syncope duration (P < 0.001), and upright posture (P < 0.001) acted as independent factors for the differentiation of VVS from PPS, which generated an area under the curve (AUC) of 0.892. A cutoff value of 0.234 yielded a sensitivity and specificity of 89.3 and 80.8%, respectively, for the differentiation between VVS and PPS in the logistic regression model. In the scoring model which consists of three variables, a cutoff score of three points yielded a sensitivity and specificity of 91.3 and 76.9%, respectively, with an AUC of 0.909. The external validation test indicated that the negative and positive predictive values of the scoring model were 78.8 and 91.7%, respectively, and the accuracy was 80.8%. Conclusion: The scoring model consisting of three variables is an easy-to-perform, inexpensive, and non-invasive measure for initial differential diagnosis between VVS and PPS.

Sulfur Dioxide Activates Cl-/HCO3 - Exchanger via Sulphenylating AE2 to Reduce Intracellular pH in Vascular Smooth Muscle Cells.

Sulfur dioxide (SO2) is a colorless and irritating gas. Recent studies indicate that SO2 acts as the gas signal molecule and inhibits vascular smooth muscle cell (VSMC) proliferation. Cell proliferation depends on intracellular pH (pHi). Transmembrane cystein mutation of Na+- independent Cl-/HCO3 - exchanger (anion exchanger, AE) affects pHi. However, whether SO2 inhibits VSMC proliferation by reducing pHi is still unknown. Here, we investigated whether SO2 reduced pHi to inhibit the proliferation of VSMCs and explore its molecular mechanisms. Within a range of 50-200 µM, SO2 was found to lower the pHi in VSMCs. Concurrently, NH4Cl pre-perfusion showed that SO2 significantly activated AE, whereas the AE inhibitor 4,4'-diisothiocyanatostilbene- 2,20-disulfonic acid (DIDS) significantly attenuated the effect of SO2 on pHi in VSMCs. While 200 µM SO2 sulphenylated AE2, while dithiothreitol (DTT) blocked the sulphenylation of AE2 and subsequent AE activation by SO2, thereby restoring the pHi in VSMCs. Furthermore, DIDS pretreatment eliminated SO2-induced inhibition of PDGF-BB-stimulated VSMC proliferation. We report for the first time that SO2 inhibits VSMC proliferation in part by direct activation of the AE via posttranslational sulphenylation and induction of intracellular acidification.

Heart Rate Variability Predicts Therapeutic Response to Metoprolol in Children With Postural Tachycardia Syndrome.

PURPOSE: To improve the metoprolol therapeutic effectiveness, we aimed to explore whether baseline heart rate variability (HRV) indicators before metoprolol treatment were useful for predicting its efficacy for postural tachycardia syndrome (POTS). METHODS: We recruited 45 children with POTS who received metoprolol and 17 healthy controls. All children underwent a standing test or basic head-up tilt test and 24-h dynamic electrocardiography before treatment. After 3 months of metoprolol, therapeutic responsiveness was evaluated. The usefulness of baseline HRV parameters in predicting the effectiveness of metoprolol was studied and the long-term cumulative symptom rate was analyzed. RESULTS: The baseline HRV frequency domain indicators for power, ultra-low frequency, very-low frequency, low frequency (LF), high frequency (HF), and total power (TP) as well as time domain indicators were significantly lower for responders than non-responders to metoprolol; however, low-frequency normalized units and LF/HF ratio were markedly greater for responders than non-responders. On series-parallel analysis, combined baseline triangular (TR) index ≤ 33.7 and standard deviation of all normal-to-normal intervals (SDNN) index ≤ 79.0 ms as cut-off values yielded sensitivity, specificity and accuracy of 85.3, 81.8, and 84.4%, respectively, to predict therapeutic responsiveness to metoprolol. On long-term follow-up, the cumulative symptom rate was significantly higher with TR index > 33.7 and SDNN index ≤ 79.0 ms, TR index ≤ 33.7 and SDNN index > 79.0 ms or TR index > 33.7 and SDNN index > 79.0 ms than TR index ≤ 33.7 and SDNN index ≤ 79.0 ms (P < 0.05). CONCLUSION: Combined TR index ≤ 33.7 and SDNN index ≤ 79.0 ms were useful preliminary measures to predict therapeutic response to metoprolol in pediatric POTS.

Gut microbiota analysis and its significance in vasovagal syncope in children.

BACKGROUND: Vasovagal syncope (VVS) is common in children and greatly affect both physical and mental health. But the mechanisms have not been completely explained. This study was designed to analyze the gut microbiota in children with VVS and explore its clinical significance. METHODS: Fecal samples from 20 VVS children and 20 matched controls were collected, and the microbiota were analyzed by 16S rRNA gene sequencing. The diversity and microbiota compositions of the VVS cases and controls were compared with the independent sample t test or Mann-Whitney U test. The correlation between the predominant bacteria and clinical symptoms was analyzed using Pearson or Spearman correlation test. RESULTS: No significant differences in diversity were evident between VVS and controls (P > 0.05). At the family level, the relative abundance of Ruminococcaceae was significantly higher in VVS children than in controls (median [Q1, Q3]: 22.10% [16.89%, 27.36%] vs. 13.92% [10.31%, 20.18%], Z = -2.40, P < 0.05), and LEfSe analysis revealed Ruminococcaceae as a discriminative feature (linear discriminant analysis [LDA] score > 4, P < 0.05). The relative abundance of Ruminococcaceae in VVS patients was positively correlated with the frequency of syncope (r = 0.616, P < 0.01). In terms of its correlation with hemodynamics, we showed that relative abundance of Ruminococcaceae was negatively correlated with the systolic and diastolic pressure reduction at the positive response in head-up tilt test (HUTT; r = -0.489 and -0.448, all P < 0.05), but was positively correlated with the mean pressure drop and decline rate (r = 0.489 and 0.467, all P < 0.05) as well as diastolic pressure drop and decline rate at the HUTT positive response (r = 0.579 and 0.589, all P < 0.01) in VVS patients. CONCLUSION: Ruminococcaceae was the predominant gut bacteria and was associated with the clinical symptoms and hemodynamics of VVS, suggesting that gut microbiota might be involved in the development of VVS.