Tumor-Associated Macrophages Correlate With Prognosis in Medulloblastoma.

Purpose: Macrophage polarization plays an essential role in the tumor microenvironment of brain tumors. However, the role of tumor-associated macrophages (TAMs) in medulloblastoma still remains controversial. Thus, we investigated the distribution of macrophages in medulloblastoma tissues and analyzed the association of TAM recruitment and medulloblastoma patients' outcomes. Methods: We obtained a total of 71 paraffin sections from patients with medulloblastoma, and detected the activated phenotype (M1/M2) by monoclonal antibodies for CD68, HLA-DR and CD163 with multiple fluorescence immunohistochemistry method. The number of polarized macrophages was quantified using the InForm software. Outcomes were analyzed according to clinical data and quantified macrophage data. Results: The study revealed that TAMs were significantly higher in sonic hedgehog (SHH) medulloblastoma than in other subgroups, and M1 macrophages in metastatic group were significantly higher than those in non-metastatic group. A Kaplan-Meier survival analysis and multivariate Cox regression model showed the correlation of high percentage of total macrophages (P = 0.038, HR = 0.241) and M1 macrophages (P = 0.034, HR = 0.333) with good 5-year progression-free survival (PFS); however, M2 macrophages had no correlation with survival of medulloblastoma patients (P> 0.05). Conclusion: High percentage of total macrophages and M1 macrophages are correlated with good outcome of medulloblastoma patients. TAMs might be a target of therapy.

Role of hydrogen sulfide in sulfur dioxide production and vascular regulation.

Both hydrogen sulfide (H2S) and sulfur dioxide (SO2) are produced endogenously from the mammalian metabolic pathway of sulfur-containing amino acids and play important roles in several vascular diseases. However, their interaction during the control of vascular function has not been fully clear. Here, we investigated the potential role of H2S in SO2 production and vascular regulation in vivo and in vitro. Wistar rats were divided into the vehicle, SO2, DL-propargylglycine (PPG) + SO2, ß-cyano-L-alanine (BCA) + SO2 and sodium hydrosulfide (NaHS) + SO2 groups. SO2 donor was administered with or without pre-administration of PPG, BCA or NaHS for 30 min after blood pressure was stabilized for 1 h, and then, the change in blood pressure was detected by catheterization via the common carotid artery. Rat plasma SO2 and H2S concentrations were measured by high performance liquid chromatography and sensitive sulfur electrode, respectively. The isolated aortic rings were prepared for the measurement of changes in vasorelaxation stimulated by SO2 after PPG, BCA or NaHS pre-incubation. Results showed that the intravenous injection of SO2 donors caused transient hypotension in rats compared with vehicle group. After PPG or BCA pretreatment, the plasma H2S content decreased but the SO2 content increased markedly, and the hypotensive effect of SO2 was significantly enhanced. Conversely, NaHS pretreatment upregulated the plasma H2S content but reduced SO2 content, and attenuated the hypotensive effect of SO2. After PPG or BCA pre-incubation, the vasorelaxation response to SO2 was enhanced significantly. While NaHS pre-administration weakened the SO2-induced relaxation in aortic rings. In conclusion, our in vivo and in vitro data indicate that H2S negatively controls the plasma content of SO2 and the vasorelaxant effect under physiological conditions.

Exploring genetic alterations in circulating tumor DNA from cerebrospinal fluid of pediatric medulloblastoma.

Medulloblastoma (MB) is the most common type of brain malignancy in children. Molecular profiling has become an important component to select patients for therapeutic approaches, allowing for personalized therapy. In this study, we successfully identified detectable levels of tumor-derived cell-free DNA (cfDNA) in cerebrospinal fluid (CSF) samples of patients with MB. Furthermore, cfDNA from CSF can interrogate for tumor-associated molecular clues. MB-associated alterations from CSF, tumor, and post-chemotherapy plasma were compared by deep sequencing on next-generation sequencing platform. Shared alterations exist between CSF and matched tumor tissues. More alternations were detected in circulating tumor DNA from CSF than those in genomic DNA from primary tumor. It was feasible to detect MB-associated mutations in plasma of patients treated with chemotherapy. Collectively, CSF supernatant can be used to monitor genomic alterations, as a superior technique as long as tumor-derived cfDNA can be isolated from CSF successfully.

[Survival of children with recurrent medulloblastoma undergoing sequential therapy: an analysis of 101 cases].

OBJECTIVE: To study the clinical features of children with recurrent medulloblastoma (MB) and treatment regimens. METHODS: A retrospective analysis was performed on 101 children with recurrent MB who were admitted to the hospital from August 1, 2011 to July 31, 2017. The children were followed up to July 31, 2020. The Kaplan-Meier method was used for survival analysis. The Cox regression model was used for multivariate regression analysis. RESULTS: Of the 101 children, 95 underwent remission induction therapy, among whom 51 had response, resulting in a response rate of 54%. The median overall survival (OS) time after recurrence was 13 months, and the 1-, 3-, and 5-year OS rates were 50.5%±5.0%, 19.8%±4.0%, and 10%±3.3% respectively. There was no significant difference in the 5-year OS rate between the children with different ages (< 3 years or 3-18 years), sexes, pathological types, or Change stages, between the children with or without radiotherapy before recurrence or re-irradiation after recurrence, and between the children with different times to recurrence (< 12 months or ≥ 12 months after surgery) (P > 0.05). There were significant differences in the 5-year OS rate between the children with or without reoperation after recurrence and between the children with different recurrence sites (P < 0.05). The children with reoperation after recurrence had a significantly longer survival time than those without reoperation (P=0.007), and the risk of death in children undergoing reoperation after recurrence was 0.389 times (95% confidence interval:0.196-0.774) that in children who did not undergo such reoperation. CONCLUSIONS: As for the recurrence of MB, although remission induction therapy again can achieve remission, such children still have a short survival time. Only reoperation can significantly prolong survival time, and therefore, early reoperation can be considered to improve the outcome of children with recurrent MB.

[Clinical effect of surgery combined with chemotherapy and radiotherapy in children with central primitive neuroectodermal tumor and prognostic analysis].

OBJCTIVE: To study the clinical effect of surgery combined with chemotherapy and radiotherapy in children with central primitive neuroectodermal tumor (cPNET), as well as the risks factors for poor prognosis. METHODS: A retrospective analysis was performed for the clinical data of 42 children who were diagnosed with cPNET from June 2012 to September 2018. RESULTS: The 42 children had a median overall survival (OS) time of 2.0 years and a median event-free survival (EFS) time of 1.3 years; the 1-, 3-, and 5-year OS rates were 76.2%±6.6%, 41.4%±8.7%, 37.3%±8.8% respectively, and the 1-, 3-, and 5-year EFS rates were 64.3%±7.4%, 32.7%±8.0%, 28.0%±8.1% respectively. The univariate analysis showed that there were significant differences in the OS and EFS rates among the children with different patterns of surgical resection, chemotherapy cycles, and risk grades (P<0.05), and there was also a significant difference in the OS rate between the children receiving radiotherapy and those not receiving radiotherapy (P<0.05). The multivariate Cox regression analysis showed that chemotherapy cycles and risk grade were independent influencing factors for EFS and OS rates (P<0.05). The EFS and OS rates increased with the increase in chemotherapy cycles and the reduction in risk grade. CONCLUSIONS: Multimodality therapy with surgery, chemotherapy, and radiotherapy is an effective method for the treatment of cPNET in children. Early diagnosis and treatment and adherence to chemotherapy for as long as possible may improve EFS and OS rates.

[Effect of bevacizumab in treatment of children with optic pathway glioma].

OBJECTIVE: To investigate the effect of bevacizumab in the treatment of children with optic pathway glioma (OPG). METHODS: A retrospective analysis was performed for the clinical data of 30 children with OPG who underwent chemotherapy. According to whether bevacizumab was used, they were divided into conventional chemotherapy (carboplatin, vincristine and etoposide) group with 12 children and combined chemotherapy (bevacizumab, carboplatin, vincristine and etoposide) group with 18 children. The children were followed up to 6 months after chemotherapy, and the two groups were compared in terms of visual acuity and tumor size before and after chemotherapy and adverse reactions during chemotherapy. RESULTS: The combined chemotherapy group had a significantly higher proportion of children achieving tumor regression than the conventional chemotherapy group (P<0.05), while there were no significant differences between the two groups in the proportion of children with improved visual acuity or adverse reactions (P>0.05). No chemotherapy-related death was observed in either group. CONCLUSIONS: Bevacizumab combined with conventional chemotherapy can effectively reduce tumor size. Compared with conventional chemotherapy, such combination does not increase adverse reactions and can thus become a new direction for the treatment of OPG in children.

[Risk factors for recurrence within 2 years in children with medulloblastoma].

OBJECTIVE: To investigate the risk factors for recurrence of medulloblastoma (MB) within 2 years and their influence on progression-free survival (PFS). METHODS: A retrospective analysis was performed for the clinical data of 123 children with MB who were admitted from January to December, 2017. According to the presence or absence of recurrence, they were divided into recurrence group with 30 children and non-recurrence group with 93 children. The risk factors for recurrence within 2 years were analyzed, and PFS was compared between the children with different risk factors. RESULTS: Large-cell/anaplastic type and M stage were risk factors for MB recurrence within 2 years. The risk of recurrence in the children with M+ MB was 3.525 times that in those with M0 MB, and the risk of recurrence in the children with large-cell/anaplastic MB was 3.358 times that in those with classic MB (P<0.05). The survival analysis showed that the median PFS time was 20 months in the children with M+ MB, and the 20-month PFS rate was 50% ±â€…11% in the children with M+ MB and 81% ±â€…5% in those with M0 MB (P<0.05). The 20-month PFS rate was 80% ±â€…5% in the children with classic MB, 65% ±â€…10% in those with desmoplastic/nodular MB, 86% ±â€…13% in those with MB with extensible nodularity, and 36% ±â€…20% in those with large-cell/anaplastic MB (P<0.05). CONCLUSIONS: Recurrence is an important influencing factor for the prognosis of MB, and M+ stage and large-cell/anaplastic MB are risk factors for recurrence. Children with such risk factors tend to have a low PFS rate.

Clinical Characteristics and Outcome of Children With Relapsed Medulloblastoma: A Retrospective Study at a Single Center in China.

Relapsed medulloblastoma (MB) has a dire prognosis, and chemotherapy remains the main therapeutic option. We retrospectively analyzed the clinical characteristics and survival rates of 60 Chinese children with relapsed MB. The patients received 11 cycles of chemotherapy in sequence, followed by 12 cycles of oral temozolomide and etoposide. Thirty patients were simultaneously administered intrathecal methotrexate (IT-MTX). The Kaplan-Meier method was used to determine survival rates; the patients' median survival time after relapse was 2.8 years, 5-year progression-free survival (PFS) and overall survival (OS) rates were 26.7%±5.7% and 31.6%±6.9%, respectively. There was no significant difference between these rates according to histology or molecular subgroup. Tumor cells were detected in the cerebrospinal fluid of over 40% of patients; such patients had significantly shorter OS and PFS rates. Patients who received IT-MTX showed significantly longer survival than those who did not (3.73 vs. 2.06 y, respectively, P=0.000); the corresponding 5-year PFS and OS rates were 43.3%±9.0% versus 10.0%±5.5% and 49.5%±11.1% versus 14.6%±6.9%, respectively (P=0.000). In addition, tumor cell-positive cerebrospinal fluid and IT-MTX use significantly influenced PFS and OS in relapsed patients. Taken together, our data show that IT-MTX improves the survival of patients with relapsed MB.

Protective Mechanism of Hydrogen Sulfide against Chemotherapy-Induced Cardiotoxicity.

Over the past few decades, the number of long term survivors of childhood cancers has been increased exponentially. However, among these survivors, treatment-related toxicity, especially cardiotoxicity, is becoming the essential cause of morbidity and mortality. Thus, preventing the treatment-related adverse effects is important to increase the event free survival during the treatment of cancer in children and adolescents. Accumulating evidence has demonstrated that hydrogen sulfide (H2S) exerts a protective role on cardiomyocytes through a variety of mechanisms. Here, we mainly reviewed the cardioprotective role of H2S in the chemotherapy, and emphatically discussed the possible mechanisms.

The protective effects of Bacillus licheniformis preparation on gastrointestinal disorders and inflammation induced by radiotherapy in pediatric patients with central nervous system tumor.

PURPOSE: we studied the effect of Bacillus licheniformis preparation (ZCS) on CNST (central nervous system tumor) patients undergoing the gastrointestinal symptoms and inflammation induced by radiotherapy. MATERIALS AND METHODS: 160 CNST patients with craniospinal irradiation (CSI) treatment were divided into experiment and control group. The experiment group patients took one capsule per time of ZCS and three times a day until the end of radiotherapy, starting one day before radiotherapy. While the patients in control group were administrated placebo without any probiotics. Serum from one day before radiotherapy and the first day after radiotherapy were collected to measure the ET, CRP, TNF-α, IL-1ß and IL-6. RESULTS: More than 70% CNST pediatric patients suffered from different degrees of gastrointestinal symptoms after radiotherapy, including mouth ulcer, nausea, vomiting, abdominal pain and diarrhea. And there was an obviously increased of serum ET, TNF-α, IL-1ß, IL-6 and CRP after RT. Importantly, a markedly decreased of ET, CRP and inflammatory cytokines were detected in the experiment group comparing to the control group after radiotherapy, as well as the relief of the gastrointestinal symptoms. However, improvement of probiotics (or ZCS) of the survival rate of CNST children and the recurrence of tumor are not observed in this study. CONCLUSIONS: Prophylactically administrated ZCS during radiotherapy for CNST patients can relieve RT-related gastrointestinal symptoms and inflammatory reaction.

Efficacy and tolerability of chemotherapy in Chinese patients with AIDS-related Burkitt lymphoma and diffuse large B-cell lymphoma: An observational study.

We evaluated the efficacy and tolerability of chemotherapy in HIV-infected patients with diffuse large B-cell lymphoma (DLBCL) receiving CHOP ± R (n = 17) or Burkitt lymphoma (BL) receiving CODOX-M/IVAC ± R (n = 15). The study was conducted in Beijing Ditan Hospital from January 2009 to August 2015. The following grade 4 adverse effects were observed in BL and DLBCL patients, respectively: neutropenia (80% versus 47.1%), anaemia (46.7% versus 5.9%), thrombocytopenia (53.3% versus 11.8%), bacterial pneumonia (33.3% versus 5.9%), and sepsis (20% versus 5.9%) (p < 0.05). In the BL group, 10 (66.7%) patients died from treatment-related or tumour-related causes, 5 (33.3%) achieved complete response, 1 achieved partial response (6.7%), and 7 developed progressive disease. The 1-year overall survival and progression-free survival rates were 33.3%. Of the DLBCL patients, 3 (17.6%) died from treatment-related causes, 14 (82.4%) achieved complete response, and 3 had progressive disease. The 1-year overall survival and progression-free survival rates were 82.4%. The strongest risk factor for death was relapse between chemotherapy cycles (adjusted hazard ratio = 47.3; 95%CI, 4.2-528.6, p = 0.002). Initiating antiretroviral therapy before chemotherapy failed to improve overall survival. DLBCL patients demonstrated good responses and survival outcomes, while BL patients could not tolerate chemotherapy due to more severe toxicity, and showed poor responses and survival outcomes.

Sulfur Dioxide Protects Against Collagen Accumulation in Pulmonary Artery in Association With Downregulation of the Transforming Growth Factor ß1/Smad Pathway in Pulmonary Hypertensive Rats.

BACKGROUND: We aimed to explore the role of endogenous sulfur dioxide (SO2) in pulmonary vascular collagen remodeling induced by monocrotaline and its mechanisms. METHODS AND RESULTS: A rat model of monocrotaline-induced pulmonary vascular collagen remodeling was developed and administered with l-aspartate-ß-hydroxamate or SO2 donor. The morphology of small pulmonary arteries and collagen metabolism were examined. Cultured pulmonary arterial fibroblasts stimulated by transforming growth factor ß1 (TGF-ß1) were used to explore the mechanism. The results showed that in monocrotaline-treated rats, mean pulmonary artery pressure increased markedly, small pulmonary arterial remodeling developed, and collagen deposition in lung tissue and pulmonary arteries increased significantly in association with elevated SO2 content, aspartate aminotransferase (AAT) activity, and expression of AAT1 compared with control rats. Interestingly, l-aspartate-ß-hydroxamate, an inhibitor of SO2 generation, further aggravated pulmonary vascular collagen remodeling in monocrotaline-treated rats, and inhibition of SO2 in pulmonary artery smooth muscle cells activated collagen accumulation in pulmonary arterial fibroblasts. SO2 donor, however, alleviated pulmonary vascular collagen remodeling with inhibited collagen synthesis, augmented collagen degradation, and decreased TGF-ß1 expression of pulmonary arteries. Mechanistically, overexpression of AAT1, a key enzyme of SO2 production, prevented the activation of the TGF-ß/type I TGF-ß receptor/Smad2/3 signaling pathway and abnormal collagen synthesis in pulmonary arterial fibroblasts. In contrast, knockdown of AAT1 exacerbated Smad2/3 phosphorylation and deposition of collagen types I and III in TGF-ß1-treated pulmonary arterial fibroblasts. CONCLUSIONS: Endogenous SO2 plays a protective role in pulmonary artery collagen accumulation induced by monocrotaline via inhibition of the TGF-ß/type I TGF-ß receptor/Smad2/3 pathway.

Causes of Death Among Patients Infected with HIV at a Tertiary Care Hospital in China: An Observational Cohort Study.

The objective of this study was to elucidate the causes of death and mortality in a cohort of inpatients infected with HIV. The causes of death and mortality were evaluated by using the clinical data of 1,076 patients admitted to the Center for Infectious Diseases, Beijing Ditan Hospital, between January 1, 2009, and November 30, 2012, and who were followed for 6 months after discharge. During the 4-year study period, 216 patients had died by the 6-month follow-up (mortality rate, 20.1%). Opportunistic infections were the most common causes of death (42.0%), followed by malignancies (23.1%), unexplained central nervous system infections and occupying lesions (18.1%), infectious shock (10.2%), severe hepatitis and decompensated cirrhosis (3.2%), sudden death (1.4%), lactic acidosis (0.9%), and uremia (0.9%). The strong risk factors for mortality were cost constraints and unaffordable further diagnosis and treatment (adjusted hazard ratio [AHR] = 134.394, 95% confidence interval [CI] = 25.748-701.481, p < .001), unexplained etiologies (AHR = 12.551, 95% CI = 6.642-23.716, p < .001), and multiple complications (AHR = 5.798, 95% CI = 2.973-11.308, p < .001). Mortality was not associated with CD4 levels or combined antiretroviral therapy (cART) in a cohort of inpatients at a special hospital for HIV/AIDS patients in China. AIDS-related infections and malignancies were the most common causes of death in patients infected with HIV, and improvement of the etiological diagnosis would help physicians provide appropriate treatment and reduce mortality rates.

The vasodilatory effect of sulfur dioxide via SGC/cGMP/PKG pathway in association with sulfhydryl-dependent dimerization.

The present study was designed to explore the role of soluble guanylate cyclase (sGC)/cyclic guanosine monophosphate (cGMP)/PKG pathway in sulfur dioxide (SO2)-induced vasodilation. We showed that SO2 induced a concentration-dependent relaxation of phenylephrine (PE)-precontracted rat aortic rings in association with an increase in cGMP concentration, whereas l-aspartic acid ß-hydroxamate (HDX), an inhibitor of SO2 synthase, contracted rings in a dose-dependent manner. Pretreatment of aortic rings with the sGC inhibitor ODQ (30 µM) attenuated the vasodilatory effects of SO2, suggesting the involvement of cGMP pathway in SO2-induced vasodilation. Mechanistically, SO2 upregulated the protein levels of sGC and PKG dimers, while HDX inhibited it, indicating SO2 could promote cGMP synthesis through sGC activation. Furthermore, the dimerization of sGC and PKG and vasodilation induced by SO2 in precontracted rings were significantly prevented by thiol reductants dithiothreitol (DTT). In addition, SO2 reduced the activity of phosphodiesterase type 5 (PDE5), a cGMP-specific hydrolytic enzyme, implying that SO2 elevated cGMP concentration by inhibiting its hydrolysis. Hence, SO2 exerted its vasodilatory effects at least partly by promoting disulfide-dependent dimerization of sGC and PKG, resulting in an activated sGC/cGMP/PKG pathway in blood vessels. These findings revealed a new mode of action and mechanisms by which SO2 regulated the vascular tone.

Endogenous sulfur dioxide alleviates collagen remodeling via inhibiting TGF-ß/Smad pathway in vascular smooth muscle cells.

The study was designed to investigate the role of endogenous sulfur dioxide (SO2) in collagen remodeling and its mechanisms in vascular smooth muscle cells (VSMCs). Overexpression of endogenous SO2 synthase aspartate aminotransferase (AAT) 1 or 2 increased SO2 levels and inhibited collagen I and III expressions induced by transforming growth factor (TGF)-ß1 in VSMCs. In contrast, AAT1 or AAT2 knockdown induced a severe collagen deposition in TGF-ß1-treated VSMCs. Furthermore, AAT1 or AAT2 overexpression suppressed procollagen I and III mRNA, upregulated matrix metalloproteinase (MMP)-13 expression, downregulated tissue inhibitors of MMP-1 level, and vice versa. Mechanistically, AAT1 or AAT2 overexpression inhibited phosphorylation of type I TGF-ß receptor (TßRI) and Smad2/3 in TGF-ß1-stimulated VSMCs. Whereas SB431542, an inhibitor of TGF-ß1/Smad signaling pathway, attenuated excessive collagen deposition induced by AAT knockdown. Most importantly, ectopically expressing AAT or exogenous addition of 100 µM SO2 blocked AAT deficiency-aggravated collagen accumulation in TGF-ß1-stimulatd VSMCs, while no inhibition was observed at 100 µM ethyl pyruvate. These findings indicated that endogenous SO2 alleviated collagen remodeling by controlling TGF-ß1/TßRI/Smad2/3-mediated modulation of collagen synthesis and degradation.

A cross-sectional study on upright heart rate and BP changing characteristics: basic data for establishing diagnosis of postural orthostatic tachycardia syndrome and orthostatic hypertension.

OBJECTIVE: We aimed to determine upright heart rate and blood pressure (BP) changes to suggest diagnostic criteria for postural orthostatic tachycardia syndrome (POTS) and orthostatic hypertension (OHT) in Chinese children. METHODS: In this cross-sectional study, 1449 children and adolescents aged 6-18 years were randomly recruited from two cities in China, Kaifeng in Henan province and Anguo in Hebei province. They were divided into two groups: 844 children aged 6-12 years (group I) and 605 adolescents aged 13-18 years (group II). Heart rate and BP were recorded during an active standing test. RESULTS: 95th percentile (P(95)) of δ heart rate from supine to upright was 38 bpm, with a maximum upright heart rate of 130 and 124 bpm in group I and group II, respectively. P(95) of δ systolic blood pressure (SBP) increase was 18 mm Hg and P(95) of upright SBP was 132 mm Hg in group I and 138 mm Hg in group II. P(95) of δ diastolic blood pressure (DBP) increase was 24 mm Hg in group I and 21 mm Hg in group II, and P(95) of upright DBP was 89 mm Hg in group I and 91 mm Hg in group II. CONCLUSIONS: POTS is suggested when δ heart rate is ≥ 38 bpm (for easy memory, ≥ 40 bpm) from supine to upright, or maximum heart rate ≥ 130 bpm (children aged 6-12 years) and ≥ 125 pm (adolescents aged 13-18 years), associated with orthostatic symptoms. OHT is suggested when δ SBP (increase) is ≥ 20 mm Hg, and/or δ DBP (increase) ≥ 25 mm Hg (in children aged 6-12 years) or ≥ 20 mm Hg (in adolescents aged 13-18 years) from supine to upright; or upright BP ≥ 130/90 mm Hg (in children aged 6-12 years) or ≥ 140/90 mm Hg (in adolescents aged 13-18 years).

Erythrocytic hydrogen sulfide production is increased in children with vasovagal syncope.

OBJECTIVES: To explore the differences in erythrocyte hydrogen sulfide (H2S) production in children with vasovagal syncope (VVS). STUDY DESIGN: A total of 54 children including 27 with VVS, aged 6-16 years (mean age 11.3 ± 3.3 years), and 27 healthy children, aged 3-17 years (mean age 10.4 ± 1.8 years) were included in the study. Children with VVS had symptoms of dizziness, pallor, blurred vision, nausea, and some had syncope. Erythrocyte H2S production was measured by a sulphur-sensitive electrode. Flow-mediated dilation (FMD) of brachial artery was measured for each patient by vascular ultrasound. RESULTS: H2S production from erythrocytes was significantly increased in the children with VVS compared with controls (P < .01). The erythrocytic H2S production in the VVS-vasoinhibitory subgroup was obviously higher than that in VVS-cardioinhibitory (P < .05) and VVS-mixed inhibitory subgroups (P < .05). FMD in the VVS-vasoinhibitory subgroup was greater than that in the VVS-cardioinhibitory (P < .05) and the VVS-mixed subgroups (P < .05). The erythrocytic H2S production had a positive linear correlation with FMD in children with VVS (P < .05). CONCLUSIONS: Increased erythrocyte H2S production may be involved in the pathogenesis of VVS in children.

Immune regulation of hydrogen sulfide in children with acute lymphoblastic leukemia.

BACKGROUND: Acute lymphoblastic leukemia (ALL) and chemotherapy can cause immune imbalance, and gaseous molecule hydrogen sulfide (H2S) can participate in the process of immune response. This study aimed to investigate the immune regulation of H2S in pediatric ALL. METHODS: Children (n = 78) with ALL admitted during 2010-2013 were included in this study. Two blood samples were collected in period of before chemotherapy, bone marrow remission and two days after chemotherapy, respectively. Serum contents of H2S and cytokines, including interleukin-1ß (IL-1ß), interleukin-2 (IL-2), interferon-γ (IFN-γ), tumor necrosis factor (TNF-α), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-10 (IL-10) and macrophage inflammatory protein-1α (MIP-1α), were detected using ELISA method. Stepwise regression was used to analyze the correlation between H2S and cytokines. Furthermore, human Jurkat cells were cultured in vitro, and nucleoprotein of Jurkat cells and peripheral blood mononuclear cells (PBMCs) were collected, contents of cystathionine γ-lyase (CSE) and certain cytokines were measured by Western blotting. RESULTS: Serum concentrations of H2S, IL-1ß, IL-6, IL-10 and MIP-1a in children with ALL were increased significantly (P < 0.01), while concentrations of IL-2, TNF-α, IFN-γ and IL-4 decreased obviously (P < 0.01). In patients after chemotherapy, concentrations of H2S and IL-10 were decreased significantly (P < 0.05), but IL-4 and IFN-γ concentrations increased markedly (P < 0.05). At remission stage, H2S, IL-1ß, IL-4, IL-6, IL-10 and MIP-1α concentrations were further decreased markedly (P < 0.05), but concentrations of IL-2, TNF-α and IFN-γ increased again (P < 0.05). Protein contents of CSE, IL-10, IL-4 and IL-2 of PBMCs also increased markedly in children with ALL. Moreover, changes of CSE protein contents of PBMCs were consistent with serum H2S contents, and there were significant correlation between H2S and certain cytokines based on stepwise regression analysis. Furthermore, compared with those of PBMCs group, in vitro study indicated that Jurkat cells of H2S group expressed IFN-γ, IL-10, IL-4 and IL-2 protein increased obviously (P < 0.05), while IL-4, IL-2 and CSE expression of PPG group decreased markedly (P < 0.05). CONCLUSION: Gaseous molecule H2S might participate in the process of immune regulation in pediatric ALL through modulating transcription and expression of cytokines.

Changes of sulfur dioxide, nuclear factor-κB, and interleukin-8 levels in pediatric acute lymphoblastic leukemia with bacterial inflammation.

BACKGROUND: Bacterial inflammation is a common complication in patients with leukemia, and sulfur dioxide (SO2) is a bioactive molecule in modulating Gram-negative bacilli infection. This study aimed to examine the changes in SO2, nuclear factor-κB (NF-κB), and interleukin-8 (IL-8) levels in pediatric acute lymphoblastic leukemia (ALL) with Gram-negative bacterial inflammation. METHODS: Fifty-five ALL children were enrolled in this study, including 30 males and 25 females, aged 3-13 years, and the median age was 7.8 years. All these children who accepted chemotherapy for ALL were divided into the control group (before chemotherapy), the infection group (after chemotherapy with infection), and the recovery group (the infection was controlled after 1 week). The serum level of SO2 was detected using high performance liquid chromatography with fluorescence assay, and NF-κB and IL-8 levels were measured by enzyme-linked immunosorbent assay (ELISA). Human THP-1 cells were cultured, induced, and differentiated into macrophages, which were divided into five groups and each group was cultured with different stimulators: lipopolysaccharide (LPS) group, LPS+L-aspartate-ß-hydroxamate (HDX) group, LPS+SO2 group, SO2, and control groups. NF-κB level and IL-8 protein contents by ELISA were examined in each group. RESULTS: In comparison with those of the control group, levels of serum SO2, NF-κB, and IL-8 of the infection group were significantly increased (P < 0.05), while those of the recovery group were significantly decreased (P < 0.05). A positive correlation was found between levels of serum SO2 and intracellular NF-κB/IL-8, and the correlation coefficients were 0.671 and 0.798 (P < 0.05), respectively. According to the results found in human THP-1 cells, levels of NF-κB and IL-8 in LPS group were significantly increased compared with those of the control group (P < 0.05); when compared with those in LPS group, levels of NF-κB in LPS+HDX group further increased significantly (P < 0.05); however, the NF-κB levels of LPS+SO2 group decreased significantly (P < 0.05). CONCLUSION: SO2 may play an anti-inflammatory role during the process of inflammation by inhibiting the activation and transcription of NF-κB.

Usefulness of plasma copeptin as a biomarker to predict the therapeutic effectiveness of metoprolol for postural tachycardia syndrome in children.

Metoprolol is clinically used to treat postural tachycardia syndrome (POTS) in children, but its effectiveness is unsatisfactory. Biomarkers to predict therapeutic efficacy are needed. We aimed to explore changes in the plasma copeptin level for assessing the therapeutic efficacy of metoprolol for POTS in children. We included 49 children with POTS and 25 healthy children as controls. Patients received metoprolol for 1.5 to 3 months. The plasma copeptin level was measured by sandwich immunoluminometric assay. The area under the receiver operating characteristic curve was used to explore the predictive value of the plasma copeptin level. The baseline plasma copeptin level was higher in children with POTS than controls (10.524 ± 2.016 vs 8.750 ± 1.419 pmol/L, p <0.001) and was lower for responders than nonresponders to metoprolol (9.377 ± 1.411 vs 12.054 ± 1.662 pmol/L, p = 0.003). The area under the receiver operating characteristic curve was 0.889 (95% confidence interval 0.799 to 0.980). With a baseline plasma copeptin level of 10.225 pmol/L as a cutoff, the sensitivity was 90.5% and specificity 78.6% in predicting the efficacy of metoprolol in children with POTS. In conclusion, the baseline plasma copeptin level can be used as a biomarker to predict the therapeutic effectiveness of metoprolol in children with POTS.