[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.

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.

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.

Postural orthostatic tachycardia syndrome with increased erythrocytic hydrogen sulfide and response to midodrine hydrochloride.

OBJECTIVES: To evaluate the use of erythrocytic hydrogen sulfide (H2S) in predicting the therapeutic efficacy of midodrine hydrochloride for children with postural orthostatic tachycardia syndrome (POTS). STUDY DESIGN: Fifty-five children were included in this study, involving 28 children with POTS (POTS group) and 27 healthy children (control group). Children in the POTS group received midodrine hydrochloride treatment. Erythrocytic H2S production was measured; a receiver operating characteristic curve was used to assess if erythrocytic H2S could predict the therapeutic response to midodrine hydrochloride treatment. RESULTS: H2S production from erythrocytes was significantly higher in the POTS group than in the control group (P < .01). H2S production was also significantly higher in responders to midodrine hydrochloride than in non-responders (P < .05). The change in symptom score and baseline erythrocytic H2S production had a positive linear relationship (P < .01). There was also a positive correlation with the change in heart rate (P < .05). The receiver operating characteristic curve showed an area under curve value of 0.813. Erythrocytic H2S production yielded a sensitivity of 78.9% and a specificity of 77.8% in predicting the efficacy of midodrine hydrochloride therapy for children with POTS. CONCLUSION: Erythrocytic H2S could serve as a useful predictor of therapeutic response to midodrine hydrochloride in children with POTS.

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.

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.

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.

Endogenously generated sulfur dioxide and its vasorelaxant effect in rats.

AIM: The present study was designed to explore the endogenous production and localization of the sulfur dioxide (SO2)/aspartate aminotransferase pathway in vascular tissues of rats and to examine its vasorelaxant effect on isolated aortic rings,as well as the possible mechanisms. METHODS: The content of SO2 in the samples was determined by using high performance liquid chromatography with fluorescence detection. Aspartate aminotransferase activity and its gene expression were measured by an enzymatic method and quantitative RT-PCR, respectively. Aspartate aminotransferase mRNA location in aorta was detected by in situ hybridization. The vasorelaxant effect of SO2 on isolated aortic rings of the rats was investigated in vitro. L-type calcium channel blocker, nicardipine, and L-type calcium channel agonist, Bay K8644, were used to explore the mechanisms by which SO2 relaxed the aortic rings. RESULTS: Aorta had the highest SO2 content among the vascular tissues tested (P<0.01). The aortic aspartate aminotransferase mRNA located in endothelia and vascular smooth muscle cells beneath the endothelial layer.Furthermore, a physiological dose of the SO2 derivatives (Na2SO3/NaHSO3) relaxed isolated artery rings slightly, whereas higher doses (1-12 mmol/L) relaxed rings in a concentration-dependent manner. Pretreatment with nicardipine eliminated the vasorelaxant response of the norepinephrine-contracted rings to SO2 completely. Incubation with nicardipine or SO2 derivatives successfully prevented vasoconstriction induced by Bay K8644. CONCLUSION: Endogenous SO2 and its derivatives have a vasorelaxant function, the mechanisms of which might involve the inhibition of the L-type calcium channel.

Effects of endogenous sulfur dioxide on monocrotaline-induced pulmonary hypertension in rats.

AIM: The present study aimed to explore the protective effect of endogenous sulfur dioxide (SO2) in the development of monocrotaline (MCT)-induced pulmonary hypertension (PH) in rats. METHODS: Forty Wistar rats were randomly divided into the MCT group receiving MCT treatment, the MCT+L-aspartate-beta- hydroxamate (HDX) group receiving MCT plus HDX treatment, the MCT+SO2 group receiving MCT plus SO2 donor treatment, and the control group. Mean pulmonary artery pressure (mPAP) and structural changes in pulmonary arteries were evaluated. SO2 content, aspartate aminotransferase activity, and gene expression were measured. Superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), reduced glutathione (GSH), oxidized glutathione, and malondialdehyde (MDA) levels were assayed. RESULTS: In the MCT-treated rats, mPAP and right ventricle/(left ventricle+septum) increased significantly (P<0.01), pulmonary vascular structural remodeling developed, and SOD, GSHPx, CAT, GSH, and MDA levels of lung homogenates significantly increased (P<0.01) in association with the elevated SO2 content, aspartate aminotransferase activity, and gene expression, compared with the control rats. In the MCT+HDXtreated rats, lung tissues and plasma SO2 content and aspartate aminotransferase activities decreased significantly, whereas the mPAP and pulmonary vascular structural remodeling were markedly aggravated with the decreased SOD, CAT, and GSH levels of lung tissue homogenates compared with the MCT-treated rats (P<0.01). In contrast, with the use of a SO2 donor, the pulmonary vascular structural remodeling was obviously lessened with elevated lung tissue SOD, GSH-Px, and MDA content, and plasma SOD, GSH-Px, and CAT levels. CONCLUSION: Endogenous SO2 might play a protective role in the pathogenesis of MCT-induced PH and promote endogenous antioxidative capacities.

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.

[Advances in study of physiologic effects of endogenous sulfur dioxide and its derivatives].

Sulfur dioxide (SO2) is an ordinary air pollutant globally and harm to human health. L-cysteine is the major sulfur-containing amino acid and its normal metabolism can produce hydrogen sulfur (H2S) and SO2. It is realized that H2S has various bioactivities and is the third gasotransmitter after nitric oxide (NO) and carbon monoxide (CO). Recently, attention has been paid to the physiologic effects of endogenous SO2 and its derivatives (bisulfite and sulfite) in vivo, and recognized that SO2 and its derivatives can lower blood pressure, change heart rates, participate in inflammatory reactions, and so on, suggesting that endogenous SO2 may modulate the physiologic functions in vivo as a bioactive molecule.

[Vasorelaxant effect of sulfur dioxide derivatives on isolated aortic rings of rats and its mechanisms].

OBJECTIVE: To investigate the vasorelaxant effect of sulfur dioxide (SO(2)) on isolated aortic rings of rats in vitro and its relaxation mechanisms. METHODS: We perffused the isolated aortic rings of rats, and precontracted the rings with noradrenaline (NE), then observed the relaxant reactivity of SO(2) derivatives, mixture of sulfite and hydrogen sulfite [Na(2)SO(3)/NaHSO(3) 3:1(amount of substance)], to the aortic rings. Meanwhile, we studied the influence of glibenclamide and nicardipine, blockers of K(ATP) and L-calcium channels, on the vasorelaxant reactivity of SO(2) derivatives. We further incubated the aortic rings with hydroxamate (HDX), the inhibitor of SO(2) endogenous generating enzymes, and SO(2) derivatives (4 mmol/L) in vitro, then observed the contraction of the aortic rings to NE. RESULTS: Isolated aortic rings of rats exhibited relaxant reactivity to Na(2)SO(3)/NaHSO(3) (0-12 mmol/L) in a concentration-dependent manner. IC(50) of the relaxation curve was (7.28+/-0.12) mmol/Lìand Emax was 78.79%+/-3.24%. Glibenclamide (1x10(-6) mol/L) inhibited the vasorelaxation to low dose Na(2)SO(3)/NaHSO(3) (6 mmol/L). Nicardipine (1x10(-9) mol/L) could decrease the contraction of the rings to NE, and even could inhibit the relaxation of Na(2)SO(3)/NaHSO(3) almost completely. The inhibition of the endogenous SO(2) production with HDX (1x10(-4) mol/L), resulted in an increase in the contraction of rings. The contraction curve to NE shifted to the left, and IC(50) also changed from (6.48+/-0.84)x10(-7) mol/L to (3.97+/-1.63)x10(-7) mol/L (P<0.01). However, after the incubation of aortic rings with Na(2)SO(3)/NaHSO(3) (4 mmol/L), the contraction curve to NE shifted to the right, and IC(50) changed from (6.48+/-0.84)x10(-7) mol/L to (4.93+/-0.81)x10(-5) mol/L (P<0.01). CONCLUSION: SO(2) could relax vascular smooth muscles, and the mechanism might be associated with calcium channels and K(ATP) channels, suggesting that endogenous SO(2) could modulate the cardiovascular function.

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.

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.