BACKGROUND: The purpose of this study was to determine the adequate loading and maintenance doses of N-acetylcyseteine (NAC) for patients suffering from acute ROS-induced injury. METHODS: Concentrations of extra cellular NAC, cysteine (Cys), cystine (Cyst2), and methionine (Met) were measured in vitro, at which more than 50% of the intracellular ROS raised by paraquat were suppressed using Swiss 3T3 fibroblasts. An in vivo pharmacokinetic study followed on a healthy subject to determine the proper loading and maintenance doses of reduced NAC following intravenous administration of 25 mg/kg NAC. RESULTS: In vivo, NAC suppressed ROS in a dose dependant manner. 10 mM of NAC suppressed about 50% of ROS, and was comparable to 10 micro M of Cys and Met and 400 micro M of Cys2. In vitro, the elimination of half-life was achieved at 2.88+/-1.14 h for NAC and at 3.68+/-1.84 h for total NAC. The body clearances were 1.23+/-0.77 L h (-1) kg (-1) and 0.56+/-0.27 L h (-1) kg (-1) and the volumes of distribution were 3.07+/-0.10 L kg (-1) and 3.00+/-0.11 L kg (-1), respectively. The loading and maintenance NAC doses used to reach the target concentration of 10 mM, were 5010 mg. kg (-1) and 2250 mg min (-1) kg (-1), respectively. CONCLUSION: NAC provides an antioxidant effect on ROS produced by paraquat in vivo. However, in vitro, our results showed that the intravenous NAC dose could not be estimated from NAC plasma concentration or its metabolites.
Sulfur/*blood ; Reactive Oxygen Species ; Humans ; Glutathione/blood ; Amino Acids/*blood/chemistry ; Acetylcysteine/*administration & dosage/pharmacokinetics/pharmacology

This study was designed to investigate the cardiovascular effects of sulfur dioxide (SO₂) in the caudal ventrolateral medulla (CVLM) of anesthetized rats and its mechanism. Different doses of SO₂ (2, 20, 200 pmol) or artificial cerebrospinal fluid (aCSF) were injected into the CVLM unilaterally or bilaterally, and the effects of SO₂ on blood pressure and heart rate of rats were observed. In order to explore the possible mechanisms of SO₂ in the CVLM, different signal pathway blockers were injected into the CVLM before the treatment with SO₂ (20 pmol). The results showed that unilateral or bilateral microinjection of SO₂ reduced blood pressure and heart rate in a dose-dependent manner (P < 0.01). Moreover, compared with unilateral injection of SO₂ (2 pmol), bilateral injection of 2 pmol SO₂ produced a greater reduction in blood pressure. Local pre-injection of the glutamate receptor blocker kynurenic acid (Kyn, 5 nmol) or soluble guanylate cyclase (sGC) inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 1 pmol) into the CVLM attenuated the inhibitory effects of SO₂ on both blood pressure and heart rate. However, local pre-injection of nitric oxide synthase (NOS) inhibitor N^G-Nitro-L-arginine methyl ester (L-NAME, 10 nmol) only attenuated the inhibitory effect of SO₂ on heart rate but not blood pressure. In conclusion, SO₂ in rat CVLM has cardiovascular inhibitory effects, and its mechanism is related to the glutamate receptor and NOS/cGMP signal pathways.
Animals ; Rats ; Heart Rate ; Sulfur Dioxide ; Blood Pressure ; Cyclic GMP ; Receptors, Glutamate

OBJECTIVEHypoxic pulmonary hypertension is an important pathophysiologic process of various cardiovascular diseases. Sulfur dioxide (SO2) was considered as a kind of toxic gas previously, but recent studies suggested that SO2 could act as a key bioactive molecule in the pathogenesis of cardiovascular diseases. Therefore, this study was designed to examine the effect of sulfur dioxide on pulmonary vascular structure of hypoxic pulmonary hypertensive rats treated with SO2 donor substances.

METHODSThe rats were randomly divided into 3 groups: control group(n = 8), hypoxic group(n = 8) and hypoxic + SO2 group (n = 10, treated with SO2 donor Na2SO3/NaHSO3). The rats of hypoxic group and hypoxic + SO2 group were under a hypoxic condition for 21 days, while the rats of control group were exposed to room air. The mean pulmonary artery pressure was tested by means of right cardiac catheterization and the content of SO2 in plasma was investigated by high performance liquid chromatography (HPLC). The change in relative medial thickness (RMT) of pulmonary arteries was examined under optical microscope. The ultra-structural changes were observed under a transmission electron microscope. The data were analyzed through one-way analysis of variance (ANOVA) by SPSS 13.0 software.

RESULTSCompared with control group [(2.25 +/- 0.50) kPa], the mean pulmonary artery pressure of hypoxic group [(5.12 +/- 0.51) kPa] raised significantly (t = 5.091, P < 0.01) and RMT of hypoxic group (9.66 +/- 1.27) compared with control group (6.83 +/- 1.57) significantly raised (t = 3.392, P < 0.01). Ultrastructural observation showed the proliferation and degeneration of endothelial cells in small pulmonary arteries in rats with pulmonary hypertension. The internal elastic lamina was irregular. The proliferation of medial smooth muscle cells of arteries was shown at the level of respiratory bronchioles. The collagens also increased. Meanwhile, compared with control group [(33.36 +/- 5.62) micromol/L], the content of SO2 in plasma of hypoxic group [(27.01 +/- 4.17) micromol/L] declined (t = 2.067, P < 0.05). Whereas compared with that of hypoxic group [(5.12 +/- 0.51) kPa], the mean pulmonary artery pressure of hypoxic + SO2 group [(3.94 +/- 0.33) kPa] declined (t = 2.712, P < 0.01) and RMT of hypoxic + SO2 group (6.97 +/- 1.83) decreased compared with hypoxic group (9.66 +/- 1.27) (t = 3.009, P < 0.01). Compared with those of hypoxic group, the pulmonary artery ultrastructural changes in hypoxic group ameliorated obviously after using exogenous sulfur dioxide donor. The endothelial cells became flat and the smooth muscle cells of arteries slightly enlarged and arranged regularly. At the same time, compared with hypoxic group [(27.01 +/- 4.17) micromol/L], the content of SO2 in plasma of hypoxic + SO2 group [(29.89 +/- 4.52) micromol/L] raised (t = 1.263, P > 0.05).

CONCLUSIONSulfur dioxide plays an important role in the regulation of small pulmonary artery structural changes in hypoxic pulmonary hypertensive rats. The hypoxic pulmonary hypertensive damages can be ameliorated significantly after using exogenous SO2 donor.

Animals ; Hypertension, Pulmonary ; blood ; pathology ; physiopathology ; Hypoxia ; blood ; pathology ; physiopathology ; Male ; Pulmonary Artery ; drug effects ; pathology ; Rats ; Rats, Wistar ; Sulfur Dioxide ; adverse effects ; blood

BACKGROUNDBacterial 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.

METHODSFifty-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-β-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.

RESULTSIn 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).

CONCLUSIONSO2 may play an anti-inflammatory role during the process of inflammation by inhibiting the activation and transcription of NF-κB.

Adolescent ; Bacterial Infections ; blood ; metabolism ; Cell Line ; Child ; Child, Preschool ; Female ; Humans ; Inflammation ; blood ; metabolism ; Interleukin-8 ; blood ; Male ; NF-kappa B ; blood ; metabolism ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; blood ; metabolism ; Sulfur Dioxide ; blood

The injury of tumor blood vessels will break up the nutrition supply for the tumor. In this paper, we investigated the effects exerted by high intensity focused ultrasound (HIFU) combined with ultrasound microbubble agent on blood vessels. Ultrasound diagnosis was used to find the goat hepatic blood vessels each being approximately 3mm in diameter. HIFU was focused on the blood vessels. The acoustic power was 250W; HIFU irradiating Mode was line scan (the length of the line: 10 mm; speed: 3 mm/s; irradiating time: 30s). In the experimental group, 0.03 ml/kg SonoVue was injected into the goat before HIFU irradiation,while normal saline was given to the control group. The goats were killed at 24h after HIFU irradiation, then goat liver tissues and blood vessels of target area were taken out. HE staining and Victoria's blue and Ponceau's staining of tissue section showed that the endothelial cells of blood vessels dropped off and became necrosed, and the continuity of blood vessels was interrupted. HIFU combined with SonoVue will damage large blood vessels on HIFU focus, but there is no evident discrepancy between the group with SonoVue and the group without SonoVue.
Animals ; Blood Vessels ; diagnostic imaging ; pathology ; Female ; Goats ; High-Intensity Focused Ultrasound Ablation ; methods ; Male ; Microbubbles ; Phospholipids ; pharmacology ; Sulfur Hexafluoride ; pharmacology ; Ultrasonic Therapy ; methods ; Ultrasonography

OBJECTIVETo study the modulatory effect of sulfur dioxide (SO(2)) on the accumulation of collagen type I and type III in the wall of aorta during spontaneously hypertensive rat (SHR) vascular remodeling.

METHODSEight male Wistar Kyoto rats at the age of 4 weeks with normal blood pressure were used as a control group. And sixteen male SHRs at the age of 4 weeks were randomly divided into an SHR control group and SHR + Na(2)SO(3)/NaHSO(3) (SO(2) donor) group. Na(2)SO(3)/NaHSO(3) solution was injected intraperitoneally everyday to the rats in the SHR + Na(2)SO(3)/NaHSO(3) group. After 5 weeks, the systemic blood pressure was measured. The weight ratio of left ventricle to the whole heart was also measured. The rat aorta was dyed with Hart's method. The morphometric parameters including outer radius, lumen radius and the wall thickness were calculated by Leica workstation. The plasma level of SO(2) was determined by HPLC method. The expressions of collagen type I and type III in aorta were detected by immunohistochemistry.

RESULTS(1) Compared with the WKY rat control group, the systolic blood pressure increased by 53%, the weight ratio of left ventricle to the whole heart increased by 6% but the plasma level of SO(2) decreased by 44% for rats in the SHR group (P < 0.01 or P < 0.05). Compared with the SHR control group, the systolic blood pressure decreased by 26%, but the plasma level of SO(2) increased by 28% (all P < 0.01) for rats in the SHR + Na(2)SO(3)/NaHSO(3) group. (2) Compared with the WKY rats, the ratio of media to lumen radius increased by 28% for SHR. Compared with the SHR group, the ratio of media to lumen radius decreased by 10% (P < 0.01) in rats of the SHR + Na(2)SO(3)/NaHSO(3) group. (3) Compared with rats in the WKY control group, collagen type I expression increased by 10% for rats in the SHR group (P < 0.01). Compared with the SHR group, however, the expression decreased by 58% for rats in the SHR + Na(2)SO(3)/NaHSO(3) group (P < 0.01). (4) Compared with rats in the WKY control group, the expression increased by 13% for rats in the hypoxia SHR group (P < 0.01); however, compared with rats in the SHR group, the expression decreased by 8% in the rats of the SHR +Na(2)SO(3)/NaHSO(3) group (P < 0.01).

CONCLUSIONSIn the process of SHR vascular collagen remodeling in the rats, SO(2) could inhibit the abnormal accumulation of collagen type I and type III in the wall of aorta. This effect may be one of the mechanisms by which SO(2) ameliorates SHR vascular remodeling.

Animals ; Aorta, Thoracic ; drug effects ; metabolism ; physiopathology ; Blood Pressure ; drug effects ; Collagen ; metabolism ; Male ; Rats ; Rats, Inbred SHR ; Rats, Inbred WKY ; Sulfur Dioxide ; pharmacology

OBJECTIVETo determine the relationship between the serum sulfur dioxide, homocysteine and the pulmonary arterial pressure in children with congenital heart defects who generated a pulmonary arterial hypertension syndrome (PAH-CHD), and analyze their role in the pathological process of the disease.

METHODThis was a prospective cohort study, children with systemic pulmonary shunt CHD were selected. The patients were divided into three groups: the CHD with no PAH group:n = 20, 10 males, 10 females, 5 with ventricular septal defect (VSD), 8 with atrial septal defect (ASD) and 7 with patent ductus arteriosus (PDA), mean age (1.9 ± 1.8) years; the CHD with mild PAH group:n = 20, 10 males, 10 females, 12 with VSD, 6 with ASD, and 2 with PDA, mean age (1.0 ± 0.8) year; the CHD with moderate or severe PAH group:n = 20, 8 males, 12 females, 12 with VSD, 6 with ASD, and 1 with PDA, 1 with ASD+VSD, mean age (1.8 ± 1.6) year. Twenty healthy children were enrolled from outpatient department as the control group [included 8 males, 12 females, mean age (1.9 ± 1.5) years]. The homocysteine and SO2 concentrations in the serum samples were detected by a modified high performance liquid chromatographic method with fluorescence detection (HPLC-FD), then, multiple comparisons among the groups were performed with analysis of variance, and the pearson correlation.

RESULTThe serum homocysteine concentrations were respectively (11.0 ± 2.7) , (11.7 ± 2.5), (12.0 ± 2.1), (14.3 ± 3.2) µmol/L in the control group, CHD with no PAH group, CHD with mild PAH group, and CHD with moderate or severe PAH group. According to the multiple comparisons, the CHD with moderate or severe PAH group had the highest level (P all < 0.05) .While the comparison within the control group, CHD with none PAH group, and CHD with mild PAH group, the differences were not significant (P all > 0.05). The serum sulfur dioxide strength (concentrated as SO3(2-)) were respectively (10.6 ± 2.4), (8.9 ± 2.3), (7.3 ± 2.9), (4.3 ± 2.1) µmol/L in the control group, CHD with none PAH group, CHD with mild PAH group, and CHD with moderate or severe PAH group. CHD with moderate or severe PAH group had the highest level of serum sulfur dioxide (P < 0.05) . The pearson correlation analysis indicated that in the CHD children, the serum homocysteine were positively correlated with the pulmonary arterial pressure (r = 0.481, P < 0.01), while, the sulfur dioxide were negatively correlated with pulmonary arterial pressure (r = -0.553, P < 0.01).In all children, the serum homocysteine levels were negatively correlated with the sulfur dioxide (r = -0.231, P = 0.039).

CONCLUSIONThe PAH-CHD children had higher homocysteine levels and lower sulfur dioxide levelsl, which demonstrated the disturbance of homocysteine-sulfur dioxide pathway in the sulfur containing amino acids metabolish in the disease. The homocysteine may become a biological marker which reflecting the severities of the PAH-CHD, while the sulfur dioxide can be a new target for the therapy of PAH-CHD.

Biomarkers ; blood ; Case-Control Studies ; Child, Preschool ; Ductus Arteriosus, Patent ; blood ; complications ; physiopathology ; Familial Primary Pulmonary Hypertension ; blood ; etiology ; physiopathology ; Female ; Heart Defects, Congenital ; blood ; complications ; physiopathology ; Heart Septal Defects ; blood ; complications ; physiopathology ; Hemodynamics ; Homocysteine ; blood ; Humans ; Infant ; Male ; Sulfur Dioxide ; blood

OBJECTIVE: To determine whether contrast-enhanced harmonic ultrasonography can be used to predict the aggressiveness of prostate cancer. MATERIALS AND METHODS: Contrast-enhanced harmonic ultrasonography was performed in 103 patients suspected of prostate cancer before biopsy. Time intensity curves were reconstructed for systematic biopsy sites and sonographic abnormalities. The characteristics of the curves were described using hemodynamic indices including arrival time (AT), time-to-peak (TTP), and peak intensity (PI). The differences of hemodynamic indices between high-grade and low-grade cancer were analyzed and the correlations between the hemodynamic indices and biopsy Gleason score were studied. RESULTS: Prostate cancer was detected in 41 of 103 patients and there were significant differences in the hemodynamic indices between the biopsy sites of the non-malignant patients and prostate cancer lesions (p < 0.05). The prostate biopsies revealed 154 prostate cancer lesions, including 31 low-grade lesions and 123 high-grade lesions. The hemodynamic indices AT and TTP of high-grade tumors were significantly shorter than those of low-grade tumors (p = 0.001, 0.002). In addition, high-grade peripheral zone (PZ) tumors had higher PI than low-grade PZ tumors (p = 0.009). The PZ prostate cancer Gleason score correlated with PI, AT and TTP, with Spearman correlation coefficients of 0.223, -0.335, and -0.351, respectively (p = 0.013, < 0.001 and < 0.001). CONCLUSION: Contrast-enhanced ultrasound measurements of hemodynamic indices correlate with the prostate cancer Gleason score.
Aged ; Aged, 80 and over ; Biopsy, Needle ; *Contrast Media ; Hemodynamics ; Humans ; Male ; Middle Aged ; Phospholipids/*diagnostic use ; Prostate/pathology ; Prostatic Neoplasms/blood supply/diagnosis/*ultrasonography ; Sulfur Hexafluoride/*diagnostic use ; Ultrasonography, Doppler ; Ultrasonography, Interventional

OBJECTIVES: The deleterious effects of air pollution on various health outcomes have been demonstrated. However, few studies have examined the effects of air pollution on liver enzyme levels. METHODS: Blood samples were drawn up to three times between 2008 and 2010 from 545 elderly individuals who regularly visited a community welfare center in Seoul, Korea. Data regarding ambient air pollutants (particulate matter < or =2.5 mum [PM2.5], nitrogen dioxide [NO2], ozone [O3], carbon monoxide, and sulfur dioxide) from monitoring stations were used to estimate air pollution exposure. The effects of the air pollutants on the concentrations of three liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], and gamma-glutamyltranspeptidase [gamma-GTP)]) were evaluated using generalized additive and linear mixed models. RESULTS: Interquartile range increases in the concentrations of the pollutants showed significant associations of PM2.5 with AST (3.0% increase, p=0.0052), ALT (3.2% increase, p=0.0313), and gamma-GTP (5.0% increase, p=0.0051) levels; NO2 with AST (3.5% increase, p=0.0060) and ALT (3.8% increase, p=0.0179) levels; and O3 with gamma-GTP (5.3% increase, p=0.0324) levels. Significant modification of these effects by exercise and alcohol consumption was found (p for interaction <0.05). The effects of air pollutants were greater in non-exercisers and heavy drinkers. CONCLUSIONS: Short-term exposure to air pollutants such as PM2.5, NO2, and O3 is associated with increased liver enzyme levels in the elderly. These adverse effects can be reduced by exercising regularly and abstinence from alcohol.
Aged ; Aged, 80 and over ; Air Pollutants/analysis/*toxicity ; Alanine Transaminase/blood ; *Alcohol Drinking ; Aspartate Aminotransferases/blood ; Environmental Exposure ; *Exercise ; Female ; Humans ; Linear Models ; Liver/*drug effects/enzymology ; Male ; Nitrogen Dioxide/chemistry/toxicity ; Ozone/chemistry/toxicity ; Particulate Matter/analysis/toxicity ; Sulfur Dioxide/chemistry/toxicity ; gamma-Glutamyltransferase/blood

OBJECTIVETo analyze the clinical features and gene mutations in an adolescent patient affected with late-onset multiple aeyl-CoA dehydrogenase deficiency (MADD) with severe fatty liver.

METHODSPotential mutations of the ETFDH gene were detected with polymerase chain reaction (PCR) and DNA sequencing.

RESULTSThe 13-year-and-10-month girl has presented with weakness without any other special manifestation. Laboratory tests demonstrated an elevation of myocardial enzyme levels, total cholesterol, lactic acid and abnormal serum free fatty acids. H magnetic resonance spectroscopy revealed severe fatty liver. An increase in multiple plasma acyl-carnitines was detected by gas chromatography/mass spectrometry and isobutyrylglycine in urine by screening with tandem mass spectrometry. Genetic analysis demonstrated 2 heterozygous missense mutations c.250G>A (p.Ala84Thr) and c.353G>T (p.Cys118Phe) in the ETFDH gene. The diagnosis of MADD was confirmed. The patient was given large dose of vitamin B2, which resulted in rapid clinical and biochemical improvement.

CONCLUSIONA common mutation c.250G>A and a novel mutation c.353G>T in the ETFDH gene were identified in the patient. The pathogenic role of c.353G>T (p.Cys118Phe) deserves further study. Early diagnosis of MADD and appropriate therapy is crucial for the prognosis.

Adolescent ; Adult ; Base Sequence ; Electron-Transferring Flavoproteins ; genetics ; Fatty Acids, Nonesterified ; blood ; Fatty Liver ; blood ; enzymology ; genetics ; Female ; Humans ; Infant ; Iron-Sulfur Proteins ; genetics ; Male ; Molecular Sequence Data ; Multiple Acyl Coenzyme A Dehydrogenase Deficiency ; blood ; enzymology ; genetics ; Mutation ; Oxidoreductases Acting on CH-NH Group Donors ; genetics ; Pedigree