Application of peripherally inserted central catheter in immune tolerance induction treatment of children with hemophilia A and accompanying inhibitors in China.

OBJECTIVE: To explore the feasibility, safety and cost effectiveness of the use of peripherally inserted central catheter (PICC) in children with hemophilia A and inhibitors who underwent ITI treatment. METHOD: This retrospective cohort study evaluated the effect of PICC placement and ITI on bleeding rates, costs, and parents' satisfaction before and within 6 months after PICC placement in children with hemophilia A and inhibitors. RESULTS: A total of 20 children with hemophilia A and high-titer inhibitors were included, with a success rate for PICC placement of 100%, at a cost of ¥6730.50. Parents' satisfaction with PICC was 100%, and the total length of catheter indwelling was 6055 days. In terms of curative effect, the success rate of ITI treatment was 75%, and the annualized bleeding rate was decreased from 10.90 ± 12.16 times before placement to 2.10 ± 3.32 times (p < 0.05). The transportation expense for children and their parents to the clinic decreased from ¥20,920 ± 32,274.57 before catheter placement to ¥2915 ± 2195.99 (p < 0.05). Time of children missed school and their parents missed work decreased from 10.85 ± 22.36 days to 1.90 ± 3.58 (p < 0.05) days and 40.33 ± 46.11 days to 3.83 ± 7.11 days (p < 0.05), respectively. CONCLUSION: The use of PICC for ITI treatment in children with hemophilia A and accompanying inhibitors in developing countries (e.g. China) can ensure the effect of ITI, reducing expense and improving the quality of life without obvious side effects.

Central venous access devices implantation in children with severe hemophilia a: data from the children comprehensive care center of China.

Objectives: To report the perioperative management experience of central venous access devices (CVAD) in Chinese children with severe hemophilia A (SHA) in China. Methods: This retrospective study included SHA children who underwent Port-A-Cath or peripherally inserted central catheter (PICC) implantation between 2020/01 and 2021/07. Collected data included baseline characteristics, factor replacement regimen and CVAD-related complications. Results: Nine patients had nine ports placed, and eight patients underwent 10 PICCs placement. Patients without or with low-titer inhibitor (<5 BU) received a port. The median preoperative and postoperative plasma-derived factor VIII (pd-FVIII) doses were 53.0 (44.4-61.1) and 315.9 (88.2-577.8) IU/kg. The median port duration was 189 (15-512) days, with infection incidence of 0.06 per 1000 CVAD days. Patients with high-titer inhibitors (>10 BU) received PICC. The median recombinant factor VIIa (rFVIIa) dose was 87.47 µg/kg before and for 5-7 doses after implantation over 2-3 days. The median PICC duration was 226.5 days, with infection incidence of 0.12 per 1000 catheter-days. Conclusions: CVADs can be safely implanted in China. PICC implantation is a practical and safe option for SHA children with high-titer inhibitors.

[Adrenomedullin alleviates collagen accumulation in pulmonary arteries of rats with hypoxic pulmonary hypertension].

OBJECTIVE: To observe the effect of adrenomedullin (ADM) on the pulmonary vascular collagen metabolism in hypoxic rats in order to study the effect of ADM on chronic hypoxic pulmonary vascular structural remodeling and its possible mechanism. METHODS: Nineteen male Wistar rats were randomly divided into three groups: normal control (n=6), hypoxia (n=7) and ADM-treated hypoxia (n=6). ADM was subcutaneously administered into rats of the ADM-treated hypoxia group by mini-osmotic pump (300 ng/h) for two weeks. After two weeks of hypoxic challenge, mean pulmonary arterial pressure (mPAP) was evaluated using a right cardiac catheterization procedure. The ratio of right ventricular mass to left ventricular plus septal mass[RV/ (LV+S)] was measured. The changes of pulmonary vascular microstructure were observed. Meanwhile, the expression levels of collagen I, collagen III and transforming growth factor (TGF)-ß in pulmonary arteries were detected by immunohistochemical assay. RESULTS: mPAP and RV/(LV+S) increased significantly in the hypoxia group compared with normal controls (P<0.01). The muscularization of small pulmonary vessels and the relative medial thickness of pulmonary arteries increased obviously in the hypoxia group compared with those in the normal control group (P<0.01). Meanwhile, the expression levels of collagen I, collagen III and TGF-ß of pulmonary arteries in the hypoxia group increased markedly compared with those in the normal control group. However, mPAP and RV/(LV+S) were significantly reduced in the ADM-treated hypoxia group compared with those in the hypoxia group (P<0.01). ADM ameliorated pulmonary vascular structural remodeling of hypoxic rats, with a decrease in the expression of collagen I, collagen III and TGF-ß of pulmonary arteries. CONCLUSIONS: ADM might play a regulatory role in the development of hypoxic pulmonary hypertension and hypoxic pulmonary vascular remodeling, through inhibiting the expression of TGF-ß and alleviating the collagen accumulation of pulmonary arteries.

[Alterations of proadrenomedullin N-terminal 20-peptide in rats with pulmonary hypertension induced by high pulmonary blood flow].

OBJECTIVE: The mechanism of high pulmonary blood flow-induced pulmonary hypertension remains unclear. The aim of this study was to explore the effect of proadrenomedullin N-terminal 20-peptide (PAMP) on pulmonary hypertension, through examining the alterations of pulmonary PAMP expression and plasma PAMP concentration in rats with pulmonary hypertension induced by high pulmonary blood flow. METHODS: Sixteen male Sprague-Dawley rats were randomly divided into control (n=8) and shunt groups (n=8). Aortocaval shunting was produced in the shunt group. After 11 weeks of shunting, systolic pulmonary artery pressure (sPAP), diastolic pulmonary artery pressure (dPAP) and mean pulmonary artery pressure (mPAP) were evaluated by using a right cardiac catheterization procedure. The ultrastructural changes in intra-acinar pulmonary arteries were observed. The concentration of plasma PAMP was measured by radioimmunoassay. The expression of PAMP in pulmonary arteries was detected by immunohistochemical assay. RESULTS: sPAP, dPAP and mPAP were significantly increased in shunt rats compared with controls (P < 0.01). Ultrastructural changes, such as hyperplasia and swelling of endothelial cells, irregularity of internal elastic laminar, and hypertrophy and increased number of synthetic phenotype of smooth muscle cells, were found in intra-acinar pulmonary muscularized arteries in the shunt group. Plasma PAMP concentration (616 +/- 195 pg /mL vs 427 +/- 90 pg /mL) and PAMP expression in endothelial cells (0.62 +/- 0.09 vs 0.38 +/- 0.12) and in smooth muscle cells (0.24 +/- 0.07 vs 0.14 +/- 0.05) of pulmonary arteries increased significantly in the shut group compared with controls. CONCLUSIONS: The up-regulation of pulmonary and plasm PAMP expression might be involved in the development of high pulmonary blood flow-induced pulmonary hypertension.

Imbalance of endogenous homocysteine and hydrogen sulfide metabolic pathway in essential hypertensive children.

BACKGROUND: Hypertension is a common disease of the cardiovascular system. So far, the pathogenesis of primary hypertension remains unclear. The elaboration of its pathogenesis is an important topic in the field which calls for urgent resolution. The aim of this study was to probe into the metabolic imbalance of homocysteine (Hcy) and hydrogen sulfide (H(2)S) in children with essential hypertension, and its significance in the pathogenesis of essential hypertension. METHODS: Twenty-five children with essential hypertension and 30 healthy children with normal blood pressure were enrolled in the study. The medical history was investigated and a physical examination was conducted on the subjects. Plasma Hcy content was examined by fluorescence polarization immunoassay (FPIA). The plasma H(2)S level was detected by a modified method with a sulfide electrode. Data were presented as mean +/- standard deviation. The t test was applied to the mean values of both groups. Pearson linear correlation analysis was applied to the plasma Hcy and H(2)S as well as to the systolic pressure against the plasma H(2)S/Hcy ratio. RESULTS: Plasma Hcy, an intermittent metabolite of the endogenous methionine pathway, was markedly increased but plasma H(2)S, a final product of this pathway was significantly decreased in hypertensive cases when compared with normal subjects ((Hcy: (12.68 +/- 9.69) micromol/L vs (6.62 +/- 4.79) micromol/L (t = 2.996, P < 0.01); H(2)S: (51.93 +/- 6.01) micromol/L vs (65.70 +/- 5.50) micromol/L) (t = -8.670, P < 0.01)). The ratio of plasma H(2)S/Hcy in children with hypertension was 5.83 +/- 2.91, while that of the control group was 11.60 +/- 3.30, and the difference is significant with a t = -6.610 and P < 0.01. A negative correlation existed between plasma Hcy and H(2)S concentrations, r = -0.379, P < 0.05. And a negative correlation was found between systolic blood pressure and the plasma H(2)S/Hcy ratio, r = -0.687, P < 0.05. CONCLUSION: There was a metabolic imbalance of homocysteine and hydrogen sulfide in essential hypertensive children.

Chronic administration of adrenomedullin attenuates hypoxic pulmonary vascular structural remodeling and inhibits proadrenomedullin N-terminal 20-peptide production in rats.

Adrenomedullin (ADM) is a novel cardiovascular-active peptide involved in vasodilation, reducing blood pressure and inhibiting vascular smooth muscle cell migration and proliferation. Previous research showed that ADM might be involved in the development of pulmonary hypertension. In this study, we investigated the effect of ADM subcutaneously administered by mini-osmotic pump (300 ng/h) on pulmonary hemodynamics and pulmonary vascular structure in hypoxic rats, as well as the influence of ADM on the proadrenomedullin N-terminal 20-peptide (PAMP) protein and mRNA expressions and its plasma concentrations. The results showed that ADM obviously decreased mean pulmonary artery pressure and the ratio of right ventricular mass to left ventricular plus septal mass in hypoxic rats. Chronic infusion of ADM lessened the muscularization of small pulmonary vessels, attenuated relative medial thickness and relative medial area of pulmonary arteries, and alleviated the ultrastructural changes in pulmonary arteries of hypoxic rats. ADM inhibited the proliferation of pulmonary artery smooth muscle cells, represented by a decrease in the expression of proliferative cell nuclear antigen (PCNA) in the pulmonary artery. Meanwhile, plasma PAMP concentration and the expression of PAMP protein and mRNA by pulmonary arteries in rats of hypoxia with ADM group were markedly decreased compared with those in hypoxic group. The results suggest that ADM ameliorated the development of hypoxic pulmonary vascular structural remodeling. Intramolecular regulation of ADM may play an important role in the regulation of hypoxic pulmonary hypertension by ADM.

[The dynamic changes in endogenous hydrogen sulfide pathway at the early stage of pulmonary hypertension induced by high pulmonary flow in rats].

AIM: To explore the time-dependent changes of endogenous hydrogen sulfide system at the early stage of pulmonary hypertension induced by high pulmonary flow in rats. METHODS: Eighty male SD rats, whose weight ranged 140 - 160 g, were randomly divided into control group (n = 40) and shunt group (n = 40). Rats in shunt group were subjected to an abdominal aorta-inferior vena cava shunt to create an animal model of high pulmonary flow. After 1 d, 3 d, 1 week, 4 week and 8 weeks of experiment, systolic pulmonary artery pressure (SPAP) of each rat, the H2S of rat lung tissue and CSEmRNA of rat lung tissue were evaluated, respectively. RESULTS: SPAP increased significantly as compared with those in control group in 1 week and 8 weeks of experiment. In contrast to control group, the H2S of rat lung tissue increased significantly on 3 d and in 4 weeks, respectively. Meanwhile, in contrast to control group, relative amount of CSE mRNA of lung tissues elevated significantly on 3 d and in 4 weeks, respectively. Moreover, SPAP and the H2S of rat lung tissue, the CSE mRNA of rat lung tissue correlated negatively in 1 week, 4 weeks and 8 weeks of experiment. CONCLUSION: Animal model of rats with high pulmonary blood flow exhibited pulmonary hypertension. Lung tissue H2S and CSE mRNA of rats exhibited double peaks within 8 weeks. These results revealed that endogenous H2S system might be relevant with the development of pulmonary hypertension induced by high pulmonary blood flow, and probably, it played a protective role in the regulation of pulmonary hypertension, especially, at its early stage.

[Range of plasma hydrogen sulfide in children].

OBJECTIVE: To measure the range of plasma hydrogen sulfide (H2S) in children. METHODS: Totally 200 healthy children were classified into 4 groups based on age and sex: 7-14 years old group (n = 75, 43 boys and 32 girls), 15-19 years old group (n = 125, 64 boys and 61 girls). Plasma H2S level was detected by a modified sulfide electrode-based method. RESULTS: Plasma H2 S levels were (52.2181 +/- 17.9400) micromol/L in 7-14 years old boys, (51.9441 +/- 16.5448) micromol/L in 7-14 years old girls, (52.8771 +/- 14.1444) micromol/L in 15-19 years old boys, and (53.6551 +/- 14.5563) micromol/L in 15-19 years old girls (P > 0.05). In summary, the range of plasma H2S in children was about (52.8234 +/- 15.4339) micromol/L. CONCLUSION: The range of plasma H2S in children is about (52.8234 +/- 15.4339) micromol/L.

[Impact of hydrogen sulfide, a novel gaseous signal molecule on nitric oxide/nitric oxide synthase pathway in left-to-right shunt: experiment with rats].

OBJECTIVE: To explore the impact of endogenous hydrogen sulfide (H(2)S), a novel gaseous signal molecule, on the nitric oxide (NO)/nitric oxide synthase (NOS) pathway in left-to-right shunt. METHODS: Thirty-two male SD rats were randomly divided into 4 equal groups: shunt group undergoing abdominal aorta-inferior vena cava puncture so as to establish model of left-to-right shunt; shunt + PPG group undergoing abdominal aorta-inferior vena cava puncture so as to establish model of left-to-right shunt and then intraperitoneal injection of propargylglycine (PPG), an inhibitor of cystathionine-gamma-lyase: sham group undergoing sham operation; and sham + PPG group undergoing sham operation and then intraperitoneal injection of PPG. Four weeks later, right cardiac catheterization was conducted to measure the mean pulmonary artery pressure (MPAP). Then the rats were killed and their lung tissues and samples of plasma were collected. The contents of H(2)S, nitric oxide (NO), and nitrogen oxide synthase (NOS) activity, and the content of plasma NO were calculated. Western blotting was used to detect the endothelial nitric oxide synthase (eNOS) protein in the lung tissues. The correlation of MPAP with lung H(2)S and NO was analyzed. RESULTS: The MPAP of the shunt group was not significantly different from that of the sham group, and the MPAP of the shunt + PPG group was significantly higher then those of the shunt group and sham group by 15.82% and 20.55% respectively (both P < 0.05). The content of lung tissue H(2)S of the shunt group was 37.56 +/- 2.13 micromol/mg, significantly higher than that of the shunt group (14.35 +/- 1.76, P < 0.05), the content of lung tissue H(2)S of the shunt + PPG group was 28.76 +/- 2.24 micromol/mg, significantly lower than that of the shunt group (P < 0.05). The lung tissue NO content of the shunt group was 38.48 micro +/- 6.53 micromol/microg, significantly higher than that of the sham group (31.78 +/- 6.51 micromol/microg). The NOS activity of the shunt group was 15.12 +/- 2.44 U/mg protein, significantly higher than that of the sham group (12.00 +/- 1.40 U/mg protein, P < 0.05). The lung eNOS content of the shunt group was significantly higher than that of the sham group (P < 0.05). The plasma NO content of the shunt group was 23.18 +/- 3.56 micromol/L, significantly higher than that of the sham group (17.94 +/- 3.39 micromol/L, P < 0.05). The lung tissues NO and NOS activity, and plasma NO of the shunt + PPG group were 46.04 +/- 5.95 micromol/microg, 20.89 +/- 3.94 U/mg protein, and 27.79 +/- 4.82 micromol/L respectively, all significantly higher than those of the shunt group (38.48 +/- 6.53 micromol/microg, 15.12 +/- 2.44 U/mg protein, and 23.18 +/- 3.56 micromol/L, all P < 0.05). The eNOS content of the shunt + PPG group was significantly higher than that of the shunt group (P < 0.05). The lung H(2)S content was negatively correlated with the MPAP and lung NO content (r = -0.705, P = 0.005; and r = -0.645, P = 0.013). CONCLUSION: Endogenous H(2)S may play a regulatory role in the pulmonary artery pressure of left-to-right shunt through inhibiting NO/NOS pathway.

[Impact of hydrogen sulfide donor on experimental pulmonary hypertension induced by high pulmonary flow and endogenous carbon monoxide/heme oxygenase pathway].

OBJECTIVE: To explore the possible impact of hydrogen sulfide donor-NaHS (sodium hydrosulfide) on experimental pulmonary artery structural remodeling induced by high pulmonary flow and endogenous carbon monoxide/heme oxygenase pathway. METHODS: Thirty-two male SD rats were randomly divided into shunt group (n=8), shunt+NaHS group (n=8), sham group (n=8) and sham+NaHS group (n=8). Rats in shunt group and shunt+NaHS group were subjected to an abdominal aorta-inferior vena cava shunt to create an animal model of high pulmonary flow. In the sham group and sham+NaHS group, rats experienced the same experimental processes except the shunting procedure. After 11 weeks of operation, systolic pulmonary artery pressure (SPAP) was detected using a right cardiac catheterization procedure. The percentage of muscularized artery (MA), partly muscularized artery (PMA) and non-muscularized artery (NMA) was calculated. Relative medial thickness (RMT) and relative medial area (RMA) of MA were observed under optical-microscope, respectively. The ultra-structure of pulmonary arteries was observed under electro-microscope. Lung tissue carbon monoxide (CO) was measured. Western-blot was used to analyze lung tissue heme oxygenase (HO-1) protein expression. RESULTS: After 11 weeks of shunt, compared with sham group, SPAP in shunt group increased by 48.6%.The percentages of MA and PMA increased by 74.2% and 90.9%, but the percentage of NMA decreased 32.2%, respectively, in rats of shunt group as compared with that of sham group. In contrast to those in sham group, RMT and RMA in median MA and small MA of rats in shunt group increased by 83.6%, 86.9%, and 74.4%, 39.9%, respectively. Ultra-structural changes in rats of shunt group showed that endothelial cells were swollen and denatured, inner elastic membrane became irregular, and smooth muscle cells became synthetic phenotype. The sham and shunt groups did not differ significantly in CO and HO-1 protein expression of lung tissues. In contrast to that of shunt group, SPAP in rats of shunt+NaHS group decreased by 19.8%. The percentages of MA and PMA decreased by 14.4% and 12.2%, but the percentage of NMA increased 13.9%, respectively, in rats of shunt+NaHS group as compared with that of shunt group. In contrast to those of shunt group, RMT and RMA in median MA and small MA in rats of shunt+NaHS group decreased by 16.2%, 14.3%, and 26.9%, 14.3%, respectively. For rats in shunt+NaHS group ultra-structural changes showed that flat endothelial cells, inner elastic membrane became regular, and smooth muscle cells were contractile phenotype. The content of CO increased by 25.5% and the HO-1 protein expression increased by 114.3% in shunt+NaHS group as compared with those of shunt group. CONCLUSION: NaHS might prevent pulmonary hypertension and pulmonary artery structural remodeling induced by high pulmonary flow, and its mechanism might be associated with the changes in endogenous CO/HO pathway.

[Effect of adrenomedullin 1-50 on chronic hypoxic pulmonary hypertension in rats].

OBJECTIVE: To explore the effect of adrenomedullin(1-50) (ADM(1-50)) on hypoxic pulmonary hypertension and pulmonary vascular structural remodeling and the plasma concentration of nitric oxide (NO) and hydrogen sulfide (H(2)S) in rats. METHODS: Twenty male Wistar rats were randomly divided into control group (n=7), hypoxic group (n=6) and hypoxic with ADM(1-50) group (n=7). ADM(1-50) was subcutaneously administered into rats of hypoxic with ADM(1-50) group by mini-osmotic pump (300 ng/h). After two weeks' hypoxic challenge, mean pulmonary arterial pressure (mPAP) was evaluated by using a right cardiac catheterization procedure. The ratio of right ventricular mass to left ventricular plus septal mass [RV/(LV+S)] was detected. Pulmonary vascular microstructure was measured and the ultrastructural changes in intra-acinar pulmonary arteries were observed. Meanwhile, plasma concentrations of NO and H(2)S were measured. RESULTS: mPAP was significantly increased in hypoxic rats than that in controls [(24.9+/-6.8) mmHg vs (14.3+/-2.4) mmHg, P<0.01,1 mmHg=0.133 kPa]; RV/(LV+S) was also significantly increased in hypoxic rats than that in controls [(0.318+/-0.054) vs (0.182+/-0.007), P<0.01]. Microstructure and ultrastructure of pulmonary arteries changed obviously in hypoxic rats with the development of hypoxic pulmonary vascular structural remodeling. Meanwhile, plasma NO and H(2)S concentrations in hypoxic rats were markedly decreased compared with controls. However, mPAP was significantly decreased in hypoxic rats treated with ADM(1-50) than that in hypoxic rats [(14.9+/-3.0) mmHg vs (24.9+/-6.8) mmHg, P<0.01]; RV/(LV+S) was also significantly decreased than that in hypoxic rats [(0.185+/-0.011) vs (0.318+/-0.054), P<0.01]. ADM(1-50) ameliorated pulmonary vascular structural remodeling of hypoxic rats in association with an increase in plasma NO and H(2)S concentrations. CONCLUSION: ADM(1-50) plays an important role in regulation of the development of hypoxic pulmonary hypertension and hypoxic pulmonary vascular structural remodeling, through promoting NO and H(2)S production in hypoxic rats.

[Survey of plasma lipid value in children in Beijing area and the changes of gaseous molecule-hydrogen sulfide in the ones with dyslipidemia].

OBJECTIVE: To evaluate plasma lipid value in children in Beijing areas and to explore the relationship between plasma hydrogen sulfide (H(2)S) level and lipid components. METHODS: A total of 971 healthy school students were chosen randomly, all coming from Beijing city and its counties. They were divided into four groups according to their gender and age (boys and girls in school age and in puberty). Body mass index (BMI) was calculated according to the measurement of body height and weight. Familial history, past medical history and the history of present illness were investigated. Physical examination was also carried on. Alanine aminotransferase (ALT), total cholesterol (TC), triglyceride (TG), high density lipoprotein-cholesterol (HDL-C) and low density lipoprotein-cholesterol (LDL-C) were detected by HITACHI 7060 automatic biochemical analyzer. Forty children (31 males and 9 females) with dyslipidemia were chosen randomly among them as patients. Other 60 children (38 males and 22 females) with normal plasma lipid level served as controls. Plasma H(2)S level was detected by modified sulfide electrode. RESULTS: There were 91 children with dyslipidemia (58 males and 33 females) in 971 students. The prevalence rate was 9.37%. The average value of BMI in patients was higher than that of controls. An association of increased ALT level with the prevalence of dyslipidemia was observed. Hydrogen sulfide concentration in plasma showed out skew distribution. Measurement data were presented as median (P(25), P(75)). Hydrogen sulfide was 34.40 (32.98, 35.47) micromol/L in children with dyslipidemia and 38.81(36.53, 40.66) micromol/L in controls. There was statistical difference between the two groups (P<0.01). Average value of plasma hydrogen sulfide was 35.54 (33.41, 39.24) micromol/L in males and 37.82 (33.84, 39.80) micromol/L in females. There was no difference in plasma hydrogen sulfide between male and female subjects (P>0.05). CONCLUSION: The prevalence rate of dyslipidemia in Beijing children is relatively high as compared with what it was during the past several decades. There was a significant decrease in plasma endogenous H(2)S level in children with dyslipidemia as compared with that of healthy children. There was an obvious correlation between plasma hydrogen sulfide and plasma lipids.