Lobaplatin promotes 125I-induced apoptosis and inhibition of proliferation in hepatocellular carcinoma by upregulating PERK-eIF2α-ATF4-CHOP pathway.

We investigated the mechanism underlying the effect of a combination treatment of 125I radioactive seed implantation and lobaplatin (LBP) in hepatocellular carcinoma. The effects of administration of HCC cells and subcutaneous tumor model of mice with different doses of 125I or a sensitizing concentration of LBP alone, or in combination, on cellular apoptosis and proliferation were analyzed and it was confirmed that LBP promotes 125I-induced apoptosis and inhibition of proliferation of HCC. Furthermore, isobaric tag for relative and absolute quantification labeling analyses suggested that 125I promoted the apoptosis and inhibition of proliferation of HCC cells by upregulating the expression of PERK-eIF2α-ATF4-CHOP pathway, a well-known apoptosis-related pathway. Moreover, LBP was found to boost the 125I-induced upregulation of this pathway and increase the apoptosis. Our data indicate that LBP promotes the apoptotic and anti-proliferative effects of 125I and provide a firm foundation for better clinical application of this combination therapy.

Systematic large-scale meta-analysis identifies miRNA-429/200a/b and miRNA-141/200c clusters as biomarkers for necrotizing enterocolitis in newborn.

Necrotizing enterocolitis (NEC) is a critical neonatal disease with a high mortality. The possibility that miRNAs may play an important role in NEC has raised great attention. Hence, the present study identified biomarkers that affected NEC in newborn progression through miRNA and gene expression profile analysis. miRNA chip GSE68054 and gene chip GSE46619 of NEC in newborn were analyzed to screen out differentially expressed miRNA and differentially expressed genes (DEGs). Next, target genes of differentially expressed miRNA were predicted, and differentially expressed miRNA-DEG regulatory network was constructed to select key miRNAs. After gene ontology and kyoto encyclopedia of genes and genomes enrichment analysis on target genes of key miRNAs, the target genes enriched in pathways were extracted to establish differentially expressed miRNA-DEG-disease gene network for gene interaction analysis. Targetting relationship between miRNAs and target genes was verified. A total of 15 miRNAs were differentially expressed in NEC in newborn, amongst which miR-429/200a/b and miR-141/200c clusters were poorly expressed and might play a significant role in NEC in newborn. Besides, target genes of miR-429/200a/b and miR-141/200c clusters were enriched in 11 signaling pathways. Vascular endothelial growth factor (VEGFA), E-selectin (SELE), kinase insert domain receptor (KDR), fms-related tyrosine kinase 1 (FLT1), and hepatocyte growth factor (HGF) were highly expressed in NEC in newborn, which were negatively regulated by miR-429/200a/b and miR-141/200c clusters and shared close association with disease genes. miR-429/200a/b and miR-141/200c clusters are poorly expressed while their target genes (VEGFA, SELE, KDR, FLT1, and HGF) are highly expressed in NEC in newborn, which might be identified as important biomarkers for this disease.

Protective effects of BMSCs in combination with erythropoietin in bronchopulmonary dysplasia-induced lung injury.

Bronchopulmonary dysplasia (BPD) is the most common type of chronic lung disease in infancy, for which no effective therapy is currently available. The aim of the present study was to investigate the effect of treatment with bone marrow mesenchymal stem cells (BMSCs) in combination with recombinant human erythropoietin (rHuEPO) on BPD­induced mouse lung injury, and discuss the underlying mechanism. The BPD model was established by the exposure of neonatal mice to continuous high oxygen exposure for 14 days, following which 1x106 BMSCs and 5,000 U/kg rHuEPO were injected into the mice 1 h prior to and 7 days following exposure to hyperoxia. The animals received four treatments in total (n=10 in each group). After 14 days, the body weights, airway structure, and levels of matrix metalloproteinase­9 (MMP­9) and vascular endothelial growth factor (VEGF) were detected using histological and immunohistochemical analyses. The effect on cell differentiation was observed by examining the presence of platelet endothelial cell adhesion molecule (PECAM) and VEGF using immunofluorescence. Compared with the administration of BMSCs alone, the body weight, airway structure, and the levels of MMP­9 and VEGF were significantly improved in the BMSCs/rHuEPO group. The results of the present study demonstrated that the intravenous injection of BMSCs significantly improved lung damage in the hyperoxia­exposed neonatal mouse model. Furthermore, the injection of BMSCs in combination with intraperitoneal injection of rHuEPO had a more marked effect, compared with BMSCs alone, and the mechanism may be mediated by the promoting effects of BMSCs and EPO. The results of the present study provided information, which may assist in future clinical trials.

The effect of PS-341 on pulmonary vascular remodeling in high blood flow-induced pulmonary hypertension.

The aim of the present study was to investigate the effects of PS-341 on vascular remodeling in an experimental rat model of high blood flow-induced pulmonary arterial hypertension (PAH), as well as to elucidate its mechanisms of action. We established the PAH model by a surgical method that implanted a left-to-right shunt. Three days post-surgery, the animals were randomly assigned to 3 groups (n=15 in each group): sham-operated (control), shunt (model) and PS-341 (treated) groups. Eight weeks post-surgery, hemodynamic parameters were significantly improved in the PS-341 group compared with the shunt group (P<0.05). Immunohistochemical analysis indicated that the expression levels of ubiquitin and nuclear factor-κB (NF-κB) p65 were significantly higher in the shunt group compared with the sham-operated group (P<0.05). Semi-quantitative western blot analysis further confirmed that the levels of ubiquitin and NF-κB p65 were decreased, while those of IκB-α (an inhibitor of NF-κB) were significantly increased in the PS-341 group compared with the shunt group (P<0.05). In conclusion, PS-341 attenuates high blood flow-induced pulmonary artery remodeling in rats via inhibition of the NF-κB pathway.

Proteasome inhibitor PS-341 attenuates flow-induced pulmonary arterial hypertension.

PS-341, a proteasome inhibitor, is suggested to prevent the vascular remodeling induced by high-flow pulmonary artery hypertension (PAH), but the mechanism remains unclear. The aim of the current study was to investigate the effects and possible mechanism of PS-341 on hypertension-induced vascular remodeling. Male Sprague-Dawley rats were subjected to surgical methods to produce a shunt model of PAH. Three days after the surgical procedure, the animals randomly assigned to four groups (n = 10 in each group): I: sham group; II: shunt group; III: vehicle; IV: treated group. Eight weeks postoperative, the hemodynamics data were measured through Swan-Ganz catheter; the protein expression level of proliferating cell nuclear antigen, nuclear factor-κB (NF-κB), inhibitor of nuclear factor-κB (I-κBα), transforming growth factor beta-ß (TGF-ß), drosophila mothers against decapentaplegic protein (Smad) and vascular endothelia growth factor (VEGF) were investigated by immunohistochemical and Western blotting; the mRNA expression level of Ubiquitin (Ub), Smad3, TGF-ß1and Smad2 in lung were performed to detect by real-time reverse transcription-polymerase chain reaction analysis. The results showed that hemodynamic data and right ventricular hypertrophy were significantly improved (P < 0.05), the expression level of Ub, NF-κB, TGF-ß1, Smad2 and VEGF were decreased (P < 0.05), but the level of I-κBα was increased in PS-341 treated group as compared with the shunt and vehicle groups (P < 0.05). In conclusion, the present study indicated that PS-341 could significantly improve the lung damage, attenuate pulmonary vascular remodeling induced by high blood PAH model. The mechanism may be mediated by inhibition of NF-κB and TGF-ß/Smad signaling pathway and modulation the effect of VEGF.

The imbalance of Th17/Treg in Chinese children with Henoch-Schonlein purpura.

Interleukin 17 (IL-17)-producing T helper (Th17) cells and CD4(+)CD25(+) regulatory T (Treg) cells are two new T-cell subsets that are thought to be critically involved in mediating and regulating autoimmune responses. The imbalance of Th17/Treg cells has been implicated in a wide range of autoimmune disorders. The aim of our study was to determine whether the Th17/Treg balance was abnormal in children with Henoch-Schonlein Purpura (HSP). We examined twenty-three new-onset HSP patients and eighteen healthy children. The frequency of Th17 cells and the IL-17 concentration were higher in HSP patients than in healthy controls. The frequency of Treg cells and the interleukin 10 (IL-10) concentration were lower in HSP patients than in healthy controls. Compared to healthy controls, HSP patients exhibited an increase in the ratio of Th17/Treg. The Th17/Treg ratio was positively correlated with the erythrocyte sedimentation rate (ESR), kidney lesions and the clinical symptom of the presence of more than two organ systems with lesions. However, the ratio had no correlation with anti-streptolysin O (ASO) or complement 3 (C3) levels. These results indicate that a Th17/Treg imbalance exists in HSP, and it appears to be closely related to the disease onset.

Association between human cartilage glycoprotein 39 (YKL-40) and arterial stiffness in essential hypertension.

BACKGROUND: YKL-40, a proposed marker of inflammation and endothelial dysfunction, is associated with atherosclerosis and an increased cardiovascular mortality in the general population. However, the relationship between YKL-40 and arterial stiffness in hypertensive patients has not been adequately assessed. METHODS: The relationship between serum levels of YKL-40 and arterial stiffness was evaluated in 93 essential hypertensive subjects and 80 normal subjects. Essential hypertensive subjects were divided into two groups based upon urinary albumin-to-creatinine ratio (ACR): nonmicroalbuminuric group, (ACR <30 mg/g, n = 50) and microalbuminuric group (ACR ≥ 30 mg/g, n = 43). Large artery wall stiffness was assessed by measuring femoral arterial stiffness and carotid-femoral pulse wave velocity (cf-PWV). Serum levels of YKL-40 were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: The study demonstrated that YKL-40,cf-PWV and femoral arterial stiffness were increased significantly (P<0.05) in the hypertensive group compared with normal controls. These measurements were also increased significantly ( P<0.05) in the microalbuminuric group compared with the nonmicroalbuminuric group. YKL-40 was positively correlated with cf-PWV( r = 0.44, P = 0.000) and femoral arterial stiffness ( r = 0.42, P =0.001). Multiple linear stepwise regression analysis showed that YKL-40 was the impact factor of arterial stiffness ( P<0.05). CONCLUSION: YKL-40 levels are elevated in essential hypertension subjects with an independent association between increasing YKL-40 levels and increasing arterial stiffness. The study suggests it played a positive role of YKL-40 in the progressing vascular complications in patients with essential hypertension.

Effects of autologous bone marrow mononuclear cells implantation in canine model of pulmonary hypertension.

BACKGROUND: We investigated the safety and feasibility of intratracheal administration of autologous bone marrow-derived mononuclear cells (ABM-MNCs) and observed the effects in a canine model of pulmonary hypertension (PH). METHODS AND RESULTS: The PH model was induced by intravenous injection of 3mg/kg dehydromonocrotaline (DMCT) via the right atrium. Two weeks after DMCT administration, the animals received 4 different treatments (n=10 in each group): (I) negative control group; (II): ABM-MNCs group; (III) PH group; (IV) PH+ABM-MNCs group. Six weeks after injection of cells (107), the hemodynamic data were significantly improved in group IV compared with group III (P<0.05). The ratio of right ventricular weight to left ventricular plus septal weight was significantly decreased in group IV compared with group III (P<0.05). The mRNA levels of vascular endothelial growth factor, preproendothelin-1, interleukin-6 and tumor necrosis factor-α were significantly improved in group IV compared with group III (P<0.05). The immunofluorescence result showed that 6 weeks after administration ABM-MNCs could differentiate into pulmonary vascular endothelial cells. CONCLUSIONS: Six weeks after intratracheal administration, ABM-MNCs significantly improved the impairment caused by DMCT in a canine model of PH (ie, decreased pulmonary arteriolar narrowing, alveolar septum thickening and right ventricular hypertrophy, enhanced angiogenesis) and this provides a firm foundation for a clinical trial.

Implantation of mesenchymal stem cells improves right ventricular impairments caused by experimental pulmonary hypertension.

INTRODUCTION: Pulmonary hypertension (PH) is a rapidly progressive and fatal disease. In recent years, despite drug treatment made significant progress, the prognosis of patients with advanced PH remains extremely poor. The authors implanted bone marrow-derived mesenchymal stem cells (BMSCs) intravenously into the PH model rats and observed the effect of MSCs on right ventricular (RV) impairments. METHODS: BMSCs were isolated, cultured from bone marrow of rats and stained with the cross-linkable membrane dye in vitro. One week after, a PH model was induced by subcutaneous injection of monocrotaline, the animals were randomly divided into 4 groups (n = 20 in each group): I, control; II, MSCs implantation; III, PH and IV, PH + MSCs implantation. Two weeks after MSCs implantation, the authors observed the MSC survival and transformation by immunofluorescence microscopy. On the other hand, RV hypertrophy and the elevation of systolic pressure were detected by echocardiography. RESULT: Three weeks after monocrotaline injection, RV systolic pressure, mean right ventricular pressure and mean pulmonary arterial pressure were significantly elevated in group III than in group I and II (P < 0.05) but significantly lower in group IV than in group III (P < 0.05). These results showed that implantation of MSCs could improve RV impairments caused by experimental PH. Histochemical results confirmed that transplanted MSCs were still alive after 2 weeks and part of the cells could differentiate into pulmonary vascular endothelial cells. CONCLUSION: Intravenous implantation of MSCs could significantly reduce or even reverse the progression of MCT-induced PH, improve cardiac function and hemodynamics.

[Meta-analysis of the risk factors for coronary artery lesion secondary to Kawasaki disease in Chinese children].

OBJECTIVE: Coronary artery lesion (CAL) is a serious complication of Kawasaki disease (KD). Whether there is CAL and the severity are the most critical factors of the prognosis of KD. The incidence of KD is currently increasing year by year. KD has replaced rheumatic fever as the main entity of acquired heart disease of children. This study aimed to identify risk factors of CAL secondary to KD and take early interventions to prevent CAL or reduce its incidence. METHOD: Literature search was performed at Chinese Academic Literature Main Database, Chinese Science and Technology Periodical Database, Wanfang Periodicals and Dissertation Database, and the Chinese Biomedical Literature Database comprehensively, besides, retrospective retrieval and manual retrieval were also performed from the domestic public actions and the dissertations dating from January, 2000 to December, 2009. RavMan 4.2 provided by Cochrane was used for meta analysis. Fixed or random model was selected according to the results of heterogeneity test. Sensitivity analysis was done according to the different results. The publication bias was evaluated by funnel plots. Odds ratio (OR) and 95% confidence interval (CI) were estimated in the dissertation. RESULT: Twenty studies were confirmed to be eligible. All the 20 studies were retrospective. OR and 95%CI of the risk factors were as follows: age ≤ 1 year, OR = 1.58, and 95%CI (1.23, 2.04), P = 0.0004; male gender, OR = 1.48, 95%CI (1.29, 1.71), P < 0.000 01; WBC > 20 × 10(9)/L, OR = 1.73, 95%CI (1.32, 2.26), P < 0.0001; C-reactive protein (CRP) > 100 mg/L, OR = 2.37, 95%CI (1.49, 3.77), P = 0.0003; fever duration > 10 d, OR = 3.23, 95%CI (2.08, 5.02), P < 0.000 01; use of intravenous gamma globulin (IVIG) > 10 d, OR = 2.50, 95%CI (1.98, 3.16), P < 0.000 01. CONCLUSION: The high risk factors for coronary artery lesion secondary to Kawasaki disease are age ≤ 1 year, male, WBC > 20 × 10(9)/L, CRP > 100 mg/L, fever duration>10 d, and use of intravenous gamma globulin (IVIG) > 10 d.

[Mentality and behavior of children with congenital heart diseases].

OBJECTIVE: The present study was designed to investigate the influence of Congenital Heart Disease (CHD) on the mentality and behavior in children, and to compare post operative mentality and behavior in children receiving interventional therapy and congenital heart surgery. METHOD: Mentality and behavior of 232 children suffering from CHD were examined with Achenbach Child Behavior Checklist (CBCL) edited by XU Tao-yuan in 1992 and 100 sex, age, education and achievement-matched children with pneumonia were enrolled as controls. RESULTS: The mentality and behavior abnormal rates of the boys and girls suffering from CHD were significantly higher than those of controls (P < 0.01, P < 0.05). The behavior abnormities of the boys presented as depression, social flinch, physical complains, assault and violate rules. Whereas the girls presented as depression, social flinch, physical complains and violate rules. The total cursory mark of postoperative check result of the interventional and surgical children, both in girls and in boys, were significantly lower than those of the preoperative children (P < 0.05). The total and assault cursory mark of postoperative check result of children treated with interventional therapy were significantly lower than those of children treated with the surgical operations (P < 0.05). The abnormal rates of mentality and behavior positively correlated with the disease course. CONCLUSIONS: CHD is associated with increased abnormal mentality and behavior of the children. Early treatment, especially the interventional therapy can significantly improve the mentality and behavior of the children with CHD.

[Effect of p21 gene transfection mediated by replication deficient adenovirus on the pulmonary hypertensive rat model].

OBJECTIVE: To investigate the feasibility of transferring p21 gene into lung tissue with recombinant adenovirus with full-length cDNA of p21 inserted in the Wistar rat model of pulmonary hypertension (PAH) induced by left-to-right shunt, study the expression of the desired gene in vivo, find if overexpression of desired gene can inhibit pulmonary hypertension. METHODS: With full-length cDNA of p21 transfected HEK293 cells with clonfectin, and was packed, amplified in order to obtain the high-titer recombinant adenovirus (AdCMV-p21). The infection titer was determined by TCID50 method and was diluted into 1.67 x 10(8) pfu/L. Wistar rats were randomly allocated to control group (n = 10), model group (n = 15), test group (n = 10) and test control group (n = 10). In model group and test group left-to-right shunt pulmonary hypertension was developed by using cuff technique. AdCMV-p21 was transfected into test group and test control group using tracheal inhalation. The mPAP, mRVP and RVHI were measured and compared between every two groups. The left lung was immunohistochemically stained to observe the result of transfection. The right lung was HE stained to observe morphological changes in arteria pulmonalis and calculate WT%. RESULTS: The mRVP, mPAP and WT% in model group and test group were significantly higher than those in control (P < 0.05), which suggested that the rat model of PAH was established successfully. Brown spots in the nucleus of VSMCs of pulmonary artery were seen in test group and test control group, which indicated that AdCMV-p21 was transfected successfully. The rate of transfected cells in test group was (42.8 +/- 11.6)%, which was equal to that of test control group (P > 0.05). In test group, the mPAP was (20.06 +/- 3.40) mm Hg (1 mm Hg = 0.133 kPa), mRVP was (22.53 +/- 2.53) mm Hg, WT% was (30.8 +/- 3.5)%, which were significantly lower than those in model group (P < 0.05), but higher than those in control group and test control group (P < 0.05). CONCLUSION: The recombinant adenovirus could successfully carry p21 and transfect the lung tissue of PAH rat model, and full expression of p21. p21 gene could inhibit the development of PAH.

Analysis of osteochondro-induction using growth and differentiation factor-5 in rat muscle.

Growth and differentiation factor-5 (GDF-5) belongs to the TGF-beta super family, and reportedly plays an important role in cartilage development and differentiation. In this study, we implanted GDF-5 in rat leg muscle, and evaluated its in vivo osteochondro-inducing activity by histological and X-ray examinations. GDF-5 (0, 100, 300, and 500 microg) and the carrier type I collagen were mixed, and the mixture was implanted into rat leg muscle. Three weeks later, the site of implantation was examined by soft X-ray, and examined histologically. The GDF-5 0 and 100 microg groups showed no osteochondro-induction. The GDF-5 300 microg group showed aggregates of cartilage and some bone tissue in the carrier. The GDF-5 500 microg group revealed bone and no cartilage. This is the first report of the dose-dependent effect of GDF-5 inducing osteochondrogenesis or osteogenesis.

Survival and wound contraction of full-thickness skin grafts are associated with the degree of tissue edema of the graft bed in immediate excision and early wound excision and grafting in a rabbit model.

The objective of this study was to evaluate the survival of skin grafts on graft beds of immediate excision and early wound excision at various time periods after burns and to establish the appropriate timing of burn excision and grafting in a rabbit model. Eight groups of male Japanese white rabbits (n = 5 per group) were established. Animals of all groups were given a 5 x 10-cm full-thickness burn on their shaved back and received the autografting 3, 6, 12, 18, 24, 48, and 72 hours and 5 days after receiving burns, respectively. Weekly skin-graft evaluation was performed for 5 weeks after grafting by measurement of the secondary skin graft contracture (in size) and the survival area of grafts, with use of computerized planimetry. In addition, relative quantitative analysis of exudation on the burned wound was evaluated. Our results indicated that the exudate-related graft loss and graft contracture varied according to the timing of wound excision. The wound contractures of the grafts were maximal in both the 18-hour and 24-hour groups at 2, 3, 4, and 5 weeks after grafting. The 18-hour and 24-hour groups exhibited significantly greater graft loss than the 72-hour and 5-day groups (P < .05). An apparent increase in the amount of exudation on the graft bed was shown in the 18- and 24-hour groups vs the other groups (P < .05). A reverse correlation was detected between the survival area of the skin graft and the degree of exudation of the graft bed. In conclusion, the survival area and secondary contraction of skin grafts are associated with the degree of tissue edema of the graft bed in immediate excision and early excision in the rabbit model. The adverse affect of edema leakage on the graft bed for skin graft survival was shown. We believe that immediate excision or early wound excision and grafting performed within 12 hours after burn or 48 hours later should be considered in the rabbit model.

The use of skin allograft with donor-specific tolerance in a rabbit model of full-thickness burn.

UNLABELLED: Previous studies in our laboratory demonstrated that portal vein or intraosseous administration of donor bone marrow cells for modulation of the central immune system is likely to be beneficial for allograft tolerance induction in rabbits. We recently reported that the severity of host conditioning for donor-specific tolerance induction was reduced without loss of efficacy by using a single intraosseous injection of donor bone marrow cells without immunosuppressive agent administration or T cell depletion. We now further investigated the feasibility and effectiveness of skin allografting using donor-specific tolerance to treat full-thickness burns. MATERIALS AND METHODS: Dutch rabbits were used as recipients, and Japanese white rabbits were used as donors. Three experimental groups of burned rabbits were studied. Group I, allograft control; group II, allograft plus total-body irradiation; group III, allograft plus total-body irradiation and bone marrow infusion. Allograft survival times were determined by macroscopic and histopathologic examinations. RESULTS: Mean (S.D.) skin allograft survival was as follows: group I, 13.2 (4.1) days; group II, 15.2 (3.7) days; group III, 108.4 (14.3) days. CONCLUSION: We have shown the potential to perform long-term skin allografts by the induction of donor-specific tolerance in a rabbit model of burn.

Immunolocalization of vascular endothelial growth factor on intramuscular ectopic osteoinduction by bone morphogenetic protein-2.

When recombinant human bone morphogenetic protein-2 (rhBMP-2) is implanted in soft tissues, bony tissue is induced during the course of endochondral ossification. The relationship between endochondral ossification and vascularization is important in bone formation, and vascular endothelial growth factor (VEGF) is considered to play an important role in this process. In this study, the immunohistological localization of VEGF was investigated in rhBMP-2-induced ectopic endochondral ossification in the calf muscle of rats. In addition, the characteristics of anti-VEGF antibody-reactive cells were histologically investigated using electron microscopy to examine the cause of endochondral ossification induced by recombinant human bone morphogenetic protein-2. The role of VEGF in rhBMP-2-induced osteoinduction and vascular induction was studied by observing the relationship between the localizations of anti-VEGF antibody-reactive cells and vascularization. During the process of rhBMP-2-induced ectopic endochondral ossification, fibroblast-like cells, which were located at the margin of the implant and reactive to BMP-2 at 5 days, were positive for VEGF immunostaining. Hypertrophic chondrocytes appeared 9 days and osteoblasts appeared 14 to 21 days after implantation, and all these cells were reactive with anti-VEGF antibody. Bony trabeculae subsequently appeared in the muscle, and new blood vessels were formed alongside the trabeculae. When VEGF was added to rhBMP, more new blood vessels and bone were formed in the induced bone. These findings suggested that rhBMP-2 induced the differentiation of undifferentiated mesenchymal cells to chondrocytes and osteoblasts, and these differentiated cells expressed VEGF, creating an advantageous environment for vascularization in bony tissue.

[Plasma levels of adrenomedullin in children with congenital heart disease].

OBJECTIVE: This study was designed to investigate the pathophysiological role of adrenomedullin (ADM) in congenital heart disease. METHODS: Forty-eight children with congenital heart disease confirmed by cardiac echocardiography and catheterization were studied. The patients were divided into three groups on the basis of hemodynamic indices measured during cardiac catheterization: high pulmonary blood flow with (group 1) or without (group 2) pulmonary hypertension (mean pulmonary arterial pressure > 20 mmHg) and a cyanosis group (without high pulmonary blood flow) (group 3). Six children who recovered from Kawasaki disease were used as a Control group. Plasma ADM levels were measured by radioimmunoassay. RESULTS: The plasma ADM levels from the femoral vein were significantly higher than those from femoral artery in patients with congenital heart disease. The patients from group 1 and group 3 had higher plasma ADM levels (1.9 +/- 1.8 pmol/L and 2.4 +/- 1.3 pmol/L, respectively) than the controls (1.0 +/- 1.4 pmol/L; P < 0.01). Plasma ADM levels were significantly negatively correlated with mean systemic arterial pressure, oxygen saturation in mixed vein and oxygen saturation in systemic artery (r=-0.401, -0.562, -0.600, respectively; P < 0.01) but positively correlated with pulmonary vascular resistance (r=0.406; P < 0.01). CONCLUSIONS: Plasma ADM levels are increased in congenital heart disease with high pulmonary blood flow and hypertension or with cyanosis. Plasma ADM levels are related to pulmonary arterial resistance and hypoxemia. Increased ADM levels may play roles in reducing the pulmonary arterial resistance and alleviating hypoxemia in these patients.

Transplantation of a whole ear allograft by immunological induction of donor-specific tolerance by bone marrow transplantation: an experimental study in rabbits.

Previous studies in our laboratory have shown that giving bone marrow cells through the portal vein or intraosseous route is likely to be beneficial to tolerance of induction of allografts in rabbits. Using this model, we tested whether a less severe regimen for conditioning of the host can prevent rejection of allografts. Rabbits were given a single intraosseous injection of donor bone marrow cells and total body irradiation (7 Gy) and transplantation of skin and ear allografts. Mean skin allograft survival for this treatment was 88 days, which was similar to the results of our earlier study. A donor ear was accepted for more than a year with no signs of rejection. These results suggest that a single intraosseous injection of donor bone marrow cells is sufficient for induction of donor-specific tolerance in rabbits and that immunosuppressive agents may not be needed.

Long-term immunologic induction of donor-specific tolerance to skin allografts by bone marrow transplant in rabbits.

The induction of donor-specific tolerance to skin allografts was investigated in rabbits using bone marrow transplantation techniques reported to be effective in mice. Various routes of bone marrow transplantation (i.e., intravenous, portal venous, or intraosseous) were also examined. In regimen A, the animals were treated with portal venous injection of bone marrow cells from the donor on day 0 and intravenous injection of bone marrow cells from the same donor on posttransplant day 5. In regimen B, the animals were treated with portal venous and intraosseous injections of donor bone marrow cells on day 0 and intravenous injection of bone marrow cells from the same donor on posttransplant day 5. In regimen C, the animals were given intraosseous injection of donor bone marrow cells on day 0 and intravenous injection of bone marrow cells from the same donor on posttransplant day 5. It was found that regimens B and C were more effective than regimen A in prolonging allograft survival. The results demonstrate that induction of allograft tolerance can be achieved by bone marrow transplantation in a rabbit model. This protocol deserves further study in other large animal models.