BACKGROUND: HLA Class II antibody–initiated activation of monocytes possessing the corresponding antigen is thought to participate in the pathogenesis of transfusion‐related acute lung injury (TRALI). Pulmonary edema, a hallmark of TRALI, is caused by increasing vascular permeability. STUDY DESIGN AND METHODS: To investigate the contribution of HLA Class II antibody and monocytes to the development of pulmonary edema in TRALI, we studied whether the permeability of human lung microvascular endothelial cells (HMVECs) could be enhanced by coculturing HMVECs with peripheral blood mononuclear cells (PBMNCs) in the presence of HLA Class II antibody–containing plasma, which was implicated in TRALI (anti‐HLA‐DR plasma). In addition, similar experiments were performed with human umbilical vein endothelial cells (HUVECs). The endothelial permeability to fluoresceinated dextran, which was added from the start of coculture, was measured. RESULTS: The coculture of HMVECs or HUVECs with PBMNCs in the presence of anti‐HLA‐DR plasma resulted in the increase of endothelial permeability in the corresponding antigen‐antibody–dependent manner. CV‐3988, a platelet‐activating factor (PAF) receptor antagonist, almost completely suppressed the increase in endothelial permeability. Neutralizing antibodies to tumor necrosis factor (TNF)‐α alone and simultaneous addition of the antibodies to TNF‐α and interleukin (IL)‐1β to the coculture partially suppressed the permeability increase of HMVECs and HUVECs, respectively. CONCLUSIONS: HLA Class II antibody and monocytes in the corresponding antigen‐antibody combination caused the enhancement of endothelial permeability. PAF, TNF‐α, and/or IL‐1β might be involved in the endothelial permeability increase. HLA Class II antibody–initiated monocyte activation could lead to the development of pulmonary edema in TRALI.
The present experiments were carried out to determine the regrowth of endothelial cells (EC) after balloon denudation of the rabbit carotid artery and the changes in responsiveness of the artery with regenerated EC. Scanning electron microscopic findings revealed that 28.8% of the luminal surface was covered with regenerated EC at week 1. The regrowth of EC proceeded progressively, and a full lining was achieved at week 6. Regenerated EC were morphologically different from native ones; they were elongated (weeks 1 and 2) and irregularly oriented (weeks 4 and 6), and their numbers had significantly increased. Light microscopy revealed the intimai thickening and proliferation of smooth muscle cells. No accumulation of lipids in the vascular wall could be detected at any observation time. The experiments in an organ bath demonstrated that the altered appearance of EC was accompanied by depressed endothelium-dependent relaxations to acetylcholine. ADP and A23187. However, sodium nitroprusside-induced relaxation and contractile responses to noradrenaline, serotonin and histamine remained unchanged in the normal and denuded preparations, indicating that the dysfunction of the endothelium occurs at a time when the ability of the underlying vascular smooth muscle to relax or contract was unchanged. In addition, it is suggested that the impairment of the endothelium-dependent relaxation may be partly due to impairment of the synthesis and/or release of endothelium-derived relaxing factor(s) in EC
Background: The incidence of late complications related to the liver such as fibrosis/cirrhosis is increasing in patients who have undergone the Fontan procedure and may contribute to morbidity and mortality. Recently, magnetic resonance elastography (MRE), a novel evaluation technique of liver fibrosis, has been attracting attention. However, few reports have described the use of MRE for evaluating liver fibrosis in children with congenital heart disease (CHD). Methods: Thirty-two children were examined and divided into 4 groups: 12 children with CHD who underwent intracardiac repair (ICR; median age, 13.0 years); 10 with CHD who underwent the Fontan procedure (Fontan; 15.3 years); 8 who were included in the control group (control; 15.8 years); and 2 children with cirrhosis (cirrhosis; 16.3 years). The liver stiffness (LS) was estimated by MRE. LS was measured 3 times consecutively, and the mean value was considered for further analysis. Central venous pressure (CVP) and cardiac index (C.I.) were determined by cardiac catheterization. The levels of cardiac biomarkers (NTproBNP and PIIIP) were determined at the same time. Results: Among the 4 groups, no significant differences were observed in age, C.I., and NTproBNP levels. The PIIIP levels in the cirrhosis group were significantly higher than those in the control, but no significant difference in PIIIP levels was found among the other groups (p < 0.01). LS in the Fontan and cirrhosis group was significantly higher than that in the control group (5.6, 15.3 vs. 2.4 kPa, respectively; Fig. 1). Furthermore, there was a strong correlation between LS and CVP (r = 0.802; Fig. 2). Conclusions: This study showed that LS is a direct function of CVP, which should be considered when assessing the degree of liver fibrosis in children with CHD. In particular, in the case of children who undergo the Fontan procedure, the highly sensitive MRE can be used to evaluate liver fibrosis and help detect LS earlier than cardiac biomarkers do.
EG626 (oxagrelate), a specific inhibitor of cyclic AMP phosphodiesterase, produced in vitro a concentration-dependent inhibition of platelet aggregation induced by collagen and ADP in human platelets. When adenosine was added to the platelet rich plasma (PRP) in the presence of a threshold concentration of EG626, the potency of adenosine in inhibiting platelet aggregation was markedly potentiated. This potentiating effect of EG626 proved to be synergistic, but not additive and was accompanied by a marked accumulation of cyclic AMP in the platelets. The antiaggregating and cyclic AMP increasing activities of adenosine were little affected by S-(p-nitrobenzyl)-6-thioguanosine (6TG), an uptake inhibitor of adenosine, or 2′-deoxycoformycin, an inhibitor of adenosine deaminase. The incorporation of adenosine into platelets was abolished by 6TG. These observations indicate that incorporation of adenosine into platelets is not required for inhibition of aggregation or an increase in cyclic AMP and that the site of action of adenosine is probably extracellular. It also appears that the synergistic action by EG626 is not the result of an inhibition of adenosine uptake and/or adenosine deaminase. This speculation is supported in part by the finding that EG626 also potentiates the antiaggregating activity of 2-chloroadenosine. Antiaggregating activity of prostaglandin E1, an activator of adenylate cyclase, was markedly potentiated in combination with EG626. Dibutyryl cyclic AMP showed a time-dependent inhibition of the platelet aggregation, and the inhibitory action was markedly potentiated by EG626. Qualitatively similar results were obtained with another phosphodiesterase inhibitor, 3-isobutyl-1 -methylxanthine (IBMX). All these data suggest that the synergistic potentiation of the antiaggregating activity of adenosine by EG626 might be due to the synergistic accumulation of cyclic AMP in the platelets. This action is mediated through activation of adenylate cyclase by adenosine in combination with the inhibition of cyclic AMP phosphodiesterase by EG626.
The purpose of this study was to examine the concept of intelligence among Japanese. Male and female college students, and mothers of female students were asked to think of an intelligent person, and to rate each of 67 descriptors according to whether it fits that person or not. It was found out that some of the descriptors were highly general regardless of the background of the person to be described, and that some were specific to the sex and other backgrounds of the person. As compared to the results of studies in the U.S., descriptors related to the receptive social competence tended to be associated with high intelligence, especially when the person to be described was a woman. The factor structure found in Japanese subjects which showed the predominant factor of social competence differed from that for Americans reported by Sternberg. Sex stereotyping in the concept of intelligence was also observed: Descriptors for a female target, compared those of a male target, were distributed more heavily in the domain of social competence and the reading and writing. Sex-role differentiation in concept was more pronounced in the responses of male students as compared to those of female subjects.
POU1F1 encodes both PIT-1α, which plays pivotal roles in pituitary development and GH, PRL and TSHB expression, and the alternatively spliced isoform PIT-1β, which contains an insertion of 26-amino acids (β-domain) in the transactivation domain of PIT-1α due to the use of an alternative splice acceptor at the end of the first intron. PIT-1β is expressed at much lower levels than PIT-1α and represses endogenous PIT-1α transcriptional activity. Although POU1F1 mutations lead to combined pituitary hormone deficiency (CPHD), no patients with β-domain mutations have been reported.Here, we report that a three-generation family exhibited different degrees of CPHD, including growth hormone deficiency with intrafamilial variability of prolactin/TSH insufficiency and unexpected prolactinoma occurrence. The CPHD was due to a novel POU1F1 heterozygous variant (c.143-69T>G) in intron 1 of PIT-1α (RefSeq number NM_000306) or as c.152T>G (p.Ile51Ser) in exon 2 of PIT-1β (NM_001122757). Gene splicing experiments showed that this mutation yielded the PIT-1β transcript without other transcripts. The lymphocyte PIT-1β mRNA expression was significantly higher in the patients with the heterozygous mutation than a control. A luciferase reporter assay revealed that the PIT-1β-Ile51Ser mutant repressed PIT-1α and abolished transactivation capacity for the rat prolactin promoter in GH3 pituitary cells.We describe, for the first time, that the PIT-1β mutation can cause CPHD through a novel genetic mechanism, such as PIT-1β overexpression, and that POU1F1 mutation might be associated with a prolactinoma. Analysis of new patients and long-term follow-up are needed to clarify the characteristics of PIT-1β mutations.
Basal meningoceles are rare congenital defects and often clinically occult until they result in life-threatening complications. Therefore, it is important to know the diagnostic clues to early diagnosis. We describe three cases of congenital basal meningocele in a 3-year-old Japanese boy, a 1-month-old Japanese baby boy, and a 10-month-old Japanese baby girl. One of our patients died of sepsis due to traumatic rupture of the meningocele during nasal suction. His meningocele remained undiagnosed until it resulted in the fatal complication. The other patients underwent surgical repair without any complications. Their meningoceles were complicated by midfacial anomalies including cleft palate and hypertelorism, or a sign of nasal obstruction such as snoring. These clinical features may be a clue to the early diagnosis of congenital basal meningocele, which enables its safe preoperative management and provides an opportunity for surgical repair before the condition results in serious complications.
