Latent transforming growth factor ␤-binding protein 1 (LTBP-1) targets latent complexes of transforming growth factor ␤ to the extracellular matrix, where the latent cytokine is subsequently activated by several different mechanisms. Fibrillins are extracellular matrix macromolecules whose primary function is architectural: fibrillins assemble into ultrastructurally distinct microfibrils that are ubiquitous in the connective tissue space. LTBPs and fibrillins are highly homologous molecules, and colocalization in the matrix of cultured cells has been reported. To address whether LTBP-1 functions architecturally like fibrillins, microfibrils were extracted from tissues and analyzed immunochemically. In addition, binding studies were conducted to determine whether LTBP-1 interacts with fibrillins. LTBP-1 was not detected in extracted beaded-string microfibrils, suggesting that LTBP-1 is not an integral structural component of microfibrils. However, binding studies demonstrated interactions between LTBP-1 and fibrillins. The binding site was within three domains of the LTBP-1 C terminus, and in fibrillin-1 the site was defined within four domains near the N terminus. Immunolocalization data were consistent with the hypothesis that LTBP-1 is a fibrillin-associated protein present in certain tissues but not in others. In tissues where LTBP-1 is not expressed, LTBP-4 may substitute for LTBP-1, because the C-terminal end of LTBP-4 binds equally well to fibrillin. A model depicting the relationship between LTBP-1 and fibrillin microfibrils is proposed.The fibrillins and latent transforming growth factor ␤-binding proteins (LTBPs) 1 are members of a family of homologous molecules. The fibrillins and LTBPs contain multiple calciumbinding epidermal growth factor-like modules interspersed by a domain module (the 8-Cys or TB module), so far found only in these two proteins. Fibrillin-1 (1-4) and fibrillin-2 (5, 6) share a highly similar overall structure. Both molecules are of equivalent size (ϳ350 kDa) and domain organization. In contrast, LTBP-1 (7, 8), LTBP-2 (9), LTBP-3 (10), and LTBP-4 (11, 12) are each smaller than the fibrillins and variable in size.Extensive immunolocalization data combined with structural analyses of the fibrillin-1 monomer and fibrillin-containing microfibrils (1, 13-15) have established that fibrillin-1 is a major structural component of connective tissue microfibrils. In addition, genetic evidence in humans (16, 17) and mice (18,19) has confirmed that fibrillin-1 performs a significant role in the maintenance of microfibrils and elastic fibers.Fibrillin-2, whose structure is predicted to be highly similar to fibrillin-1, has also been immunolocalized to microfibrils (20). However, in contrast to fibrillin-1, the contribution of fibrillin-2 to microfibril structure is temporally and spatially restricted. In situ hybridization studies in mice indicated that expression of the fbn2 gene is most prominent in the early developing fetus (20). Genetic evidence in humans (5, 21) suggests that fibrillin-...

The Japan Obstetric Compensation System for Cerebral Palsy (JOCS-CP), which investigates, develops preventive mechanisms and awards monetary compensation, to cases of cerebral palsy was urgently introduced in 2009 in response to growing concern about Japan's deteriorating perinatal care and low birthrate. Under the political leadership, the Japan Council for Quality Health Care launched the JOCS-CP with support of various stakeholders. The JOCS-CP features of no-fault-based compensation which was discussed decades ago in the Japan Medical Association aiming at financial aid to patient and family and early settlement of dispute. As of 2017, 2233 petitions had been approved by the Review Committee for compensation. All the approved cases were consecutively put on analysis in the Investigation Committee which has compiled more than 1000 Investigative Reports. The reports were delivered not only to the childbirth facility but to the guardians/families. Survey revealed that most of childbirth facility and the guardians/families responded in favor of the reports. With regard to amelioration of profound cerebral palsy, the Prevention Report has been published on annual basis through analysis of all the Investigative Reports. The Prevention Reports and other educational materials were produced and distributed not only among medical professionals but among pregnant women. It is notable that the number of lawsuit filing related to obstetrics demonstrated rapid decrease compared to that of other medical specialties. The JOCS-CP could be described as a social experiment. It was overhauled in 2015 but deserves further discussion on reform for evolving into better system.

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Epidermal growth factor (EGF) or transforming growth factor‐α (TGF‐α) stimulates cell migration, proliferation and the formation of tube‐like structures of human microvascular endothelial cells in culture. Heparin‐binding EGF‐like growth factor (HB‐EGF), which shows 35% homology with EGF/ TGF‐α, is a member of the EGF family, and it is ubiquitous in many tissues and organs. We examined whether or not HB‐EGF induced angiogenic responses in human microvascular endothelial cells. HB‐EGF inhibited the binding of 125I‐EGF to the EGF receptor and induced autophosphorylation of the receptor on endothelial cells. Exogenous HB‐EGF induced the loss of more than 70% of the EGF receptor from the cell surface within 30 min, with similar kinetics to that of EGF. The level of c‐fos mRNA markedly increased at 30 min in response to HB‐EGF as well as EGF. A gel shift assay demonstrated the activation of the transcription factor p91 by HB‐EGF and EGF. This factor directly interacts with the EGF receptor and mediates the activation of c‐fos gene promoter. HB‐EGF enhanced the mRNA expression of tissue‐type plasminogen activator (t‐PA) and plasminogen activator inhlbitor‐1 (PAI‐1) mRNA. However, the enhancement of t‐PA and PAI‐1 by HB‐EGF was less than that by EGF. Heparitinase/chlorate, which digests the heparan sulfate proteoglycan of the endothelial cell surface, restored both t‐PA and PAI‐1 mRNA levels in response to HB‐EGF in a manner similar to that by EGF. HB‐EGF at 10 ng/ml developed tube‐like structures in type I collagen gel at similar levels to that of EGF at 10 ng/ml, suggesting that HB‐EGF is also a potent angiogenic factor in the model system for angiogenesis. The tubulogenesis activity of HB‐EGF is discussed in relation to the expression of the t‐PA and PAI‐1 genes.