Mitogen-activated protein kinase/extracellular signalregulated protein kinase (MAPK/ERK) is a key molecule in intracellular signal transducing pathways that transport extracellular stimuli from cell surface to nuclei. MAPK/ERK has been revealed to be involved in the physiological proliferation of mammalian cells and also to potentiate them to transform. However, its role in the outgrowth of human hepatocellular carcinoma (HCC) has yet to be clarified. Therefore, in this study, we investigated the activation of MAPK/ERK and its associated gene expression in HCC. MAPK/ERK was activated in 15 of 26 cases of HCC we examined (58%), and its activity level was significantly higher in HCC than in the adjacent non-cancerous lesions. The mitogen-activated protein kinase/extracellular signalregulated protein kinase (MAPK/ERK) was first identified as a protein serine/threonine kinase which could be activated by a number of growth factors, cytokines, and oncogenic promoters 1,2 ; the MAPK/ERK, thereafter, was revealed to be a key molecule which converges several signal transduction pathways and transduces converged signals into nuclei, resulting in various cellular responses including proliferation and differentiation. 3,4 Numerous signals through small guanosine triphosphate (GTP)-binding protein Ras, 5 protein kinase C, 6 and other signal transducing molecules both phosphorylate and activate MAPK kinase kinases. MAPK kinase kinases, in turn, phosphorylate and activate MAPK/ERK kinase. Finally, MAPK/ERK kinase activates two isozymes of MAPK/ERK, p44 ERK1 and p42 ERK2 by phosphorylation on both threonine and tyrosine residues. In this way, signals from extracellular stimuli converge upon MAPK/ERK.Once activated, MAPK/ERK translocates into nuclei, 7-9 in which it induces transcription factors, including c-Fos and c-Jun, or activate them by phosphorylation. 10 These two transcription factors consist of activator protein-1 (AP-1) 11 and bind to AP-1 binding sites of promoter regions to induce transcription of the genes, including cyclin D1, 12 which is required for cell cycle progression in the G0/G1 phase as a G1 cyclin. 13 In addition, previous works indicate that constitutive MAPK/ERK activation results in the transformation of mammalian cells, 3,14 and that its activation is necessary for oncogenic transformation. 3 In this context, alterations in expression and activity of components of the MAPK cascade have been demonstrated in human tumors. [15][16][17] With regard to human hepatocellular carcinoma (HCC), there has been only one report on five patients where MAPK expression and activity were increased in cancerous lesions over noncancerous adjacent lesions 17 ; however, little has been revealed on the involvement of MAPK/ERK in human HCCs.Therefore, the aim of this study is to determine the activation of MAPK/ERK and expression of its associated genes, i.e., transcription factors and cell-cycle related genes, in both human HCCs and their non-cancerous counterparts, and to investigate how MAPK/ERK may be involved in the p...

In most stem cell systems, the organization of the stem cell niche and the anchoring matrix required for stem cell maintenance are largely unknown. We report here that collagen XVII (COL17A1/BP180/BPAG2), a hemidesmosomal transmembrane collagen, is highly expressed in hair follicle stem cells (HFSCs) and is required for the maintenance not only of HFSCs but also of melanocyte stem cells (MSCs), which do not express Col17a1 but directly adhere to HFSCs. Mice lacking Col17a1 show premature hair graying and hair loss. Analysis of Col17a1-null mice revealed that COL17A1 is critical for the self-renewal of HFSCs through maintaining their quiescence and immaturity, potentially explaining the mechanism underlying hair loss in human COL17A1 deficiency. Moreover, forced expression of COL17A1 in basal keratinocytes, including HFSCs, in Col17a1-null mice rescues MSCs from premature differentiation and restores TGF-β signaling, demonstrating that HFSCs function as a critical regulatory component of the MSC niche.

(CQI) project for telephone-assisted cardiopulmonary resuscitation (telephone-CPR), which included instruction on chest-compression-only CPR, education on how to recognise out-of-hospital cardiac arrests (OHCAs) with agonal breathing, emesis and convulsion, recommendations for on-line or redialling instructions, and feedback from emergency physicians. This study aimed to investigate the effect of this project on the incidence of bystander CPR and the outcomes of OHCAs.Materials and Methods: The baseline data were prospectively collected on 4995 resuscitation-attempted OHCAs, which were recognised or witnessed by citizens rather than emergency medical technicians during the period of February 2004 to March 2010. The incidence of telephone-CPR and bystander CPR, as well as the outcomes of the OHCAs, were compared before and after the project.Results: The incidence of telephone-CPR and bystander CPR significantly increased after the project (from 42% to 62% and from 41% to 56%, respectively). The incidence of failed telephone-CPR due to human factors significantly decreased from 30% to 16%. The outcomes of OHCAs significantly improved after the projects. A multiple logistic regression analysis revealed that the CQI project is one of independent factors associated with one-year (1-Y) survival with favourable neurological outcomes (odds ratio = 1.81, 95% confidence interval = 1.20-2.76).Conclusions: The CQI project for telephone-CPR increased the incidence of bystander CPR and improved the outcome of OHCAs. A CQI project appeared to be essential to augment the effects of telephone-CPR.Keywords: Telephone-CPR; Continuous quality improvement; Cardiopulmonary resuscitation; Dispatcher; Emergency medical service; Out-of-hospital cardiac arrest INTRODUCTION Currently, medical control (MC) for the emergency medical service system (EMS) is active in Japan.However, MC, including education, is mainly targeted to emergency medical technicians (EMTs) and is rarely targeted to dispatchers in Japan. Since February 2004, the Ishikawa MC Council has requested that fire departments collect the reasons why dispatchers failed to provide telephone-assisted instruction on cardiopulmonary resuscitation (telephone-CPR). Telephone-CPR has been shown to increase the incidence of bystander CPR and is expected to improve the outcomes of out-of-hospital cardiac arrests (OHCAs) [1][2][3][4][5].There are no special qualifications or authorisations required for fire department staff to be dispatchers in Japan. Some dispatchers have no experience as EMTs. An educational program for dispatchers has not been established. In some fire departments, the actual condition of the OHCA patient, discovered by EMTs during a post-arrival interview, is not relayed back to the dispatchers.In March of 2007, the Ishikawa MC Council initiated the Continuous Quality Improvement (CQI) project for telephone-CPR. The project included the following: 1) a standardized manual for instruction on chest-compression-only CPR (CC-only CPR), 2) education on how to recognise OH...

This study was designed to clarify which vascular carrier, the arteriovenous shunt loop or the arteriovenous bundle, has more potential as a vascular carrier for an artificial skin flap in rats. An arteriovenous shunt loop was constructed between the femoral artery and vein using an interpositional artery (group I) or vein (group II) graft. For arteriovenous bundle groups, the femoral artery and vein were used and subdivided into two groups: distal ligation type (group III) and flow-through type (group IV). The vascular pedicle was wrapped with an artificial dermis and implanted beneath the inguinal skin for 4 weeks. For the control group, a folded sheet of artificial dermis without any vascular carrier was embedded. In experiment 1, the volumes of generated tissue within the artificial dermis were measured in the experimental and control groups (n = 5 in each group). In experiment 2, the origin of new blood vessels sprouting from the arteriovenous shunt loop and arteriovenous bundle were evaluated histologically. The volume of generated tissue in the shunt groups was significantly greater than that in the bundle groups (p < 0.01). However, the bundle groups also showed a great potential for producing new tissue. Serial histological studies showed that new capillaries were derived not only from the vasa vasorum of the femoral vessels but directly from the femoral vein in both the shunt and the bundle groups. This "sprouting" was extensively exhibited in the group III. Although the arteriovenous shunt loop showed a greater potential for producing new tissue and capillaries, the distal ligation type of bundle was thought to be an effective and practical vascular carrier for producing a tissue-engineered skin flap.

A major requirement for the microsurgical repair of contour defects of the skin, for example, following removal of a skin cancer on the face, is a mass of vascularised subcutaneous tissue. Such tissue can be generated in vivo using basic tissue engineering principles. In previous studies in our laboratory, we have used a model comprising an arteriovenous (AV) shunt loop sandwiched in artificial dermis, placed in a cylindrical plastic growth chamber, and inserted subcutaneously to grow new connective tissue progressively up to 4 weeks. To learn more about the basic growth characteristics with this model, the same AV shunt loop within a chamber without added extracellular matrix was inserted subcutaneously into the groins of rats for 2, 4, or 12 weeks (n = 5 per group). There was a progressive increase in the mass and volume of tissue such that the chamber was two-thirds full after 12 weeks. Histological examination showed that at 2 weeks there was evidence of fibroblast and vascular outgrowth from the AV shunt, with the formation of granulation tissue, surrounded by a mass of coagulated exudate. At 4 weeks the connective tissue deposition was more extensive, with a mass of more mature granulation tissue containing considerable collagen. By 12 weeks there was an extensive, well vascularized mass of mature fibrous tissue. The blood vessels and residual adventitia of the AV shunt were the likely source of growth factors and of the cells which populated the chamber with new maturing connective tissue. A patent AV shunt in an isolated chamber appears to be the minimal requirement for the generation of new vascularized tissue that is potentially suitable for microsurgical transplantation.

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Every vertebrate species has its own unique morphology adapted to a particular lifestyle and habitat. Limbs and fins are strikingly diversified in size, shape, and position along the body axis. This diversity in morphology suggests the existence of a variety of embryonic developmental programs. However, comparisons of various embryos suggest common mechanisms underlying limb/fin formation. Here, we report the existence of continuous stripes of competency for appendage formation along the dorsal midline and the lateral trunk of all of the major jawed vertebrate (gnathostome) groups. We also show that the developing fin buds of cartilaginous fish share a mechanism of anterior-posterior axis formation as well as an shh (sonic hedgehog) expression domain in the posterior bud. We hypothesize a continuous distribution of competent stripes that represents the common developmental program at the root of appendage formation in gnathostomes. This schema would have permitted subsequent divergence into various levels of limbs/fins in each animal group.

Outbreaks of an acute febrile disease of cattle occurred in Japan in 1959 and 1960. Its occurrence was limited in late summer and autumn, and in Kyushu, Shikoku and Honshu roughly south of 37 degrees north latitude, suggesting a close correlation of the incidence with the climatic conditions, hence a possibility of the presence of arthropod vector. The disease was characterized by fever and lesions affecting the mucous membrane and skin, musculature and vascular system. Degeneration of striated muscles was observed in the esophagus, larynx, pharynx, tongue and skeletal muscular system. Edema and hemorrhage were marked in the mouth, lips, abomasum, coronets etc., occasionally followed by degeneration of the epithelium leaving erosions or ulcerations. Severe lesions affecting the esophageal and laryngopharyngeal musculature caused deglutitive difficulty which in turn resulted in dehydration and emaciation, and occasionally in aspiration pneumonia, constituting the major causes of death of the affected animals. These findings indicate that the disease resembles bluetongue in sheep and cattle. The clinical materials obtained from natural cases induced a clinical illness when inoculated into calves, and the disease was transmitted serially in calves by intravenous inoculation of the blood obtained at the height of febrile reaction. The experimentally produced disease was clinically and pathologically indistinguishable from the natural disease.