Membrane type 1-matrix metalloproteinase (MT1-MMP) functions as a signaling molecules in addition to a transmembrane metalloprotease, which degrades interstitial collagens and extracellular matrix components. This review focuses on the multifunctional roles of MT1-MMP as a signaling molecule in vascular responses to pro-atherosclerotic stimuli in the pathogenesis of cardiovascular diseases. First, the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1)-MT1-MMP signaling axis contributes to endothelial dysfunction, which is mediated via small GTP-binding protein RhoA and Rac1 activation. Second, MT1-MMP plays a crucial role in reactive oxygen species (ROS) generation through the activation of receptor for advanced glycation end products (AGEs) in smooth muscle cells, indicating that MT1-MMP may be a therapeutic target for diabetic vascular complications. Third, MT1-MMP is involved in RhoA/Rac1 activation and Ca2+ signaling in the mechanism of thrombin-stimulated endothelial dysfunction and oxidant stress. Fourth, the inhibition of the MT1-MMP/Akt signaling pathway may be an attractive strategy for treating endothelial disordered hemostasis in the development of vascular diseases linked to TNF-α-induced inflammation. Fifth, MT1-MMP through RAGE induced RhoA/Rac1 activation and tissue factor protein upregulation through NF-κB phosphorylation in endothelial cells stimulated by high-mobility group box-1, which plays a key role in the systemic inflammation. These findings suggest that the MT1-MMP-mediated signaling axis may be a promising target for treating atherosclerosis and subsequent cardiovascular diseases.
Aim: To assist in the long-term health management of residents and evaluate the health impacts after the Tokyo Electric Power Company’s Fukushima Daiichi Nuclear Power Plant accident in Fukushima Prefecture, the Fukushima prefectural government decided to implement the Fukushima Health Management Survey. This report describes the results for residents aged 15 years or younger who received health checks and evaluates the data obtained from 2011 and 2012. Methods: The target group consisted of residents aged 15 years or younger who had lived in the evacuation zone. The health checks were performed on receipt of an application from any of the residents. The checks, which included the measurements of height, weight, blood pressure, biochemical laboratory findings, and peripheral blood findings, were performed as required. Results: 1) A total of 17,934 (64.5%) and 11,780 (43.5%) residents aged 15 years or younger received health checks in 2011 and 2012, respectively. 2) In both years, a number of male and female residents in the 7-15 year age group were found to suffer from obesity, hyperlipidemia, hyperuricemia, or liver dysfunction. Furthermore, pediatric aged 15 years or younger were commonly observed to suffer from hypertension or glucose metabolic abnormalities. 3) A comparison of data from 2012 and 2011 demonstrated that both males and females frequently showed increased body height and decreased body weight in 2012. The prevalence of hypertension, glucose metabolic abnormalities, or high γ-GTP values in males and females in the 7-15 year age group in 2012 was lower than that in 2011. However, the prevalence of hyperuricemia among residents in the 7-15 year age group was higher in 2012 than in 2011. Conclusions: These results suggested that some residents aged 15 years or under who had lived in the evacuation zone had developed obesity, hyperlipidemia, hyperuricemia, liver dysfunction, hypertension, or glucose metabolic abnormalities. Therefore, we think that it is necessary to continue the health checks for these residents in order to ameliorate these lifestyle-related diseases.
Many physiological, biochemical and behavioral processes operate under the circadian rhythm, which is generated by an internal time-keeping mechanism commonly referred to as the biological clock, in almost all organisms from bacteria to mammals. The core circadian oscillator is composed of an autoregulatory transcription-translation feedback loop, in which CLOCK and BMAL1 are positive regulators. A cell has two mechanisms, “cell cycle” and “cell rhythm”, the relationship between which remains controversial. Therefore, the aim of this study was to explore the effect of Clock and Bmal1 on cell cycle, especially on the G1 phase, using vectors with the tetracycline operator-repressor system. The present study revealed that simultaneous induction of Bmal1 and Clock had an influential effect on the cell cycle in SW480/T-REx/Clock/Bmal1 cells, in which both Clock and Bmal1 could be induced by tetracycline. The observation that induction of both Clock and Bmal1 inhibited cell growth and the significant increase of the G1 phase proportion of in SW480/T-REx/Clock/Bmal1 cells indicated that entry from the G1 to S phase was inhibited by the induction of Clock and Bmal1. Furthermore, overexpression of Clock and Bmal1 prevented the cells from entering into the G2/M phase induced by Paclitaxel, and made the cells more resistant to the agent. In conclusion, we found that overexpression of both Clock and Bmal1 suppressed cell growth. In addition, the present study raised the possibility that Clock and Bmal1 may in part play a role in preventing the cells from entering G1 to S phase of cell cycle via suppression of CyclinD1 expression, and thus acquiring resistance to Paclitaxel.
Objectives: Nicotine in cigarettes is metabolized primarily by CYP2A6-catalyzed oxidation. The CYP2A6*4 allele, in which CYP2A6 is a homozygous whole-deletion variant, completely lacks enzyme activity. The aim of this study was to examine the effects of CYP2A6*4 genetic polymorphism on smoking behavior and nicotine dependence in a general population of Japanese men. Methods: The subjects were 124 healthy Japanese men who gave informed consent to give saliva samples. The survey items included general information, smoking behaviors and nicotine dependence. The polymerase chain reaction restriction fragment length polymorphism method was used to analyze the genetic polymorphisms of CYP2A6. The subjects were classified into two groups: Group W (CYP2A6*4 absence: *1A/*1A, *1A/*1B and *1B/*1B) and Group D (CYP2A6*4 presence: *1B/*4A, *4A/*4A, *1A/*4A or *1B/*4D, and *1A/*4D). We analyzed the differences in the survey items between the two groups. Results: There were no significant differences in smoking behaviors between the two groups. However, Group D tended to have less difficulty in refraining from smoking after waking in the morning compared to Group W (p=0.051). Conclusions: CYP2A6*4 genetic polymorphisms may not strongly affect smoking behavior but may possibly have an effect on nicotine dependence.
Background and Objective: Skull base chordomas are clinically malignant because of the difficulty of total removal, high recurrence rate, and occasional drop metastasis. Although aggressive surgical resection and postoperative radiation have been recommended, the long-term outcome remains unsatisfactory.Methods: From 1992 to 2011, we treated 24 patients with skull base chordoma using aggressive surgical removal as a principal strategy. Skull base approaches were selected according to tumor extension to remove the tumor and surrounding bone as completely as possible. After surgery, all patients were closely observed with MRI to find small and localized recurrent tumors, which were treated with gamma-knife radiosurgery or surgical resection. The mean postoperative follow-up duration was 10.2 years (range, 1-17.2 years).Results: The 5-, 10-, and 15-year overall survival rates were 86%, 72%, and 72%, respectively. The 5- and 10-year progression-free survival rates were 47% and 35%, respectively. Tumor extension to the brainstem and partial tumor removal were the factors related to poor survival.Conclusions: Our results suggest that aggressive surgical removal improves the long-term outcome of patients with skull base chordoma. We would like to emphasize that skull base chordomas should be aggressively removed using various skull base approaches.
Background: Treatment strategies for bone defects include free bone grafting, distraction osteogenesis, and vascularized bone grafting. Because bone defect morphology is often irregular, selecting treatment strategies may be difficult. With the Masquelet technique, a fracture site is bridged and fixed with a locking plate after treating deep infection with antibiotic-containing cement, and a free cancellous bone-graft is concomitantly placed into the defects. This procedure avoids excessive bone resection. Methods:We studied 6 patients who underwent surgical treatment for deep infection occurring after extremity trauma (2004 through 2009). Ages at surgery ranged from 29 to 59 years (largest age group: 30 s). Mean follow-up was 50.7 months (minimum/maximum: 36/72 months). One patient had complete amputation of the upper extremity, 3 open forearm fractures, 1 closed supracondylar femur fracture, and 1 open tibia fracture. In all patients, bone defects were filled with antibiotic-containing cement beads after infected site debridement. If bacterial culture of infected sites during curettage was positive, surgery was repeated to refill bone defects with antibiotic-containing cement beads. After confirmation of negative bacterial culture, osteosynthesis was performed, in which bone defects were bridged and fixed with locking plates. Concomitantly, crushed cancellous bone grafts harvested from the autogenous ilium was placed in the bone defects. Results: Time from bone grafting and plate fixation to bone union was at least 3 and at most 6 months, 4 months on average. Infection relapsed in one patient with methicillin-resistant Staphylococcus aureus, necessitating vascularized fibular grafting which achieved bone union. No patients showed implant loosening or breakage or infection relapse after the last surgery during follow-up. Conclusion: The advantage of cancellous bone grafting include applicability to relatively large bone defects, simple surgical procedure, bone graft adjustability to bone defect morphology, rapid bone graft revascularization resulting in high resistance to infection, and excellent osteogenesis.
Anti-HLA antibodies reportedly exist in the one third of pregnant women. But few occurrences of neonatal alloimmune thrombocytopenia (NAIT) caused by anti-HLA antibodies have been reported. Here a male baby, who was admitted for low birth weight with Down syndrome (DS), was suffered from thrombocytopenia without transient myeloproliferative disorder (TMD). Positive reactions of HLA-specific antibodies were detected in maternal serum. Cross-matching tests between maternal serum and paternal platelets and lymphocytes were strongly positive. It is most conceivable that the previous pregnancy of the mother induced the production of anti-HLA-A2 antibody, which crossed the placenta and subsequently caused an NAIT in the case presented. This is the first case of DS with NAIT due to anti-HLA antibodies.
Backgrounds: On March 11th 2011, the Tohoku region of Japan was struck by catastrophic disasters. Thousands of people were killed due to a magnitude 9.0 earthquake and its subsequent tsunami. Furthermore, a serious nuclear crisis occurred in Fukushima Prefecture as a result of the disasters, and an emergency evacuation was ordered to people living near the nuclear power plants. There was a lot of anxiety regarding lost families as well as the influences of radioactivity on the health of people and their children. Based on these urgent and uncertain situations, a number of research projects were developed at many institutes both inside and outside Fukushima. Methods: We herein report the investigative research projects related to the Tohoku Earthquake (The Great East Japan Earthquake) conducted after the disasters. The research projects were reviewed by the Institutional Review Board in Fukushima Medical University during the two years following the disasters. The research projects conducted in universities other than Fukushima Medical University were also examined using questionnaire analysis. Results: Among the research projects conducted in Fukushima Medical University (n=424), 7% (n=32) were disaster-related investigative research. The mean duration planned to pursue the projects was 25.5 months. Among these projects, those focusing on the health of Fukushima citizens were most common (n=9), followed by the influence of chronic exposure of radiation on chronic inflammatory disorders (n=6), and the mental health of Fukushima citizens (n=5). They were carefully reviewed for the purpose, suitability, and necessity from ethical as well as scientific viewpoints. The majority of the research projects focused on the effects of the Tohoku Earthquake and/or chronic exposure to low-dose radioactivity on the health of children and pregnant women, as well as on various disorders, such as mental health and chronic inflammatory diseases. On the other hand, among 58 projects we collected from 22 institutes in prefectures other than Fukushima, mental health-related projects were the most common (n=18), followed by radiation exposure-related projects (n=10). Conclusions: Many of these projects are ongoing, and in particular, long term follow-up regarding the health of the residents of Fukushima Prefecture, especially children and pregnant women, is necessary.
Aim: Peppermint oil, which suppresses gastric peristalsis during esophagogastroduodenoscopy (EGD), is effective for determining the margin of a gastric tumor. This study was conducted to evaluate the utility of an L-menthol preparation for suppressing gastric peristalsis and for diagnosing gastric tumors. Methods: The study examined 124 patients who underwent EGD between January and April 2012. After 20 mL of 0.8% L-menthol was sprayed directly onto the mucosal surface of the gastric antrum, the degree of peristalsis suppression in the antrum was evaluated. The effectiveness of L-menthol for identifying new gastric tumors and determining tumor margins was also evaluated. Results: Gastric peristalsis was suppressed in 88.5% (69/78) of patients, with complete suppression of peristalsis achieved in 78.2%. L-menthol exerted a higher peristalsis-suppressive effect in patients with endoscopic gastric mucosal atrophy (93.3%, 56/60) than in patients without atrophy (72.2%, 13/18) (p = .014). L-menthol application caused the detection of new gastric tumors in 1.6% (2/124) of patients and clarification of the margin of three lesions (in 3 patients) identified as having an unclear margin before L-menthol application. Conclusion: These results suggest that L-menthol is effective for suppressing gastric peristalsis during EGD and suggest that it is useful for identifying gastric tumors and for determining tumor margins.