p53標的創薬による放射線防護剤の開発

The progress of high-precision radiation therapy in recent years has been remarkable, and it has become possible to obtain a high therapeutic effect by improving dose concentration. However, in order to prevent adverse events from occurring in organs at risk, the risks of radiation injury in the normal tissues still determine the limits of the tolerable dose. Now, it is hoped that improvement of tolerable dose by a biological modification of radiation sensitivity using some molecular target drugs. Since nearly half of cancer patients have a mutation in the TP53 gene that encodes p53, p53 regulatory agents are expected to exert a selective protection of normal tissues in p53‐deficient cancer therapy. We proceeded with the exploration of 8‐quinolinol (8‐HQ) derivatives that target a zinc binding site within the p53 molecule, and found several radioprotectors controlling p53 activity. 5‐chloro‐8‐quinolinol (5CHQ), which is currently in focus, has a unique p53‐modulating activity that shifts its transactivation from proapoptotic to protective responses including enhancing p21 induction and suppressing PUMA induction. The dose-reduction factors of 5CHQ in total-body and abdominally irradiated mice were about 1.2 and 1.3, respectively. It is expected to create a new radioprotective agent that can be applied to cancer therapy

A comparison of the developmental characteristics of spontaneous upper extremity movements between healthy full-term infants and premature infants with brain injuries

　This study’s aim was to evaluate the characteristics of spontaneous upper extremity movements of premature infants with brain injuries by using dynamical systems analysis. Participants were 4 infants with brain injuries (3 boys and 1 girl, median birth weight and gestational age were 1367.5 g and 30.0 weeks) and 7 healthy full-term newborn infants (3 boys and 4 girls, median birth weight and gestational age were 2990.7 g and 39.0 weeks). We measured limb movement acceleration in 3-dimentional space using a tri-axial accelerometer. Movement acceleration signals were recorded during 200 s from the right wrist when the infant was in an active alert state and lying supine (sampling rate 200 Hz). Data were analyzed nonlinearly. The optimal embedding dimension (OED) values for infants with brain injuries at 3 months were significantly higher than healthy full-term infants, and the OED and MLE values in infants with brain injuries displayed uncorrelated change profiles. Uncorrelated change profiles of the OED and MLE values revealed that incoordination of the number of motor system component and complexity of appeared spontaneous movements. It suggests that infants with brain injuries have difficulties with self-organization processes. Our results suggest that this method makes it possible to detect early developmental disorders such as cerebral palsy

Successful Fitting of a Complete Maxillary Denture in a Patient with Severe Alzheimer’s Disease Complicated by Oral Dyskinesia

There is an increasing population of elderly patients suffering from Alzheimer’s disease (AD), the most common form of dementia. In dentistry, a critical problem associated with these patients is the use of a new denture, as AD patients often refuse dental management and are disturbed by minor changes in their oral environment. Some AD patients have further complications associated with oral dyskinesia, a movement disorder that can make dental management difficult, including the stability of a complete denture. In this case, we successfully fitted a complete maxillary denture using modified bilateral balanced occlusion after multiple tooth extractions under intravenous sedation in a 66-year-old woman with severe AD complicated by oral dyskinesia. Following treatment, her appetite and food intake greatly improved. Providing a well-fitting complete denture applied by modified bilateral balanced occlusion, which removes lateral interference using zero-degree artificial teeth for movement disorder of the jaw in patients with severe AD complicated by oral dyskinesia, helps improve oral function

Long-term Antibiotics and Simple TEVAR for Treatment of Infectious Thoracic Aortic Aneurysm

Purpose: The principle treatment of infectious aortic aneurysm is to remove the infected aneurysm and replace it with Rifampicin-soaked prosthesis by omentopecxy. This study aimed to clarify the efficacy of long-term antibiotics and subsequent thoracic endovascular aneurysm repair (TEVAR) for infectious thoracic aortic aneurysm. Methods: Between July 2011 and December 2015, 213 TEVARs were performed at Hiroshima University Hospital. Six patients (2.8%) had infectious aneurysm and received long-term antibiotic therapy and secondary TEVAR. L ong-term antibiotic therapy and subsequent TEVAR is paradoxical. This study aimed to clarify the timing of TEVAR for infectious thoracic aortic aneurysm. Results: All patients presented with fever and back pain, and had positive blood cultures; five patients had significant co-morbidities. Bacteraemia was caused by Methicillin Sensitive Staphylococcus Aureus (MSSA) (2), Streptococcus sanguinis (1), Methicillin Resistant Staphylococcus Aureus (MRSA) (1), Chryseobacterium meningosepticum (1), and Enterococcus faecalis (1). B lood examination at admission revealed a WBC count ranging from 10,470 to 16,170/μl and CRP ranging from 7.9 to 16.4 mg/dl. Long-term antibiotic therapy was continued until WBC and CRP were within the normal range. TEVAR was performed emergently in 3 cases and electively in 3 cases. The time from admission to TEVAR ranged from 7 to 26 days. One stent-graft was deployed in all 6 cases. All patients survived and were followed for an average of 48 months; they were free from re-infection. Conclusion: Long-term antibiotics and simple TEVAR may be a feasible treatment for infectious thoracic aortic aneurysms

Analysis of the Optimum Tapering Angle in Microanastomosis Using Computational Fluid Dynamics

Background: In free flap transfer, size discrepancy between the vascular pedicle and recipient vessel can create a problem for microsurgeons and sometimes induces postoperative thrombus formation. When there is a major difference between the diameters of the vascular pedicle and the recipient vessel, the larger vessel is often tapered to perform the anastomosis properly. However, the decision on the tapering angle used depends mostly on the operator’s experience. In this study, computational fluid dynamics (CFD) was used to investigate the optimum tapering angle. Methods: Using ANSYS ICEM 16.0 (ANSYS Japan, Tokyo, Japan), simulated vessels of diameters 1.5 mm and 3.0 mm were designed and then used to produce four anastomosis models with the 3.0-mm vessel tapered at angles of 15º, 30º, 60º, and 90º (no tapering). Venous perfusion with a mean value of 13.0 mL/min was simulated, and this was passed through the four anastomosis models in both the forward direction (F), from the smaller to the larger vessel, and the retrograde direction (R), from the larger to the smaller vessel. The velocity, wall shear stress (WSS), and oscillatory shear index (OSI) were measured in these eight patterns and then analyzed using OpenFOAM version 5. Results: The decrease in velocity was limiting. The WSS was greater in the R direction than the F direction at every tapering angle. The OSI also tended to be almost the same in the F direction, and lower at smaller tapering angles in the R direction. And, it was greater in the F direction than in the R direction at every tapering angle. The OSI values for 15º and 30º were almost identical in the R direction. Conclusion: The risk of thrombus formation is thought to be lower when tapering is used for anastomosis if the direction of flow is from the larger to the smaller vessel, rather than vice versa. These results also suggest that the optimum tapering angle is approximately 30º in both directions

A Novel RNA Synthesis Inhibitor, STK160830, Has Negligible DNA-Intercalating Activity for Triggering A p53 Response, and Can Inhibit p53-Dependent Apoptosis

RNA synthesis inhibitors and protein synthesis inhibitors are useful for investigating whether biological events with unknown mechanisms require transcription or translation; however, the dependence of RNA synthesis has been difficult to verify because many RNA synthesis inhibitors cause adverse events that trigger a p53 response. In this study, we screened a library containing 9600 core compounds and obtained STK160830 that shows anti-apoptotic effects in irradiated wild-type-p53-bearing human T-cell leukemia MOLT-4 cells and murine thymocytes. In many of the p53-impaired cells and p53-knockdown cells tested, STK160830 did not show a remarkable anti-apoptotic effect, suggesting that the anti-apoptotic activity is p53-dependent. In the expression analysis of p53, p53-target gene products, and reference proteins by immunoblotting, STK160830 down-regulated the expression of many of the proteins examined, and the downregulation correlated strongly with its inhibitory effect on cell death. mRNA expression analyses by qPCR and nascent RNA capture kit revealed that STK160830 showed a decreased mRNA expression, which was similar to that induced by the RNA synthesis inhibitor actinomycin D but differed to some extent. Furthermore, unlike other RNA synthesis inhibitors such as actinomycin D, p53 accumulation by STK160830 alone was negligible, and a DNA melting-curve analysis showed very weak DNA-intercalating activity, indicating that STK160830 is a useful inhibitor for RNA synthesis without triggering p53-mediated damage responses

Computer-controlled closed-loop norepinephrine infusion system for automated control of mean arterial pressure in dogs under isoflurane-induced hypotension: a feasibility study

Introduction: Intra-operative hypotension is a common complication of surgery under general anesthesia in dogs and humans. Computer-controlled closed-loop infusion systems of norepinephrine (NE) have been developed and clinically applied for automated optimization of arterial pressure (AP) and prevention of intra-operative hypotension in humans. This study aimed to develop a simple computer-controlled closed-loop infusion system of NE for the automated control of the mean arterial pressure (MAP) in dogs with isoflurane-induced hypotension and to validate the control of MAP by the developed system. Methods: NE was administered via the cephalic vein, whereas MAP was measured invasively by placing a catheter in the dorsal pedal artery. The proportional-integral-derivative (PID) controller in the negative feedback loop of the developed system titrated the infusion rate of NE to maintain the MAP at the target value of 60 mmHg. The titration was updated every 2 s. The performance of the developed system was evaluated in six laboratory Beagle dogs under general anesthesia with isoflurane. Results: In the six dogs, when the concentration [median (interquartile range)] of inhaled isoflurane was increased from 1.5 (1.5-1.5)% to 4 (4-4)% without activating the system, the MAP was lowered from 95 (91-99) to 41 (37-42) mmHg. In contrast, when the concentration was increased from 1.5 (1.0-1.5)% to 4 (4-4.8)% for a 30-min period and the system was simultaneously activated, the MAP was temporarily lowered from 92 (89-95) to 47 (43-49) mmHg but recovered to 58 (57-58) mmHg owing to the system-controlled infusion of NE. If the acceptable target range for MAP was defined as target MAP ±5 mmHg (55 ≤ MAP ≤65 mmHg), the percentage of time wherein the MAP was maintained within the acceptable range was 96 (89-100)% in the six dogs during the second half of the 30-min period (from 15 to 30 min after system activation). The median performance error, median absolute performance error, wobble, and divergence were - 2.9 (-4.7 to 1.9)%, 2.9 (2.0-4.7)%, 1.3 (0.8-1.8)%, and - 0.24 (-0.34 to -0.11)%·min-1, respectively. No adverse events were observed during the study period, and all dogs were extubated uneventfully. Conclusion: This system was able to titrate the NE infusion rates in an accurate and stable manner to maintain the MAP within the predetermined target range in dogs with isoflurane-induced hypotension. This system can be a potential tool in daily clinical practice for the care of companion dogs

Combination of Myogenic and Neurogenic Motor Evoked Potential Monitoring During Thoracoabdominal Aortic Surgery

A 64-year-old woman was evaluated for thoracoabdominal aortic aneurysms (TAAAs). Preoperative computed tomography showed a TAAA extending from the level of the diaphragm to the renal arteries. The Adamkiewicz artery (AKA) arose at the Th10 level, close to the aneurysm, and an abdominal aortic prosthesis and left iliac artery aneurysm were detected. Myogenic and neurogenic motor evoked potentials (MEPs) were monitored during the surgical repair of the TAAA, and there were differences between the two types of MEPs during surgery. Both MEPs fell below 50% of their baseline levels during surgery, which suggested critical ischemia, but the decrease in the myogenic MEP occurred at a different time from the decrease in the neurogenic MEP. A time-course analysis suggested that AKA reimplantation was unnecessary and all intercostal arteries were ligated. Both MEPs recovered completely by the end of surgery and there were no postoperative neurologic deficits. Our findings suggest that the combination of myogenic and neurogenic MEP monitoring is helpful in evaluating spinal cord injury during the surgical repair of TAAAs