Gentamicin-Induced Readthrough and Nonsense-Mediated mRNA Decay of SERPINB7 Nonsense Mutant Transcripts.

Nagashima-type palmoplantar keratosis (NPPK) is an autosomal recessive skin disorder with a high, unmet medical need that is caused by mutations in SERPINB7. Almost all NPPK patients carry the founder nonsense mutation c.796C>T (p.Arg266Ter) in the last exon of SERPINB7. Here we sought to determine whether topical nonsense-suppression (readthrough) therapy using gentamicin is applicable to NPPK. First, we demonstrated that gentamicin enhanced readthrough activity in cells transfected with SERPINB7 cDNA carrying the mutation and promoted full-length SERPINB7 protein synthesis in NPPK keratinocytes. We next conducted an investigator-blinded, randomized, bilaterally controlled compassionate use study of topical gentamicin in which five NPPK patients with c.796C>T were enrolled. Patients' self-reported improvement of hyperkeratosis was significantly greater on the gentamicin side than the control side (P = 0.0349). In two patients, hyperkeratosis was improved on the gentamicin side, as determined by a blinded-investigator assessment. These results indicate the therapeutic potential of topical gentamicin for NPPK. Unexpectedly, we also found that mutant SERPINB7 mRNAs harboring r.796c>u were degraded by nonsense-mediated mRNA decay. Furthermore, the truncated SERPINB7 protein was degraded via a proteasome-mediated pathway. These findings provide important insights into the mRNA/protein quality-control system in humans, which could be a potential therapeutic target for genetic diseases.

Online estimation of a cognitive performance using heart rate variability.

This paper presents online estimation framework of a cognitive performance using heart rate variability (HRV). Although our former framework could estimate relative changes in one user's cognitive performance after it had finished measuring his/her HRV, it was unable to estimate a cognitive performance repeatedly or to compare the estimated results obtained for multiple users. To address these problems, we have developed a framework for online estimation of a cognitive performance. Experimental results show our framework estimates a cognitive performance more accurately than the previous study did using multiple vital sensors. It can also estimate a user's cognitive performance by comparing it with those estimated for others. It therefore has the potential to help managerial personnel monitor their workers' performances in real time to suggest rest periods or changes in work duties.

Time-dependent sleep stage transition model based on heart rate variability.

A new model is proposed to automatically classify sleep stages using heart rate variability (HRV). The generative model, based on the characteristics that the distribution and the transition probabilities of sleep stages depend on the elapsed time from the beginning of sleep, infers the sleep stage with a Gibbs sampler. Experiments were conducted using a public data set consisting of 45 healthy subjects and the model's classification accuracy was evaluated for three sleep stages: wake state, rapid eye movement (REM) sleep, and non-REM sleep. Experimental results demonstrated that the model provides more accurate sleep stage classification than conventional (naive Bayes and Support Vector Machine) models that do not take the above characteristics into account. Our study contributes to improve the quality of sleep monitoring in the daily life using easy-to-wear HRV sensors.

Enteric-coated aspirin versus other antiplatelet drugs in acute non-cardioembolic ischemic stroke: post-marketing study in Japan.

INTRODUCTION: Japanese guidelines recommend aspirin 160-300 mg/day, starting within 48 h, for patients with acute cerebral infarction. However, there are few reports evaluated in Japanese patients. Our objective was to examine the safety and efficacy of enteric-coated aspirin, compared with other oral antiplatelet drugs, in Japanese patients with acute ischemic stroke. METHODS: We performed a prospective, non-randomized, observational and multicenter study between June 2005 and December 2007. Patients with symptomatic acute ischemic stroke, including transient ischemic attack (TIA), who started enteric-coated aspirin or other antiplatelet drugs within 7 days of hospitalization were registered. Outcome measures evaluated within 3 months were incidence of cerebral and non-cerebral hemorrhagic events, recurrence of ischemic stroke or TIA, non-cerebral ischemic events and death from any cause. RESULTS: Overall, 2,548 and 830 patients treated with enteric-coated aspirin (100-300 mg/day) or other antiplatelet drugs, respectively, were registered; approximately 60% were male, mean age was 70 years, 85% had pre-existing cardiovascular disease or other complications. Enteric-coated aspirin of 100 mg was mainly prescribed, and only approximately half of the patients were started on it within 48 h after onset of ischemic stroke. Safety and efficacy population excluded patients without follow-up data were 2,521 in enteric-coated aspirin and 807 in other antiplatelets. Hemorrhagic events occurred in 46 (1.8%) in the enteric-coated aspirin group and in 13 (1.6%) in the other antiplatelet drugs group, there was not significant. Recurrent ischemic stroke or TIA occurred in 39 (1.5%) of the enteric-coated aspirin and in 18 (2.2%) of other antiplatelet drugs, and there were any-cause death in 16 (0.6%) and 8 (1.0%). Incidences were slightly lower in the enteric-coated aspirin group compared with the other antiplatelet drugs group, but not statistically significant. CONCLUSION: It seems that these results showed the safety and efficacy of the enteric-coated aspirin in acute stroke care in Japanese patients. Incidence of hemorrhagic events was comparable between the enteric-coated aspirin group and the other antiplatelet drugs group.

Biosignal-based relaxation evaluation of head-care robot.

Such popular head care procedures as shampooing and scalp massages provide physical and mental relaxation. However, they place a big burden such as chapped hands on beauticians and other practitioners. Based on our robot hand technology, we have been developing a head care robot. In this paper, we quantitatively evaluated its relaxation effect using the following biosignals: accelerated plethymography (SDNN, HF/TP, LF/HF), heart rate (HR), blood pressure, salivary amylase (sAA) and peripheral skin temperature (PST). We compared the relaxation of our developed head care robot with the head care provided by nurses. In our experimental result with 54 subjects, the activity of the autonomic nerve system changed before and after head care procedures performed by both a human nurse and our proposed robot. Especially, in the proposed robot, we confirmed significant differences with the procedure performed by our proposed head care robot in five indexes: HF/TP, LF/HF, HR, sAA, and PST. The activity of the sympathetic nerve system decreased, because the values of its indexes significantly decreased: LF/HF, HR, and sAA. On the other hand, the activity of the parasympathetic nerve system increased, because of the increase of its indexes value: HF/TP and PST. Our developed head care robot provided satisfactory relaxation in just five minutes of use.

Kidney-protective effects of azelnidipine versus a diuretic in combination with olmesartan in hypertensive patients with diabetes and albuminuria: a randomized study.

BACKGROUND: A thiazide diuretic used in combination with benazepril is superior to amlodipine plus benazepril in reducing albuminuria in hypertensive patients with diabetes. However, calcium channel blockers have diverse characteristics. Thus, we investigated whether combining an angiotensin receptor blocker with either azelnidipine or a thiazide diuretic produced similar reductions in albuminuria in hypertensive diabetic patients for the same levels of blood pressure achieved. METHODS: Hypertensive patients with type 2 diabetes and albuminuria (30-600 mg/g creatinine) under antihypertensive treatment (mean age 67.0±7.6 years) were instructed to stop all antihypertensive treatment and take a combination of olmesartan (20 mg/day) and amlodipine (5 mg/day) for 3 months (run-in period). Then, patients were randomly assigned to receive either olmesartan plus azelnidipine (16 mg/day; n=71) or olmesartan plus trichlormethiazide (1 mg/day; n=72) for an additional 6 months. The primary end point was urinary excretion of albumin at 6 months after randomization. RESULTS: At the time of randomization, urinary albumin was 116.0 and 107.8 mg/g creatinine (geometric mean) in the azelnidipine and diuretic arms, respectively, and was reduced to a similar extent [79.8 (95% confidence interval 66.4-96.0) and 89.7 (74.6-107.7) mg/g creatinine, respectively, after adjustment for baseline values]. Blood pressure did not differ between the two groups throughout the study period. CONCLUSIONS: Azelnidipine is equally effective as a thiazide diuretic in reducing urinary albumin when used in combination with olmesartan.

Management of occluded metallic stents in malignant hilar biliary stricture.

BACKGROUND/AIMS: Little is known about the management of occluded multiple metallic stent (MS) deployed in malignant hilar biliary strictures (HBS). The purpose of this study was to evaluate the endoscopic management of occluded multiple MSs deployed in HBS. METHODOLOGY: Fifty-five patients with unresectable biliary tract carcinoma had multiple MSs inserted due to HBS. The endoscopic intervention through the duodenal papilla was performed on 30 cases that had MS occlusion. The procedure success rate, the survival time after the procedure and the number of endoscopic interventions before death were analyzed, retrospectively. RESULTS: The causes of MS obstruction were tissue ingrowth (n=20), sludge (n=7), tumor overgrowth (n=2), and hemobilia (n=1). Endoscopic cleaning or deployment of plastic stents or metallic stents was performed on these patients and was successfully accomplished only via the transpapillary approach. The survival time after MS obstruction was 219 days. The median number of endoscopic interventions before death was 3. The median interval of endoscopic intervention after the first plastic stent occlusion was 84 days. CONCLUSIONS: Our long-term data regarding the endoscopic management of occluded MSs deployed in malignant hilar biliary strictures are acceptable although the patency time of plastic stents deployed after MS occlusion was relatively short.

A 4-week versus a 3-week schedule of gemcitabine monotherapy for advanced pancreatic cancer: a randomized phase II study to evaluate toxicity and dose intensity.

BACKGROUND: This randomized phase II study compared the efficacy and toxicity between 4-week and 3-week schedules of gemcitabine monotherapy in advanced pancreatic cancer. METHODS: Patients with advanced pancreatic cancer were randomly assigned to either a 4-week schedule (gemcitabine at 1000 mg/m² as a 30-min infusion weekly for 3 consecutive weeks every 4 weeks) or a 3-week schedule (gemcitabine at 1000 mg/m² as a 30-min infusion weekly for 2 consecutive weeks every 3 weeks). The primary endpoint was the compliance rate during the first 8 weeks between the two groups. RESULTS: A total of 90 patients were enrolled. The compliance rate during the first 8 weeks was the same (53.3%). For the 4- and 3-week schedules, the tumor response rates were 14.2 and 17.1% (p = 0.92), median progression free survival was 112 and 114 days (p = 0.82), and median overall survival was 206 and 250 days (p = 0.84), respectively. Grade 3-4 neutropenia was the major adverse event in both schedules: 37.7 and 35.5% (p = 0.82). In contrast, thrombocytopenia (platelet count <70000/mm³) was significantly higher for the 4-week schedule: 26.6 and 4.4% (p = 0.008). The mean received dose intensity was equal: 588 and 550 mg/m²/week (p = 0.14). CONCLUSIONS: The 3-week schedule of gemcitabine did not improve the compliance rate during 8 weeks compared with the 4-week schedule, but it attained a comparable efficacy with lower toxicity. Further investigation will be needed to introduce it into daily practice. CLINICAL TRIAL REGISTRATION NUMBER: UMIN ID 974.

Combined duodenal stent placement and endoscopic ultrasonography-guided biliary drainage for malignant duodenal obstruction with biliary stricture.

Patients with malignant pancreatobiliary neoplasm sometimes manifest duodenal obstruction and biliary stricture synchronously or metachronously. In this paper, we reviewed our experience with and technique for combined endoscopic duodenal stent placement and endoscopic ultrasonography (EUS)-guided biliary drainage. Between May 2007 and September 2009, this combined technique was performed on seven patients with distal biliary strictures and duodenal obstructions. The clinical success rate of the procedure, complications, patency periods of duodenal stents and patency periods of biliary stents were retrospectively evaluated. Clinical success was achieved in all seven cases for both procedures. Complications related to EUS-biliary drainage, namely localized peritonitis due to bile leakage, occurred in two cases. Both patients recovered without additional interventions. Occlusion of a duodenal stent was observed in one patient, but additional intervention could not be performed due to sepsis. Occlusion of both a duodenal stent and a biliary stent was also observed in one patient, and this was resolved with the insertion of an additional duodenal stent and a biliary stent exchange. In conclusion, combined duodenal stent placement and EUS-guided biliary drainage is a therapeutic option in case of failed endoscopic retrograde cannulation of malignant strictures with a malignant duodenal obstruction.

Single-pattern convergence of K-ras mutation correlates with surgical indication of intraductal papillary mucinous neoplasms.

OBJECTIVES: One or more patterns of 6 K-ras mutations are detected in cells from the pancreatic juice of patients with intraductal papillary mucinous neoplasms (IPMNs). We investigated whether these mutations are associated with malignant progression. METHODS: Between January 2002 and December 2007, 53 patients with IPMN were subjected to collection of pure pancreatic juice to evaluate K-ras mutation. According to the histological and radiological findings, the IPMNs were classified into 4 groups: carcinoma group, adenoma group, high-risk group, and low-risk group. We retrospectively investigated the mutation with these groups. RESULTS: In patients with a positive K-ras mutation, a single pattern of K-ras mutation was observed in 80% (8/10) of the carcinoma group, in 71% (5/7) of the adenoma group, in 40% (2/5) of the high-risk group, and in 38% (8/21) of the low-risk group. The rate of a single pattern of K-ras mutation decreased in a stepwise order (P = 0.017). The incidence of a single pattern of K-ras mutation was significantly higher in the patients who received surgical therapy (75%, 12/16) than in those who did not (38%, 10/26; P = 0.033). CONCLUSIONS: The present study suggests that the single-clonal convergence of K-ras mutation is associated with the malignant progression of IPMNs.