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Poor sleep impedes children's cognitive, emotional, and psychosocial development. Pediatric sleep dysregulation is common, and children who live in communities of low socioeconomic status experience additional risk factors for short sleep duration and poor sleep quality. School-based training in mindfulness and yoga-informed practices can improve children's behavior and well-being, but effects on objectively measured sleep are unknown.Effects of a school-based health and mindfulness curriculum, which taught practices such as paced breathing, on sleep and stress were examined in 115 children (49 girls, ages 8 to 11 at baseline). Fifty-eight children in a community of low socioeconomic status received the curriculum twice weekly for 2 years. Fifty-seven children in a socioeconomic status-matched community engaged in their usual physical education class instead. In-home ambulatory polysomnography and perceived social stress were measured in all children at 3 time points: at baseline (ie, prior to curriculum exposure) and at 2 yearly follow-ups.Children receiving the curriculum gained an average of 74 minutes of total sleep time, and 24 minutes of rapid eye movement sleep, per night over the 2-year study period. Children not receiving the curriculum experienced a decrease in total sleep time averaging 64 minutes per night, with no changes in rapid eye movement sleep. Sleep improved within the first 3 months of curriculum exposure, in a dose-dependent fashion. Higher curriculum engagement (eg, using the breathing exercises outside of class) was associated with larger gains in total and rapid eye movement sleep duration. Aggregate within-group changes in social stress were not significant. However, among children receiving the curriculum, those who experienced larger gains in total and rapid eye movement sleep duration also experienced larger increases in perceived social stress.A school-based health and mindfulness curriculum improved children's objectively measured sleep over 2 years. Social stress did not mediate these effects; instead, mindfulness training may have increased awareness of environmental stressors, while developing tools to reduce stress vulnerability.Chick CF, Singh A, Anker LA, et al. A school-based health and mindfulness curriculum improves children's objectively measured sleep: a prospective observational cohort study.

Pulmonary vein (PV) stenosis after atrial fibrillation (AF) ablation is rare; however, it remains a serious complication. PV angioplasty is reportedly an effective therapy; however, a dedicated device for PV angioplasty has not been developed, and the detailed procedural methods remain undetermined. This study describes the symptoms, indications, treatment strategies, and long-term outcomes for PV stenosis after AF ablation.Methods and Results: This study retrospectively analyzed 7 patients with PV stenosis after catheter ablation for AF and who had undergone PV angioplasty at our hospital during 2015-2021. PV stenosis occurred in the left superior (5 patients) and left inferior (2 patients) PV. Six patients had hemoptysis, chest pain, and dyspnea. Seven de novo lesions were treated using balloon angioplasty (BA) (3 patients), a bare metal stent (BMS) (3 patients), and a drug-coated balloon (DCB) (1 patient). The restenosis rate was 42.9% (n=3; 2 patients in the BA group and 1 patient in the DCB group). The repeat treatment rate was 28.6% (2 patients in the BA group). Stenting was performed as repeat treatment. One patient with subsequent repeat restenosis development underwent BA. Ten PV angioplasties were performed; there were no major complications.Regarding PV angioplasty after ablation therapy for AF, stenting showed superior long-term PV patency than BA alone; therefore, it should be considered as a standard first-line approach.

In the transcatheter aortic valve implantation (TAVI) era, the indications for balloon aortic valvuloplasty (BAV) are increasing. Previously, the INOUE-BALLOON® (IB) was used only for antegrade BAV, but recently, it has also been used for retrograde BAV. However, the safety and feasibility of retrograde BAV using an IB are not fully understood. In this study, we investigated the safety and feasibility of retrograde BAV using an IB in elderly Japanese patients with severe aortic stenosis (AS). We compared 39 cases of retrograde BAV using an IB performed from June 2018 to September 2020 and 34 cases of antegrade BAV using an IB performed from August 2013 to May 2018. The total number of complications was lower in retrograde BAV than in antegrade BAV (p = 0.020). The procedure time was significantly shorter in retrograde BAV than in antegrade BAV (p 0.001), and the maximum balloon size and number of balloon inflations were smaller in retrograde BAV than in antegrade BAV (p = 0.002 and p 0.001, respectively). There was no significant difference in the degree of improvement in the aortic valve area or ejection fraction between retrograde and antegrade BAV. In conclusion, the present study showed the safety and feasibility of retrograde BAV using an IB in elderly Japanese patients with severe AS compared with antegrade BAV using an IB.

BACKGROUND The aim of this study was to clarify the clinical outcomes of patients with atrial functional mitral regurgitation (FMR) who underwent the MitraClip procedure compared with those with conventional FMR and sinus rhythm (SR).Methods and Results:Of 303 patients with FMR who underwent the MitraClip procedure, 40 with "atrial-FMR" defined as FMR with permanent atrial fibrillation and normal left ventricular (LV) function/size and 115 with "sinus-FMR" defined as FMR with SR and LV dysfunction were reviewed. Transthoracic and 3D transesophageal echocardiography, and the cardiac complication rate (composite of all-cause death, heart failure admission, mitral valve (MV) surgery, and redo MitraClip procedure) during the 12-month follow-up were compared between the groups. After the MitraClip procedure, reductions in the mitral annular area and its anteroposterior dimension and in the leaflet closure area were observed in both groups. MV orifice area was smaller with greater transmitral pressure gradient (P

Viral hemorrhagic fevers caused by members of the order Bunyavirales comprise endemic and emerging human infections that are significant public health concerns. Despite the disease severity, there are few therapeutic options available, and therefore effective antiviral drugs are urgently needed to reduce disease burdens. Bunyaviruses, like influenza viruses (IFVs), possess a cap-dependent endonuclease (CEN) that mediates the critical cap-snatching step of viral RNA transcription. We screened compounds from our CEN inhibitor (CENi) library and identified specific structural compounds that are 100 to 1,000 times more active in vitro than ribavirin against bunyaviruses, including Lassa virus, lymphocytic choriomeningitis virus (LCMV), and Junin virus. To investigate their inhibitory mechanism of action, drug-resistant viruses were selected in culture. Whole-genome sequencing revealed that amino acid substitutions in the CEN region of drug-resistant viruses were located in similar positions as those of the CEN α3-helix loop of IFVs derived under drug selection. Thus, our studies suggest that CENi compounds inhibit both bunyavirus and IFV replication in a mechanistically similar manner. Structural analysis revealed that the side chain of the carboxyl group at the seventh position of the main structure of the compound was essential for the high antiviral activity against bunyaviruses. In LCMV-infected mice, the compounds significantly decreased blood viral load, suppressed symptoms such as thrombocytopenia and hepatic dysfunction, and improved survival rates. These data suggest a potential broad-spectrum clinical utility of CENis for the treatment of both severe influenza and hemorrhagic diseases caused by bunyaviruses.

Trauma is associated with debilitating acute and posttraumatic stress disorders, which have limited treatment options. We report on a patient undergoing surgical hand repair after a recent knife attack who experienced vivid dreaming and subsequent remission of acute stress disorder. After local anesthesia with propofol sedation she recalled a dream wherein she relived the attack, sought medical care, completed surgery, and returned home with a healed hand. While intraoperative dreaming is common, this case details potential associations between anesthetic state, dreaming, intraoperative electroencephalography, and remission of a psychiatric disorder. Our experience suggests a novel intervention for stress disorders.

It is generally believed that risk factors damage the coronary arteries, cause myocardial ischemia, and consequently change the shape of the heart. On the other hand, each of the risk factors may also have a negative effect on the heart. However, it is very difficult to examine the effects of each of these risk factors independently. Therefore, it is necessary to select an appropriate statistical method and apply it efficiently. In this study, the effects of coronary risk factors on left ventricular size and cardiac function were investigated using structure equation modeling (SEM), and were shown as Bayesian SEM-based frequency polygons using selected two-dimensional contours. This study showed that each risk factor directly affected the shape of the heart. Because vascular risk and heart failure risk are likely to evolve at the same time, managing risk factors is very important in reducing the heart failure pandemic.

Background Baloxavir acid, the active form of the orally available prodrug baloxavir marboxil, is a novel cap-dependent endonuclease inhibitor of influenza virus. Baloxavir marboxil has been shown to rapidly reduce virus titres compared with oseltamivir in clinical studies. Objectives We investigated the relationship between pharmacokinetic (PK) parameters and antiviral activity of baloxavir acid based on virus titre reduction in lungs of infected mice. Methods BALB/c mice infected with a sub-lethal dose of influenza A(H1N1), A(H1N1)pdm09, A(H3N2) or type B virus were treated on day 5 with oral baloxavir marboxil (0.5–50 mg/kg q12h), subcutaneous baloxavir acid (0.25–8 mg/kg/day), oseltamivir phosphate (5 or 50 eq mg/kg q12h) or other antivirals for 1 day. Lung virus titres were assessed 24 h after initial antiviral dosing. PK testing was performed at up to 24 h post-dosing of baloxavir marboxil or baloxavir acid in A/WSN/33-infected mice and the PK/pharmacodynamic (PD) relationship was evaluated for baloxavir acid. Results Oral baloxavir marboxil administration showed dose-dependent virus titre reductions in lungs of mice infected with the different types/subtypes of influenza viruses 24 h post-dosing. Baloxavir marboxil at 15 mg/kg q12h resulted in ≥100-fold and ≥10-fold reductions in influenza A and B virus titres, respectively, compared with oseltamivir phosphate. PK/PD analysis showed that the plasma concentration at the end of the dosing interval (Cτ) or the plasma concentration at 24 h after initial dosing (C24) was the PK parameter predicting the virus titres at 24 h post-dosing of baloxavir acid. Conclusions PK/PD analysis of baloxavir acid based on virus titre reduction in this mouse model could be helpful in predicting and maximizing virological outcomes in clinical settings.

OBJECTIVES The short form or s-allele variant of the serotonin transporter polymorphism (5-HTTLPR), as compared with the long-form or l-allele variant, has been associated with the presence of cognitive dysfunction, and particularly memory impairment in older adults. This body of cross-sectional work has culminated in the hypothesis that presence of the s-allele predicts greater memory decline in older adults. Yet, to date, there are no longitudinal studies that have investigated this issue. METHODS/DESIGN Here, we examine 109 community-dwelling older adults (mean and SD of age = 70.7 ± 8.7 years) who underwent blood draw for genotyping, cognitive, and psychological testing at baseline, 12-, and 24-monthfollow-ups. RESULTS Multilevel modeling found that s-allele carriers (ss or ls) performed worse than ll homozygotes at baseline on delayed verbal recall. Yet, s-allele carriers' memory performance was stable over the two-yearfollow-up period, while l-allele homozygotes experienced significant memory decline. l-allele homozygote status was associated with both increased cortisol and decreased memory over time, resulting in attenuated verbal memory performance differences compared to s-allele carriers with age. CONCLUSIONS Overall, our findings do not support the hypothesis that presence of the 5-HTTLPRs-allele is a marker for memory decline in older adults. J Am Geriatr Soc 68:-, 2020.

Human infections caused by the H5 highly pathogenic avian influenza virus (HPAIV) sporadically threaten public health. The susceptibility of HPAIVs to baloxavir acid (BXA), a new class of inhibitors for the influenza virus cap-dependent endonuclease, has been confirmed in vitro, but it has not yet been fully characterized. Here, the efficacy of BXA against HPAIVs, including recent H5N8 variants, was assessed in vitro. The antiviral efficacy of baloxavir marboxil (BXM) in H5N1 virus-infected mice was also investigated. BXA exhibited similar in vitro activities against H5N1, H5N6, and H5N8 variants tested in comparison with seasonal and other zoonotic strains. Compared with oseltamivir phosphate (OSP), BXM monotherapy in mice infected with the H5N1 HPAIV clinical isolate, the A/Hong Kong/483/1997 strain, also caused a significant reduction in viral titers in the lungs, brains, and kidneys, thereby preventing acute lung inflammation and reducing mortality. Furthermore, compared with BXM or OSP monotherapy, combination treatments with BXM and OSP using a 48-hour delayed treatment model showed a more potent effect on viral replication in the organs, accompanied by improved survival. In conclusion, BXM has a potent antiviral efficacy against H5 HPAIV infections.

Invasive fungal infections (IFIs) are fatal infections, but treatment options are limited. The clinical efficacies of existing drugs are unsatisfactory because of side effects, drug-drug interaction, unfavorable pharmacokinetic profiles, and emerging drug-resistant fungi. Therefore, the development of antifungal drugs with a new mechanism is an urgent issue. Herein, we report novel aryl guanidine antifungal agents, which inhibit a novel target enzyme in the ergosterol biosynthesis pathway. Structure-activity relationship development and property optimization by reducing lipophilicity led to the discovery of 6h, which showed potent antifungal activity against Aspergillus fumigatus in the presence of serum, improved metabolic stability, and PK properties. In the murine systemic A. fumigatus infection model, 6h exhibited antifungal efficacy equivalent to voriconazole (1e). Furthermore, owing to the inhibition of a novel target in the ergosterol biosynthesis pathway, 6h showed antifungal activity against azole-resistant A. fumigatus.

Glucose is an important preferential substrate for energy metabolism during acute coronary syndrome (ACS) attack, although insulin resistance (IR) increases during ACS. Increasing evidence indicates that natriuretic peptides (NP) regulate glucose homeostasis. We investigated possible compensatory actions of NP in collaboration with other neurohumoral factors that facilitate glucose utilization during ACS. The study population consisted of 1072 consecutive cases with ischemic heart disease who underwent cardiac catheterization (ACS, n = 216; non-ACS, n = 856). Among ACS subjects, biochemical data after acute-phase treatment were available in 91 cases, defined as ACS-remission phase (ACS-rem). Path models based on covariance structure analyses were proposed to clarify the direct contribution of B-type NP (BNP) and noradrenaline to glucose and HOMA-IR levels while eliminating confounding biases. In non-ACS and ACS-rem subjects, although noradrenaline slightly increased glucose and/or HOMA-IR levels (P

Human infections with avian-origin influenza A(H7N9) virus represent a serious threat to global health; however, treatment options are limited. Here, we show the inhibitory effects of baloxavir acid (BXA) and its prodrug baloxavir marboxil (BXM), a first-in-class cap-dependent endonuclease inhibitor, against A(H7N9), in vitro and in vivo. In cell culture, BXA at four nanomolar concentration achieved a 1.5–2.8 log reduction in virus titers of A(H7N9), including the NA-R292K mutant virus and highly pathogenic avian influenza viruses, whereas NA inhibitors or favipiravir required approximately 20-fold or higher concentrations to achieve the same levels of reduction. A(H7N9)-specific amino acid polymorphism at position 37, implicated in BXA binding to the PA endonuclease domain, did not impact on BXA susceptibility. In mice, oral administration of BXM at 5 and 50 mg/kg twice a day for 5 days completely protected from a lethal A/Anhui/1/2013 (H7N9) challenge, and reduced virus titers more than 2–3 log in the lungs. Furthermore, the potent therapeutic effects of BXM in mice were still observed when a higher virus dose was administered or treatment was delayed up to 48 hours post infection. These findings support further investigation of BXM for A(H7N9) treatment in humans.

Study Objectives We performed a systematic review to identify the best patient-reported outcome measure (PROM) of postpartum sleep in women. Methods We searched four databases for validated PROMs used to assess postpartum sleep. Studies were considered if they evaluated at least one psychometric measurement property of a PROM. An overall performance rating was assigned for each psychometric measurement property of each PROM based upon COSMIN criteria. A modified GRADE approach was used to assess the level of evidence and recommendations were then made for each PROM. Results We identified 15 validation studies of eight PROMs, in 9,070 postpartum women. An adequate number of sleep domains was assessed by five PROMs: Bergen Insomnia Scale (BIS), Pittsburgh Sleep Quality Index (PSQI), General Sleep Disturbance Scale (GSDS), Athens Insomnia Scale (AIS), and the Sleep Symptom Checklist (SSC). BIS and GSDS were the only PROMs to demonstrate adequate content validity and at least a low level of evidence of sufficient internal consistency, resulting in Class A recommendations. The BIS was the only PROM, which is easily accessible and free to use for noncommercial research, that achieved a Class A recommendation. Conclusion The BIS is the best currently available PROM of postpartum sleep. However, this PROM fails to assess several important domains such as sleep duration (and efficiency), chronotype, sleep-disordered breathing and medication usage. Future studies should focus on evaluating the psychometric measurement properties of BIS in the North American setting and in different cultural groups, or to develop a more specific PROM of postpartum sleep.

To assess the impact of interactions between kidney stone formation and conventional risk factors on incident chronic kidney disease (CKD). A total of 11,402 subjects (men 30–69 years of age, Japanese) without CKD at baseline were observed over an average period of 4 years. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) to determine the association between incident CKD, kidney stone formation, and conventional risk factors (diabetes mellitus, hypertension, overweight/obesity, dyslipidemia, and hyperuricemia/gout). We also examined the interactions of renal stones and the conventional risk factors for CKD. In total, 2301 men (20.2%) developed incident CKD during the follow-up period. After multivariable adjustment, kidney stones were found to increase the risk of incident CKD (HR 1.16; 95% CI 1.03–1.32). Kidney stone formers with hypertension, dyslipidemia, or hyperuricemia/gout presented a greater risk for incident CKD than those who had either kidney stones or other risk factors. However, no significant interactions between kidney stones and other risk factors were found to increase CKD risk. On the other hand, a negative interactive effect between kidney stones and overweight/obesity was observed, leading to reversed risk of incident CKD in coexistence of both factors. Kidney stones were linked to a higher risk for the development of CKD. However, no positive interactive effects were identified between renal stones and conventional risk factors on the risk of incident CKD.

Background In addition to various biological effects of natriuretic peptides (NP) on cardiovascular systems, we recently reported that NP raises intracellular temperature in cultured adipocytes. We herein examined the possible thermogenic action of NP in consideration of hemodynamic parameters and inflammatory reaction by proposing structural equation models. Methods and Results The study population consisted of 1985 consecutive patients who underwent cardiac catheterization. Covariance structure analyses were performed to clarify the direct contribution of plasma B-type NP (BNP) to body temperature (BT) by excluding other confounding factors. A hierarchical path model showed increase in BNP, increase in C-reactive protein and decrease in left ventricular ejection fraction were mutually associated. As expected, C-reactive protein was positively correlated with BT. Importantly, despite a negative correlation between BNP and left ventricular ejection fraction, a decrease in the left ventricular ejection fraction was associated with BT decrease, whereas elevation in BNP level was associated with BT increase independently of C-reactive protein level (P = .007). Conclusions Patients with LV dysfunction tend to manifest a decrease in BT, whereas BNP elevation is associated with an increase in BT independently of inflammatory response. These findings suggest the adaptive heat-retaining property of NP (and/or NP-associated factors) when BT falls owing to unfavorable hemodynamic conditions in a state of impaired cardiac function.

Baloxavir acid (BXA), derived from the prodrug baloxavir marboxil (BXM), potently and selectively inhibits the cap-dependent endonuclease within the polymerase PA subunit of influenza A and B viruses. In clinical trials, single doses of BXM profoundly decrease viral titers as well as alleviating influenza symptoms. Here, we characterize the impact on BXA susceptibility and replicative capacity of variant viruses detected in the post-treatment monitoring of the clinical studies. We find that the PA I38T substitution is a major pathway for reduced susceptibility to BXA, with 30- to 50-fold and 7-fold EC50 changes in A and B viruses, respectively. The viruses harboring the I38T substitution show severely impaired replicative fitness in cells, and correspondingly reduced endonuclease activity in vitro. Co-crystal structures of wild-type and I38T influenza A and B endonucleases bound to BXA show that the mutation reduces van der Waals contacts with the inhibitor. A reduced affinity to the I38T mutant is supported by the lower stability of the BXA-bound endonuclease. These mechanistic insights provide markers for future surveillance of treated populations.

Malondialdehyde-modified low-density lipoprotein (MDA-LDL) level has been reported to be strongly associated with the pathogenesis of cardiovascular diseases. We focused on diabetic status and investigated its possible contribution to MDA-LDL level.The study sample consisted of 2705 patients who were admitted to our hospital and underwent cardiac catheterization. Blood samples were obtained to measure the levels of fasting blood sugar (FBS), hemoglobin A1c (HbA1c), insulin, LDL, MDA-LDL and others. Body mass index (BMI) was also used in constructing structural equation modeling and Bayesian estimation.To explore the factors theoretically associated with MDA-LDL level, we performed structural equation modeling. We generated a path model that revealed that BMI, LDL level and FBS were significantly associated with MDA-LDL level (P 0.001 for each factor), whereas insulin level and HbA1c level were not significantly associated (P = NS for both factors). Noted above was clearly demonstrated on the image of 2-D contour line by Bayesian structure equation modeling.This study clearly showed that hyperglycemia affects MDA-LDL level. An interaction between diabetes and dyslipidemia was shown in terms of activation of lipid oxidation.

Background Fabry disease is one of the causes of left ventricular hypertrophy (LVH) and can be treated with enzyme replacement therapy or pharmacological chaperone therapy. Late gadolinium enhancement (LGE) in cardiac magnetic resonance (CMR) can identify myocardial fibrosis and be used for the stratification in LVH. However, the details of the prevalence and characteristics of LGE in Japanese Fabry patients have not been reported. Methods We evaluated myocardial involvement in 26 Fabry patients (10 males, 16 females) using gadolinium-enhanced CMR. LGE areas were analyzed using the previously reported scoring method. Echocardiography was also performed to evaluate the left ventricular function and left ventricular mass. Results LGE on CMR images was positive in 5 out of 26 patients, and all patients with LGE-positive findings suffered from LVH (2 out of 5 male patients and 3 out of 4 female patients with LVH on echocardiography). LGE was specifically localized at the mid-wall in the infero-lateral area of the left ventricle. LGE-positive patients seemed to be older, and tended to have a larger left ventricular mass index and higher B-type natriuretic peptide level than LGE-negative patients. Conclusions These results revealed that specific localization of LGE was present in Fabry patients.

ObjectivesAnaemia is a risk of worsening heart failure. However, anaemia sometimes remains undetected because the superficial cardiac function does not precisely reflect the adverse impact of anaemia. Plasma B-type natriuretic peptide (BNP) could be helpful in these cases. However, the direct anaemic effects on BNP remain unknown. Herein, we compared the direct effect of anaemia on BNP and left ventricular ejection fraction (LVEF) using an advanced statistical procedure.DesignA retrospective study.SettingSecondary care (cardiology), single-centre study.ParticipantsThe study consisted of 3756 inpatients, including 684 without ischaemic heart disease (IHD) and 3072 with IHD.Primary and secondary outcome measuresRelationship between plasma BNP levels and LVEF values.ResultsA path model was constructed to simultaneously examine the adverse impact of anaemia on LVEF and plasma BNP, allowing for renal function. The path model revealed that LVEF increased in response to low haemoglobin (Hb), and the phenomenon was prominent in non-IHD (standardised regression coefficients (St.β): −0.264, pConclusionThe current study demonstrated that anaemia was a substantial risk for worsening cardiac overload as estimated by plasma BNP. The anaemic response of LVEF likely changed depending on underlying cardiac disorders (IHD or not). However, the response of BNP was robustly observed.

High serum uric acid (UA) has been reported to be associated with left ventricular (LV) dysfunction; however, the relationship between UA and plasma B-type natriuretic peptide (BNP), a sensitive biomarker of heart failure, is still unclear. This study investigated their relationship to provide an accurate assessment of high UA. The study patients consisted of 3,077 subjects who underwent cardiac catheterization because of various cardiovascular disorders. Since the explanatory factors of multiple regression analysis were mostly confounding with each other, subgroup analysis was performed by quartering the study population using the respective risk factors and by covariance structure analysis. This analysis revealed that UA was almost always well associated with a reduced LV ejection fraction (LVEF), but generally not with BNP. UA was significantly associated with BNP in lean aged females, but not in obese adolescent males, although LVEF was significantly reduced in response to a high UA in both groups. A high UA is a direct risk factor for cardiac dysfunction from the perspective of BNP; however, augmentation of BNP in response to a high UA would likely be restricted among obese adolescent males. On the other hand, the observed LV systolic dysfunction, such as LVEF, reflects a high UA on an almost constant basis.

Background: Manual evaluation is an important method for assessing ankle instability, but it is not quantitative. Capacitance-type sensors can be used to measure the distance on the basis of the capacitance value. We applied the sensor to the noninvasive device for measuring ankle instability and showed its utility. Methods: First, 5 ankles embalmed by Thiel’s method were used in an experiment using a cadaver. The capacitance-type sensor was fixed alongside the anterior talofibular ligament (ATFL) of a specially made brace, and the anterior drawer test was performed. The test had been performed for the intact ankle, with the ATFL transected and with both the ATFL and calcaneofibular ligament (CFL) transected. The anterior drawer distance was calculated by the sensor. Intra- and interinvestigator reliability were also analyzed. Next, as a clinical study, a brace with a sensor was fitted to 22 ankles of 20 patients with a history of ankle sprain. An anterior drawer test at a load of 150 N was conducted using a Telos stress device. The anterior drawer distances measured by the sensor and based on radiographic images were then compared. Results: The mean anterior drawer distances were 3.7 ± 1.0 mm for the intact cadavers, 6.1 ± 1.6 mm with the ATFL transected ( P < .001), and 7.9 ± 1.8 mm with the ATFL and CFL transected ( P < .001). The intrainvestigator intraclass correlation coefficients (ICCs) were 0.862 to 0.939, and the interinvestigator ICC was 0.815. In the experiments on patients, the mean anterior drawer distance measured by the sensor was 2.9 ± 0.9 mm, and it was 2.7 ± 0.9 mm for the radiographic images. The correlation coefficient between the sensor and the radiographic images was 0.843. Conclusion: We quantitatively evaluated anterior drawer laxity using a capacitance-type sensor and found it had high reproducibility and strongly correlated with stress radiography measurements in patients with ankle instability. Capacitance-type sensors can be used for the safe, simple, and accurate evaluation of ankle instability.

A diabetic state is causally related to heart failure (HF); therefore, there should be a close correlation between the severity of diabetes and HF. However, a direct relationship between these conditions has rarely been reported and remains unclear. This study was designed to precisely examine this relationship, taking into consideration the possible association between natriuretic peptide (NP) levels and insulin resistance.We examined various hemodynamic parameters and simultaneously performed blood biochemical analyses of consecutive patients who underwent cardiac catheterization at our institution (n=840).Simple regression analyses showed that hemoglobin A1c (HbA1c) levels were not significantly changed by the left ventricular end-diastolic pressure (LVEDP) and left ventricular ejection fraction (LVEF), which were correlated with a low cardiac index. Rather, there was a negative correlation between the HbA1c levels and plasma BNP levels as a marker of HF. A multivariate analysis showed no correlations between the HbA1c levels and cardiac functional parameters (LVEDP, LVEF or the plasma BNP levels), suggesting that the trend toward high HbA1c levels in HF cases is likely to be limited for unknown reasons. To search for an explanation of this finding, we examined the potential biological interactions between BNP and insulin resistance. A multivariate analysis revealed that the plasma BNP levels were positively correlated with age, creatinine levels and LVEDP and inversely correlated with the male gender, body mass index and HOMA-IR (homeostasis model assessment-insulin resistance) (P0.001, respectively), but not HbA1c levels. This analysis indicated a close correlation between plasma BNP levels and insulin effectiveness in HF.HF and diabetes tend to worsen with each other; however, the appearance of an association between them was likely blunted due to the considerable effect of NP in counteracting insulin resistance, even during the metabolically harmful condition of HF.

Severe trauma injuries, such as open pelvic fractures and degloving injuries, have recently become salvageable. However, extensive soft-tissue defects often remain and can lead to disuse atrophy of the extremities, prolonged hospital stays, and numerous other problems. Such injuries can be easily and effectively treated by a general trauma surgeon performing the pedicled omental flap technique. We report on 2 highly diverse and complicated cases of soft-tissue defect that were both successfully treated with this technique. One case was an extensive right-sided defect of the pelvic soft-tissue in a 20-year-old woman. The other case was in a 55-year-old man who underwent emergency artificial vessel replacement surgery for a femoral artery tear with severe damage to the surrounding muscle. Although the surgery was successful, a methicillin-resistant Staphylococcus aureus infection developed around the artificial vessel 10 days after surgery. In both cases, the pedicled omental flap technique was successfully performed and yielded epithelization without serious infection and with the infection subsiding with wound-area healing. To our knowledge, the pedicled omental flap technique has rarely been used to treat severe trauma, and our results suggest its usefulness for both preventing infection in large wounds and healing infected wounds.

Cell models to investigate intestinal absorption functions, such as those of transporters and metabolic enzymes, are essential for oral drug discovery and development. The purpose of this study was to generate intestinal epithelial cells from human induced pluripotent stem cells (hiPSC-IECs) and then clarify whether the functions of hydrolase and transporters in them reflect oral drug absorption in the small intestine. The hiPSC-IECs showed the transport activities of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and peptide transporter 1 (PEPT1), revealed by using their probe substrates ([3H]digoxin, sulfasalazine, and [14C]glycylsarcosine), and the metabolic activities of CYP3A4, CES2, and CES1, which were clarified using their probe substrates (midazolam, irinotecan, and temocapril). The intrinsic clearance by hydrolysis of six ester prodrugs into the active form in hiPSC-IECs was correlated with the plasma exposure (Cmax , AUC, and bioavailability) of the active form after oral administration of these prodrugs to rats. Also, the permeability coefficients of 14 drugs, containing two substrates of P-gp (doxorubicin and [3H]digoxin), one substrate of BCRP (sulfasalazine), and 11 nonsubstrates of transporters (ganciclovir, [14C]mannitol, famotidine, sulpiride, atenolol, furosemide, ranitidine, hydrochlorothiazide, acetaminophen, propranolol, and antipyrine) in hiPSC-IECs were correlated with their values of the fraction of intestinal absorption (Fa) in human clinical studies. These findings suggest that hiPSC-IECs would be a useful cell model to investigate the hydrolysis of ester prodrugs and to predict drug absorption in the small intestine.

Fabry disease is a hereditary disorder that occurs due to the reduction or absence of alpha-galactosidase A activity, which leads to cardiac involvement including left ventricular hypertrophy (LVH). Enzyme replacement therapy (ERT) provides better patient outcomes by preventing serious complications. However, there have been very few studies on the long-term effects of ERT on the cardiac manifestations in Japanese Fabry patients. We retrospectively analyzed the data from the medical records of 42 Fabry patients (male, n = 17; female, n = 25) who were followed at Jikei University Hospital, and in whom the long-term effects of ERT could be evaluated (median follow-up period: male, 11 years; female, 8 years). The slope of the left ventricular mass (LVM) increase was 3.02 ± 3.41 g/m2/year in males and 1.69 ± 2.73 g/m2/year in females. In a subgroup analysis, the slopes of males with and without LVH did not differ to a statistically significant extent; however, the slope in female patients without LVH was significantly smaller than that of female patients with LVH. We then compared our data to the natural historical data that have previously been reported. In comparison to the previously reported data, we found a significant reduction in the LVM changes (g/height2.7/year) of patients who received long-term ERT (male, 4.07 ± 1.03 to 1.25 ± 1.39; female, 2.31 ± 0.81 to 0.78 ± 1.23). Long-term ERT effectively prevents LVH in Fabry patients. This effect was also observed in the patients with LVH prior to the initiation of ERT.

B-type natriuretic peptide (BNP) secretion is stimulated by cardiac dysfunction. However, it is unclear how finely myocardial ischaemia contributes to BNP secretion and whether increases in BNP secretion contribute to coronary vasodilation. This study investigated the direct interaction between plasma BNP levels and cardiac ischaemia using the baseline distal-to-aortic pressure ratio (Pd/Pa). We examined the baseline Pd/Pa and fractional flow reserve (FFR) in 167 patients with intermediate coronary stenosis. The plasma BNP level appeared to be associated with the baseline Pd/Pa in the study population, and this association appeared to become clear only in patients with an FFR ≤ 0.80. To examine the effect of the baseline Pd/Pa on the BNP level in these patients, structural equation modeling (SEM) was performed. The baseline Pd/Pa significantly affected the BNP level (β: −0.37, p = 0.003) and the left ventricular ejection fraction (β: 0.43, p = 0.001). To examine the role of BNP in coronary vasodilation, we proposed another path model using a novel value obtained by dividing the FFR by the baseline Pd/Pa (FFR/baseline Pd/Pa) as an index of the hyperaemic response. The BNP level significantly affected the FFR/baseline Pd/Pa (β: 0.48, p = 0.037). This study demonstrated that BNP finely responded to an exacerbation of cardiac ischaemia and that increases in BNP secretion effectively ameliorated coronary vasoconstriction.

Objective To examine the relationship between subclinical anxiety and depressive symptoms and objective sleep architecture measures and subjective sleep reports in older adults. Methods Community-dwelling older adults (N = 167) self-rated their current severity of anxiety symptoms, depressive symptoms, daytime sleepiness, and global sleep quality. Participants received overnight ambulatory polysomnography to assess sleep architecture. Multivariate linear regression models examined associations between anxiety and depressive symptoms and objective and subjective sleep measures. Results Significant findings emerged for subjective sleep, with higher depression and anxiety scores associated with worse global sleep quality and greater anxiety scores associated with greater daytime sleepiness. No significant associations were observed between subclinical levels of anxiety or depressive symptoms with sleep architecture. Conclusion Subclinical levels of late-life anxiety and depression have distinct associations with subjective sleep disturbance. Findings implicate subjective measures of sleep quality and daytime sleepiness as stronger trait markers for subthreshold psychiatric symptoms than objective sleep biomarkers.

High serum uric acid (UA) level has been assumed to be a risk factor for left ventricular (LV) dysfunction; however, the precise relationship between these conditions has not been fully examined because many confounding factors are associated with UA level. We herein examined the precise relationship by proposing structural equation models. The study population consisted of 1432 cases with ischemic heart disease who underwent cardiac catheterization. Multiple regression analyses and covariance structure analyses were performed to elucidate the cause-and-effect relationship between UA level and LV ejection fraction (LVEF). A path model exploring the factors contributing to LVEF showed that high UA was a significant cause of reduced LVEF (P = 0.004), independent of other significant factors. The degree of atherosclerosis, as estimated by the number of diseased coronary vessels, was significantly affected by high UA (P = 0.005); and the number of diseased coronary vessels subsequently led to reduced LVEF (P

The effects of left ventricular (LV) cavity size on cardiac function and overload have not yet been fully elucidated. We performed a covariance structure analysis and drew theoretical path models to clarify the effects of hemodynamic parameters on the stroke volume index (SVI) as a marker of cardiac function and on the plasma B-type natriuretic peptide (BNP) level as a marker of cardiac overload. We simultaneously measured various hemodynamic parameters and the BNP levels during cardiac catheterization in 1,715 inpatients of our institution. The current path models tested the validity of the Frank-Starling law in patients with heart failure using the SVI, the LV end-systolic volume index (LVESVI) and the LV end-diastolic volume index (LVEDVI). Using the BNP levels, the path models clearly demonstrated that LVESVI substantially augmented cardiac overload, whereas LVEDVI palliated this parameter. These volume indices exerted opposite effects on cardiac function and overload. These results advance the understanding of the relationships between LV cavity size and both cardiac function and overload and indicate the increasing importance of LV diastolic volume in heart failure and the utility of LVESVI as an important marker of cardiac remodeling for further relevant studies.

Objective Although glucose-insulin-potassium (GIK) therapy ought to be beneficial for ischemic heart disease in general, variable outcomes in many clinical trials of GIK in acute coronary syndrome (ACS) had a controversial impact. This study was designed to examine whether “insulin resistance” is involved in ACS and to clarify other potential intrinsic compensatory mechanisms for GIK tolerance through highly statistical procedure. Methods and results We compared the degree of insulin resistance during ACS attack and remission phase after treatment in individual patients (n = 104). During ACS, homeostasis model assessment of insulin resistance (HOMA-IR) values were significantly increased (P

Background The healing process of bone fracture requires a well-controlled multistage and sequential order beginning immediately after the injury. However, complications leading to nonunion exist, creating serious problems and costs for patients. Transforming growth factor-beta 1 (TGF-β1) and bone morphogenic protein 2 (BMP-2) are two major growth factors involved in human bone fracture healing by promoting various stages of bone ossification. In this study, we aimed to determine the role of these factors during the fracture healing of human long bones and assess their impacts on nonunion condition. Materials and methods We performed a comprehensive analysis of plasma TGF-β1 and BMP-2 levels in blood samples from 10 patients with proved nonunion and 10 matched patients with normal union following a predetermined time schedule. The concentrations of TGF-β1 and BMP-2 were measured at each time point using a solid-phase ELISA. Results TGF-β1 and BMP-2 levels were detectable in all patients. For all patients, a maximal peak for TGF-β1 was found at 3-week. In normal union group, TGF-β1 showed a maximal peak at 2-week while nonunion group had a delayed maximal peak at 3-week. Plasma levels of BMP-2 for all patients and for normal union group reached a maximal peak at 1-week, but nonunion group showed a delayed maximal peak at 2-week. In general, plasma TGF-β1 or BMP-2 level was not significantly different between normal union and nonunion groups. Conclusion The expression levels of TGF-β1 and BMP-2 appeared to be delayed in nonunion patients which could play an important role in developing an early marker of fracture union condition and facilitate improved patient's management.

Background It is widely accepted that progression of organic stenosis in the coronary arteries and onset of acute coronary syndrome (ACS) are similar in the development of atherosclerosis. However, the extent of the association of each risk factor with the respective pathological conditions has not been fully elucidated. Objectives We investigated the differences in risk factors between these conditions using a statistical procedure. Methods The study population consisted of 1,029 patients with ischemic heart disease (IHD). We divided the study population into two groups (ACS and non-ACS) and by diseased vessels (organic stenosis). Covariance structure analysis was simultaneously performed in one equation model for determination and comparison of the risk factors for organic stenosis and ACS. Results The analysis revealed that age (standardized regression coefficient, β: 0.206, P < 0.001), male gender (β: 0.126, P < 0.001), HbA1c level (β: 0.109, P < 0.001), HDL level (β: -0.109, P < 0.001) and LDL level (β: 0.127, P = 0.002) were significant for the advancement of organic stenosis. HDL level (β: 0100, P = 0.002) and MDA-LDL level (β: 0.335, P < 0.001) were significant for the onset of ACS, but age, HbA1c and LDL (P = NS or β < 0.1, respectively) were not. Among the risk factors, age, HbA1c and LDL were significantly more strongly associated with organic stenosis than ACS, while MDA-LDL was significantly more strongly associated with ACS than organic stenosis. Conclusions The current statistical analysis revealed clear differences among the risk factors between the progression of organic stenosis and the onset of ACS. Among them, the MDA-LDL level should be considered to indicate a substantial risk of ACS.

BACKGROUND It is conceivable that contemporary valvular heart disease (VHD) is affected largely by an age-dependent atherosclerotic process, which is similar to that observed in coronary artery disease (CAD). However, a comorbid condition of VHD and CAD has not been precisely examined. The first objective of this study was to examine a possible comorbid condition. Provided that there is no comorbidity, the second objective was to search for the possible reasons by using conventional risk factors and plasma B-type natriuretic peptide (BNP) because BNP has a potentiality to suppress atherosclerotic development. METHODS The study population consisted of 3,457 patients consecutively admitted to our institution. The possible comorbid condition of VHD and CAD and the factors that influence the comorbidity were examined by covariance structure analysis and multivariate analysis. RESULTS The distribution of the patients with VHD and those with CAD in the histograms showed that the incidence of VHD and the severity of CAD rose with seniority in appearance. The real statistical analysis was planned by covariance structure analysis. The current path model revealed that aging was associated with VHD and CAD severity (P < 0.001 for each); however, as a notable result, there was an inverse association regarding the comorbid condition between VHD and CAD (Correlation coefficient [β]: -0.121, P < 0.001). As the second objective, to clarify the factors leading to this inverse association, the contribution of conventional risk factors, such as age, gender, hypertension, smoking, diabetes, obesity and dyslipidemia, to VHD and CAD were examined by multivariate analysis. However, these factors did not exert an opposing effect on VHD and CAD, and the inverse association defied explanation. Since different pathological mechanisms may contribute to the formation of VHD and CAD, a differentially proposed path model using plasma BNP revealed that an increase in plasma BNP being drawn by VHD suppressed the progression of CAD (β: -0.465, P < 0.001). CONCLUSIONS The incidence of VHD and CAD showed a significant conflicting relationship. This result supported the likely presence of unknown diverse mechanisms on top of the common cascade of atherosclerosis. Among them, the continuous elevation of plasma BNP due to VHD might be one of the explicable factors suppressing the progression of CAD.

Background/Objectives Obesity is believed to be one of the major risk factors for cardiovascular disease in Western countries. However, the effects of obesity should be continuously examined in the Japanese population because the average bodily habitus differs among countries. In this study, we collectively examined the significance of obesity and obesity-triggered risk factors including the low reactivity of B-type natriuretic peptide (BNP), for ischemic heart disease (IHD) in Japanese patients. Methods and results The study patients consisted of 1252 subjects (IHD: n = 970; non-IHD: n = 282). Multiple logistic regression analysis revealed that dyslipidemia, hypertension, diabetes, and the low reactivity of BNP were significant risk factors for IHD, but body mass index (BMI) was not. A theoretical path model was proposed by positioning BMI at the top of the hierarchical model. Exploratory factor analysis revealed that BMI did not play a causative role in IHD (P = NS). BMI was causatively linked to other risk factors (P

Baloxavir marboxil (BXM) is an orally available small molecule inhibitor of cap-dependent endonuclease (CEN), an essential enzyme in the initiation of mRNA synthesis of influenza viruses. In the present study, we evaluated the efficacy of BXM against influenza virus infection in mouse models. Single-day oral administration of BXM completely prevented mortality due to infection with influenza A and B virus in mice. Moreover, 5-day repeated administration of BXM was more effective for reducing mortality and body weight loss in mice infected with influenza A virus than oseltamivir phosphate (OSP), even when the treatment was delayed up to 96 hours post infection (p.i.). Notably, administration of BXM, starting at 72 hours p.i. led to significant decrease in virus titers of >2-log10 reduction compared to the vehicle control within 24 hours after administration. Virus reduction in the lung was significantly greater than that observed with OSP. In addition, profound and sustained reduction of virus titer was observed in the immunocompromised mouse model without emergence of variants possessing treatment-emergent amino acid substitutions in the target protein. In our immunocompetent and immunocompromised mouse models, delayed treatment with BXM resulted in rapid and potent reduction in infectious virus titer and prevention of signs of influenza infection, suggesting that BXM could extend the therapeutic window for patients with influenza virus infection regardless of the host immune status.

We investigated the association between kidney stones and coronary heart disease risk factors in Japanese men.This cross-sectional study included 13,418 Japanese men 30 to 69 years old who voluntarily underwent medical examination between April 1995 and March 2001. Participants were divided into controls, and past and current kidney stone formers based on ultrasound results and medical history. We evaluated conventional risk factors of coronary heart disease, including overweight/obesity, hypertension, diabetes mellitus, gout/hyperuricemia, dyslipidemia and chronic kidney disease. Associations between coronary heart disease risk factors and kidney stones were investigated.Of the 13,418 participants 404 current kidney stone formers (3.0%) had kidney stones on ultrasound and 1,231 past kidney stone formers (9.2%) had a history of kidney stones but no kidney stones on medical examination. Body mass index, systolic and diastolic blood pressure, and serum uric acid were significantly higher in past and current kidney stone formers than in controls. Logistic regression analysis indicated that the multivariate adjusted OR for overweight/obesity, hypertension, gout/hyperuricemia and chronic kidney disease significantly increased in the order corresponding to controls, and past and current kidney stone formers.Kidney stone formers, even past stone formers, are likely to have accumulated risk factors for coronary heart disease. They could be preferentially targeted for coronary heart disease prevention.

Objective The present study was undertaken to establish a useful range for the B-type natriuretic peptide (BNP) level, with the ultimate goal of determining a cut-off BNP level that will make it possible to identify patients with clinically important organic heart disorders among patients encountered in clinical practice. Methods A total of 11,967 outpatients were evaluated for this study, and, after applying the exclusion criteria, 361 patients were finally recruited for the analysis. Compared to the factors of gender and body mass index, aging was considered to be an indispensable factor in this analysis. The 'median' plasma BNP level was found to increase slowly with age, but remained lower than 30 pg/mL, even in patients aged 60 years or older. In contrast, the overall '95th percentile' of the plasma BNP level in the patients younger than 60 years was 41 pg/mL, which increased to 139.8 pg/mL in the patients aged 60 years or older. Conclusion These findings suggest that the lower range of the BNP level allowing for identification of patients with clinically important organic heart disorders increases with age; however, it might be appropriate to adopt a level of approximately 40 pg/mL, even in elderly patients, in order to avoid any possible age-related effects of diastolic dysfunction or other factors.

Background Thrombin is a serine protease known to be the final product of the coagulation cascade. However, thrombin plays other physiological roles in processes such as gastric contractions and vessel wound healing, and a state of coagulability is increased in patients with dilated cardiomyopathy (DCM). In this study, we investigate the role of thrombin in the pathogenesis of DCM. The purpose of this study is to clarify the role of thrombin in the pathogenesis of DCM and investigate the possibility of treatment against DCM by thrombin inhibition. Methods We investigated the expression of thrombin in the left ventricles of five patients with DCM who underwent the Batista operation and four patients without heart disease. Furthermore, we investigated the involvement of thrombin in the development of DCM using knock-in mice with a deletion mutation of cardiac troponin T that causes human DCM (∆K210 knock-in mouse) (B6;129- Tnnt2 tm2Mmto ) and assessed the effects of a direct thrombin inhibitor, dabigatran on ∆K210 knock-in mice using echocardiographic examinations, the Kaplan-Meier method and Western blotting. Results The immunohistochemical analysis showed a strong thrombin expression in the DCM patients compared to the patients without heart disease. In immunohistochemical analysis, a strong thrombin expression was observed in the heart tissues analysis in the ∆K210 knock-in mice. Dabigatran administration significantly improved fractional shortening according to the echocardiographic examination and the survival outcomes in ∆K210 knock-in mice. Conclusion Tissue thrombin is involved in the pathogenesis of DCM and thrombin inhibition can be beneficial for the treatment of DCM.

The aim of this study was to analyze the frequency and appearances of coronary sinus (CS) anomalies on cardiac computed tomography (CT) of adult patients and to compare them with transthoracic echocardiography (TTE) findings. We retrospectively evaluated cardiac CT images for the presence of CS anomalies in 6936 adult patients who underwent imaging from April 1 2008 to March 31 2015 at our institution. We also reviewed and compared with TTE findings for the cases of CS anomalies. CS anomalies were diagnosed in 23 of the 6936 (0.33 %) and included persistence of the left superior vena cava (PLSVC) in 19 cases, unroofed CS (UCS) in two, coronary artery-CS fistula in two, and CS atresia in one. TTE revealed CS dilatation in only five of the 16 cases of PLSVC and suggested CS anomaly in the two cases of coronary artery-CS fistula. The other cases of CS anomaly were detected incidentally on CT. The incidence of CS anomalies was 0.33 %. Precise diagnosis of CS anomalies with TTE and the original transverse images on cardiac CT alone was difficult for some conditions. We should be alert for the presence of CS anomalies which can cause clinical or procedural complications.

OBJECTIVE: Current data indicate that the rate of trauma in children during gymnastic formation is increasing, especially while creating a structure with a certain height, such as the human pyramid. The goal of the present study was to clarify the clinical characteristics of these injuries. METHODS: In this single-institution review, all children treated for a gymnastic formation-related injury at Nippon Medical School Hospital from 2013 through 2015 were identified through the institution's registry. The injury mechanism was classified, and injury severity, interventions, and outcome were examined. RESULTS: Eight children were treated for a gymnastic formation-related injury. They were 7 boys and 1 girl aged 10 to 15 years (mean age, 13.1±1.8 years). Neurotrauma ranging from concussion to spinal cord injury without radiographic abnormality occurred in 6 patients (75%). No intracranial hemorrhagic lesions were detected. The Glasgow Coma Scale score on arrival was 15 in all 8 patients, and neurological deficits were present in 1 patient. No patient required surgical intervention. All patients made a full recovery after discharge from the hospital. No patients died. The average follow-up period was 2.1±0.9 weeks. CONCLUSIONS: Neurotrauma is a frequent result of gymnastic formation accidents in children. Healthcare workers and teachers should recognize this type of injury, and public education that targets parents should be introduced. Language: en

This investigation sought to determine whether delta activity at sleep onset (DASO) in the sleep electroencephalography of older adults represents normal variation or is associated with clinical pathology. To this end, we examined its longitudinal associations with cognitive and affective function in older adults without dementia.Participants were 153 community-dwelling older adults without dementia. We evaluated polysomnography (PSG), cognitive performance, and affective function at four time points: baseline, 12, 24, and 36 months. All participants completed PSG and measures of global cognition, delayed verbal memory, information processing speed, attention, inhibition, verbal naming, visuospatial ability, and measures of anxiety and depression. DASO was defined as sequences of rhythmic anterior delta activity on PSG in the transition from awake to sleep during the baseline assessment (Figure ).At the baseline, 83 women and 70 men, mean age 71.3 ± 0.6 years participated and 19.6% of participants exhibited DASO. Age, years of education, gender, and body mass index did not differ according to DASO status. Linear mixed modeling showed that the presence of DASO was actually associated with lower levels of anxiety and depression. Further, participants with DASO, versus those without DASO, exhibited a trend towards better cognitive performance over time, although none of these associations reached statistical significance.Whereas DASO was associated with better affective function, no significant association was found between DASO and cognitive change over time. These longitudinal findings support the view that the presence of DASO in healthy older adults represents normal variation rather than pathological aging. Copyright © 2016 John WileySons, Ltd.

When renal artery occlusion occurs secondary to blunt trauma, the recovery rate of renal function after open revascularization is varied and far from satisfactory. Although the optimal treatment for this type of injury has not been established, percutaneous revascularization by endovascular stenting has recently been advocated for patients with unilateral renal artery occlusion. We herein report a case of blunt renal artery occlusion treated with an endovascular stent. After the placement of the stent, renal arteriography showed multiple nonflow-limiting contrast defects in the distal renal arteries, suggesting peripheral thrombosis. Although the duration of warm renal ischemia appears to be the crucial determinant of renal function, multiple thrombi in the distal renal arteries, which would be undetectable during open surgery, could also affect the functional outcome. The presence of these thrombi may explain the limited success of surgical revascularization in such cases.

This report describes our onsite medical rounds and fact-finding activities conducted in the acute phase and medical relief work conducted in the subacute phase in Miyagi prefecture following the Great East Japan Earthquake and subsequent tsunami that occurred off northeastern Honshu on March 11, 2011. As part of the All-Japan Hospital Association medical team deployed to the disaster area, a Nippon Medical School team conducted fact-finding and onsite medical rounds and evaluated basic life and medical needs in the affected areas of Shiogama and Tagajo. We performed triage for more than 2,000 casualties, but in our medical rounds of hospitals, clinics, and nursing homes, we found no severely injured person but did find 1 case of hyperglycemia. We conducted medical rounds at evacuation shelters in Kesennuma City during the subacute phase of the disaster, from March 17 through June 1, as part of the Tokyo Medical Association medical teams deployed. Sixty-seven staff members (17 teams), including 46 physicians, 11 nurses, 3 pharmacists, and 1 clinical psychotherapist, joined this mission. Most patients complained of a worsening of symptoms of preexisting conditions, such as hypertension, respiratory problems, and diabetes, rather than of medical problems specifically related to the tsunami. In the acute phase of the disaster, the information infrastructure was decimated and we could not obtain enough information about conditions in the affected areas, such as how many persons were severely injured, how severely lifeline services had been damaged, and what was lacking. To start obtaining this information, we conducted medical rounds. This proved to be a good decision, as we found many injured persons in evacuation shelters without medication, communication devices, or transportation. Also, basic necessities for life, such as water and food, were lacking. We were able to evaluate these basic needs and inform local disaster headquarters of them. In Kesennuma City, we found that some evacuation shelters could not contact others even after 1 week after the earthquake. We realized from our experiences that, unlike our activities following more localized earthquake disasters, the first task following such large-scale disasters is to acquire information on basic life needs, including medication needs, and the number of persons requiring assistance. We must provide medical relief according to the unique characteristics of the disaster-affected areas as well as the specific nature of the disaster, in this case, a tsunami.

Chronic and subclinical sympathetic over-activity may underlie development of type-2 diabetes mellitus (DM). Since longer heart rate-corrected QT interval (QTc) represents predominance of sympathetic activity within autonomic balance, we investigated influences of QTc on the incidence of DM in a follow-up study. The subjects were 12,530 men and 7,163 women aged 30-59 years and apparently healthy at baseline. QTc in resting ECG was obtained using Bazett's formula (QTcB), Fridericia's formula (QTcF) and the linear regression technique (QTcLR). Incident DM was identified by 'fasting serum glucose > or =7.00 mmol l(-1) (126 mg dl(-1))' or/and 'on medication for DM'. Using Cox proportional hazard models, hazard ratio (HR) for incident DM was estimated according to the quartiles (Q1-Q4) of QTcB, QTcF or QTcLR, and its linear trends across the quartiles were checked. Baseline age, BMI, smoking, drinking, exercise and education were computed as conventional confounders. During the follow-up of 93,337 person-years for men and 51,517 person-years for women, 637 men and 192 women developed DM. The multivariate-adjusted HRs(95% confidence interval) for Q4 of QTcB, QTcF and QTcLR against corresponding Q1 were 1.85(1.46, 2.34), 1.31(1.04, 1.65) and 1.58(1.26, 1.99), respectively, for men, and 2.03(1.31, 3.16), 1.34(0.91, 2.00) and 1.58(1.04, 2.38), respectively, for women. Both sexes showed increasing trends in the HRs across the quartiles of QTcB, QTcF and QTcLR. In conclusion, QTc in resting ECG moderately but proportionally predicts the risk for development of DM in middle-aged healthy men and women. Moreover, the adverse effects of prolonged QTc are independent of those of conventional risk factors.

Background Previously, we found characteristic triton-slowed bands of aminopeptidase N (APN) in cholestatic serum by triton-polyacrylamide gel electrophoresis (triton-PAGE) [Makoto Kawai, Yukichi Hara, Triton-polyacrylamide gel electrophoresis and leucine aminopeptidase activity staining detect Triton-slowed bands including high-molecular-mass aminopeptidase N (CD13) isoform in cholestatic patient sera. Clin Chim Acta 2006; 364:188–195]. Methods Sera from 14 normal pregnant women were electrophoresed on polyacrylamide gel containing 0.02 l/l triton (triton-PAGE) or a 0–0.02 l/l horizontal gradient of triton (gradient-triton-PAGE), and stained with leucine-β-naphthylamide. Some samples were pretreated with a monoclonal APN antibody or rabbit anti-placental leucine aminopeptidase (PLAP) serum. The stained bands were eluted from the gel, treated with N- and O-glycosidase, and analyzed by Western blotting with rabbit anti-APN or anti-PLAP serum. Results Triton-PAGE clearly differentiated 5 LAP activity bands (1–5 from the front). Gradient-triton-PAGE revealed that bands 4–5 were slowed by triton (triton-slowed bands) much more than bands 1–3. Triton-PAGE of antibody-treated serum showed that bands 1, 2, 4, and 5 are mainly APN and that band 3 is PLAP. The molecular mass of PLAP was about 130–140 kDa before treatment with glycosidases but 100 kDa after. Triton-PAGE detected PLAP in 13 and triton-slowed APN in 4 of the 14 women. Conclusions Triton-PAGE differentiates PLAP from APN. Triton-slowed APN as well as PLAP is present in the serum of pregnant women.

Purpose To investigate interactive effects of cigarette smoking and body mass index (BMI, measured in kilograms per square meter) on the risk for type 2 diabetes mellitus (DM). Methods We conducted a follow-up study in 16,829 apparently healthy men 30 to 59 years of age. At baseline, 23.1%, 24.6%, 24.0%, and 28.4% of the men were ‘never’ smokers, ex-smokers, light smokers (≤20 cigarettes/d), and heavy smokers (>20 cigarettes/d), respectively. BMI was expediently categorized into quartiles (Q1: 24.7 kg/m 2 ). Incident DM was identified by a fasting serum glucose level of 7.00 mmol/L or higher or the criterion ‘under treatment for DM.’ The risk ratio for incident DM, hazard ratio (HR) and the 95% confidence interval (CI), according to smoking and BMI, were estimated by using Cox proportional hazard models. Age, drinking, exercise, and education were computed as confounders. Results During mean follow-up of 7.4 years, 869 men developed DM. In Q4 of BMI, heavy smoking raised the risk against ‘never smoking’ (multivariate-adjusted HR (95%CI): 1.37 [1.05–1.80]), but neither light smoking nor ex-smoking did. In Q1 of BMI, light and heavy smoking reduced the risk (multivariate-adjusted HR (95% CI): 0.45 (0.23–0.88) and 0.74 (0.41–1.33), respectively). Conclusions Smoking and BMI interactively influence risk for DM and the interaction is considerably complex. Heavy smoking moderately increases the risk for DM in obese men. But, light smoking reduces the risk in lean men.