Tracing Photoinduced Hydrogen Migration in Alcohol Dications from Time-Resolved Molecular-Frame Photoelectron Angular Distributions.

The recent implementation of attosecond and few-femtosecond X-ray pump/X-ray probe schemes in large-scale free-electron laser facilities has opened the way to visualize fast nuclear dynamics in molecules with unprecedented temporal and spatial resolution. Here, we present the results of theoretical calculations showing how polarization-averaged molecular-frame photoelectron angular distributions (PA-MFPADs) can be used to visualize the dynamics of hydrogen migration in methanol, ethanol, propanol, and isopropyl alcohol dications generated by X-ray irradiation of the corresponding neutral species. We show that changes in the PA-MFPADs with the pump-probe delay as a result of intramolecular photoelectron diffraction carry information on the dynamics of hydrogen migration in real space. Although visualization of this dynamics is more straightforward in the smaller systems, methanol and ethanol, one can still recognize the signature of that motion in propanol and isopropyl alcohol and assign a tentative path to it. A possible pathway for a corresponding experiment requires an angularly resolved detection of photoelectrons in coincidence with molecular fragment ions used to define a molecular frame of reference. Such studies have become, in principle, possible since the first XFELs with sufficiently high repetition rates have emerged. To further support our findings, we provide experimental evidence of H migration in ethanol-OD from ion-ion coincidence measurements performed with synchrotron radiation.

Long-term safety and efficacy of anacetrapib in patients with atherosclerotic vascular disease.

AIMS: REVEAL was the first randomized controlled trial to demonstrate that adding cholesteryl ester transfer protein inhibitor therapy to intensive statin therapy reduced the risk of major coronary events. We now report results from extended follow-up beyond the scheduled study treatment period. METHODS AND RESULTS: A total of 30 449 adults with prior atherosclerotic vascular disease were randomly allocated to anacetrapib 100 mg daily or matching placebo, in addition to open-label atorvastatin therapy. After stopping the randomly allocated treatment, 26 129 survivors entered a post-trial follow-up period, blind to their original treatment allocation. The primary outcome was first post-randomization major coronary event (i.e. coronary death, myocardial infarction, or coronary revascularization) during the in-trial and post-trial treatment periods, with analysis by intention-to-treat. Allocation to anacetrapib conferred a 9% [95% confidence interval (CI) 3-15%; P = 0.004] proportional reduction in the incidence of major coronary events during the study treatment period (median 4.1 years). During extended follow-up (median 2.2 years), there was a further 20% (95% CI 10-29%; P < 0.001) reduction. Overall, there was a 12% (95% CI 7-17%, P < 0.001) proportional reduction in major coronary events during the overall follow-up period (median 6.3 years), corresponding to a 1.8% (95% CI 1.0-2.6%) absolute reduction. There were no significant effects on non-vascular mortality, site-specific cancer, or other serious adverse events. Morbidity follow-up was obtained for 25 784 (99%) participants. CONCLUSION: The beneficial effects of anacetrapib on major coronary events increased with longer follow-up, and no adverse effects emerged on non-vascular mortality or morbidity. These findings illustrate the importance of sufficiently long treatment and follow-up duration in randomized trials of lipid-modifying agents to assess their full benefits and potential harms. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN) 48678192; ClinicalTrials.gov No. NCT01252953; EudraCT No. 2010-023467-18.

Cold acclimation increases cold tolerance independently of diapause programing in the bean bug, Riptortus pedestris.

The bean bug (Riptortus pedestris) is a pest of soybeans and other legumes in Japan and other Asian countries. It enters a facultative adult diapause on exposure to short days. While photoperiodism and diapause are well understood in R. pedestris, knowledge of cold tolerance is very limited, as is information on the effect of diapause on cold tolerance. We examined the effect of photoperiod, cold acclimation, and feeding status on cold tolerance in R. pedestris. We found that cold acclimation significantly increased survival at -10°C in both long- and short-day adult R. pedestris. Since the difference in cold survival between long- and short-day cold-acclimated groups was only marginal, we conclude that entering diapause is not crucial for R. pedestris to successfully pass through cold acclimation and become cold tolerant. We observed similar effects in 5th instar nymphs, with both long- and short-day cold-acclimated groups surviving longer cold exposures compared with non-acclimated groups. Starvation, which was tested only in adult bugs, had only a negligible and negative impact on cold survival. Although cold tolerance significantly increased with cold acclimation in adult bugs, supercooling capacity unexpectedly decreased. Our results suggest that changes in supercooling capacity as well as in water content are unrelated to cold tolerance in R. pedestris. An analysis of metabolites revealed differences between the treatments, and while several metabolites markedly increased with cold acclimation, their concentrations were too low to have a significant effect on cold tolerance.

Role of Multichance Fission in the Description of Fission-Fragment Mass Distributions at High Energies.

Fission-fragment mass distributions were measured for ^{237-240}U, ^{239-242}Np, and ^{241-244}Pu populated in the excitation-energy range from 10 to 60 MeV by multinucleon transfer channels in the reaction ^{18}O+^{238}U at the Japan Atomic Energy Agency tandem facility. Among them, the data for ^{240}U and ^{240,241,242}Np were observed for the first time. It was found that the mass distributions for all the studied nuclides maintain a double-humped shape up to the highest measured energy in contrast to expectations of predominantly symmetric fission due to the washing out of nuclear shell effects. From a comparison with the dynamical calculation based on the fluctuation-dissipation model, this behavior of the mass distributions was unambiguously attributed to the effect of multichance fission.

Microvascular proliferation of brain metastases mimics glioblastomas in squash cytology.

OBJECTIVE: Although microvascular proliferation is a key feature in the diagnosis of high-grade glioma, the characteristics of metastatic tumour vessels in smear preparations have not been documented. In this study, the vascular changes in metastatic brain tumours, using squash cytology to examine the vascular patterns in brain metastases, were reviewed. METHODS: One hundred and forty-three squash smears of brain tissue, including 25 normal or reactive tissue, 23 malignant lymphomas, 8 grade I glioma (pilocytic astrocytoma), 23 grade II glioma (diffuse astrocytoma and oligodendroglioma), 42 grade IV glioma (glioblastoma), and 22 metastasis, were assessed. Two vascular patterns were assessed: thick and branching, and glomeruloid. The vessel density, nuclear layer and the number of vessel branches were compared. Furthermore, tumour vessels of brain metastases were analysed by histology and for immunohistochemical expression of CD34, α-smooth muscle actin (SMA) and high-molecular-weight caldesmon (h-CD). RESULTS: Among 22 metastatic tumours, thick and branching vessels were found in 17 (77%) and glomeruloid vessels in 13 (59%). These incidences of microvascular proliferation patterns were similar to those of glioblastomas or pilocytic astrocytomas. Vessel density, nuclear layer and vessel wall branches were significantly higher in metastatic tumours than malignant lymphomas, grade II gliomas or normal brain tissues. Glomeruloid vessels consisted of CD34-positive cells and α-SMA-positive cells, and α-SMA-positive cells had a low h-CD expression. These immunohistochemical patterns were similar to those of high-grade gliomas. CONCLUSIONS: The vascular features of metastatic brain tumours are similar to those of glioblastomas, suggesting that these microvascular proliferations contribute to the progression of metastatic tumours.

Immunocytochemistry for Claudin-18 and Maspin in biliary brushing cytology increases the accuracy of diagnosing pancreatobiliary malignancies.

OBJECTIVE: Biliary brush cytology is an important diagnostic tool in the evaluation of pancreatobiliary malignancies. However, it is difficult to distinguish between malignant and benign cells. The present study evaluated the utility of immunocytochemical expression of Claudin-18 and Maspin in brushing cytology specimens of pancreatobiliary lesions in the diagnosis of pancreatobiliary malignancies. METHODS: The study retrospectively assessed biliary and pancreatic duct brushing cytology specimens of 43 patients whose pancreatobiliary lesions were histologically diagnosed at the University of Miyazaki Hospital. Scanty cellularity slides and cases with no histological confirmation were excluded. Alcohol-fixed and Papanicolaou-stained slides were immunostained with monoclonal antibodies to Claudin-18 and Maspin. RESULTS: Of the 43 patients, 35 (81.4%) were finally histologically diagnosed with invasive adenocarcinomas. The sensitivity of routine cytology for the detection of malignancy was 63%, and the specificity was 100%. The sensitivity of cytology in combination with immunocytochemical expression of Claudin-18 (89%) or Claudin-18 and/or Maspin (97%) was significantly higher than that of cytology alone (P < 0.01). CONCLUSION: Immunocytochemical staining for Claudin-18 and Maspin improved the diagnostic sensitivity for pancreatobiliary adenocarcinomas.

RISING beamline (BL28XU) for rechargeable battery analysis.

The newly installed BL28XU beamline at SPring-8 is dedicated to in situ structural and electronic analysis of rechargeable batteries. It supports the time range (1 ms to 100 s) and spatial range (1 µm to 1 mm) needed for battery analysis. Electrochemical apparatus for battery charging and discharging are available in experimental hutches and in a preparation room. Battery analysis can be carried out efficiently and effectively using X-ray diffraction, X-ray absorption fine-structure analysis and hard X-ray photoelectron spectroscopy. Here, the design and performance of the beamline are described, and preliminary results are presented.

Atomic-scale quantification of grain boundary segregation in nanocrystalline material.

Grain boundary segregation leads to nanoscale chemical variations that can alter a material's performance by orders of magnitude (e.g., embrittlement). To understand this phenomenon, a large number of grain boundaries must be characterized in terms of both their five crystallographic interface parameters and their atomic-scale chemical composition. We demonstrate how this can be achieved using an approach that combines the accuracy of structural characterization in transmission electron microscopy with the 3D chemical sensitivity of atom probe tomography. We find a linear trend between carbon segregation and the misorientation angle ω for low-angle grain boundaries in ferrite, which indicates that ω is the most influential crystallographic parameter in this regime. However, there are significant deviations from this linear trend indicating an additional strong influence of other crystallographic parameters (grain boundary plane, rotation axis). For high-angle grain boundaries, no general trend between carbon excess and ω is observed; i.e., the grain boundary plane and rotation axis have an even higher influence on the segregation behavior in this regime. Slight deviations from special grain boundary configurations are shown to lead to unexpectedly high levels of segregation.

Sagittal focusing of synchrotron radiation X-rays using a winged crystal.

A Si(111) winged crystal has been designed to minimize anticlastic bending and improve sagittal focusing efficiency. The crystal was thin with wide stiffening wings. The length-to-width ratio of the crystal was optimized by finite element analysis, and the optimal value was larger than the `golden value'. The analysis showed that the slope error owing to anticlastic bending is less than the Darwin width. The X-rays were focused two-dimensionally using the crystal and a tangentially bent mirror. The observed profiles of the focal spot agreed well with the results of a ray-tracing calculation in the energy range from 8 to 17.5 keV. X-ray diffraction measurements with a high signal-to-noise ratio using this focusing system were demonstrated for a small protein crystal.

Mutation in Npps in a mouse model of ossification of the posterior longitudinal ligament of the spine.

Ossification of the posterior longitudinal ligament of the spine (OPLL) is a common form of human myelopathy caused by a compression of the spinal cord by ectopic ossification of spinal ligaments. To elucidate the genetic basis for OPLL, we have been studying the ttw (tiptoe walking; previously designated twy) mouse, a naturally occurring mutant which exhibits ossification of the spinal ligaments very similar to human OPLL (refs 3,4). Using a positional candidate-gene approach, we determined the ttw phenotype is caused by a nonsense mutation (glycine 568 to stop) in the Npps gene which encodes nucleotide pyrophosphatase. This enzyme regulates soft-tissue calcification and bone mineralization by producing inorganic pyrophosphate, a major inhibitor of calcification. The accelerated bone formation characteristic of ttw mice is likely to result from dysfunction of NPPS caused by predicted truncation of the gene product, resulting in the loss of more than one-third of the native protein. Our results may lead to novel insights into the mechanism of ectopic ossification and the aetiology of human OPLL.

Effects of statin therapy on abdominal aortic aneurysm growth: a meta-analysis and meta-regression of observational comparative studies.

OBJECTIVE: To determine whether statin therapy reduces the growth rate of small abdominal aortic aneurysms (AAAs). DESIGN: A meta-analysis and a meta-regression of comparative studies. MATERIALS: Eligible studies were randomized controlled trials or observational comparative studies of statin therapy versus placebo or no statin, enrolling individuals with small (<55 mm in diameter) AAAs and reporting AAA growth rate as an outcome. METHODS: Study-specific estimates (standardized mean differences [SMDs]) were combined in the fixed- and random-effects model. RESULTS: Seven adjusted and 4 unadjusted observational comparative studies enrolling 4647 patients with a small AAA were identified. Pooled analysis of all 11 studies suggested a significant reduction in AAA growth rate among patients assigned to statin therapy versus no statin (SMD, -0.420; 95% confidence interval [CI], -0.651 to -0.189). Combining the 7 high-quality studies providing adjusted data for growth rates generated an attenuated but still statistically significant result favoring statin therapy (SMD, -0.367; 95% CI, -0.566 to -0.168). The meta-regression coefficient for the baseline diameter was statistically significant (-0.096; 95% CI, -0.132 to -0.061). CONCLUSION: Statin therapy is likely effective in prevention of the growth of small AAAs, and may be more beneficial as the baseline diameter increases.

Causal involvement of mammalian-type cryptochrome in the circadian cuticle deposition rhythm in the bean bug Riptortus pedestris.

Mammalian-type CRYPTOCHROME (CRY-m) is considered to be a core repressive component of the circadian clock in various insect species. However, this role is based only on the molecular function of CRY-m in cultured cells and it therefore remains unknown whether CRY-m is indispensable for governing physiological rhythms at the organismal level. In the present study, we show that RNA interference (RNAi) targeting of cry-m in the bean bug Riptortus pedestris disrupts the circadian clock governing the cuticle deposition rhythm and results in the generation of a single cuticle layer. Furthermore, period expression was induced in cry-m RNAi insects. These results verified that CRY-m functions as a negative regulator in the circadian clock that generates physiological rhythm at the organismal level.

UDP-sugar transporter implicated in glycosylation and processing of Notch.

Glycosylation modifies protein activities in various biological processes. Here, we report the functions of a novel UDP-sugar transporter (UST74C, an alternative name for Fringe connection (Frc)) localized to the Golgi apparatus in cellular signalling of Drosophila. Mutants in the frc gene exhibit phenotypes resembling wingless and Notch mutants. Both Fringe-dependent and Fringe-independent Notch pathways are affected, and both glycosylation and proteolytic maturation of Notch are defective in mutant larvae. The results suggest that changes in nucleotide-sugar levels can differently affect Wingless and two distinct aspects of Notch signalling.

Three-dimensional conformal radiation therapy for canine aortic body tumour: 6 cases (2014-2019).

OBJECTIVE: To determine the feasibility of three-dimensional conformal radiation therapy for canine aortic body tumours. MATERIALS AND METHODS: Medical records of dogs that had undergone three-dimensional conformal radiation therapy with presumptive diagnosis of aortic body tumour were reviewed for clinical characteristics, treatment modality and outcomes. RESULTS: Eight dogs were diagnosed with aortic body tumour and were treated with three-dimensional conformal radiation therapy. One dog had proliferation of a mass in the right atrium during treatment and died of respiratory distress. Another dog did not undergo follow-up CT to evaluate the treatment response due to the increased blood urea nitrogen values. The remaining 6 dogs were included in the case series. Radiotherapy was performed using a median dose per fraction of 7 Gy (3.3-7.14 Gy), a median of seven divided doses (7-15) and a total median dose of 49 Gy (45-50 Gy). The median number of CT scans during the follow-up period was 5 (range: 3-8 times). CT revealed acute side effects in four dogs-grade 1 effects related to the lung (n = 4) and skin (n = 2). Self-limiting or asymptomatic late side effects (grade 1 lung-related effect) were observed in three dogs. After therapy, one dog demonstrated a complete response, another demonstrated a partial response and the disease remained stable in four animals. The median follow-up period was 514.5 (235-1219) days. After three-dimensional conformal radiation therapy, the aortic body tumour reduced gradually over time without regrowth in all these 6 dogs. CLINICAL SIGNIFICANCE: In this small case series, aortic body tumours responded to three-dimensional conformal radiation therapy. Transient and self-limiting side effects of the treatments were common. Further controlled studies are required to prove the effectiveness and the safety of this intervention.

Worse blood pressure control in patients with cerebrovascular or peripheral arterial disease compared with coronary artery disease.

OBJECTIVES: Poor blood pressure (BP) control is common amongst patients with symptomatic atherothrombotic disease. It is unclear whether BP control and management differ across atherothrombotic disease subtypes. METHODS: We analysed the baseline data of 44,984 patients with documented coronary artery disease (CAD) only (n = 30,414), cerebrovascular disease (CVD) only (n = 11,359) and peripheral arterial disease (PAD) only (n = 3211) from the international REduction of Atherothrombosis for Continued Health Registry and investigated the impact of atherothrombotic disease subtype on BP control and use of antihypertensive drugs. RESULTS: The proportion of patients with BP controlled (<140/90 mmHg) was higher in CAD (58.1%) than in CVD (44.8%) or PAD (38.9%) patients (P < 0.001). Amongst patients with treated hypertension, CAD patients were more likely to have BP controlled than were CVD patients [odds ratio (OR) = 1.67; 95% confidence interval (CI) = 1.59-1.75] or PAD (OR = 2.30; 95% CI = 2.10-2.52). These differences were smaller in women than in men and decreased with age. Amongst treated patients, CAD patients were more likely to receive > or =3-drug combination therapies than were CVD (OR = 1.73; 95% CI = 1.64-1.83) or PAD (OR = 1.64; 95% CI = 1.49-1.80) patients. Adjustment for age, gender, waist obesity, diabetes, education level and world region did not alter the results. CONCLUSIONS: Coronary artery disease patients are more likely than CVD or PAD patients to have BP controlled and to receive antihypertensive drugs, particularly combination therapies. Promotion of more effective BP control through combination antihypertensive therapies could improve secondary prevention and therefore prevent complications in CVD and PAD patients.

Prognosis of atrial fibrillation in patients with symptomatic peripheral arterial disease: data from the REduction of Atherothrombosis for Continued Health (REACH) Registry.

BACKGROUND: Atrial fibrillation (AF) is a significant risk factor for cardiovascular (CV) mortality. This study aims to evaluate the prognostic implication of AF in patients with peripheral arterial disease (PAD). METHODS: The International Reduction of Atherothrombosis for Continued Health (REACH) Registry included 23,542 outpatients in Europe with established coronary artery disease, cerebrovascular disease (CVD), PAD and/or > or =3 risk factors. Of these, 3753 patients had symptomatic PAD. CV risk factors were determined at baseline. Study end point was a combination of cardiac death, non-fatal myocardial infarction (MI) and stroke (CV events) during 2 years of follow-up. Cox regression analysis adjusted for age, gender and other risk factors (i.e., congestive heart failure, coronary artery re-vascularisation, coronary artery bypass grafting (CABG), MI, hypertension, stroke, current smoking and diabetes) was used. RESULTS: Of 3753 PAD patients, 392 (10%) were known to have AF. Patients with AF were older and had a higher prevalence of CVD, diabetes and hypertension. Long-term CV mortality occurred in 5.6% of patients with AF and in 1.6% of those without AF (p<0.001). Multivariable analyses showed that AF was an independent predictor of late CV events (hazard ratio (HR): 1.5; 95% confidence interval (CI): 1.09-2.0). CONCLUSION: AF is common in European patients with symptomatic PAD and is independently associated with a worse 2-year CV outcome.

Homocysteine and folic acid levels in hemodialysis patients treated with sevelamer hydrochloride.

BACKGROUND/AIMS: Folic acid deficiency has been reported to elevate plasma homocysteine levels and result in hyperhomocystinemia, which is an independent risk factor for cardiovascular disease. Sevelamer hydrochloride has the potential to bind with folic acid. To determine this effect of sevelamer hydrochloride on plasma homocysteine levels, change in serum folic acid and plasma homocysteine levels after administration of sevelamer hydrochloride in chronic hemodialysis patients was evaluated. METHODS: Sevelamer hydrochloride was administered to 26 outpatients undergoing hemodialysis for 3 months. Serum and plasma samples were collected just before the dialysis session at baseline and 3 months. RESULTS: Three months after the administration of sevelamer hydrochloride, serum folic acid levels significantly decreased (baseline vs. 3 months; 5.48 +/- 1.81 vs. 4.79 +/- 1.79 ng/ml, p < 0.05), whereas plasma homocysteine levels significantly increased (baseline vs. 3 months; 50.8 +/- 35.9 vs. 67.6 +/- 44.7 nmol/ml, p < 0.01). CONCLUSION: These findings suggest that sevelamer hydrochloride elevates plasma homocysteine levels, possibly by inhibiting the absorption of folic acid. Thus, the effect of sevelamer hydrochloride should be excluded while evaluating the increased plasma levels of homocysteine.

Demineralized dentin matrix acts as a scaffold for repair of articular cartilage defects.

Articular cartilage repair remains a major obstacle in tissue engineering. In the present study, we investigated the potential for demineralized dentin matrix (DDM; organic material derived from dentin) obtained from extracted teeth to be used as bone graft material. To evaluate the extent to which DDM induces osteochondral regeneration, we implanted DDM from bovine teeth in rabbit knees with full-thickness articular cartilage defects. Thirty-three 13-week-old male rabbits weighing 2.5-3.0 kg were randomly assigned to a control group (n = 11) and two experimental groups (n = 11 for each group). The knees were divided into three groups according to the subsequent treatment: in group I (n = 22), the control group, the defect was left untreated; and in groups II (n = 22) and III (n = 22), 50 and 100 mg of DDM, respectively, was implanted. The rabbits were killed 1, 3, 6, or 9 weeks after the surgical procedure, and the knees were collected. The harvested tissues were examined radiographically and histologically. The 100-mg DDM group (group III) had significantly more new bone forming inside the defect (as measured using the BV/TV value) compared with the other two groups as early as at week 3 postoperatively, but thereafter, the difference gradually decreased. Cartilage repair in the surface region remained significantly better in group III because hyaline-like cartilage appeared in the peripheral area of the defect at week 6 and the surface was covered with hyaline-like cartilage with a thickness similar to that of normal cartilage at week 9. In conclusion, the results of this study suggest that DDM acts as a scaffold for osteochondral regeneration, yielding active new bone formation early in the postoperative period. Thus, DDM may represent an effective bone implant material.

High cardiovascular event rates in patients with asymptomatic carotid stenosis: the REACH Registry.

BACKGROUND AND PURPOSE: Data on current cardiovascular event rates in patients with asymptomatic carotid artery stenosis (ACAS) are sparse. We compared the 1-year outcomes of patients with ACAS > or =70% versus patients without ACAS in an international, prospective cohort of outpatients with or at risk of atherothrombosis. METHODS: The Reduction of Atherothrombosis for Continued Health Registry enrolled patients with either > or =3 atherothrombotic risk factors or established atherothrombotic disease. We investigated the 1-year follow-up data of patients for whom physicians reported presence/absence of ACAS at the time of inclusion. RESULTS: Compared with patients without ACAS (n = 30 329), patients with ACAS (n = 3164) had higher age- and sex-adjusted 1-year rates of transient ischaemic attack (3.51% vs. 1.61%, P < 0.0001), non-fatal stroke (2.65% vs. 1.75%, P = 0.0009), fatal stroke (0.49% vs. 0.26%, P = 0.04), cardiovascular death (2.29% vs. 1.52%, P = 0.002), the composite end-point cardiovascular death/myocardial infarction/stroke (6.03% vs. 4.29%, P < 0.0001) and bleeding events (1.41% vs. 0.81%, P = 0.002). In patients with ACAS, Cox regression analyses identified history of cerebrovascular ischaemic events as most important predictor of future stroke (HR 3.21, 95% CI 1.82-5.65, P < 0.0001). CONCLUSION: Asymptomatic carotid artery stenosis was associated with high 1-year rates of cardiovascular and cerebrovascular ischaemic events. Stroke was powerfully predicted by prior cerebrovascular ischaemic events.