Impairment of an Endothelial NAD+-H2S Signaling Network Is a Reversible Cause of Vascular Aging.

A decline in capillary density and blood flow with age is a major cause of mortality and morbidity. Understanding why this occurs is key to future gains in human health. NAD precursors reverse aspects of aging, in part, by activating sirtuin deacylases (SIRT1-SIRT7) that mediate the benefits of exercise and dietary restriction (DR). We show that SIRT1 in endothelial cells is a key mediator of pro-angiogenic signals secreted from myocytes. Treatment of mice with the NAD+ booster nicotinamide mononucleotide (NMN) improves blood flow and increases endurance in elderly mice by promoting SIRT1-dependent increases in capillary density, an effect augmented by exercise or increasing the levels of hydrogen sulfide (H2S), a DR mimetic and regulator of endothelial NAD+ levels. These findings have implications for improving blood flow to organs and tissues, increasing human performance, and reestablishing a virtuous cycle of mobility in the elderly.

Unraveling the mechanistic features of RNA polymerase II termination by the 5'-3' exoribonuclease Rat1.

Within a complex with Rai1, the 5'-3' exoribonuclease Rat1 promotes termination of RNA polymerase II (RNAPII) on protein-coding genes, but its underlying molecular mechanism is still poorly understood. Using in vitro transcription termination assays, we have found that RNAPII is prone to more effective termination by Rat1/Rai1 when its catalytic site is disrupted due to NTP misincorporation, implying that paused RNAPII, which is often found in vivo near termination sites, could adopt a similar configuration to Rat1/Rai1 and trigger termination. Intriguingly, yeast Rat1/Rai1 does not terminate Escherichia coli RNAP, implying that a specific interaction between Rat1/Rai1 and RNAPII may be required for termination. Furthermore, the efficiency of termination increases as the RNA transcript undergoing degradation by Rat1 gets longer, which suggests that Rat1 may generate a driving force for dissociating RNAPII from the template while degrading the nascent transcripts to catch up to the polymerase. These results indicate that multiple mechanistic features contribute to Rat1-mediated termination of RNAPII.

Initial phantom study comparing image quality in computed tomography using adaptive statistical iterative reconstruction and new adaptive statistical iterative reconstruction v.

PURPOSE: The purpose of this study was to assess the image quality of a novel advanced iterative reconstruction (IR) method called as "adaptive statistical IR V" (ASIR-V) by comparing the image noise, contrast-to-noise ratio (CNR), and spatial resolution from those of filtered back projection (FBP) and adaptive statistical IR (ASIR) on computed tomography (CT) phantom image. MATERIALS AND METHODS: We performed CT scans at 5 different tube currents (50, 70, 100, 150, and 200 mA) using 3 types of CT phantoms. Scanned images were subsequently reconstructed in 7 different scan settings, such as FBP, and 3 levels of ASIR and ASIR-V (30%, 50%, and 70%). The image noise was measured in the first study using body phantom. The CNR was measured in the second study using contrast phantom and the spatial resolutions were measured in the third study using a high-resolution phantom. We compared the image noise, CNR, and spatial resolution among the 7 reconstructed image scan settings to determine whether noise reduction, high CNR, and high spatial resolution could be achieved at ASIR-V. RESULTS: At quantitative analysis of the first and second studies, it showed that the images reconstructed using ASIR-V had reduced image noise and improved CNR compared with those of FBP and ASIR (P < 0.001). At qualitative analysis of the third study, it also showed that the images reconstructed using ASIR-V had significantly improved spatial resolution than those of FBP and ASIR (P < 0.001). CONCLUSIONS: Our phantom studies showed that ASIR-V provides a significant reduction in image noise and a significant improvement in CNR as well as spatial resolution. Therefore, this technique has the potential to reduce the radiation dose further without compromising image quality.

Vasospastic Amaurosis Fugax Diagnosed by Cerebral Angiography.

UNLABELLED: We report a case of recurrent monocular blindness presumed to be caused by vasospasm, demonstrated by digital subtraction angiography. CASE REPORT: A 65-year-old man presented with recurrent visual loss in the left eye for 2 years. He had histories of hypertension, cigarette smoking, and May-Thurner syndrome. The symptom occurred variably from twice a day to once a week and usually lasted for 5 minutes. Brain magnetic resonance imaging, magnetic resonance angiography, and ophthalmologic evaluation did not reveal any abnormality. Cerebral digital subtraction angiography was performed. On the left internal carotid angiogram, vasospasm occurred in the cervical portion of the left internal carotid artery and, subsequently, the blood flow to the left ophthalmic artery diminished. This phenomenon was reproducible and, in the absence of vasospasm, the ophthalmic artery was well visualized with no steno-occlusive lesion. Examination of the carotid duplex showed diffuse luminal narrowing and increased flow velocities in the left cervical internal carotid artery without atherosclerotic plaque. Treatment was started with nimodipine, which markedly reduced the attacks. CONCLUSION: We assumed that vasomotor instability, which made the vessels vulnerable to spasm, may have caused a recurrent ocular symptom in our patient.

Outcomes after tissue plasminogen activator administration under the drip and ship paradigm may differ according to the regional stroke care system.

The drip and ship paradigm for stroke patients enhances the rate of using intravenous tissue plasminogen activator (IVT) in community hospitals. The safety and outcomes of patients treated with IVT for acute ischemic stroke (AIS) under the drip and ship paradigm were compared with patients directly treated at a comprehensive stroke center in the Busan metropolitan area of Korea. This was a retrospective study of patients with AIS treated with IVT between January 2009 and January 2012. Information on patients' baseline characteristics, neuroimaging, symptomatic intracerebral hemorrhage (sICH), and outcome 90 days after using IVT was obtained from our stroke registry. We surveyed stroke neurologists regarding their pattern of post-thrombolysis care. During the observation periods, we selected 317 patients using IVT. Among these, 239 patients received IVT at our stroke center, and 78 were treated at 21 community hospitals under the drip and ship paradigm. Initial neurologic deficits and the size of ischemic lesions on magnetic resonance imaging were much more severe in patients treated with IVT under the drip and ship paradigm compared with patients treated at our comprehensive stroke center. The prevalence of a poor outcome (modified Rankin Scale score 3-6) 90 days after IVT was much higher in patients treated with the drip and ship paradigm than in those treated at our comprehensive stroke center. Regarding the occurrence of sICH, there was no significant difference between the 2 groups. The clinical characteristics and outcomes after using IVT under the drip and ship paradigm may differ greatly among stroke care systems.

SIRT2 transgenic over-expression does not impact lifespan in mice.

The NAD+ -dependent deacylase family of sirtuin enzymes have been implicated in biological ageing, late-life health and overall lifespan, though of these members, a role for sirtuin-2 (SIRT2) is less clear. Transgenic overexpression of SIRT2 in the BubR1 hypomorph model of progeria can rescue many aspects of health and increase overall lifespan, due to a specific interaction between SIRT2 and BubR1 that improves the stability of this protein. It is less clear whether SIRT2 is relevant to biological ageing outside of a model where BubR1 is under-expressed. Here, we sought to test whether SIRT2 over-expression would impact the overall health and lifespan of mice on a nonprogeroid, wild-type background. While we previously found that SIRT2 transgenic overexpression prolonged female fertility, here, we did not observe any additional impact on health or lifespan, which was measured in both male and female mice on standard chow diets, and in males challenged with a high-fat diet. At the biochemical level, NMR studies revealed an increase in total levels of a number of metabolites in the brain of SIRT2-Tg animals, pointing to a potential impact in cell composition; however, this did not translate into functional differences. Overall, we conclude that strategies to enhance SIRT2 protein levels may not lead to increased longevity.

Reduced rCBV ratio in perfusion-weighted MR images predicts poor outcome after thrombolysis in acute ischemic stroke.

Recent research has suggested that a perfusion-weighted image (PWI) relative cerebral blood volume (rCBV) map after acute ischemic stroke (AIS) provides information about the collateral circulation in the ischemic region. In this study, we demonstrate the usefulness of the rCBV ratio in PWI in predicting poor outcome after using IV t-PA in AIS. We recruited 58 stroke patients who were treated with IV t-PA after diagnostic magnetic resonance imaging (MRI). Poor outcome was defined as a Modified Rankin Scale (mRS) score >2 measured 90 days after ischemic insult. In total, 21 patients (36.2%) demonstrated poor outcome (i.e. mRS score 3-6). Poor outcome after t-PA correlated with age (p = 0.03), serum glucose level (p = 0.01), NIHSS (p = 0.05), and the presence of T-occlusion (p = 0.05). Poor outcome also correlated with diffusion-weighted MR images of the lesion volume (p < 0.01), lower rCBV ratio on PWI (p < 0.01), and non-recanalization (p < 0.01). Among these, non-recanalization (p < 0.01), reduced rCBV ratio on PWI (p < 0.01), age (p = 0.04), and serum glucose level (p = 0.01) had an independent significance for predicting it. This suggests that the rCBV ratio on PWI may be used to determine prognosis after thrombolysis in AIS.

Factors associated with early dramatic recovery following successful recanalization of occluded artery by endovascular treatment in anterior circulation stroke.

Endovascular treatment (EVT) significantly increases the recanalization rate and improves functional outcomes in acute ischemic stroke. However, despite successful recanalization by EVT, some stroke patients demonstrate no early dramatic recovery (EDR). We assessed factors associated with EDR following recanalization by EVT. We included subjects with anterior circulation stroke treated with EVT who met the following criteria: Thrombolysis in Cerebral Ischemia scores (TICI) 2b-3 after EVT, lesion volume <70mL as seen on the pre-treatment diffusion-weighted imaging (DWI) scan and a baseline NIHSS score ≥6. EDR was defined as a ≥8-point reduction in the NIHSS score, or NIHSS score of 0 or 1 measured 24h following treatment. Multivariate regression analyses were performed to identify the predictors associated with EDR. Of the 102 patients (mean age, 64.3years; median National Institutes of Health Stroke Scale score, 14), EDR was achieved in 39 patients (38.2%). The median DWI lesion volume was 12mL (interquartile range, 5-25mL). Median onset-to-recanalization time in these patients was 320min (interquartile range, 270-415min). Logistic regression analysis identified a higher initial NIHSS score (OR 1.17, 95% CI 1.03-1.33, P=0.016) and shorter time from onset to recanalization (OR 0.99, 95% CI 0.986-0.997, P=0.003), to be independently associated with EDR. In the setting of pretreatment DWI lesion volume <70mL, a higher initial NIHSS score and faster time from onset to recanalization may be important predictors of EDR following successful EVT.

Relative CBV ratio on perfusion-weighted MRI indicates the probability of early recanalization after IV t-PA administration for acute ischemic stroke.

BACKGROUND: We hypothesized that the relative cerebral blood volume (rCBV) ratio on perfusion-weighted imaging (PWI) using MRI might serve as a predictor of early recanalization (ER) after intravenous tissue plasminogen activator (IV t-PA) administration for acute ischemic stroke. METHODS: Patients with acute middle cerebral artery (MCA) ischemic stroke (IS) were enrolled in the study. They were evaluated by MRI, including PWI and diffusion-weighted imaging, before administration of IV t-PA and underwent digital subtraction angiography (DSA) of the brain within 2 h after t-PA administration. We compared the rCBV ratio on PWI between patients with and without ER on DSA and investigated the proportion of patients with an excellent outcome at 90 days after t-PA administration (modified Rankin Scale score 0-1) among those with and without ER. RESULTS: 85 patients with acute MCA IS were included; 16 patients (18.8%) experienced ER on DSA after IV t-PA administration. Patients with ER more frequently had an excellent outcome at 90 days than those without ER. The rCBV ratio on PWI was higher in the ER group (1.01±0.21, p<0.01) than in the non-ER group (0.82±0.18). After adjusting for the presence of atrial fibrillation and the serum glucose level, the rCBV ratio on PWI (OR 1.07; 95% CI 1.02 to 1.12; p<0.01) was a significant independent indicator of ER. CONCLUSIONS: The results of this study suggest that the rCBV ratio on PWI might serve as a useful indicator of ER after IV t-PA administration.

Direct access to a hospital offering intravenous thrombolysis therapy improves functional outcome of acute ischemic stroke patients.

Referral from other hospitals is one of the primary causes of delayed thrombolysis therapy after acute ischemic stroke (AIS). We aimed to evaluate whether direct access to a hospital offering intravenous thrombolysis therapy was associated with good functional outcome in AIS patients treated with thrombolysis. We enrolled patients who received intravenous thrombolysis within 3 hours of symptom onset at our stroke center. We divided these patients into two groups: those with a direct admission to our stroke center and those with indirect admission by referral from other community hospitals. We investigated onset-to-door time and onset-to-recombinant tissue plasminogen activator (rtPA) time according to admission mode. We then assessed the association between a direct admission and favorable outcome at 90 days. A total of 232 patients (mean age of 66.6 years, median National Institutes of Health Stroke Scale score of 10) were included. A total of 48.7% of AIS patients treated with intravenous thrombolytic therapy were transferred from other hospitals. Patients who were directly admitted to our stroke center had a shorter onset-to-door time (61 versus 120 minutes, p<0.001) and onset-to-rtPA time (103 versus 155 minutes, p<0.001) than those referred from other hospitals. Direct admission was associated with a good outcome with an odds ratio of 2.03 (95% confidence interval 1.051-3.917, p=0.035), after adjusting for baseline variables. Thrombolysis after direct admission to a hospital offering intravenous thrombolysis therapy could shorten onset-to-rtPA time and improve stroke outcome in patients with AIS.

Serial change of liver stiffness measured by acoustic radiation force impulse imaging in chronic liver disease: correlation with biochemical markers.

PURPOSE: In patients with chronic diffuse liver diseases, liver fibrosis severity is an important element for prognosis and for selecting therapy. Acoustic radiation force impulse (ARFI) imaging techniques were recently developed to measure liver fibrosis, but their specificity is impaired by cholestasis, inflammation, or edema in acute hepatitis. Herein, our objectives were to evaluate serial changes in shear wave velocity (SWV) and to correlate these changes with biochemical activity. METHODS: This study included 108 patients who underwent ARFI because of viral hepatitis [hepatitis B (HBV) or C (HCV)] with serial follow-up after 3-6 months at our institution between August 2011 and May 2013. Based on baseline and follow-up ARFI, we divided patients with HBV and HCV into two groups: a decreasing SWV group and a non-decreasing SWV group. We evaluated serial SWV changes and correlated these changes with biochemical activity changes. RESULTS: The patients were divided into SWV groups as follows: decreasing SWV group (HBV, n = 23; HCV, n = 7) and non-decreasing SWV group (HBV, n = 40; HCV, n = 38). In both HBV and HVC patients, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were significantly decreased at follow-up in the decreasing SWV group. CONCLUSIONS: The liver stiffness value assessed by ARFI became lower over time in patients who had decreasing AST and ALT levels. According to this study, ARFI overestimates fibrosis grade in patients with high AST and ALT. Thus, assessment of liver fibrosis by ARFI elastography should include consideration of biochemical markers such as AST and ALT levels and additional follow-up using ARFI elastography.

Systemic VEGF-A neutralization ameliorates diet-induced metabolic dysfunction.

The vascular endothelial growth factor (VEGF) family of cytokines are important regulators of angiogenesis that have emerged as important targets for the treatment of obesity. While serum VEGF levels rise during obesity, recent studies using genetic models provide conflicting evidence as to whether VEGF prevents or accelerates metabolic dysfunction during obesity. In the current study, we sought to identify the effects of VEGF-A neutralization on parameters of glucose metabolism and insulin action in a dietary mouse model of obesity. Within only 72 h of administration of the VEGF-A-neutralizing monoclonal antibody B.20-4.1, we observed almost complete reversal of high-fat diet-induced insulin resistance principally due to improved insulin sensitivity in the liver and in adipose tissue. These effects were independent of changes in whole-body adiposity or insulin signaling. These findings show an important and unexpected role for VEGF in liver insulin resistance, opening up a potentially novel therapeutic avenue for obesity-related metabolic disease.

Long-term operation of biomass-to-liquid systems coupled to gasification and Fischer-Tropsch processes for biofuel production.

Long-term operation of the biomass-to-liquid (BTL) process was conducted with a focus on the production of bio-syngas that satisfies the purity standards for the Fischer-Tropsch (FT) process. The integrated BTL system consisted of a bubbling fluidized bed (BFB) gasifier (20 kW(th)), gas cleaning unit, syngas compression unit, acid gas removing unit, and an FT reactor. Since the raw syngas from the gasifier contains different types of contaminants, such as particulates, condensable tars, and acid gases, which can cause various mechanical problems or deactivate the FT catalyst, the syngas was purified by passing through cyclones, a gravitational dust collector, a two-stage wet scrubber (packing-type), and a methanol absorption tower. The integrated system was operated for 500 h over several runs, and stable operating conditions for each component were achieved. The cleaned syngas contained no sulfur compounds (under 1 ppmV) and satisfied the requirements for the FT process.

Organized Comprehensive Stroke Center is Associated with Reduced Mortality: Analysis of Consecutive Patients in a Single Hospital.

BACKGROUND AND PURPOSE: Organized inpatient stroke care is one of the most effective therapies for improving patient outcomes. Many stroke centers have been established to meet this need, however, there are limited data on the effectiveness of these organized comprehensive stroke center (CSC) in the real-world setting. Our aim is to determine whether inpatient care following the establishment of CSC lowers mortality of patients with acute ischemic stroke (AIS). METHODS: Based on a prospective stroke registry, we identified AIS patients hospitalized before and after the establishment of a CSC. We observed all-cause mortality within 30 days from time of admission. Logistic regression was used to determine whether the establishment of the CSC affects independently the 30-day all-cause mortality. RESULTS: A total of 3,117 consecutive patients with AIS were admitted within seven days after the onset of the symptoms. Unadjusted 30-day mortality was lower for patients admitted to our hospital after the establishment of the CSC than before (5.9% vs. 8.2%, P=0.012). Advanced age, female gender, previous coronary artery disease, non-smoking, stroke subtype, admission on a holiday, referral from other hospitals, high NIHSS on admission, and admission before the establishment of CSC were associated with increased 30-day stroke case fatality. After adjustment for these factors, stroke inpatient care subsequent to the establishment of the CSC was independently associated with lower 30-day mortality (OR, 0.57; 95% CI, 0.412-0.795). CONCLUSIONS: Patients treated after the establishment of a CSC had lower 30-mortality rates than ever before, even adjusting for the differences in the baseline characteristics. The present study reveals that organized stroke care in a CSC might improve the outcome after AIS.

Influence of clinical and anatomic features on treatment decisions for anterior communicating artery aneurysms.

OBJECTIVE: The purpose of this study was to analyze the clinical and anatomic features involved in determining treatment modalities for anterior communicating artery (AcoA) aneurysms. METHODS: The authors retrospectively evaluated 112 AcoA aneurysms with pretreatment clinical features including age, Hunt and Hess grade, medical or neurological comorbidity, and anatomical features including aneurysm size, neck size, dome-to-neck ratio, vessel incorporation, multiple lobulation, and morphologic scoring system. Post-treatment clinical results were classified according to the Glasgow Outcome Scale, and anatomic results in coiled patients were classified according to the modified Raymond scale. Using multivariate logistic regression, the probabilities for decision making between surgical clipping and coil embolization were calculated. RESULTS: Sixty-seven patients (60%) were treated with surgical clipping and 45 patients (40%) with endovascular coil embolization. The clinical factor significantly associated with treatment decision was age (≥65 vs. <65 years) and anatomical factors including aneurysm size (small or large vs. medium), dome-to-neck ratio (<2 vs. ≥2), presence of vessel incorporation, multiple lobulation, and morphologic score (≥2 vs. <2). In multivariate analysis, older patients (age, >65 years) had significantly higher odds of being treated with coil embolization relative to clipping (adjusted OR=3.78; 95% CI, 1.39-10.3; p=0.0093) and higher morphological score patients (≥2) had a higher tendency toward surgical clipping than endovascular coil embolization (OR=0.23; 95% CI, 0.16-0.93; p=0.0039). CONCLUSION: The optimal decision for treating AcoA aneurysms cannot be determined by any single clinical or anatomic characteristics. All clinical and morphological features need to be considered, and a collaborative neurovascular team approach to AcoA aneurysms is essential.

Hip joint center location by fitting conchoid shape to the acetabular rim region of MR images.

This paper proposes a hip joint center (HJC) location method based on the approximating of the acetabulum with a conchoid shape to acetabular rim in MR images. As the human hip joint is not a perfect sphere but it is close to a conchoid shape, the accurate location of the HJC cannot be computed as the center of a sphere. By approximating the acetabulum with a conchoid shape, it is possible to compensate a possible hip joint center location error due to the inaccuracy of 3D surface models for using functional method to calculate HJC location. For the hip joint surgery planning, it is necessary to assess patients' hip range of motions based on the HJC, thus the accurate HJC location is important.