Angular Correlations in the ß Decay of

We present the first measurement of the α-ß-ν angular correlation in the Gamow-Teller ß^{+} decay of ^{8}B. This was accomplished using the Beta-decay Paul Trap, expanding on our previous work on the ß^{-} decay of ^{8}Li. The ^{8}B result is consistent with the V-A electroweak interaction of the standard model and, on its own, provides a limit on the exotic right-handed tensor current relative to the axial-vector current of |C_{T}/C_{A}|^{2}<0.013 at the 95.5% confidence level. This represents the first high-precision angular correlation measurements in mirror decays and was made possible through the use of an ion trap. By combining this ^{8}B result with our previous ^{8}Li results, we demonstrate a new pathway for increased precision in searches for exotic currents.

Direct Oral Anticoagulants in Cirrhosis Patients Pose Similar Risks of Bleeding When Compared to Traditional Anticoagulation.

BACKGROUND AND AIMS: Direct oral anticoagulants (DOAC) are important new anticoagulant therapies that are not well studied in patients with chronic liver disease. The aim of this study was to compare rates of bleeding in cirrhosis patients treated with DOAC (factor Xa inhibitors: rivaroxaban and apixaban) to those in cirrhosis patients treated with traditional anticoagulation (warfarin and low molecular weight heparin). METHODS: We identified a total of 39 patients with cirrhosis who received anticoagulation therapy over a 3-year period (20 DOAC and 19 traditional anticoagulation) from a research database. Medical records were reviewed to obtain clinical data to compare between the groups. RESULTS: Clinical characteristics between the two groups were similar. There were three documented bleeding events in the traditional anticoagulation group and four bleeding events in the DOAC group (p = 0.9). There were two major bleeding events in the traditional anticoagulation group and one major bleeding event in the DOAC group. There were no documented reports of drug-induced liver injury during this study period. Among all patients, no significant predictors of bleeding were identified using univariate regression and Cox proportional hazard modeling. CONCLUSIONS: This is the first clinical study evaluating the use of DOAC in patients with cirrhosis. DOAC display similar safety characteristics when compared to traditional anticoagulation in patients with cirrhosis and are potentially attractive agents for anticoagulation therapy. Larger studies are now needed to better understand the safety and efficacy of these agents in cirrhosis.

Limit on Tensor Currents from

In the standard model, the weak interaction is formulated with a purely vector-axial-vector (V-A) structure. Without restriction on the chirality of the neutrino, the most general limits on tensor currents from nuclear ß decay are dominated by a single measurement of the ß-ν[over ¯] correlation in ^{6}He ß decay dating back over a half century. In the present work, the ß-ν[over ¯]-α correlation in the ß decay of ^{8}Li and subsequent α-particle breakup of the ^{8}Be^{*} daughter was measured. The results are consistent with a purely V-A interaction and in the case of couplings to right-handed neutrinos (C_{T}=-C_{T}^{'}) limits the tensor fraction to |C_{T}/C_{A}|^{2}<0.011 (95.5% C.L.). The measurement confirms the ^{6}He result using a different nuclear system and employing modern ion-trapping techniques subject to different systematic uncertainties.

Organelle reorganization in bovine oocytes during dominant follicle growth and regression.

BACKGROUND: We tested the hypothesis that organelles in bovine oocytes undergo changes in number and spatial distribution in a manner specific for phase of follicle development. METHODS: Cumulus-oocyte-complexes were collected from Hereford heifers by ultrasound-guided follicle aspiration from dominant follicles in the growing phase (n = 5; Day 0 = ovulation), static phase (n = 5), regressing phase (n = 7) of Wave 1 and from preovulatory follicles (n = 5). Oocytes were processed and transmission electron micrographs of ooplasm representing peripheral, perinuclear and central regions were evaluated using standard stereological methods. RESULTS: The number of mitochondria and volume occupied by lipid droplets was higher (P < 0.03) in oocytes from regressing follicles (193.0 ± 10.4/1000 µm(3) and 3.5 ± 0.7 %) than growing and preovulatory stages (118.7 ± 14.4/1000 µm(3) and 1.1 ± 0.3 %; 150.5 ± 28.7/1000 µm(3) and 1.6 ± 0.2 %, respectively). Oocytes from growing, static and preovulatory follicles had >70 % mitochondria in the peripheral regions whereas oocytes from regressing follicles had an even distribution. Oocytes from growing follicles had more lipid droplets in peripheral region than in central region (86.9 vs. 13.1 %). Percent surface area of mitochondria in contact with lipid droplets increased from growing (2.3 %) to static, regressing or preovulatory follicle stage (8.9, 6.1 and 6.2 %). The amount, size and distribution of other organelles did not differ among phases (P > 0.11). CONCLUSIONS: Our hypothesis was supported in that mitochondrial number increased and translocation occurred from a peripheral to an even distribution as follicles entered the regressing phase. In addition, lipid droplets underwent spatial reorganization from a peripheral to an even distribution during the growing phase and mitochondria-lipid contact area increased with follicle maturation.

First results from the CARIBU facility: mass measurements on the r-process path.

The Canadian Penning Trap mass spectrometer has made mass measurements of 33 neutron-rich nuclides provided by the new Californium Rare Isotope Breeder Upgrade facility at Argonne National Laboratory. The studied region includes the 132Sn double shell closure and ranges in Z from In to Cs, with Sn isotopes measured out to A=135, and the typical measurement precision is at the 100 ppb level or better. The region encompasses a possible major waiting point of the astrophysical r process, and the impact of the masses on the r process is shown through a series of simulations. These first-ever simulations with direct mass information on this waiting point show significant increases in waiting time at Sn and Sb in comparison with commonly used mass models, demonstrating the inadequacy of existing models for accurate r-process calculations.

ß-delayed neutron spectroscopy using trapped radioactive ions.

A novel technique for ß-delayed neutron spectroscopy has been demonstrated using trapped ions. The neutron-energy spectrum is reconstructed by measuring the time of flight of the nuclear recoil following neutron emission, thereby avoiding all the challenges associated with neutron detection, such as backgrounds from scattered neutrons and γ rays and complicated detector-response functions. (137)I(+) ions delivered from a (252)Cf source were confined in a linear Paul trap surrounded by radiation detectors, and the ß-delayed neutron-energy spectrum and branching ratio were determined by detecting the ß(-) and recoil ions in coincidence. Systematic effects were explored by determining the branching ratio three ways. Improvements to achieve higher detection efficiency, better energy resolution, and a lower neutron-energy threshold are proposed.

Tensor interaction limit derived from the α-ß-ν[over ¯] correlation in trapped 8Li ions.

A measurement of the α-ß-ν[over ¯] angular correlation in the Gamow-Teller decay (8)Li→(8)Be(*)+ν[over ¯]+ß, (8)Be(*)→α+α has been performed using ions confined in a linear Paul trap surrounded by silicon detectors. The energy difference spectrum of the α particles emitted along and opposite the direction of the ß particle is consistent with the standard model prediction and places a limit of 3.1% (95.5% confidence level) on any tensor contribution to the decay. From this result, the amplitude of any tensor component C(T) relative to that of the dominant axial-vector component C(A) of the electroweak interaction is limited to |C(T)/C(A)|<0.18 (95.5% confidence level). This experimental approach is facilitated by several favorable features of the (8)Li ß decay and has different systematic effects than the previous ß-ν[over ¯] correlation results for a pure Gamow-Teller transition obtained from studying (6)He ß decay.

Clinical validation of cutoff target ranges in newborn screening of metabolic disorders by tandem mass spectrometry: a worldwide collaborative project.

PURPOSE: To achieve clinical validation of cutoff values for newborn screening by tandem mass spectrometry through a worldwide collaborative effort. METHODS: Cumulative percentiles of amino acids and acylcarnitines in dried blood spots of approximately 25­30 million normal newborns and 10,742 deidentified true positive cases are compared to assign clinical significance, which is achieved when the median of a disorder range is, and usually markedly outside, either the 99th or the 1st percentile of the normal population. The cutoff target ranges of analytes and ratios are then defined as the interval between selected percentiles of the two populations. When overlaps occur, adjustments are made to maximize sensitivity and specificity taking all available factors into consideration. RESULTS: As of December 1, 2010, 130 sites in 45 countries have uploaded a total of 25,114 percentile data points, 565,232 analyte results of true positive cases with 64 conditions, and 5,341 cutoff values. The average rate of submission of true positive cases between December 1, 2008, and December 1, 2010, was 5.1 cases/day. This cumulative evidence generated 91 high and 23 low cutoff target ranges. The overall proportion of cutoff values within the respective target range was 42% (2,269/5,341). CONCLUSION: An unprecedented level of cooperation and collaboration has allowed the objective definition of cutoff target ranges for 114 markers to be applied to newborn screening of rare metabolic disorders.

IL-10 delivery by AAV5 vector attenuates inflammation in mice with Pseudomonas pneumonia.

Lung infections with Pseudomonas aeruginosa and other pathogens in cystic fibrosis (CF) cause progressive airway obstruction and tissue damage, the predominant cause of morbidity and mortality in CF. We investigated whether a recombinant adeno-associated virus type 5 (AAV5) vector expressing murine interleukin (IL)-10 (AAV5.Cbeta-mIL-10), a regulatory/anti-inflammatory cytokine, could decrease airway inflammation in IL-10 knockout mice chronically infected with mucoid P. aeruginosa. Mice that received AAV5.Cbeta-mIL10 through intratracheal inoculation produced IL-10 at an average of 25 000 pg/ml in the epithelial lining fluid (ELF) and 12 000 pg/g-lung tissue 6 weeks post-vector delivery, significantly higher levels than in placebo-treated mice. At 3 days post-infection, proinflammatory cytokines (IL-1beta, tumor necrosis factor (TNF)-alpha, macrophage inhibitory protein (MIP)-1alpha and (KC) in the ELF and lung homogenate were decreased (1-9 folds) in the AAV5.Cbeta-mIL10-treated mice accompanied by less pronounced and more localized neutrophil infiltration in lung sections, when compared with placebo-treated mice. These results suggest that AAV5.Cbeta-mIL10 induces IL-10 levels in the lungs mediating a significant anti-inflammatory response and making AAV-IL-10 gene transfer a potentially useful therapy in the treatment of CF lung disease.

The International Normalized Ratio (INR) in the MELD score: problems and solutions.

The Model for End-Stage Liver Disease (MELD) score is widely used to prioritize patients for liver transplantation. One of the pitfalls of the MELD score is the interlaboratory variability in all three components of the score (INR, bilirubin, creatinine). The interlaboratory variability in the INR has the largest impact on the MELD score, with a mean difference of around 5 MELD points in most studies. During the 3rd conference on Coagulopathy and Liver disease, a multidisciplinary group of scientists and physicians discussed possible solutions for the INR problem in the MELD score with the intention to provide a constructive contribution to the international debate on this issue. Here we will discuss possible solutions and highlight advantages and disadvantages.

Running up and down hills: some consequences of size.

Small mammals are able to run at about the same maximum speed vertically as horizontally, but larger mammals cannot do this. During level running a mouse weighing 30 grams uses about eight times as much energy per unit of body weight as does a chimpanzee weighing 17.5 kilograms (42.6 joules per kilogram meter versus 5.17 joules per kilogram meter). The additional energy required to lift 1 kilogram of body weight 1 meter while running uphill was similar for the two species (about 15.5 joules per kilogram meter). Therefore the increment in energy expenditure for mice to run uphill compared to running horizontally is about one-eighth that for a chimpanzee. Both mice and chimpanzees were able to recover about 90 percent of the energy stored running uphill on the way down.

Relative information from thermal infrared imagery via unoccupied aerial vehicle informs simulations and spatially-distributed assessments of stream temperature.

Stream temperature is a measure of water quality that reflects the balance of atmospheric heat exchange at the air-water interface and gains or losses of water along a stream reach. In urban areas, stormwater sewers deliver water with varying magnitude and temperature to streams at variable timescales. Understanding the impacts of stormwater through space and time is therefore difficult to do with conventional approaches like in situ sensors. To study the impacts of stormwater on creek water temperatures, we combined in situ water temperature observations with thermal infrared (TIR) imagery collected via unoccupied aerial vehicle (UAV). Imagery was collected in May, June, and July of 2017. As ongoing work with UAV-based TIR suggests that this imagery is prone to poor accuracy, we focused on creating several data products beyond absolute water temperatures that can be used to assess temporal and spatial water temperature variations. In particular, TIR data products were used to extract the length of the observed stormwater plume as well as the width of the creek cross-section impacted by stormwater. From these values, we conclude that relatively narrow stormwater plumes affecting a small fraction of creek width can alter creek water temperatures for considerable distances downstream. We also applied TIR data to constrain results of a deterministic stream temperature model (HFLUX 3.0) that simulates the physical processes affecting stream heat exchanges. Stormwater plume lengths obtained from TIR imagery were used to refine spatially-distributed simulations, demonstrating that relative temperature information obtained from UAV imagery can provide useful calibration targets for stream temperature models. Overall, our work demonstrates the added value of UAV datasets for understanding urban stream temperatures, calibrating water quality models, and for modeling and monitoring of the impact of spatially explicit hydrologic processes on stream temperature.

Hypercoagulation and thrombophilia in liver disease.

A complex balance exists between endogenous procoagulants and the anticoagulant system in liver disease patients. Hypercoagulable events occur in cirrhosis patients despite the well-known bleeding diathesis of liver disease. These events may be clinically evident, such as in portal vein thrombosis or pulmonary embolism, but these conditions may also be a silent contributor to certain disease states, such as portopulmonary hypertension or parenchymal extinction with liver atrophy as well as thrombosis of extracorporeal circuits in dialysis or liver assist devices. Moreover, liver disease-related hypercoagulability may contribute to vascular disease in the increasingly common condition of non-alcoholic fatty liver disease. Despite the incidence of these problems, there are few widely accessible and practical laboratory tests to evaluate the risk of a hypercoagulable event in cirrhosis patients. Furthermore, there is little research on the use of commonly accepted anticoagulants in patients with liver disease. This article is a result of an international symposium on coagulation disorders in liver disease and addresses several areas of specific interest in hypercoagulation in liver disease. Critical areas lacking clinical information are highlighted and future areas of research interest are defined with an aim to foster clinical research in this field.

Physical deconditioning is the common denominator in both obese and overweight subjects with nonalcoholic steatohepatitis.

BACKGROUND: Obesity and decreased physical activity mirror increasing prevalence of nonalcoholic fatty liver disease (NAFLD). AIM: We aimed to investigate associations between aerobic fitness, anthropometrics and disease parameters in patients with nonalcoholic steatohepatitis (NASH). We hypothesised that NASH subjects have lower aerobic power and capacity than untrained, sedentary, normal subjects. METHODS: Forty subjects (60% obese, 40% overweight) with biopsy-confirmed NASH and NAFLD activity score (NAS) ≥4 were enrolled in a clinical trial where anthropometrics, laboratories, liver fat content by MRI, activity, and aerobic fitness by cycle ergometry data were obtained. RESULTS: NASH subjects were significantly deconditioned compared to 148 untrained, sedentary, healthy subjects from our laboratory in aerobic power (VO2peak) (NASH 16.8 ± 6.6 vs control 28.4 ± 10.6 mL/kg/min, P < 0.0001) and capacity (VO2 at lactate threshold [LT]) (NASH 8.3 ± 2.5 vs control 14.1 ± 5.9 mL/kg/min, P < 0.0001). NASH subjects' fitness was comparable to the "least fit" tertile of controls: VO2peak [NASH 16.8 ± 6.6 vs "least fit" 17.3 ± 3.3, P = 0.64]) and VO2 at LT (NASH 8.3 ± 2.5 vs "least fit" 9.3 ± 2.1, P = 0.31). Fitness was similar in obese compared to overweight subjects (adjusted for gender) and was not correlated with visceral adiposity or NAS. Engaging in dedicated cardiovascular activity correlated with higher VO2peak and VO2peak at LT. CONCLUSIONS: Aerobic deconditioning was universally present in NASH subjects. NASH subjects' fitness was similar to our laboratory's "least fit" untrained, sedentary control subjects. Further research investigating NASH patients' ability to improve low baseline aerobic fitness is warranted.

Coregulation of NADPH oxidase activation and phosphorylation of a 48-kD protein(s) by a cytosolic factor defective in autosomal recessive chronic granulomatous disease.

The mechanisms regulating activation of the respiratory burst enzyme, NADPH oxidase, of human neutrophils (PMN) are not yet understood, but protein phosphorylation may play a role. We have utilized a defect in a cytosolic factor required for NADPH oxidase activation observed in two patients with the autosomal recessive form of chronic granulomatous disease (CGD) to examine the role of protein phosphorylation in activation of NADPH oxidase in a cell-free system. NADPH oxidase could be activated by SDS in reconstitution mixtures of cytosolic and membrane subcellular fractions from normal PMN, and SDS also enhanced phosphorylation of at least 16 cytosolic and 14 membrane-associated proteins. However, subcellular fractions from CGD PMN plus SDS expressed little NADPH oxidase activity, and phosphorylation of a 48-kD protein(s) was selectively defective. The membrane fraction from CGD cells could be activated for NADPH oxidase when mixed with normal cytosol and phosphorylation of the 48-kD protein(s) was restored. In contrast, the membrane fraction from normal cells expressed almost no NADPH oxidase activity when mixed with CGD cytosol, and phosphorylation of the 48-kD protein(s) was again markedly decreased. Protein kinase C (PKC) activity in PMN from the two patients appeared to be normal, suggesting that a deficiency of PKC is not the cause of the defective 48-kD protein phosphorylation and that the cytosolic factor is not PKC. These results demonstrate that the cytosolic factor required for activation of NADPH oxidase also regulates phosphorylation of a specific protein, or family of proteins, at 48 kD. Although the nature of this protein(s) is still unknown, it may be related to the functional and phosphorylation defects present in CGD PMN and to the activation of NADPH oxidase in the cell-free system.

Recombinant tumor necrosis factor/cachectin and interleukin 1 pretreatment decreases lung oxidized glutathione accumulation, lung injury, and mortality in rats exposed to hyperoxia.

Single, preexposure, parenteral injection with both recombinant tumor necrosis factor/cachectin (TNF/C) and interleukin-1 (IL-1) prolonged the survival of rats (144 +/- 9 h) in continuous hyperoxia (greater than 99% O2 at 1 atm) when compared with rats injected with boiled TNF/C and boiled IL-1 (61 +/- 2 h), TNF/C alone (61 +/- 2 h), IL-1 alone (62 +/- 2 h), or saline (64 +/- 3 h). After exposure to hyperoxia for 52 h, pleural effusion volume, pulmonary artery pressure, total pulmonary resistance, and lung morphologic damage were decreased in those rats given TNF/C and IL-1 as compared with saline-injected rats. In parallel, ratios of reduced (GSH) to oxidized (GSSG) glutathione were greater (P less than 0.05) in lungs of TNF/C + IL-1-injected rats (91 +/- 20) than of saline-injected rats (30 +/- 4) that had been exposed to hyperoxia for 52 h. No differences were found in superoxide dismutase, glutathione peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase, or catalase activities in lungs of TNF/C + IL-1- or saline-treated, hyperoxia-exposed rats. Our results indicate that pretreatment with TNF/C and IL-1 favorably altered lung glutathione redox status, decreased lung injury, and enhanced survival of rats exposed to hyperoxia.

Review article: the prothrombin time test as a measure of bleeding risk and prognosis in liver disease.

BACKGROUND: Prothrombin time (PT)-derived international normalized ratio (INR) is used to assess bleeding risk and prognosis in cirrhosis, and to guide management of associated coagulation disturbances. Recent studies cast doubt on the validity of the assumptions that form the basis for these applications. AIMS: To review and critique the use of the PT-INR in cirrhosis. METHODS: Search of the literature. RESULTS: In cirrhosis, there is a decrease in both pro- and anti-coagulants. The PT-INR measures only the activity of procoagulants and fails to capture changes in anticoagulants. It is therefore not surprising that the PT does not predict the bleeding risk. The PT-INR provides a robust measure of liver function but recent data showed INR inter-laboratory variability in this setting. This is not surprising as the INR was validated to normalize results for patients on vitamin-K antagonists, not for cirrhosis. This limitation was not appreciated, but the INR is used to construct the model for end-stage liver disease score to prioritize patients for liver transplantation. Reports showed that model for end-stage liver disease is modified by the thromboplastin used for testing. CONCLUSIONS: Alternate tests to predict bleeding risk should be developed. The potential for misuse of the PT-INR should drive the development of alternate algorithms for organ allocation.

Enbucrilate for gastric varices: extended experience in 92 patients.

AIM: We assessed N-2-butyl-cyanoacrylate (enbucrilate) in 92 patients with gastric variceal bleeding under an FDA-approved investigation. These results extend our prior report of the first 44 patients. METHOD: Injection was performed with enbucrilate and ethiodol (1:1). Eighty patients had portal hypertension and 12 had splenic vein thrombosis. RESULTS: In the portal hypertensive group, re-bleeding from gastric varices was seen in 4 of 80 (5%) from 0 to 72 h, 5 of 76 (6.5%) from > 72 h to 3 months and 9 of 51 (17%) from > 3 months to 1 year. Re-bleeding and survival were significantly related to the Child-Pugh class. In the splenic vein thrombosis group (n = 12), there was early rebleeding in 2 (17%) patients from 0 to 72 h, 1 (8%) from > 72 h to 3 months and none in the chronic phase (> 3 months to 1 year) although 1-year survival in this group was only 6 (50%) due to the underlying malignancy in most. Serious embolization was suspected in 2 patients (2%). CONCLUSION: Enbucrilate offers an important intervention in gastric variceal bleeding which should be further studied in the US. A randomized trial is warranted to compare this intervention to radiological therapy.

Two-year outcomes of balloon-occluded retrograde transvenous obliteration of gastric varices in liver transplant recipients: A multi-institutional study.

PURPOSE: To assess the 2-year effectiveness and safety of balloon-occluded retrograde transvenous obliteration (BRTO) for gastric varices (GVs) in liver transplant recipients. MATERIALS AND METHODS: Eleven liver transplant recipients underwent consecutive BRTO for GVs at four institutions. Patients included eight (73%) men and three (27%) women with mean age of 56 years±12 (SD) (range: 26-67 years). Underlying cause of liver transplantation was hepatitis C virus (HCV)-related cirrhosis in five (45%), alcohol- and HCV-related cirrhosis in three (27%), primary biliary cirrhosis in two (18%), and alcoholic cirrhosis in one (9%). Five (45%) patients underwent BRTO for actively bleeding GVs, three (17%) for high-risk GVs, and three (17%) for augmentation of portal venous flow through obliteration of gastrorenal shunts. Mean time between liver transplantation and BRTO was 78 months (range: 0.1-276 months). Technical success, GVs obliterative rates, and immediate complications were recorded. Post-BRTO hemorrhagic, transplant, and overall survival rates were evaluated at 6, 12, and 24 months. RESULTS: All (100%) procedures were technically successful. Complete GVs obliteration was achieved in ten patients (91%). Two major complications (18%) occurred in the immediate post-procedure period. One patient developed complete portal vein thrombosis, and another patient developed consumptive coagulopathy, ultimately leading to death. No post-BRTO hemorrhagic recurrences were seen at 6, 12, or 24 months. One patient (9%) had delayed upper gastrointestinal bleeding at 34 months after the procedure which was managed conservatively. Transplant and overall survival rates were 91% at 6, 12, and 24 months. CONCLUSION: BRTO has high technical success and complete GVs obliterative rates in liver transplant recipients with few complications and high graft survival rates.