Serum transthyretin levels in senile systemic amyloidosis: effects of age, gender and ethnicity

PubMed Central

Buxbaum, Joel; Koziol, James; Connors, Lawreen H.

2017-01-01

Serum transthyretin (TTR) levels are reduced in familial amyloidotic polyneuropathy (FAP). A single study of patients with senile systemic amyloidosis (SSA) in Sweden found that those individuals also had a significantly lower mean serum TTR concentration than age- and gender-matched controls. To determine if the same phenomenon prevailed in an ethnically more heterogeneous population, we compared the serum TTR levels, as determined by ELISA, in 45 documented SSA patients with congestive heart failure, 20 AL patients with congestive heart failure and population controls. Serum TTR concentrations in the controls were influenced in a statistically significant manner by age, gender and ethnicity. Although it is unlikely that such differences are clinically relevant, they must be considered when assessing the meaning of serum TTR concentrations in any clinically defined population. The serum concentrations in patients with SSA did not differ from age, gender and ethnically matched controls or from a group of AL patients with significant clinical cardiac involvement. We also compared TTR concentrations in 12 African-Americans carrying the TTR V122I allele with those in 826 African-Americans who were homozygous wild type at the TTR locus. The TTR V122I carriers had significantly lower serum TTR concentrations than appropriate controls even though the majority of such individuals had not reached the age of clinical or anatomic risk, i.e. over 60. Thus, as in carriers of other TTR mutations the serum TTR level is lower than normal, despite having a much later appearance of clinical disease. PMID:19065297

Caenorhabditis elegans as a model system to study post-translational modifications of human transthyretin

NASA Astrophysics Data System (ADS)

Henze, Andrea; Homann, Thomas; Rohn, Isabelle; Aschner, Michael; Link, Christopher D.; Kleuser, Burkhard; Schweigert, Florian J.; Schwerdtle, Tanja; Bornhorst, Julia

2016-11-01

The visceral protein transthyretin (TTR) is frequently affected by oxidative post-translational protein modifications (PTPMs) in various diseases. Thus, better insight into structure-function relationships due to oxidative PTPMs of TTR should contribute to the understanding of pathophysiologic mechanisms. While the in vivo analysis of TTR in mammalian models is complex, time- and resource-consuming, transgenic Caenorhabditis elegans expressing hTTR provide an optimal model for the in vivo identification and characterization of drug-mediated oxidative PTPMs of hTTR by means of matrix assisted laser desorption/ionization - time of flight - mass spectrometry (MALDI-TOF-MS). Herein, we demonstrated that hTTR is expressed in all developmental stages of Caenorhabditis elegans, enabling the analysis of hTTR metabolism during the whole life-cycle. The suitability of the applied model was verified by exposing worms to D-penicillamine and menadione. Both drugs induced substantial changes in the oxidative PTPM pattern of hTTR. Additionally, for the first time a covalent binding of both drugs with hTTR was identified and verified by molecular modelling.

Central transthyretin acts to decrease food intake and body weight

PubMed Central

Zheng, Fenping; Kim, Yonwook J.; Moran, Timothy H.; Li, Hong; Bi, Sheng

2016-01-01

Transthyretin (TTR) is a blood and cerebrospinal fluid transporter of thyroxine and retinol. Gene expression profiling revealed an elevation of Ttr expression in the dorsomedial hypothalamus (DMH) of rats with exercise-induced anorexia, implying that central TTR may also play a functional role in modulating food intake and energy balance. To test this hypothesis, we have examined the effects of brain TTR on food intake and body weight and have further determined hypothalamic signaling that may underlie its feeding effect in rats. We found that intracerebroventricular (icv) administration of TTR in normal growing rats decreased food intake and body weight. This effect was not due to sickness as icv TTR did not cause a conditioned taste aversion. ICV TTR decreased neuropeptide Y (NPY) levels in the DMH and the paraventricular nucleus (P < 0.05). Chronic icv infusion of TTR in Otsuka Long-Evans Tokushima Fatty rats reversed hyperphagia and obesity and reduced DMH NPY levels. Overall, these results demonstrate a previously unknown anorectic action of central TTR in the control of energy balance, providing a potential novel target for treating obesity and its comorbidities. PMID:27053000

DOE Office of Scientific and Technical Information (OSTI.GOV)

Buxbaum, J.; Pastore, R.; Yaghoubian, R.

Point mutations in the protein transthyretin (TTR) cause familial amyloidosis involving mainly the heart and peripheral nerves. To determine the TTR Ile 122 gene frequency in African Americans, the allele encoding TTR Ile 122 was identified by PCR-Primer Introduced Restriction Analysis of TTR exon 4 and FokI digestion on 1659 control DNA samples from 1659 African Americans: 64 were heterozygous and one homozygous (allele frequency .02). To determine the risk to gene carriers of developing cardiac amyloidosis, immunohistochemical and genetic studies were performed on amyloid-containing samples identified among 52,370 autopsy samples examined over 32 years. In autopsy samples from patientsmore » over age 60, isolated cardiac amyloidosis was more common in African Americans (1.6%) than in White Americans (.40%), suggesting a genetic risk factor. All 29 samples from African Americans were immunohistochemically TTR-positive, and 5 were heterozygous for the TTR Ile 122 allele (17%), as compared with 5/108 heterozygotes (4.6%) among age-matched (over age 60) African American controls without amyloidosis from the same autopsy study (one-tailed P value < .03). Among the 29 amyloid-positive samples were 16 with 1+ or 2+ deposition and 13 with 3+ or 4+ deposition. All 5 TTR Ile 122 heterozygotes had 3+ or 4+ deposition. None of 15 samples from White Americans with cardiac amyloidosis was TTR Ile 122-positive. Extrapolating from the 5/29 samples from which we were able to obtain genetic data, we estimate that 9/54 samples containing cardiac amyloid were TTR Ile 122 heterozygotes. We conclude that heterozygosity for TTR Ile 122 is associated with a greater frequency (relative risk 5.8) and greater severity of cardiac amyloid deposition than in non-carriers of the TTR Ile 122 gene. Of over 40 TTR point mutations associated with amyloidosis described to date, TTR Ile 122 appears to be the most common worldwide and to have the lowest penetrance in causing disease.« less

Warfarin time in therapeutic range and its impact on healthcare resource utilization and costs among patients with nonvalvular atrial fibrillation.

PubMed

Deitelzweig, Steve; Evans, Michael; Hillson, Eric; Trocio, Jeffrey; Bruno, Amanda; Tan, Wilson; Lingohr-Smith, Melissa; Singh, Prianka; Lin, Jay

2016-01-01

Warfarin is efficacious for reducing stroke risk among patients with nonvalvular atrial fibrillation (NVAF). However, the efficacy and safety of warfarin are influenced by its time in therapeutic range (TTR). To assess differences in healthcare resource utilization and costs among NVAF patients with low (<60%) and high (≥60%) warfarin TTRs in an integrated delivery network (IDN) setting. Patients with NVAF were identified from an electronic medical record database. Patients were required to have ≥6 international normalized prothrombin time ratio (INR) tests. NVAF patients were grouped into two cohorts: those with warfarin TTR <60% (low TTR) and those with warfarin TTR ≥60% (high TTR). Healthcare resource utilization and costs were evaluated during a 12 month follow-up period. Multivariable regressions were used to assess the impact of different warfarin TTRs on healthcare costs. Among the study population, greater than half (54%, n = 1595) had a low TTR, and 46% (n = 1356) had a high TTR. Total all-cause healthcare resource utilization was higher among patients in the low TTR cohort vs. the high TTR cohort (number of encounters: 70.2 vs. 56.1, p < 0.001). After adjusting for patient characteristics, total all-cause healthcare costs and stroke-related healthcare costs were $2398 (p < 0.001) and $687 (p = 0.02) higher, respectively, for patients in the low TTR cohort vs. the high TTR cohort. In this retrospective study, we were only able to evaluate the association and not the causality between healthcare resource utilization and costs with the different warfarin TTRs. Many warfarin-treated NVAF patients have a low warfarin TTR. NVAF patients with low vs. patients with high warfarin TTR used healthcare resources to a greater extent, which was reflected in higher healthcare costs.

Geodetic positioning of the Aerospace Electronics Research Lab (ERL) Osborne Time Transfer Receiver (TTR) using the GPS NAVSTAR Block I satellites

NASA Technical Reports Server (NTRS)

Liu, Anthony S.

1990-01-01

Aerospace has routinely processed the Osborne Time Transfer Receiver (TTR) data for the purpose of monitoring the performance of ground and GPS atomic clocks in near real-time with on-line residual displays and characterizing clock stability with Allan Variance calculations. Recently, Aerospace added the ability to estimate the TTR's location by differentially correcting the TTR's location in the WGS84 reference system. This new feature is exercised on a set of TTR clock phase data and Sub-meter accurate station location estimates of the TTR at the Aerospace Electronic Research Lab (ERL) are obtained.

Transthyretin-binding activity of contaminants in blood from polar bear (Ursus maritimus) cubs.

PubMed

Bytingsvik, Jenny; Simon, Eszter; Leonards, Pim E G; Lamoree, Marja; Lie, Elisabeth; Aars, Jon; Derocher, Andrew E; Wiig, Oystein; Jenssen, Bjørn M; Hamers, Timo

2013-05-07

We determined the transthyretin (TTR)-binding activity of blood-accumulating contaminants in blood plasma samples of approximately 4-months-old polar bear (Ursus maritimus) cubs from Svalbard sampled in 1998 and 2008. The TTR-binding activity was measured as thyroxine (T4)-like equivalents (T4-EQMeas). Our findings show that the TTR-binding activity related to contaminant levels was significantly lower (45%) in 2008 than in 1998 (mean ± standard error of mean: 1998, 2265 ± 231 nM; 2008, 1258 ± 170 nM). Although we cannot exclude a potential influence of between-year differences in capture location and cub body mass, our findings most likely reflect reductions of TTR-binding contaminants or their precursors in the arctic environment (e.g., polychlorinated biphenyls [PCBs]). The measured TTR-binding activity correlated positively with the cubs' plasma levels of hydroxylated PCBs (OH-PCBs). No such association was found between TTR-binding activity and the plasma levels of perfluoroalkyl substances (PFASs). The OH-PCBs explained 60 ± 7% and 54 ± 4% of the TTR-binding activity in 1998 and 2008, respectively, and PFASs explained ≤1.2% both years. Still, almost half the TTR-binding activity could not be explained by the contaminants we examined. The considerable levels of TTR-binding contaminants warrant further effect directed analysis (EDA) to identify the contaminants responsible for the unexplained part of the observed TTR-binding activity.

Recommendations for presymptomatic genetic testing and management of individuals at risk for hereditary transthyretin amyloidosis.

PubMed

Obici, Laura; Kuks, Jan B; Buades, Juan; Adams, David; Suhr, Ole B; Coelho, Teresa; Kyriakides, Theodore

2016-02-01

These recommendations highlight recent experience in genetic counselling for the severe autosomal-dominant, late-onset transthyretin familial amyloid polyneuropathy (TTR-FAP) disease, and present a structured approach towards identification and monitoring of asymptomatic carriers of the mutated gene. The effectiveness of current treatment options is still limited in patients with TTR-FAP beyond stage I. Diagnosis in the early stages of TTR-FAP is essential to prevent or delay the progression of disease. Existing legal and cultural issues differ among countries within Europe. Experts of the European Network for TTR-FAP (ATTReuNET) concluded that genetic counselling for diagnosed individuals and at-risk family members is mostly beneficial and should be carried out with care by trained professionals. Systematic and regular monitoring of an asymptomatic carrier is necessary to detect early signs of TTR-FAP and maximize the effectiveness of treatment. This includes five areas of assessment: history/clinical examination, sensorimotor function, autonomic dysfunction, cardiac function, and renal function. At least two related symptoms and positive biopsy findings are required to confirm diagnosis of TTR-FAP. Early detection of TTR-FAP is essential to improve the prognosis of TTR-FAP. ATTReuNET recommends genetic counselling and routine monitoring for asymptomatic carriers of TTR-FAP.

Cysteinylated transthyretin as a discriminator of cardiovascular risk in patients with diabetes mellitus.

PubMed

Wakabayashi, Ichiro; Marumo, Mikio; Nonaka, Daisuke; Lee, Lyang-Ja; Mukai, Jun; Ohki, Makoto; Tanaka, Kenji; Uchida, Kagehiro

2017-07-01

The cysteine residue on transthyretin (TTR) is susceptible to be oxidized, and serum cysteinylated TTR (Cys-TTR) level is thought to reflect oxidative stress. The purpose of this study was to elucidate the relationship between Cys-TTR and arterial stiffness, a known predictor of cardiovascular disease, in patients with type 2 diabetes. The subjects were 105 male outpatients with type 2 diabetes. Arterial stiffness was evaluated by measuring cardio-ankle vascular index (CAVI). The relationship between CAVI and ratio of Cys-TTR to total TTR (Cys-TTR ratio) was analyzed. Cys-TTR ratio was significantly correlated with CAVI (Pearson's correlation coefficient: 0.316, p<0.01), and CAVI was significantly higher in the 3rd tertile group for Cys-TTR ratio than in its 1st tertile group. These relationships were also significant after adjusting for age, smoking, alcohol drinking, body mass index, mean arterial pressure, hemoglobin A1c, LDL cholesterol-to-HDL cholesterol ratio and eGFR. Prevalence of high CAVI (≥10.0) was significantly higher in the 3rd tertile for Cys-TTR ratio than in its 1st tertile and tended to be higher with an increase in tertile (28.6% in the 1st tertile, 42.9% in the 2nd tertile and 60.0% in the 3rd tertile). Odds ratio (OR) for high CAVI of the 3rd vs. 1st tertile groups for Cys-TTR ratio was significantly higher than the reference level of 1.00 both before and after adjustment for the above cardiovascular risk factors (crude OR, 3.75 [1.38-10.17]; adjusted OR, 5.09 [1.39-18.64]). Cys-TTR ratio is associated with arterial stiffness in patients with diabetes and is proposed as a new discriminator of cardiovascular risk. Copyright © 2017 Elsevier B.V. All rights reserved.

Use of Serum Transthyretin as a Prognostic Indicator and Predictor of Outcome in Cardiac Amyloid Disease Associated With Wild-Type Transthyretin.

PubMed

Hanson, Jacquelyn L S; Arvanitis, Marios; Koch, Clarissa M; Berk, John L; Ruberg, Frederick L; Prokaeva, Tatiana; Connors, Lawreen H

2018-02-01

Wild-type transthyretin amyloidosis (ATTRwt), an underappreciated cause of heart failure in older adults, is challenging to diagnose and monitor in the absence of validated, disease-specific biomarkers. We examined the prognostic use and survival association of serum TTR (transthyretin) concentration in ATTRwt. Patients with biopsy-proven ATTRwt were retrospectively identified. Serum TTR, cardiac biomarkers, and echocardiographic parameters were assessed at baseline and follow-up evaluations. Statistical analyses included Kaplan-Meier method, Cox proportional hazard survival models, and receiver-operating characteristic curve analysis. Median serum TTR concentration at presentation was 23 mg/dL (n=116). Multivariate predictors of shorter overall survival were decreased TTR, left ventricular ejection fraction and elevated cTn-I (cardiac troponin I); an inclusive model demonstrated superior accuracy in 4-year survival prediction by receiver-operating characteristic curve analysis (area under the curve, 0.77). TTR values lower than the normal limit, <18 mg/dL, were associated with shorter survival (2.8 versus 4.1 years; P =0.03). Further, TTR values at 1- and 2-year follow-ups were significantly lower ( P <0.001) in untreated patients (n=23) compared with those treated with TTR stabilizer, diflunisal (n=12), after baseline evaluation. During 2-year follow-up, unchanged TTR corresponded to increased cTn-I ( P =0.006) in untreated patients; conversely, the diflunisal-treated group showed increased TTR ( P =0.001) and stabilized cTn-I and left ventricular ejection fraction at 1 year. In this series of biopsy-proven ATTRwt, lower baseline serum TTR concentration was associated with shorter survival as an independent predictor of outcome. Longitudinal analysis demonstrated that decreasing TTR corresponded to worsening cardiac function. These data suggest that TTR may be a useful prognostic marker and predictor of outcome in ATTRwt. © 2018 American Heart Association, Inc.

The evolutionary and integrative roles of transthyretin in thyroid hormone homeostasis.

PubMed

Schreiber, G

2002-10-01

In larger mammals, thyroid hormone-binding plasma proteins are albumin, transthyretin (TTR) and thyroxine (T4)-binding globulin. They differ characteristically in affinities and release rates for T4 and triiodothyronine (T3). Together, they form a 'buffering' system counteracting thyroid hormone permeation from aqueous to lipid phases. Evolution led to important differences in the expression pattern of these three proteins in tissues. In adult liver, TTR is only made in eutherians and herbivorous marsupials. During development, it is also made in tadpole and fish liver. More intense TTR synthesis than in liver is found in the choroid plexus of reptilians, birds and mammals, but none in the choroid plexus of amphibians and fish, i.e. species without a neocortex. All brain-made TTR is secreted into the cerebrospinal fluid, where it becomes the major thyroid hormone-binding protein. During ontogeny, the maximum TTR synthesis in the choroid plexus precedes that of the growth rate of the brain and occurs during the period of maximum neuroblast replication. TTR is only one component in a network of factors determining thyroid hormone distribution. This explains why, under laboratory conditions, TTR-knockout mice show no major abnormalities. The ratio of TTR affinity for T4 over affinity for T3 is higher in eutherians than in reptiles and birds. This favors T4 transport from blood to brain providing more substrate for conversion of the biologically less active T4 into the biologically more active T3 by the tissue-specific brain deiodinases. The change in affinity of TTR during evolution involves a shortening and an increase in the hydrophilicity of the N-terminal regions of the TTR subunits. The molecular mechanism for this change is a stepwise shift of the splice site at the intron 1/exon 2 border of the TTR gene. The shift probably results from a sequence of single base mutations. Thus, TTR evolution provides an example for a molecular mechanism of positive Darwinian evolution. The amino acid sequences of fish and amphibian TTRs are very similar to those in mammals, suggesting that substantial TTR evolution occurred before the vertebrate stage. Open reading frames for TTR-like sequences already exist in Caenorhabditis elegans, yeast and Escherichia coli genomes.

Quality of warfarin control in atrial fibrillation patients in South East Queensland, Australia.

PubMed

Bernaitis, N; Badrick, T; Davey, A K; Anoopkumar-Dukie, S

2016-08-01

Warfarin is widely prescribed to decrease the risk of stroke in atrial fibrillation (AF) patients. Due to patient variability in response, regular monitoring is required, and time in therapeutic range (TTR) used to indicate quality of warfarin control with a TTR>60% is recommended. Recently, an Australian Government review of anticoagulants identified the need to establish current warfarin control and determine the potential place of the newer oral anticoagulants. To determine warfarin control by a pathology practice in Queensland, Australia and identify factors influencing TTR. Retrospective data were collected from Sullivan Nicolaides Pathology, a major pathology practice offering a warfarin care programme in Australia. Patients enrolled in their programme as of September 2014 were included in the study. TTR was calculated using INR test results, and test dates using the Rosendaal method with mean patient TTR were used for analysis and comparison. Exclusions were target therapeutic range outside 2.0-3.0, less than two INR tests and programme treatment time of less than 30 days. The eligible 3692 AF patients had 73.6% of INR tests within the therapeutic range. The mean TTR was 81%, with 97% of patients above a TTR of 60%. TTR was not significantly influenced by age, gender or socioeconomic factors. The observed mean TTR of over 80% is superior to the minimum recommended threshold of 60%. The TTR achieved by the Queensland pathology practice demonstrates that dedicated warfarin programmes can produce high-quality warfarin care, ensuring the full benefit of warfarin for Australian patients. © 2016 Royal Australasian College of Physicians.

Iodine Atoms: A New Molecular Feature for the Design of Potent Transthyretin Fibrillogenesis Inhibitors

PubMed Central

Pinto, Marta; Almeida, Maria Rosário; Gales, Luis; Ballesteros, Alfredo; Barluenga, José; Pérez, Juan J.; Vázquez, Jesús T.; Centeno, Nuria B.; Saraiva, Maria Joao; Damas, Ana M.; Planas, Antoni; Arsequell, Gemma; Valencia, Gregorio

2009-01-01

The thyroid hormone and retinol transporter protein known as transthyretin (TTR) is in the origin of one of the 20 or so known amyloid diseases. TTR self assembles as a homotetramer leaving a central hydrophobic channel with two symmetrical binding sites. The aggregation pathway of TTR into amiloid fibrils is not yet well characterized but in vitro binding of thyroid hormones and other small organic molecules to TTR binding channel results in tetramer stabilization which prevents amyloid formation in an extent which is proportional to the binding constant. Up to now, TTR aggregation inhibitors have been designed looking at various structural features of this binding channel others than its ability to host iodine atoms. In the present work, greatly improved inhibitors have been designed and tested by taking into account that thyroid hormones are unique in human biochemistry owing to the presence of multiple iodine atoms in their molecules which are probed to interact with specific halogen binding domains sitting at the TTR binding channel. The new TTR fibrillogenesis inhibitors are based on the diflunisal core structure because diflunisal is a registered salicylate drug with NSAID activity now undergoing clinical trials for TTR amyloid diseases. Biochemical and biophysical evidence confirms that iodine atoms can be an important design feature in the search for candidate drugs for TTR related amyloidosis. PMID:19125186

Gene therapy approach to FAP: in vivo influence of T119M in TTR deposition in a transgenic V30M mouse model.

PubMed

Batista, A R; Gianni, D; Ventosa, M; Coelho, A V; Almeida, M R; Sena-Esteves, M; Saraiva, M J

2014-12-01

Familial amyloidotic polyneuropathy (FAP) is a neurodegenerative disorder characterized by extracellular deposition of amyloid fibrils composed by mutated transthyretin (TTR) mainly in the peripheral nervous system. At present, liver transplantation is still the standard treatment to halt the progression of clinical symptoms in FAP, but new therapeutic strategies are emerging, including the use of TTR stabilizers. Here we propose to establish a new gene therapy approach using adeno-associated virus (AAV) vectors to deliver the trans-suppressor TTR T119M variant to the liver of transgenic TTR V30M mice at different ages. This TTR variant is known for its ability to stabilize the tetrameric protein. Analysis of the gastrointestinal tract of AAV-treated animals revealed a significant reduction in deposition of TTR non-fibrillar aggregates in as much as 34% in stomach and 30% in colon, as well as decreased levels of biomarkers associated with TTR deposition, namely the endoplasmic reticulum stress marker BiP and the extracellular matrix protein MMP-9. Moreover, we showed with different studies that our approach leads to an increase in tetrameric and more stable forms of TTR, in favor of destabilized monomers. Altogether our data suggest the possibility to use this gene therapy approach in a prophylactic manner to prevent FAP pathology.

Sixty years of transthyretin familial amyloid polyneuropathy (TTR-FAP) in Europe: where are we now? A European network approach to defining the epidemiology and management patterns for TTR-FAP.

PubMed

Parman, Yesim; Adams, David; Obici, Laura; Galán, Lucía; Guergueltcheva, Velina; Suhr, Ole B; Coelho, Teresa

2016-02-01

Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a highly disabling, life-threatening disease characterized by progressive sensorimotor and autonomic neuropathy. The profile of the disease across Europe is inadequately understood at present. The incidence and clinical presentation of TTR-FAP varies widely within Europe, with early and late-onset disease subtypes. In those regions in which the disease is endemic (Portugal, Sweden, Cyprus, and Majorca), a Val30Met substitution in the TTR gene is the predominant genetic cause, whereas in the rest of Europe, cases of TTR-FAP are mainly sporadic with genetic heterogeneity. Current management strategies lack cohesion and patients can experience years of misdiagnosis and suboptimal treatment. The article aims to disseminate the findings and recommendations from two recent meetings of the European Network for TTR-FAP (ATTReuNET), a panel comprising representatives from 10 European countries (Bulgaria, Cyprus, France, Germany, Italy, the Netherlands, Portugal, Spain, Sweden, and Turkey) with expertise in the diagnosis and management of TTR-FAP. We explore the epidemiology and genetic mark of TTR-FAP across Europe and assess current management strategies, with a view to developing an alternative framework - a networked approach to disease management with an emphasis on collaboration and sharing of best practice.

The trading time risks of stock investment in stock price drop

NASA Astrophysics Data System (ADS)

Li, Jiang-Cheng; Tang, Nian-Sheng; Mei, Dong-Cheng; Li, Yun-Xian; Zhang, Wan

2016-11-01

This article investigates the trading time risk (TTR) of stock investment in the case of stock price drop of Dow Jones Industrial Average (ˆDJI) and Hushen300 data (CSI300), respectively. The escape time of stock price from the maximum to minimum in a data window length (DWL) is employed to measure the absolute TTR, the ratio of the escape time to data window length is defined as the relative TTR. Empirical probability density functions of the absolute and relative TTRs for the ˆDJI and CSI300 data evidence that (i) whenever the DWL increases, the absolute TTR increases, the relative TTR decreases otherwise; (ii) there is the monotonicity (or non-monotonicity) for the stability of the absolute (or relative) TTR; (iii) there is a peak distribution for shorter trading days and a two-peak distribution for longer trading days for the PDF of ratio; (iv) the trading days play an opposite role on the absolute (or relative) TTR and its stability between ˆDJI and CSI300 data.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Saelices, Lorena; Johnson, Lisa M.; Liang, Wilson Y.

The tetrameric thyroxine transport protein transthyretin (TTR) forms amyloid fibrils upon dissociation and monomer unfolding. The aggregation of transthyretin has been reported as the cause of the life-threatening transthyretin amyloidosis. The standard treatment of familial cases of TTR amyloidosis has been liver transplantation. Although aggregation-preventing strategies involving ligands are known, understanding the mechanism of TTR aggregation can lead to additional inhibition approaches. Several models of TTR amyloid fibrils have been proposed, but the segments that drive aggregation of the protein have remained unknown. Here we identify β-strands F and H as necessary for TTR aggregation. Based on the crystal structuresmore » of these segments, we designed two non-natural peptide inhibitors that block aggregation. Lastly, this work provides the first characterization of peptide inhibitors for TTR aggregation, establishing a novel therapeutic strategy.« less

Comparing the Cost Effectiveness of Non-vitamin K Antagonist Oral Anticoagulants with Well-Managed Warfarin for Stroke Prevention in Atrial Fibrillation Patients at High Risk of Bleeding.

PubMed

Hospodar, Alexa R; Smith, Kenneth J; Zhang, Yuting; Hernandez, Inmaculada

2018-05-09

Several studies have compared the cost effectiveness of non-vitamin K antagonist oral anticoagulants (NOACs) and warfarin using results from clinical trials evaluating NOACs. However, the time in therapeutic range (TTR) of warfarin groups ranged across clinical trials, and all were below the therapeutic goal of 70%. We compared the cost effectiveness of edoxaban 60 mg, apixaban 5 mg, dabigatran 150 mg, dabigatran 110 mg, rivaroxaban 20 mg, and well-managed warfarin with a TTR of 70% in preventing stroke among patients with atrial fibrillation at high risk of bleeding. For the six treatments, we used a Markov state-transition model to quantify lifetime costs in $US and effectiveness in quality-adjusted life-years (QALYs). We simulated relative risk ratios of clinical events with each NOAC versus warfarin with a TTR of 70% using published regression models that predict how the incidence of thrombotic or hemorrhagic events changes for each unit change in TTR. We re-ran our analysis for two other estimates of TTR: 65 and 75%. Treatment with edoxaban 60 mg cost $US127,520/QALY gained compared with warfarin with a TTR of 70% and cost $US41,860/QALY gained compared with warfarin with a TTR of 65%. However, warfarin with a TTR of 75% was more effective and less expensive than all NOACs. For three levels of TTR, apixaban 5 mg, dabigatran 150 mg, dabigatran 110 mg, and rivaroxaban 20 mg were dominated strategies. The comparative cost effectiveness of edoxaban and warfarin is highly sensitive to TTR. At the $US100,000/QALY willingness-to-pay threshold, our results suggest that warfarin is the most cost-effective treatment for patients who can achieve a TTR of 70%.

Transthyretin Protects against A-Beta Peptide Toxicity by Proteolytic Cleavage of the Peptide: A Mechanism Sensitive to the Kunitz Protease Inhibitor

PubMed Central

Costa, Rita; Ferreira-da-Silva, Frederico; Saraiva, Maria J.; Cardoso, Isabel

2008-01-01

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of amyloid β-peptide (A-Beta) in the brain. Transthyretin (TTR) is a tetrameric protein of about 55 kDa mainly produced in the liver and choroid plexus of the brain. The known physiological functions of TTR are the transport of thyroid hormone T4 and retinol, through binding to the retinol binding protein. TTR has also been established as a cryptic protease able to cleave ApoA-I in vitro. It has been described that TTR is involved in preventing A-Beta fibrilization, both by inhibiting and disrupting A-Beta fibrils, with consequent abrogation of toxicity. We further characterized the nature of the TTR/A-Beta interaction and found that TTR, both recombinant or isolated from human sera, was able to proteolytically process A-Beta, cleaving the peptide after aminoacid residues 1, 2, 3, 10, 13, 14,16, 19 and 27, as determined by mass spectrometry, and reversed phase chromatography followed by N-terminal sequencing. A-Beta peptides (1–14) and (15–42) showed lower amyloidogenic potential than the full length counterpart, as assessed by thioflavin binding assay and ultrastructural analysis by transmission electron microscopy. A-Beta cleavage by TTR was inhibited in the presence of an αAPP peptide containing the Kunitz Protease Inhibitor (KPI) domain but not in the presence of the secreted αAPP derived from the APP isoform 695 without the KPI domain. TTR was also able to degrade aggregated forms of A-Beta peptide. Our results confirmed TTR as a protective molecule in AD, and prompted A-Beta proteolysis by TTR as a protective mechanism in this disease. TTR may prove to be a useful therapeutic agent for preventing or retarding the cerebral amyloid plaque formation implicated in AD pathology. PMID:18682830

Analysis of transthyretin in human serum by capillary zone electrophoresis electrospray ionization time-of-flight mass spectrometry. Application to familial amyloidotic polyneuropathy type I.

PubMed

Pont, Laura; Benavente, Fernando; Barbosa, José; Sanz-Nebot, Victoria

2015-06-01

Transthyretin (TTR) is known to misfold and aggregate, causing different types of amyloidosis. Familial amyloidotic polyneuropathy type I (FAP-I), which is the most common hereditary systemic amyloidosis, is associated with a TTR variant that presents a single amino acid substitution of valine for methionine at position 30 (Met 30). To screen for TTR-related amyloidosis rapidly and reliably, we have developed a novel procedure based on the analysis of monomers from the homotetrameric protein (∼56 kDa). First, we established a CZE-ESI-TOF-MS method to detect wild-type (normal) TTR with or without several PTMs, as well as an extra minor isoform in TTR standard solutions. Later, a sample pretreatment based on immunoprecipitation (IP) and centrifugal filtration was optimized to analyze serum samples from healthy controls and FAP-I patients (including an asymptomatic patient, a symptomatic patient, a liver-transplanted patient with the specific mutation, and a patient originally without the mutation who received a liver transplant from an FAP-I patient (iatrogenic FAP-I)). The mutant TTR (Met 30) variant with a relative molecular mass 32.07 higher than the wild-type TTR was found in the asymptomatic, the symptomatic and the iatrogenic FAP-I patients, who interestingly also presented the same concentration ratio between both variants of TTR (abnormal and normal). In contrast, as in the healthy controls, the abnormal TTR variant was not detected in the liver-transplanted patient with the specific mutation, which confirms the effectiveness of the treatment. The proposed procedure could be regarded as a suitable screening system for individuals with suspected TTR amyloidosis, and to gain insight into TTR structure, to understand the mechanism underlying the disease. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Characterization of little skate (Leucoraja erinacea) recombinant transthyretin: Zinc-dependent 3,3',5-triiodo-l-thyronine binding.

PubMed

Suzuki, Shunsuke; Kasai, Kentaro; Yamauchi, Kiyoshi

2015-01-01

Transthyretin (TTR) diverged from an ancestral 5-hydroxyisourate hydrolase (HIUHase) by gene duplication at some early stage of chordate evolution. To clarify how TTR had participated in the thyroid system as an extracellular thyroid hormone (TH) binding protein, TH binding properties of recombinant little skate Leucoraja erinacea TTR was investigated. At the amino acid level, skate TTR showed 37-46% identities with the other vertebrate TTRs. Because the skate TTR had a unique histidine-rich segment in the N-terminal region, it could be purified by Ni-affinity chromatography. The skate TTR was a 46-kDa homotetramer of 14.5kDa subunits, and had one order of magnitude higher affinity for 3,3',5-triiodo-l-thyronine (T3) and some halogenated phenols than for l-thyroxine. However, the skate TTR had no HIUHase activity. Ethylenediaminetetraacetic acid (EDTA) treatment inhibited [(125)I]T3 binding activity whereas the addition of Zn(2+) to the EDTA-treated TTR recovered [(125)I]T3 binding activity in a Zn(2+) concentration-dependent manner. Scatchard analysis revealed the presence of two classes of binding site for T3, with dissociation constants of 0.24 and 17nM. However, the high-affinity sites were completely abolished with 1mM EDTA, whereas the remaining low-affinity sites decreased binding capacity. The number of zinc per TTR was quantified to be 4.5-6.3. Our results suggest that skate TTR has tight Zn(2+)-binding sites, which are essential for T3 binding to at least the high-affinity sites. Zn(2+) binding to the N-terminal histidine-rich segment may play an important role in acquisition or reinforcement of TH binding ability during early evolution of TTR. Copyright © 2015 Elsevier Inc. All rights reserved.

Estimation of the impact of warfarin's time-in-therapeutic range on stroke and major bleeding rates and its influence on the medical cost avoidance associated with novel oral anticoagulant use-learnings from ARISTOTLE, ROCKET-AF, and RE-LY trials.

PubMed

Amin, Alpesh; Deitelzweig, Steve; Jing, Yonghua; Makenbaeva, Dinara; Wiederkehr, Daniel; Lin, Jay; Graham, John

2014-01-01

Warfarin's time-in-therapeutic range (TTR) is highly variable among patients with nonvalvular atrial fibrillation (NVAF). The objective of this study was to estimate the impact of variations in wafarin's TTR on rates of stroke/systemic embolism (SSE) and major bleedings among NVAF patients in the ARISTOTLE, ROCKET-AF, and RE-LY trials. Additionally, differences in medical costs for clinical endpoints when novel oral anticoagulants (NOACs) were used instead of warfarin at different TTR values were estimated. Quartile ranges of TTR values and corresponding event rates (%/patient - year = %/py) of SSE and major bleedings among NVAF patients treated with warfarin were estimated from published literature and FDA documents. The associations of SSE and major bleeding rates with TTR values were evaluated by regression analysis and then the calculated regression coefficients were used in analysis of medical cost differences associated with use of each NOAC versus warfarin (2010 costs; US payer perspective) at different TTRs. Each 10 % increase in warfarin's TTR correlated with a -0.32%/py decrease in SSE rate (R(2) = 0.61; p < 0.001). Although, the rate of major bleedings decreased as TTR increased, it was not significant (-0.035%/py, p = 0.63). As warfarin's TTR increased from 30 to 90% the estimated medical cost decreased from -$902 to -$83 for apixaban, from -$506 to +$314 for rivaroxaban, and from -$596 to +$223 for dabigatran. Among NVAF patients there is a significant negative correlation between warfarin's TTR and SSE rate, but not major bleedings. The variations in warfarin's TTR impacted the economic comparison of use of individual NOACs versus warfarin.

Uncovering the mechanism of aggregation of human transthyretin

DOE PAGES

Saelices, Lorena; Johnson, Lisa M.; Liang, Wilson Y.; ...

2015-10-12

The tetrameric thyroxine transport protein transthyretin (TTR) forms amyloid fibrils upon dissociation and monomer unfolding. The aggregation of transthyretin has been reported as the cause of the life-threatening transthyretin amyloidosis. The standard treatment of familial cases of TTR amyloidosis has been liver transplantation. Although aggregation-preventing strategies involving ligands are known, understanding the mechanism of TTR aggregation can lead to additional inhibition approaches. Several models of TTR amyloid fibrils have been proposed, but the segments that drive aggregation of the protein have remained unknown. Here we identify β-strands F and H as necessary for TTR aggregation. Based on the crystal structuresmore » of these segments, we designed two non-natural peptide inhibitors that block aggregation. Lastly, this work provides the first characterization of peptide inhibitors for TTR aggregation, establishing a novel therapeutic strategy.« less

Impairment of autophagy by TTR V30M aggregates: in vivo reversal by TUDCA and curcumin.

PubMed

Teixeira, Cristina A; Almeida, Maria do Rosário; Saraiva, Maria João

2016-09-01

Transthyretin (TTR)-related amyloidoses are diseases characterized by extracellular deposition of amyloid fibrils and aggregates in tissues composed of insoluble misfolded TTR that becomes toxic. Previous studies have demonstrated the ability of small compounds in preventing and reversing TTR V30M deposition in transgenic mice gastrointestinal (GI) tract as well as lowering biomarkers associated with cellular stress and apoptotic mechanisms. In the present study we aimed to study TTR V30M aggregates effect in autophagy, a cellular mechanism crucial for cell survival that has been implicated in the development of several neurodegenerative diseases. We were able to demonstrate in cell culture that TTR V30M aggregates cause a partial impairment of the autophagic machinery as shown by p62 accumulation, whereas early steps of the autophagic flux remain unaffected as shown by autophagosome number evaluation and LC3 turnover assay. Our studies performed in TTR V30M transgenic animals demonstrated that tauroursodeoxycholic acid (TUDCA) and curcumin effectively reverse p62 accumulation in the GI tract pointing to the ability of both compounds to modulate autophagy additionally to mitigate apoptosis. Overall, our in vitro and in vivo studies establish an association between TTR V30M aggregates and autophagy impairment and suggest the use of autophagy modulators as an additional and alternative therapeutic approach for the treatment of TTR V30M-related amyloidosis. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

Why is Leu55→Pro55 transthyretin variant the most amyloidogenic: Insights from molecular dynamics simulations of transthyretin monomers

PubMed Central

Yang, Mingfeng; Lei, Ming; Huo, Shuanghong

2003-01-01

Transthyretin (TTR) is one of the known human amyloidogenic proteins. Its native state is a homotetramer with each monomer having a β-sandwich structure. Strong experimental evidence suggests that TTR dissociates into monomeric intermediates and that the monomers subsequently self-assemble to form amyloid deposits and insoluble fibrils. However, details on the early steps along the pathway of TTR amyloid formation are unclear, although various experimental approaches with resolutions at the molecular or residue level have provided some clues. It is highly likely that the stability and flexibility of monomeric TTR play crucial roles in the early steps of amyloid formation; thereby, it is essential to characterize initial conformational changes of TTR monomers. In this article we probe the possibility that the differences in the monomeric forms of wild-type (WT) TTR and its variants are responsible for differential amyloidogenesis. We begin with the simulations of WT, Val30→Met (V30M), and Leu55→Pro (L55P) TTR monomers. Nanosecond time scale molecular dynamics simulations at 300 K were performed using AMBER. The results indicate that the L55P-TTR monomer undergoes substantial structural changes relative to fluctuations observed in the WT and V30M TTR monomers. The observation supports earlier speculation that the L55P mutation may lead to disruption of the β-sheet structure through the disorder of the “edge strands” that might facilitate amyloidogenesis. PMID:12761393

Photogrammetric Deflection Measurements for the Tiltrotor Test Rig (TTR) Multi-Component Rotor Balance Calibration

NASA Technical Reports Server (NTRS)

Solis, Eduardo; Meyn, Larry

2016-01-01

Calibrating the internal, multi-component balance mounted in the Tiltrotor Test Rig (TTR) required photogrammetric measurements to determine the location and orientation of forces applied to the balance. The TTR, with the balance and calibration hardware attached, was mounted in a custom calibration stand. Calibration loads were applied using eleven hydraulic actuators, operating in tension only, that were attached to the forward frame of the calibration stand and the TTR calibration hardware via linkages with in-line load cells. Before the linkages were installed, photogrammetry was used to determine the location of the linkage attachment points on the forward frame and on the TTR calibration hardware. Photogrammetric measurements were used to determine the displacement of the linkage attachment points on the TTR due to deflection of the hardware under applied loads. These measurements represent the first photogrammetric deflection measurements to be made to support 6-component rotor balance calibration. This paper describes the design of the TTR and the calibration hardware, and presents the development, set-up and use of the photogrammetry system, along with some selected measurement results.

Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial.

PubMed

Wallentin, Lars; Yusuf, Salim; Ezekowitz, Michael D; Alings, Marco; Flather, Marcus; Franzosi, Maria Grazia; Pais, Prem; Dans, Antonio; Eikelboom, John; Oldgren, Jonas; Pogue, Janice; Reilly, Paul A; Yang, Sean; Connolly, Stuart J

2010-09-18

Effectiveness and safety of warfarin is associated with the time in therapeutic range (TTR) with an international normalised ratio (INR) of 2·0-3·0. In the Randomised Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial, dabigatran versus warfarin reduced both stroke and haemorrhage. We aimed to investigate the primary and secondary outcomes of the RE-LY trial in relation to each centre's mean TTR (cTTR) in the warfarin population. In the RE-LY trial, 18 113 patients at 951 sites were randomly assigned to 110 mg or 150 mg dabigatran twice daily versus warfarin dose adjusted to INR 2·0-3·0. Median follow-up was 2·0 years. For 18 024 patients at 906 sites, the cTTR was estimated by averaging TTR for individual warfarin-treated patients calculated by the Rosendaal method. We compared the outcomes of RE-LY across the three treatment groups within four groups defined by the quartiles of cTTR. RE-LY is registered with ClinicalTrials.gov, number NCT00262600. The quartiles of cTTR for patients in the warfarin group were: less than 57·1%, 57·1-65·5%, 65·5-72·6%, and greater than 72·6%. There were no significant interactions between cTTR and prevention of stroke and systemic embolism with either 110 mg dabigatran (interaction p=0·89) or 150 mg dabigatran (interaction p=0·20) versus warfarin. Neither were any significant interactions recorded with cTTR with regards to intracranial bleeding with 110 mg dabigatran (interaction p=0·71) or 150 mg dabigatran (interaction p=0·89) versus warfarin. There was a significant interaction between cTTR and major bleeding when comparing 150 mg dabigatran with warfarin (interaction p=0·03), with less bleeding events at lower cTTR but similar events at higher cTTR, whereas rates of major bleeding were lower with 110 mg dabigatran than with warfarin irrespective of cTTR. There were significant interactions between cTTR and effects of both 110 mg and 150 mg dabigatran versus warfarin on the composite of all cardiovascular events (interaction p=0·036 and p=0·0006, respectively) and total mortality (interaction p=0·066 and p=0·052, respectively) with reduced event rates at low cTTR, and similar rates at high cTTR. The benefits of 150 mg dabigatran at reducing stroke, 110 mg dabigatran at reducing bleeding, and both doses at reducing intracranial bleeding versus warfarin were consistent irrespective of centres' quality of INR control. For all vascular events, non-haemorrhagic events, and mortality, advantages of dabigatran were greater at sites with poor INR control than at those with good INR control. Overall, these results show that local standards of care affect the benefits of use of new treatment alternatives. Boehringer Ingelheim. Copyright © 2010 Elsevier Ltd. All rights reserved.

Post-translational modifications of transthyretin affect the triiodonine-binding potential

PubMed Central

Henze, Andrea; Homann, Thomas; Serteser, Mustafa; Can, Ozge; Sezgin, Ozlem; Coskun, Abdurrahman; Unsal, Ibrahim; Schweigert, Florian J; Ozpinar, Aysel

2015-01-01

Transthyretin (TTR) is a visceral protein, which facilitates the transport of thyroid hormones in blood and cerebrospinal fluid. The homotetrameric structure of TTR enables the simultaneous binding of two thyroid hormones per molecule. Each TTR subunit provides a single cysteine residue (Cys10), which is frequently affected by oxidative post-translational modifications. As Cys10 is part of the thyroid hormone-binding channel within the TTR molecule, PTM of Cys10 may influence the binding of thyroid hormones. Therefore, we analysed the effects of Cys10 modification with sulphonic acid, cysteine, cysteinylglycine and glutathione on binding of triiodothyronine (T3) by molecular modelling. Furthermore, we determined the PTM pattern of TTR in serum of patients with thyroid disease by immunoprecipitation and mass spectrometry to evaluate this association in vivo. The in silico assays demonstrated that oxidative PTM of TTR resulted in substantial reorganization of the intramolecular interactions and also affected the binding of T3 in a chemotype- and site-specific manner with S-glutathionylation as the most potent modulator of T3 binding. These findings were supported by the in vivo results, which indicated thyroid function-specific patterns of TTR with a substantial decrease in S-sulphonated, S-cysteinylglycinated and S-glutathionylated TTR in hypothyroid patients. In conclusion, this study provides evidence that oxidative modifications of Cys10 seem to affect binding of T3 to TTR probably because of the introduction of a sterical hindrance and induction of conformational changes. As oxidative modifications can be dynamically regulated, this may represent a sensitive mechanism to adjust thyroid hormone availability. PMID:25311081

A New Folding Kinetic Mechanism for Human Transthyretin and the Influence of the Amyloidogenic V30M Mutation.

PubMed

Jesus, Catarina S H; Almeida, Zaida L; Vaz, Daniela C; Faria, Tiago Q; Brito, Rui M M

2016-08-31

Protein aggregation into insoluble amyloid fibrils is the hallmark of several neurodegenerative diseases, chief among them Alzheimer's and Parkinson's. Although caused by different proteins, these pathologies share some basic molecular mechanisms with familial amyloidotic polyneuropathy (FAP), a rare hereditary neuropathy caused by amyloid formation and deposition by transthyretin (TTR) in the peripheral and autonomic nervous systems. Among the amyloidogenic TTR mutations known, V30M-TTR is the most common in FAP. TTR amyloidogenesis (ATTR) is triggered by tetramer dissociation, followed by partial unfolding and aggregation of the low conformational stability monomers formed. Thus, tetramer dissociation kinetics, monomer conformational stability and competition between refolding and aggregation pathways do play a critical role in ATTR. Here, we propose a new model to analyze the refolding kinetics of WT-TTR and V30M-TTR, showing that at pH and protein concentrations close to physiological, a two-step mechanism with a unimolecular first step followed by a second-order second step adjusts well to the experimental data. Interestingly, although sharing the same kinetic mechanism, V30M-TTR refolds at a much slower rate than WT-TTR, a feature that may favor the formation of transient species leading to kinetic partition into amyloidogenic pathways and, thus, significantly increasing the probability of amyloid formation in vivo.

A New Folding Kinetic Mechanism for Human Transthyretin and the Influence of the Amyloidogenic V30M Mutation

PubMed Central

Jesus, Catarina S. H.; Almeida, Zaida L.; Vaz, Daniela C.; Faria, Tiago Q.; Brito, Rui M. M.

2016-01-01

Protein aggregation into insoluble amyloid fibrils is the hallmark of several neurodegenerative diseases, chief among them Alzheimer’s and Parkinson’s. Although caused by different proteins, these pathologies share some basic molecular mechanisms with familial amyloidotic polyneuropathy (FAP), a rare hereditary neuropathy caused by amyloid formation and deposition by transthyretin (TTR) in the peripheral and autonomic nervous systems. Among the amyloidogenic TTR mutations known, V30M-TTR is the most common in FAP. TTR amyloidogenesis (ATTR) is triggered by tetramer dissociation, followed by partial unfolding and aggregation of the low conformational stability monomers formed. Thus, tetramer dissociation kinetics, monomer conformational stability and competition between refolding and aggregation pathways do play a critical role in ATTR. Here, we propose a new model to analyze the refolding kinetics of WT-TTR and V30M-TTR, showing that at pH and protein concentrations close to physiological, a two-step mechanism with a unimolecular first step followed by a second-order second step adjusts well to the experimental data. Interestingly, although sharing the same kinetic mechanism, V30M-TTR refolds at a much slower rate than WT-TTR, a feature that may favor the formation of transient species leading to kinetic partition into amyloidogenic pathways and, thus, significantly increasing the probability of amyloid formation in vivo. PMID:27589730

Synergy of combined Doxycycline/TUDCA treatment in lowering Transthyretin deposition and associated biomarkers: studies in FAP mouse models

PubMed Central

2010-01-01

Familial Amyloidotic Polyneuropathy (FAP) is a disorder characterized by the extracellular deposition of fibrillar Transthyretin (TTR) amyloid, with a special involvement of the peripheral nerve. We had previously shown that doxycycline administered for 3 months at 40 mg/Kg/ml in the drinking water, was capable of removing TTR amyloid deposits present in stomachs of old TTR-V30M transgenic mice; the removal was accompanied by a decrease in extracellular matrix remodeling proteins that accompany fibrillar deposition, but not of non-fibrillar TTR deposition and/or markers associated with pre-fibrillar deposits. On the other hand, Tauroursodeoxycholic acid (TUDCA), a biliary acid, administrated to the same mouse model was shown to be effective at lowering deposited non-fibrillar TTR, as well as the levels of markers associated with pre-fibrillar TTR, but only at young ages. In the present work we evaluated different doxycycline administration schemes, including different periods of treatment, different dosages and different FAP TTR V30M animal models. Evaluation included CR staining, immunohistochemistry for TTR, metalloproteinase 9 (MMP-9) and serum amyloid P component (SAP). We determined that a minimum period of 15 days of treatment with a 8 mg/Kg/day dosage resulted in fibril removal. The possibility of intermittent treatments was also assessed and a maximum period of 15 days of suspension was determined to maintain tissues amyloid-free. Combined cycled doxycycline and TUDCA administration to mice with amyloid deposition, using two different concentrations of both drugs, was more effective than either individual doxycycline or TUDCA, in significantly lowering TTR deposition and associated tissue markers. The observed synergistic effect of doxycycline/TUDCA in the range of human tolerable quantities, in the transgenic TTR mice models prompts their application in FAP, particularly in the early stages of disease. PMID:20673327

Non-vitamin K antagonist oral anticoagulants compared with warfarin at different levels of INR control in atrial fibrillation: A meta-analysis of randomized trials.

PubMed

Carmo, João; Ferreira, Jorge; Costa, Francisco; Carmo, Pedro; Cavaco, Diogo; Carvalho, Salomé; Morgado, Francisco; Adragão, Pedro; Mendes, Miguel

2017-10-01

The efficacy and safety of warfarin for stroke prevention in atrial fibrillation (AF) depend on the time in the therapeutic range (TTR) with an international normalised ratio (INR) of 2.0-3.0. This meta-analysis focused the relative efficacy and safety of non-VKA oral anticoagulants (NOAC) compared with warfarin at different thresholds of centre's TTR (cTTR). We searched PubMed, Embase, CENTRAL and websites of regulatory agencies, limiting searches to randomized phase 3 trials. Primary outcomes were stroke or systemic embolism (SSE) and major or non-major clinically relevant (NMCR) bleeding. We used a random-effects model to pool effect on outcomes according to different thresholds of cTTR. Four TTR sub-studies with a total of 71,222 patients were included. The benefit of NOAC in reducing SSE compared with warfarin was significantly higher in patients at cTTR<60% (HR 0.79, 95% CI 0.68-0.90) and at 60% to <70% (0.82, 0.71-0.95) but not at ≥70% (1.00, 0.82-1.23) with a significant interaction for cTTR<70% or ≥70% (p=0.042). The risk of major or NMCR bleeding was significantly lower with NOAC as compared with warfarin in patients at all sub-groups (0.67, 0.54-0.83 for patients at cTTR<60% and 0.75, 0.63-0.89 at 60% to <70%) except for cTTR≥70% (HR 0.84, 0.64-1.11), but the interaction for cTTR<70% or ≥70% was not statistically significant (p=0.271). The superiority in efficacy of NOAC compared with warfarin for stroke prevention is lost above a cTTR threshold of approximately 70%, but the relative safety appears to be less modified by the centre-based quality of INR control. Copyright © 2017 Elsevier B.V. All rights reserved.

Inadequate anticoagulation by Vitamin K Antagonists is associated with Major Adverse Cardiovascular Events in patients with atrial fibrillation.

PubMed

Pastori, Daniele; Pignatelli, Pasquale; Saliola, Mirella; Carnevale, Roberto; Vicario, Tommasa; Del Ben, Maria; Cangemi, Roberto; Barillà, Francesco; Lip, Gregory Y H; Violi, Francesco

2015-12-15

Time in therapeutic range (TTR) reflects the quality of anticoagulation and is inversely correlated with ischemic stroke in atrial fibrillation (AF) patients. Few data on the relationship between TTR and myocardial infarction (MI) are available. We investigated the association between TTR and Major Adverse Cardiovascular Events (MACE) in a cohort of anticoagulated AF patients. We calculated TTR for 627 AF patients on vitamin K antagonists, who were followed for a median of 30.8 months (1755 patients/year). The primary outcome was a combined endpoint of MACE including fatal/nonfatal MI and cardiovascular death. Mean age was 73.3 (±8.2) years, and 40.2% were women. During follow-up, we recorded 67 events: 19 stroke/TIA (1.1%/year) and 48 MACE (2.9%/year): 24 MI and 24 cardiovascular deaths. The cohort was categorized according to tertiles of TTR values: TTR 13-58%, 59-74%, and 75-100%. There was a significant increased rate of MACE across tertiles of TTR (Log-Rank test: p<0.001). On Cox proportion hazard analysis, the 2nd vs. 1st tertile of TTR (p=0.002, hazard ratio [HR] 0.347, confidence interval [CI] 95% 0.177-0.680), 3rd vs. 1st tertile of TTR (p<0.001, HR 0.164, CI 95% 0.067-0.402), age (p<0.001, HR 1.094, CI 95% 1.042-1.148), history of stroke/TIA (p=0.015, HR 2.294, CI 95% 1.172-4.490) and smoking (p=0.003, HR 3.450, CI 95% 1.532-7.769) predicted MACE. TTR was an independent predictor of MACE in our cohort of AF patients. Our findings suggest that a good anticoagulation control is necessary to reduce not only the risk of stroke but also that of MACE. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Epigallocatechin-3-gallate as a potential therapeutic drug for TTR-related amyloidosis: "in vivo" evidence from FAP mice models.

PubMed

Ferreira, Nelson; Saraiva, Maria João; Almeida, Maria Rosário

2012-01-01

Familial amyloidotic polyneuropathy (FAP) is a neurodegenerative disease caused by the extracellular deposition of mutant transthyretin (TTR), with special involvement of the peripheral nervous system (PNS). Currently, hepatic transplantation is considered the most efficient therapy to halt the progression of clinical symptoms in FAP since more than 95% of TTR is produced by the liver. However, less invasive and more reliable therapeutic approaches have been proposed for FAP therapy, namely based on drugs acting as inhibitors of amyloid formation or as amyloid disruptors. We have recently reported that epigallocatechin-3-gallate (EGCG), the most abundant catechin in green tea, is able to inhibit TTR aggregation and fibril formation, "in vitro" and in a cellular system, and is also able to disrupt pre-formed amyloid fibrils "in vitro". In the present study, we assessed the effect of EGCG subchronic administration on TTR amyloidogenesis "in vivo", using well characterized animal models for FAP. Semiquantitative immunohistochemistry (SQ-IHC) and Western blot analysis of mice tissues after treatment demonstrated that EGCG inhibits TTR toxic aggregates deposition in about 50% along the gastrointestinal tract (GI) and peripheral nervous system (PNS). Moreover EGCG treatment considerably lowered levels of several biomarkers associated with non-fibrillar TTR deposition, namely endoplasmic reticulum (ER)-stress, protein oxidation and apoptosis markers. Treatment of old FAP mice with EGCG resulted not only in the decrease of non-fibrillar TTR deposition but also in disaggregation of amyloid deposits. Consistently, matrix metalloproteinase (MMP)-9 and serum amyloid P component (SAP), both markers of amyloid deposition, were also found reduced in treated old FAP mice. The dual effect of EGCG both as TTR aggregation inhibitor and amyloid fibril disruptor together with the high tolerability and low toxicity of EGCG in humans, point towards the potential use of this compound, or optimized derivatives, in the treatment of TTR-related amyloidoses.

[Transthyretin: it's miracle function and pathogenesis].

PubMed

Ando, Yukio

2009-03-01

Transthyretin (TTR) was previously called prealbumin because the band it formed on agarose gel electrophoresis at pH 8.6 was at the prealbumin position. However, it has been well documented that TTR of rodents does not show a prealbumin position on electrophoresis. Now, its name describes its function, binding to retinol binding protein (RBP) and T4. The serum concentration of the protein is 20-40 mg/dl, and TTR forms a tetramer. The plasma half life of the protein is 1.9 days. TTR is synthesized by the liver, retina, pancreas, and choroid plexus. In cerebro-spinal fluid (CSF), it is the second most abundant protein, and is considered as an important protein in the pathogenesis of Alzheimer's disease, depression, and lead intoxication. In addition, TTR is a tryptophan-rich protein, it is used as one of the nutrition assessment proteins, it acts as an anti acute phase protein, and its plasma concentration decreases during inflammation and bacterial infection. Since TTR is a highly amyloidogenic protein because it contains a beta-sheet structure, it becomes a precursor protein in familial amyloidotic polyneuropathy(FAP). Moreover, TTR plays important roles in various CNS disorders, diabetes melitus, and lipid metabolism.

The effect of the amiodarone-warfarin interaction on anticoagulation quality in a single, high-quality anticoagulation center.

PubMed

White, Ryan D; Riggs, Kyle W; Ege, Ed J; Petroski, Gregory F; Koerber, Scott M; Flaker, Greg

2016-03-01

Clinical trials have reported a low time in therapeutic range (TTR) in patients with atrial fibrillation treated with both warfarin andamiodarone. These trials included centers and countries with both high and low TTRs. What is the impact of amiodarone on the TTR in a single, high-quality anticoagulation clinic? TTR was assessed in amiodarone and nonamiodarone-treated patients from a University anticoagulation clinic. Baseline characteristics between patients ever-taking or never-taking amiodarone were similar, except more amiodarone patients were smokers (19.5 vs. 6.1%, P = 0.0031). The TTR calculated from 8901international normalized ratios (INRs) in 249 nonamiodarone patients with a mean follow-up of 34 ± 20 months (mean INR 36 ± 18) was 66 ± 16.6% compared with 61.3 ± 16.2% (P = 0.111) from 1455 INRs in 41 amiodarone-treated patients with a mean follow-up of 28 ± 20 months (mean INR 35 ± 22). Factors associated with a low TTR were male sex (P = 0.0013), smoker (P = 0.0048), and amiodarone use (P = 0.0374). A second on-treatment analysis, in which the TTR was calculated only during amiodarone therapy, resulted in similar findings; however, amiodarone did not emerge as a predictor of a low TTR. In 11 patients, the TTR prior to amiodarone (54.5 ± 22.2%) was not significantly different in the first 3 months (54.6 ± 33.4%) or after 3 months (67.2 ± 33.7%) of amiodarone. In a single high-quality anticoagulation center, anticoagulation quality, as measured by the TTR, can be comparable in amiodarone and nonamiodarone-treated patients.

The Importance of a Gatekeeper Residue on the Aggregation of Transthyretin

PubMed Central

Sant'Anna, Ricardo; Braga, Carolina; Varejão, Nathalia; Pimenta, Karinne M.; Graña-Montes, Ricardo; Alves, Aline; Cortines, Juliana; Cordeiro, Yraima; Ventura, Salvador; Foguel, Debora

2014-01-01

Protein aggregation into β-sheet-enriched amyloid fibrils is associated with an increasing number of human disorders. The adoption of such amyloid conformations seems to constitute a generic property of polypeptide chains. Therefore, during evolution, proteins have adopted negative design strategies to diminish their intrinsic propensity to aggregate, including enrichment of gatekeeper charged residues at the flanks of hydrophobic aggregation-prone segments. Wild type transthyretin (TTR) is responsible for senile systemic amyloidosis, and more than 100 mutations in the TTR gene are involved in familial amyloid polyneuropathy. The TTR 26–57 segment bears many of these aggressive amyloidogenic mutations as well as the binding site for heparin. We demonstrate here that Lys-35 acts as a gatekeeper residue in TTR, strongly decreasing its amyloidogenic potential. This protective effect is sequence-specific because Lys-48 does not affect TTR aggregation. Lys-35 is part of the TTR basic heparin-binding motif. This glycosaminoglycan blocks the protective effect of Lys-35, probably by neutralization of its side chain positive charge. A K35L mutation emulates this effect and results in the rapid self-assembly of the TTR 26–57 region into amyloid fibrils. This mutation does not affect the tetrameric protein stability, but it strongly increases its aggregation propensity. Overall, we illustrate how TTR is yet another amyloidogenic protein exploiting negative design to prevent its massive aggregation, and we show how blockage of conserved protective features by endogenous factors or mutations might result in increased disease susceptibility. PMID:25086037

Flavonoid interactions with human transthyretin: combined structural and thermodynamic analysis.

PubMed

Trivella, Daniela B B; dos Reis, Caio V; Lima, Luís Maurício T R; Foguel, Débora; Polikarpov, Igor

2012-10-01

Transthyretin (TTR) is a carrier protein involved in human amyloidosis. The development of small molecules that may act as TTR amyloid inhibitors is a promising strategy to treat these pathologies. Here we selected and characterized the interaction of flavonoids with the wild type and the V30M amyloidogenic mutant TTR. TTR acid aggregation was evaluated in vitro in the presence of the different flavonoids. The best TTR aggregation inhibitors were studied by Isothermal Titration Calorimetry (ITC) in order to reveal their thermodynamic signature of binding to TTRwt. Crystal structures of TTRwt in complex with the top binders were also obtained, enabling us to in depth inspect TTR interactions with these flavonoids. The results indicate that changing the number and position of hydroxyl groups attached to the flavonoid core strongly influence flavonoid recognition by TTR, either by changing ligand affinity or its mechanism of interaction with the two sites of TTR. We also compared the results obtained for TTRwt with the V30M mutant structure in the apo form, allowing us to pinpoint structural features that may facilitate or hamper ligand binding to the V30M mutant. Our data show that the TTRwt binding site is labile and, in particular, the central region of the cavity is sensible for the small differences in the ligands tested and can be influenced by the Met30 amyloidogenic mutation, therefore playing important roles in flavonoid binding affinity, mechanism and mutant protein ligand binding specificities. Copyright © 2012 Elsevier Inc. All rights reserved.

Identification of Transthyretin Fibril Formation Inhibitors Using Structure-Based Virtual Screening.

PubMed

Ortore, Gabriella; Martinelli, Adriano

2017-08-22

Transthyretin (TTR) is the primary carrier for thyroxine (T 4 ) in cerebrospinal fluid and a secondary carrier in blood. TTR is a stable homotetramer, but certain factors, genetic or environmental, could promote its degradation to form amyloid fibrils. A docking study using crystal structures of wild-type TTR was planned; our aim was to design new ligands that are able to inhibit TTR fibril formation. The computational protocol was thought to overcome the multiple binding modes of the ligands induced by the peculiarity of the TTR binding site and by the pseudosymmetry of the site pockets, which generally weaken such structure-based studies. Two docking steps, one that is very fast and a subsequent step that is more accurate, were used to screen the Aldrich Market Select database. Five compounds were selected, and their activity toward inhibiting TTR fibril formation was assessed. Three compounds were observed to be actives, two of which have the same potency as the positive control, and the other was found to be a promising lead compound. These results validate a computational protocol that is able to archive information on the key interactions between database compounds and TTR, which is valuable for supporting further studies. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Sex-based comparison of limb segmentation in ostriches aged 14 months with and without tibiotarsal rotation.

PubMed

Cooper, R G; Naranowicz, H; Maliszewska, E; Tennett, A; Horbańczuk, J O

2008-09-01

The aim of this study was to propose equations to predict changes that occur over time in the angular position of the bones during motion and the angular velocity of the bones in forward motion as a consequence of tibiotarsal rotation (TTR) in ostriches aged 14 months. Twenty-four normal 14-month-old ostriches (12 cocks and 12 hens) and 20 birds with TTR (9 cocks and 11 hens) were used in the study. Daily readings of temperature, relative humidity and rainfall, the lengths of the different segments of the legs and wings, the perpendicular height from the top of the torso to ground level and the length of the erect neck were recorded. Measurements of the degree of valgus deformity in the left foot were made where applicable. TTR hens and cocks were smaller in stature than normal birds. Comparing TTR hens and cocks, the toe, claw, humerus, perpendicular height and angle of rotation were larger in cocks, indicating a larger body in cocks. Hens were more severely affected by TTR. We suggest that the equations used in this study will assist in measuring movement of ostriches and how movement is compromised by overcrowding and TTR. Birds suffering from TTR may experience an increased degree of stress due to movement restrictions in confinement.

Nitrofen interferes with trophoblastic expression of retinol-binding protein and transthyretin during lung morphogenesis in the nitrofen-induced congenital diaphragmatic hernia model.

PubMed

Kutasy, Balazs; Gosemann, Jan H; Doi, Takashi; Fujiwara, Naho; Friedmacher, Florian; Puri, Prem

2012-02-01

Retinoids play a key role in lung development. Retinoid signaling pathway has been shown to be disrupted in the nitrofen model of congenital diaphragmatic hernia (CDH) but the exact mechanism is not clearly understood. Retinol-binding protein (RBP) and transthyretin (TTR) are transport proteins for delivery of retinol to the tissues via circulation. Previous studies have shown that pulmonary retinol levels are decreased during lung morphogenesis in the nitrofen CDH model. In human newborns with CDH, both retinol and RBP levels are decreased. It has been reported that maternal RBP does not cross the placenta and the fetus produces its own RBP by trophoblast. RBP and TTR synthesized in the fetus are essential for retinol transport to the developing organs including lung morphogenesis. We hypothesized that nitrofen interferes with the trophoblastic expression of RBP and TTR during lung morphogenesis and designed this study to examine the trophoblastic expression of RBP and TTR, and the total level of RBP and TTR in the lung in the nitrofen model of CDH. Pregnant rats were exposed to either olive oil or nitrofen on day 9 of gestation (D9). Fetal lungs and placenta harvested on D21 and divided into two groups: control (n = 8) and nitrofen with CDH (n = 8). Total lung RBP and TTR levels using protein extraction were compared with enzyme linked immunoassay (ELISA). Immunohistochemistry was performed to evaluate trophoblastic RBP and TTR expression. Total protein levels of lung RBP and TTR were significantly lower in CDH (0.26 ± 0.003 and 6.4 ± 0.5 μg/mL) compared with controls (0.4 ± 0.001 and 9.9 ± 1.6 μg/mL, p < 0.05). In the control group, immunohistochemical staining showed strong immunoreactivity of RBP and TTR in the trophoblast compared to CDH group. Decreased trophoblast expression of retinol transport proteins suggest that nitrofen may interfere with the fetal retinol transport resulting in reduced pulmonary RBP and TTR levels and causing pulmonary hypoplasia in CDH.

Interval to Testosterone Recovery After Hormonal Therapy for Prostate Cancer and Risk of Death

DOE Office of Scientific and Technical Information (OSTI.GOV)

D'Amico, Anthony V.; Chen, M.-H.; Renshaw, Andrew A.

Purpose: To assess whether the risk of death is associated with the time to testosterone recovery (TTR) after radiotherapy (RT) and hormonal therapy (HT) for prostate cancer (PCa). Patients and Methods: Between 1995 and 2001, 206 men with localized, unfavorable-risk PCa were randomized to receive RT or RT plus 6 months of HT. A multivariate postrandomization Cox regression analysis was used to assess whether the TTR in years was associated with the risk of death after adjusting for the known prognostic factors, age, Adult Comorbidity Evaluation-27 score, and the use of HT for recurrence. Results: Of the 102 men randomizedmore » to receive RT and HT, 57 (56%) had a TTR of >2 years, and none of these men had died of PCa after a median follow-up of 7.6 years. As the TTR increased, the risk of death decreased significantly (adjusted hazard ratio, 0.60; 95% confidence interval, 0.43-0.84; p = .003). A significant interaction was noted between the TTR and the comorbidity score (p = .002). The survival estimates were similar (p = 0.17) across the TTR values in men with moderate to severe comorbidity; however, these estimates increased significantly (p < .001) with decreasing PCa-specific mortality (p = .006) as the TTR increased in men with no or minimal comorbidity. Conclusion: The results of our study have shown that a longer TTR after RT plus 6 months of HT for unfavorable-risk PCa is associated with a lower risk of death in men with no or minimal comorbidity.« less

Transthyretin amyloid polyneuropathies mimicking a demyelinating polyneuropathy.

PubMed

Lozeron, Pierre; Mariani, Louise-Laure; Dodet, Pauline; Beaudonnet, Guillemette; Théaudin, Marie; Adam, Clovis; Arnulf, Bertrand; Adams, David

2018-06-15

To clearly define transthyretin familial amyloid polyneuropathies (TTR-FAPs) fulfilling definite clinical and electrophysiologic European Federation of Neurological Societies/Peripheral Nerve Society criteria for chronic inflammatory demyelinating polyneuropathy (CIDP). From a cohort of 194 patients with FAP, 13 of 84 patients (15%) of French ancestry had late-onset demyelinating TTR-FAP. We compared clinical presentation and electrophysiology to a cohort with CIDP and POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) syndrome. We assessed nerve histology and the correlation between motor/sensory amplitudes/velocities. Predictors of demyelinating TTR-FAP were identified from clinical and electrophysiologic data. Pain, dysautonomia, small fiber sensory loss above the wrists, upper limb weakness, and absence of ataxia were predictors of demyelinating TTR-FAP ( p < 0.01). The most frequent demyelinating features were prolonged distal motor latency of the median nerve and reduced sensory conduction velocity of the median and ulnar nerves. Motor axonal loss was severe and frequent in the median, ulnar, and tibial nerves ( p < 0.05) in demyelinating FAP. Ulnar nerve motor amplitude <5.4 mV and sural nerve amplitude <3.95 μV were distinguishing characteristics of demyelinating TTR-FAP. Nerve biopsy showed severe axonal loss and occasional segmental demyelination-remyelination. Misleading features of TTR-FAP fulfilling criteria for CIDP are not uncommon in sporadic late-onset TTR-FAP, which highlights the limits of European Federation of Neurological Societies/Peripheral Nerve Society criteria. Specific clinical aspects and marked electrophysiologic axonal loss are red flag symptoms that should alert to this diagnosis and prompt TTR gene sequencing. © 2018 American Academy of Neurology.

Therapeutic Oligonucleotides Targeting Liver Disease: TTR Amyloidosis.

PubMed

Niemietz, Christoph; Chandhok, Gursimran; Schmidt, Hartmut

2015-09-30

The liver has become an increasingly interesting target for oligonucleotide therapy. Mutations of the gene encoding transthyretin (TTR), expressed in vast amounts by the liver, result in a complex degenerative disease, termed familial amyloid polyneuropathy (FAP). Misfolded variants of TTR are linked to the establishment of extracellular protein deposition in various tissues, including the heart and the peripheral nervous system. Recent progress in the chemistry and formulation of antisense (ASO) and small interfering RNA (siRNA) designed for a knockdown of TTR mRNA in the liver has allowed to address the issue of gene-specific molecular therapy in a clinical setting of FAP. The two therapeutic oligonucleotides bind to RNA in a sequence specific manner but exploit different mechanisms. Here we describe major developments that have led to the advent of therapeutic oligonucleotides for treatment of TTR-related disease.

Impact of co-morbidities and patient characteristics on international normalized ratio control over time in patients with nonvalvular atrial fibrillation.

PubMed

Nelson, Winnie W; Choi, Jiyoon C; Vanderpoel, Julie; Damaraju, Chandrasekharra V; Wildgoose, Peter; Fields, Larry E; Schein, Jeffrey R

2013-08-15

This study determined the association between co-morbidities, including heart failure (HF) and time in therapeutic range (TTR), in patients with nonvalvular atrial fibrillation. Longitudinal patient-level anticoagulation management records collected from 2006 to 2010 were analyzed. Adult patients with nonvalvular atrial fibrillation who used warfarin for a 12-month period with no gap of >60 days between visits were identified. TTR <55% was defined as "lower" TTR. CHADS₂ score of ≥2 was defined as "higher" CHADS₂. Logistic regression analyses were conducted to determine the association between co-morbidities and TTR. A total of 23,425 patients met the study criteria. The mean age ± SD was 74.8 ± 9.7 years, with 84.8% aged ≥65 years. The most common co-morbidities were hypertension (41.7%), diabetes (24.1%), HF (11.7%), and previous stroke (11.1%). The mean TTR ± SD was 67.3 ± 14.4%, with 18.6% of patients in the lower TTR range. In multivariate analyses using age, gender, hypertension, diabetes, stroke, and region as covariates, HF (adjusted odds ratio [OR] 1.41, 95% confidence interval [CI] 1.28 to 1.56; p <0.001), diabetes (OR 1.28, 95% CI 1.19 to 1.38; p <0.001), and previous stroke (OR 1.15, 95% CI 1.04 to 1.27; p <0.001) were associated with lower TTR. In a second set of multivariate analyses using gender and region as covariates, a higher CHADS₂ score was associated with lower TTR (OR 1.11, 95% CI 1.04 to 1.18; p <0.001). In conclusion, HF was associated with the greatest likelihood of a lower TTR, followed by diabetes, then stroke. Anticoagulation control may be more challenging for patients with these conditions. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

Quality of Anticoagulation Control in Preventing Adverse Events in Heart Failure Patients in Sinus Rhythm: A Warfarin Aspirin Reduced Cardiac Ejection Fraction Trial (WARCEF) Substudy

PubMed Central

Homma, Shunichi; Thompson, John L.P.; Qian, Min; Ye, Siqin; Di Tullio, Marco R.; Lip, Gregory Y.H.; Mann, Douglas L.; Sacco, Ralph L.; Levin, Bruce; Pullicino, Patrick M.; Freudenberger, Ronald S.; Teerlink, John R.; Graham, Susan; Mohr, J.P.; Labovitz, Arthur J.; Buchsbaum, Richard; Estol, Conrado J.; Lok, Dirk J.; Ponikowski, Piotr; Anker, Stefan D.

2015-01-01

Background The aim of this study is to examine the relationship between time in therapeutic range (TTR) and clinical outcomes in heart failure (HF) patients in sinus rhythm (SR) treated with warfarin. Methods and Results We used data from the Warfarin vs. Aspirin in Reduced Cardiac Ejection Fraction Trial (WARCEF) to assess the relationship of TTR with the WARCEF primary outcome (ischemic stroke, intracerebral hemorrhage, or death); with death alone; ischemic stroke alone; major hemorrhage alone; and net clinical benefit (primary outcome and major hemorrhage combined). Multivariable Cox models were used to examine how the event risk changed with TTR and to compare the high TTR, low TTR, and aspirin patients, with TTR being treated as a time-dependent covariate. 2,217 patients were included in the analyses, among whom 1,067 were randomized to warfarin and 1,150 were randomized to aspirin. The median (IQR) follow-up duration was 3.6 (2.0–5.0) years. Mean (±SD) age was 61±11.3 years, with 80% being men. The mean (±SD) TTR was 57% (±28.5%). Increasing TTR was significantly associated with reduction in primary outcome (adjusted p<0.001), death alone (adjusted p=0.001), and improved net clinical benefit (adjusted p<0.001). A similar trend was observed for the other two outcomes but significance was not reached (adjusted p=0.082 for ischemic stroke, adjusted p=0.109 for major hemorrhage). Conclusions In HF patients in SR, increasing TTR is associated with better outcome and improved net clinical benefit. Patients in whom good quality anticoagulation can be achieved may benefit from the use of anticoagulants. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00041938. PMID:25850425

Alternative calculations of individual patient time in therapeutic range while taking warfarin: results from the ROCKET AF trial.

PubMed

Singer, Daniel E; Hellkamp, Anne S; Yuan, Zhong; Lokhnygina, Yuliya; Patel, Manesh R; Piccini, Jonathan P; Hankey, Graeme J; Breithardt, Günter; Halperin, Jonathan L; Becker, Richard C; Hacke, Werner; Nessel, Christopher C; Mahaffey, Kenneth W; Fox, Keith A A; Califf, Robert M

2015-03-03

In the ROCKET AF (Rivaroxaban-Once-daily, oral, direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) trial, marked regional differences in control of warfarin anticoagulation, measured as the average individual patient time in the therapeutic range (iTTR) of the international normalized ratio (INR), were associated with longer inter-INR test intervals. The standard Rosendaal approach can produce biased low estimates of TTR after an appropriate dose change if the follow-up INR test interval is prolonged. We explored the effect of alternative calculations of TTR that more immediately account for dose changes on regional differences in mean iTTR in the ROCKET AF trial. We used an INR imputation method that accounts for dose change. We compared group mean iTTR values between our dose change-based method with the standard Rosendaal method and determined that the differences between approaches depended on the balance of dose changes that produced in-range INRs ("corrections") versus INRs that were out of range in the opposite direction ("overshoots"). In ROCKET AF, the overall mean iTTR of 55.2% (Rosendaal) increased up to 3.1% by using the dose change-based approach, depending on assumptions. However, large inter-regional differences in anticoagulation control persisted. TTR, the standard measure of control of warfarin anticoagulation, depends on imputing daily INR values for the vast majority of follow-up days. Our TTR calculation method may better reflect the impact of warfarin dose changes than the Rosendaal approach. In the ROCKET AF trial, this dose change-based approach led to a modest increase in overall mean iTTR but did not materially affect the large inter-regional differences previously reported. URL: ClinicalTrials.gov. Unique identifier: NCT00403767. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Alternative Calculations of Individual Patient Time in Therapeutic Range While Taking Warfarin: Results From the ROCKET AF Trial

PubMed Central

Singer, Daniel E.; Hellkamp, Anne S.; Yuan, Zhong; Lokhnygina, Yuliya; Patel, Manesh R.; Piccini, Jonathan P.; Hankey, Graeme J.; Breithardt, Günter; Halperin, Jonathan L.; Becker, Richard C.; Hacke, Werner; Nessel, Christopher C.; Mahaffey, Kenneth W.; Fox, Keith A. A.; Califf, Robert M.

2015-01-01

Background In the ROCKET AF (Rivaroxaban–Once‐daily, oral, direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) trial, marked regional differences in control of warfarin anticoagulation, measured as the average individual patient time in the therapeutic range (iTTR) of the international normalized ratio (INR), were associated with longer inter‐INR test intervals. The standard Rosendaal approach can produce biased low estimates of TTR after an appropriate dose change if the follow‐up INR test interval is prolonged. We explored the effect of alternative calculations of TTR that more immediately account for dose changes on regional differences in mean iTTR in the ROCKET AF trial. Methods and Results We used an INR imputation method that accounts for dose change. We compared group mean iTTR values between our dose change–based method with the standard Rosendaal method and determined that the differences between approaches depended on the balance of dose changes that produced in‐range INRs (“corrections”) versus INRs that were out of range in the opposite direction (“overshoots”). In ROCKET AF, the overall mean iTTR of 55.2% (Rosendaal) increased up to 3.1% by using the dose change–based approach, depending on assumptions. However, large inter‐regional differences in anticoagulation control persisted. Conclusions TTR, the standard measure of control of warfarin anticoagulation, depends on imputing daily INR values for the vast majority of follow‐up days. Our TTR calculation method may better reflect the impact of warfarin dose changes than the Rosendaal approach. In the ROCKET AF trial, this dose change–based approach led to a modest increase in overall mean iTTR but did not materially affect the large inter‐regional differences previously reported. Clinical Trial Registration URL: ClinicalTrials.gov. Unique identifier: NCT00403767. PMID:25736441

Relations of Anticoagulant Therapy with Cognitive Impairment among Patients with Atrial Fibrillation: A Meta-Analysis and Systematic Review.

PubMed

Cheng, Wenke; Liu, Weijun; Li, Bin; Li, Dongfang

2018-03-02

Currently, it is considered that atrial fibrillation (AF) is a risk factor for cognitive impairment and dementia, which is independent of stroke. However, the relationship between anticoagulant drugs and cognitive function in patients with atrial fibrillation is unknown. This study aimed to complete a meta-analysis, and investigate the association between Anticoagulant therapy and cognitive impairment in patients undergoing AF. Two investigators systematically searched the Cochrane Library, PubMed, Embase databases and Web of Science for all studies showing associations. Hazard ratios (HRs) were extracted and pooled. 8 studies included 471057 participants; TTR < 25% vs TTR> 75%; (HR 3.02, 95% CI 1.12-8.91; P=0.03); TTR 25-50% vs TTR> 75% (HR 2.44, 95% CI 0.95-6.22; P=0.06); TTR 50-75% vs TTR> 75% (HR 1.75, 95% CI 0.90-3.99; P=0.1); OAC vs No OAC (HR 0.71, 95% CI.69-0.74; P<0.00001) NOAC vs warfarin (HR0.51, 95% CI0.37-0.71; P<0.00001). Oral anticoagulants (OAC) significantly reduce the occurrence of cognitive impairment in patients with atrial fibrillation. Compared with warfarin, NOAC has an efficiently protective effect on cognition. In the range of INR2-3, with the increase of TTR, the incidence of cognitive impairment is lower.

The recombinant adeno-associated virus vector (rAAV2)-mediated apolipoprotein B mRNA-specific hammerhead ribozyme: a self-complementary AAV2 vector improves the gene expression

PubMed Central

Zhong, Shumei; Sun, Shihua; Teng, Ba-Bie

2004-01-01

Background In humans, overproduction of apolipoprotein B (apoB) is positively associated with premature coronary artery diseases. To reduce the levels of apoB mRNA, we have designed an apoB mRNA-specific hammerhead ribozyme targeted at nucleotide sequences GUA6679 (RB15) mediated by adenovirus, which efficiently cleaves and decreases apoB mRNA by 80% in mouse liver and attenuates the hyperlipidemic condition. In the current study, we used an adeno-associated virus vector, serotype 2 (AAV2) and a self-complementary AAV2 vector (scAAV2) to demonstrate the effect of long-term tissue-specific gene expression of RB15 on the regulation apoB mRNA in vivo. Methods We constructed a hammerhead ribozyme RB15 driven by a liver-specific transthyretin (TTR) promoter using an AAV2 vector (rAAV2-TTR-RB15). HepG2 cells and hyperlipidemic mice deficient in both the low density lipoprotein receptor and the apoB mRNA editing enzyme genes (LDLR-/-Apobec1-/-; LDb) were transduced with rAAV2-TTR-RB15 and a control vector rAAV-TTR-RB15-mutant (inactive ribozyme). The effects of ribozyme RB15 on apoB metabolism and atherosclerosis development were determined in LDb mice at 5-month after transduction. A self-complementary AAV2 vector expressing ribozyme RB15 (scAAV2-TTR-RB15) was also engineered and used to transduce HepG2 cells. Studies were designed to compare the gene expression efficiency between rAAV2-TTR-RB15 and scAAV2-TTR-RB15. Results The effect of ribozyme RB15 RNA on reducing apoB mRNA levels in HepG2 cells was observed only on day-7 after rAAV2-TTR-RB15 transduction. And, at 5-month after rAAV2-TTR-RB15 treatment, the apoB mRNA levels in LDb mice were significantly decreased by 43%, compared to LDb mice treated with control vector rAAV2-TTR-RB15-mutant. Moreover, both the rAAV2-TTR-RB15 viral DNA and ribozyme RB15 RNA were still detectable in mice livers at 5-month after treatment. However, this rAAV2-TTR-RB15 vector mediated a prolonged but low level of ribozyme RB15 gene expression in the mice livers, which did not produce the therapeutic effects on alteration the lipid levels or the inhibition of atherosclerosis development. In contrast, the ribozyme RB15 RNA mediated by scAAV2-TTR-RB15 vector was expressed immediately at day-1 after transduction in HepG2 cells. The apoB mRNA levels were decreased 47% (p = 0.001), compared to the control vector scAAV2-TTR-RB15-mutant. Conclusion This study provided evidence that the rAAV2 single-strand vector mediated a prolonged but not efficient transduction in mouse liver. However, the scAAV2 double-strand vector mediated a rapid and efficient gene expression in liver cells. This strategy using scAAV2 vectors represents a better approach to express small molecules such as ribozyme. PMID:15193153

Transthyretin familial amyloid polyneuropathy (TTR-FAP): Parameters for early diagnosis.

PubMed

Escolano-Lozano, Fabiola; Barreiros, Ana Paula; Birklein, Frank; Geber, Christian

2018-01-01

Familial transthyretin amyloidosis is a life-threatening disease presenting with sensorimotor and autonomic polyneuropathy. Delayed diagnosis has a detrimental effect on treatment and prognosis. To facilitate diagnosis, we analyzed data patterns of patients with transthyretin familial amyloid polyneuropathy (TTR-FAP) and compared them to polyneuropathies of different etiology for clinical and electrophysiological discriminators. Twenty-four patients with TTR-FAP and 48 patients with diabetic polyneuropathy (dPNP) were investigated (neurological impairment score NIS; neurological disability score NDS) in a cross-sectional design. Both groups were matched for gender and presence of pain. Quantitative sensory testing (QST), sympathetic skin response (SSR), heart rate variability (HRV), and nerve conduction studies (NCV) were performed. Both groups were compared using univariate analysis. In a stepwise discriminant analysis, discriminators between both neuropathies were identified. These discriminators were validated comparing TTR-FAP patients with a cohort of patients with chemotherapy-induced polyneuropathy (CIN) and chronic inflammatory demyelinating neuropathy (CIDP). TTR-FAP patients scored higher in NDS and NIS and had impaired cold detection (CDT, p  = .024), cold-warm discrimination (TSL, p  = .019) and mechanical hyperalgesia (MPT, p  = .029) at the hands, SSR (upper limb, p  = .022) HRV and ulnar and sural NCS (all p  < .05) were more affected in TTR-FAP. Ulnar nerve sensory NCV, CDT, and the MPT but not the other parameters discriminated TTR-FAP from dPNP (82% of cases), from CIN (86.7%) and from CIDP (68%; only ulnar sNCV). Low ulnar SNCV, impaired cold perception, and mechanical hyperalgesia at the hands seem to characterize TTR-FAP and might help to differentiate from other polyneuropathies.

Post-Closure Inspection Report for the Tonopah Test Range, Nevada, for Calendar Year 2014

DOE Office of Scientific and Technical Information (OSTI.GOV)

Silvas, A. J.; Lantow, Tiffany A.

This report provides the results of the annual post-closure inspections conducted at the closed Corrective Action Units (CAUs) located on the Tonopah Test Range (TTR), Nevada. This report covers calendar year 2014 and includes inspection and repair activities completed at the following CAUs; CAU 400: Bomblet Pit and Five Points Landfill (TTR); CAU 407: Roller Coaster RadSafe Area (TTR); CAU 424: Area 3 Landfill Complexes (TTR); CAU 453: Area 9 UXO Landfill (TTR); and CAU 487: Thunderwell Site (TTR) Inspections were conducted according to the post-closure plans in the approved Closure Reports and subsequent correspondence with the Nevada Division ofmore » Environmental Protection. The post-closure inspection plans and subsequent correspondence modifying the requirements for each CAU are included in Appendix B. The inspection checklists are included in Appendix C. Photographs taken during inspections are included in Appendix D. The annual post-closure inspections were conducted on May 28, 2014. Maintenance was required at CAU 407. Animal burrows were backfilled and erosion repairs were performed. Vegetation monitoring was performed at CAU 407 in June 2014. The vegetation monitoring report is included in Appendix E.« less

Structural aspects of inotropic bipyridine binding. Crystal structure determination to 1.9 A of the human serum transthyretin-milrinone complex.

PubMed

Wojtczak, A; Luft, J R; Cody, V

1993-03-25

The crystal structure of human transthyretin (TTR) complexed with milrinone (2-methyl-5-cyano-3,4'-bipyridin-6(1H)-one), a positive inotropic cardiac agent, has been refined to R = 17.4% for 8-1.9-A resolution data. This report provides the first detailed description of protein interactions for an inotropic bipyridine agent which is an effective thyroid hormone binding competitor to transthyretin. Milrinone is bound along the 2-fold axis in the binding site with its substituted pyridone ring located deep within the channel of the two identical binding domains of the TTR tetramer. In this orientation the 5-cyano group occupies the same site as the 3'-iodine in the TTR complex with 3,3'-diiodothyronine (Wojtczak, A., Luft, J., and Cody, V. (1992) J. Biol. Chem. 267, 353-357), which is 3.5 A deeper in the channel than thyroxine (Blake, C. C. F., and Oately, S. J., (1977) Nature 268, 115-120). These structural results confirm computer modeling studies of milrinone structural homology with thyroxine and its TTR binding interactions and explain the effectiveness of milrinone competition for thyroxine binding to TTR. To understand the weaker binding affinity of the parent inotropic drug, amrinone (5-amino-3,4'-bipyridin-6(1H)-one), modeling studies of its TTR binding were carried out which indicate that the 5-amino group cannot participate in strong interactions with TTR and the lack of the 2-methyl further weakens amrinone binding.

Comparative study on 2,2′,4,5,5′-pentachlorobiphenyl-mediated decrease in serum thyroxine level between C57BL/6 and its transthyretin-deficient mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kato, Yoshihisa, E-mail: kato@kph.bunri-u.ac.jp; Tamaki, Sekihiro; Haraguchi, Koichi

The relationships between the changes in the levels of serum total thyroxine (T{sub 4}), serum T{sub 4}-transthyretin (TTR) complex, and accumulation of T{sub 4} in tissues by 2,2′,4,5,5′-pentachlorobiphenyl (PentaCB) were examined using wild-type C57BL/6 (WT) and its TTR-deficient (TTR-null) mice. The constitutive level of serum total T{sub 4} was much higher in WT mice than in TTR-null mice. In WT mice 4 days after a single intraperitoneal injection with PentaCB (112 mg/kg), serum total T{sub 4} level was significantly decreased along with a decrease in serum T{sub 4}–TTR complex, and the levels of serum total T{sub 4} in the PentaCB-treatedmore » WT mice were almost the same to those in PentaCB-untreated (control) TTR-null mice. In addition, a slight decrease in serum total T{sub 4} by PentaCB treatment was observed in TTR-null mice. Furthermore, clearance of [{sup 125}I]T{sub 4} from the serum after [{sup 125}I]T{sub 4}-administration was promoted by the PentaCB-pretreatment in either strain of mice, especially WT mice. On the other hand, accumulation level of [{sup 125}I]T{sub 4} in the liver, but not in extrahepatic tissues, was strikingly enhanced in the PentaCB-pretreated WT and TTR-null mice. Furthermore, in both strains of mice, PentaCB-pretreatment led to significant increases in the steady-state distribution volume of [{sup 125}I]T{sub 4} and the concentration ratio of the liver to serum. The present findings demonstrate that PentaCB-mediated decrease in serum T{sub 4} level occurs mainly through increase in accumulation level of T{sub 4} in the liver and further indicate that the increased accumulation of T{sub 4} in the liver of WT mice is primarily dependent on the PentaCB-mediated inhibition of serum T{sub 4}–TTR complex formation.« less

Cavity filling mutations at the thyroxine-binding site dramatically increase transthyretin stability and prevent its aggregation.

PubMed

Sant'Anna, Ricardo; Almeida, Maria Rosário; Varejāo, Nathalia; Gallego, Pablo; Esperante, Sebastian; Ferreira, Priscila; Pereira-Henriques, Alda; Palhano, Fernando L; de Carvalho, Mamede; Foguel, Debora; Reverter, David; Saraiva, Maria João; Ventura, Salvador

2017-03-24

More than a hundred different Transthyretin (TTR) mutations are associated with fatal systemic amyloidoses. They destabilize the protein tetrameric structure and promote the extracellular deposition of TTR as pathological amyloid fibrils. So far, only mutations R104H and T119M have been shown to stabilize significantly TTR, acting as disease suppressors. We describe a novel A108V non-pathogenic mutation found in a Portuguese subject. This variant is more stable than wild type TTR both in vitro and in human plasma, a feature that prevents its aggregation. The crystal structure of A108V reveals that this stabilization comes from novel intra and inter subunit contacts involving the thyroxine (T 4 ) binding site. Exploiting this observation, we engineered a A108I mutation that fills the T 4 binding cavity, as evidenced in the crystal structure. This synthetic protein becomes one of the most stable TTR variants described so far, with potential application in gene and protein replacement therapies.

Management of asymptomatic gene carriers of transthyretin familial amyloid polyneuropathy.

PubMed

Schmidt, Hartmut H-J; Barroso, Fabio; González-Duarte, Alejandra; Conceição, Isabel; Obici, Laura; Keohane, Denis; Amass, Leslie

2016-09-01

Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a rare, severe, and irreversible, adult-onset, hereditary disorder caused by autosomal-dominant mutations in the TTR gene that increase the intrinsic propensity of transthyretin protein to misfold and deposit systemically as insoluble amyloid fibrils in nerve tissues, the heart, and other organs. TTR-FAP is characterized by relentless, progressively debilitating polyneuropathy, and leads to death, on average, within 10 years of symptom onset without treatment. With increased availability of disease-modifying treatment options for a wider spectrum of patients with TTR-FAP, timely detection of the disease may offer substantial clinical benefits. This review discusses mutation-specific predictive genetic testing in first-degree relatives of index patients diagnosed with TTR-FAP and the structured clinical follow-up of asymptomatic gene carriers for prompt diagnosis and early therapeutic intervention before accumulation of substantial damage. Muscle Nerve 54: 353-360, 2016. © 2016 The Authors Muscle & Nerve Published by Wiley Periodicals, Inc.

First European consensus for diagnosis, management, and treatment of transthyretin familial amyloid polyneuropathy

PubMed Central

Adams, David; Suhr, Ole B.; Hund, Ernst; Obici, Laura; Tournev, Ivailo; Campistol, Josep M.; Slama, Michel S.; Hazenberg, Bouke P.; Coelho, Teresa

2016-01-01

Purpose of review Early and accurate diagnosis of transthyretin familial amyloid polyneuropathy (TTR-FAP) represents one of the major challenges faced by physicians when caring for patients with idiopathic progressive neuropathy. There is little consensus in diagnostic and management approaches across Europe. Recent findings The low prevalence of TTR-FAP across Europe and the high variation in both genotype and phenotypic expression of the disease means that recognizing symptoms can be difficult outside of a specialized diagnostic environment. The resulting delay in diagnosis and the possibility of misdiagnosis can misguide clinical decision-making and negatively impact subsequent treatment approaches and outcomes. Summary This review summarizes the findings from two meetings of the European Network for TTR-FAP (ATTReuNET). This is an emerging group comprising representatives from 10 European countries with expertise in the diagnosis and management of TTR-FAP, including nine National Reference Centres. The current review presents management strategies and a consensus on the gold standard for diagnosis of TTR-FAP as well as a structured approach to ongoing multidisciplinary care for the patient. Greater communication, not just between members of an individual patient's treatment team, but also between regional and national centres of expertise, is the key to the effective management of TTR-FAP. PMID:26734952

[Therapeutic strategy for familial amyloid polyneuropathy (FAP)].

PubMed

Ikeda, Shu-ichi

2009-11-01

Familial amyloid polyneuropathy (FAP) was long considered to be an incurable disease, but a new therapeutic approach was developed 15 years ago. As the liver produces most of the transthyretin (TTR) in serum, it was assumed that the replacement of a liver expressing an abnormal TTR gene should stop the production of the variant TTR, the serum amyloid precursor in FAP. Until now about 1,500 FAP patients underwent liver transplantation, and the 10-year-survival rate is about 77%. After operation the progression of FAP symptoms certainly stopped, and patients who were in an early stage of the disease and underwent successful operations showed considerable improvement in their quality of life. Electrophysiological study of peripheral nerve function has demonstrated that liver transplantation can halt the progression of peripheral neuropathy in FAP patients, and histopathological regression of amyloid deposits was seen on the patients with long post-transplatation courses. Pharmacological therapies have been considered for FAP patients and among them, diflunisal, one of non-steroidal antiinflammatory drugs, is very promising. TTR tetramer dissociation is an initial step for the process of TTR-derived amyloid fibril formation associated with FAP and diflinisal can inhibit this process by stabilization of the TTR tetramer. Clinical trial of this drug for FAP patients is now going worldwide.

Effect of a combined education and eHealth programme on the control of oral anticoagulation patients (PORTALS study): a parallel cohort design in Dutch primary care.

PubMed

Talboom-Kamp, Esther P W A; Verdijk, Noortje A; Kasteleyn, Marise J; Harmans, Lara M; Talboom, Irvin J S H; Numans, Mattijs E; Chavannes, Niels H

2017-09-27

To analyse the effect on therapeutic control and self-management skills of the implementation of self-management programmes, including eHealth by e-learning versus group training. Primary Care Thrombosis Service Center. Of the 247 oral anticoagulation therapy (OAT) patients, 63 started self-management by e-learning, 74 self-management by group training and 110 received usual care. Parallel cohort design with two randomised self-management groups (e-learning and group training) and a group receiving usual care. The effect of implementation of self-management on time in therapeutic range (TTR) was analysed with multilevel linear regression modelling. Usage of a supporting eHealth platform and the impact on self-efficacy (Generalised Self-Efficacy Scale (GSES)) and education level were analysed with linear regression analysis. After intervention, TTR was measured in three time periods of 6 months. (1) TTR, severe complications,(2) usage of an eHealth platform,(3) GSES, education level. Analysis showed no significant differences in TTR between the three time periods (p=0.520), the three groups (p=0.460) or the groups over time (p=0.263). Comparison of e-learning and group training showed no significant differences in TTR between the time periods (p=0.614), the groups (p=0.460) or the groups over time (p=0.263). No association was found between GSES and TTR (p=0.717) or education level and TTR (p=0.107). No significant difference was found between the self-management groups in usage of the platform (0-6 months p=0.571; 6-12 months p=0.866; 12-18 months p=0.260). The percentage of complications was low in all groups (3.2%; 1.4%; 0%). No differences were found between OAT patients trained by e-learning or by a group course regarding therapeutic control (TTR) and usage of a supporting eHealth platform. The TTR was similar in self-management and regular care patients. With adequate e-learning or group training, self-management seems safe and reliable for a selected proportion of motivated vitamin K antagonist patients. NTR3947. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Sulfated Metabolites of Polychlorinated Biphenyls Are High-Affinity Ligands for the Thyroid Hormone Transport Protein Transthyretin

PubMed Central

Grimm, Fabian A.; Lehmler, Hans-Joachim; He, Xianran; Robertson, Larry W.

2013-01-01

Background: The displacement of l-thyroxine (T4) from binding sites on transthyretin (TTR) is considered a significant contributing mechanism in polychlorinated biphenyl (PCB)-induced thyroid disruption. Previous research has discovered hydroxylated PCB metabolites (OH-PCBs) as high-affinity ligands for TTR, but the binding potential of conjugated PCB metabolites such as PCB sulfates has not been explored. Objectives: We evaluated the binding of five lower-chlorinated PCB sulfates to human TTR and compared their binding characteristics to those determined for their OH-PCB precursors and for T4. Methods: We used fluorescence probe displacement studies and molecular docking simulations to characterize the binding of PCB sulfates to TTR. The stability of PCB sulfates and the reversibility of these interactions were characterized by HPLC analysis of PCB sulfates after their binding to TTR. The ability of OH-PCBs to serve as substrates for human cytosolic sulfotransferase 1A1 (hSULT1A1) was assessed by OH-PCB–dependent formation of adenosine-3´,5´-diphosphate, an end product of the sulfation reaction. Results: All five PCB sulfates were able to bind to the high-affinity binding site of TTR with equilibrium dissociation constants (Kd values) in the low nanomolar range (4.8–16.8 nM), similar to that observed for T4 (4.7 nM). Docking simulations provided corroborating evidence for these binding interactions and indicated multiple high-affinity modes of binding. All OH-PCB precursors for these sulfates were found to be substrates for hSULT1A1. Conclusions: Our findings show that PCB sulfates are high-affinity ligands for human TTR and therefore indicate, for the first time, a potential relevance for these metabolites in PCB-induced thyroid disruption. PMID:23584369

Is all hypoglycaemia treated as equal? An observational study of how the type of diabetes and treatment prescribed prior to admission influences quality of treatment of inpatient hypoglycaemia.

PubMed

Jones, Gregory C; Khan, Jansher; Sainsbury, Christopher A R

2017-03-01

Inpatient hypoglycaemia is common and associated with adverse outcomes. There is often increased vigilance of hypoglycaemia in inpatients with type 1 diabetes (T1DM) compared to type 2 diabetes (T2DM). We aimed to investigate this apparent discrepancy, utilising the time to repeat (TTR) capillary blood glucose (CBG) measurement as a surrogate for engagement with guidelines stating that CBG should be rechecked following intervention within 15 min of an initial CBG of <4 mmol/L. This is an observational study of inpatient CBG data from 8 hospitals over a 7-year period. A national diabetes registry allowed identification of individual's diagnosis and diabetes therapy. For each initial (index) CBG, the TTR for individuals with T2DM-on insulin or sulphonylurea-was compared with the TTR for individuals with T1DM, using a t test for significance performed on log(TTR). The median TTR was plotted for each group per index CBG. In total, 1480,335 CBG measurements were obtained. A total of 26,664 were <4 mmol/L. The TTR in T2DM individuals on sulphonylurea was significantly greater than in T1DM individuals where index CBG was ≥2.3 mmol/L (except index CBG 2.6 mmol/L). For T2DM patients receiving insulin significance exists for index CBGs of ≥3.2 mmol/L. This analysis suggests that quality of care of hypoglycaemia varies according to diagnosis and medication. The group with the highest TTR (T2DM sulphonylurea treated) are possibly the clinical group in whom hypoglycaemia is most concerning. These data therefore suggest a need for education and raising awareness within the inpatient nursing staff.

Post-Closure Inspection Report for the Tonopah Test Range, Nevada. For Calendar Year 2015, Revision 0

DOE Office of Scientific and Technical Information (OSTI.GOV)

Matthews, Patrick; Petrello, Jaclyn

This report provides the results of the annual post-closure inspections conducted at the closed corrective action units (CAUs) located on the Tonopah Test Range (TTR), Nevada. This report covers calendar year 2015 and includes inspection and repair activities completed at the following CAUs; CAU 400: Bomblet Pit and Five Points Landfill (TTR); CAU 407: Roller Coaster RadSafe Area (TTR); CAU 424: Area 3 Landfill Complexes (TTR); CAU 453: Area 9 UXO Landfill (TTR); and CAU 487: Thunderwell Site (TTR) Inspections were conducted according to the post-closure plans in the approved closure reports and subsequent correspondence with the Nevada Division ofmore » Environmental Protection. The post-closure inspection plans and subsequent correspondence modifying the requirements for each CAU are included in Appendix B. The inspection checklists are included in Appendix C. Field notes are included in Appendix D. The annual post-closure inspections were conducted on May 12, 2015. Maintenance was required at CAU 453. Cracking along the north trench was repaired. One monument is missing at CAU 424; it will be replaced in 2016. Postings at CAUs 407, 424, 453, and 487 contain contact information for TTR Security. It was noted that protocols may not be in place to ensure that the U.S. Department of Energy, National Nuclear Security Administration Nevada Field Office (NNSA/NFO) is notified if access is needed at these sites. NNSA/NFO is working with the U.S. Air Force and Sandia to determine whether more appropriate contact information or new protocols are warranted for each CAU. Based on these inspections, there has not been a significant change in vegetation, and vegetation monitoring was not recommended at CAU 400 or CAU 407 in 2015.« less

A chemometric approach for characterization of serum transthyretin in familial amyloidotic polyneuropathy type I (FAP-I) by electrospray ionization-ion mobility mass spectrometry.

PubMed

Pont, Laura; Sanz-Nebot, Victoria; Vilaseca, Marta; Jaumot, Joaquim; Tauler, Roma; Benavente, Fernando

2018-05-01

In this study, we describe a chemometric data analysis approach to assist in the interpretation of the complex datasets from the analysis of high-molecular mass oligomeric proteins by ion mobility mass spectrometry (IM-MS). The homotetrameric protein transthyretin (TTR) is involved in familial amyloidotic polyneuropathy type I (FAP-I). FAP-I is associated with a specific TTR mutant variant (TTR(Met30)) that can be easily detected analyzing the monomeric forms of the mutant protein. However, the mechanism of protein misfolding and aggregation onset, which could be triggered by structural changes in the native tetrameric protein, remains under investigation. Serum TTR from healthy controls and FAP-I patients was purified under non-denaturing conditions by conventional immunoprecipitation in solution and analyzed by IM-MS. IM-MS allowed separation and characterization of several tetrameric, trimeric and dimeric TTR gas ions due to their differential drift time. After an appropriate data pre-processing, multivariate curve resolution alternating least squares (MCR-ALS) was applied to the complex datasets. A group of seven independent components being characterized by their ion mobility profiles and mass spectra were resolved to explain the observed data variance in control and patient samples. Then, principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) were considered for exploration and classification. Only four out of the seven resolved components were enough for an accurate differentiation. Furthermore, the specific TTR ions identified in the mass spectra of these components and the resolved ion mobility profiles provided a straightforward insight into the most relevant oligomeric TTR proteoforms for the disease. Copyright © 2018 Elsevier B.V. All rights reserved.

Factors influencing warfarin control in Australia and Singapore.

PubMed

Bernaitis, Nijole; Ching, Chi Keong; Teo, Siew Chong; Chen, Liping; Badrick, Tony; Davey, Andrew K; Crilly, Julia; Anoopkumar-Dukie, Shailendra

2017-09-01

Warfarin is widely used for patients with non-valvular atrial fibrillation (NVAF). Variations in warfarin control, as measured by time in therapeutic range (TTR), have been reported across different regions and ethnicities, particularly between Western and Asian countries. However, there is limited data on comparative factors influencing warfarin control in Caucasian and Asian patients. Therefore, the aim of this study was to determine warfarin control and potential factors influencing this in patients with NVAF in Australia and Singapore. Retrospective data was collected for patients receiving warfarin for January to June 2014 in Australia and Singapore. TTR was calculated for individuals with mean patient TTR used for analysis. Possible influential factors on TTR were analysed including age, gender, concurrent co-morbidities, and concurrent medication. The mean TTR was significantly higher in Australia (82%) than Singapore (58%). At both sites, chronic kidney disease significantly lowered this TTR. Further factors influencing control were anaemia and age<60years in Australia, and vascular disease, CHA 2 DS 2 -VASc score of 6, and concurrent platelet inhibitor therapy in Singapore. Warfarin control was significantly higher in Australia compared to Singapore, however chronic kidney disease reduced control at both sites. The different levels of control in these two countries, together with patient factors further reducing control may impact on anticoagulant choice in these countries with better outcomes from warfarin in Australia compared to Singapore. Copyright © 2017 Elsevier Ltd. All rights reserved.

Different binding mechanisms of neutral and anionic poly-/perfluorinated chemicals to human transthyretin revealed by In silico models.

PubMed

Yang, Xianhai; Lyakurwa, Felichesmi; Xie, Hongbin; Chen, Jingwen; Li, Xuehua; Qiao, Xianliang; Cai, Xiyun

2017-09-01

Chemical forms-dependent binding interactions between phenolic compounds and human transthyretin (hTTR) have been elaborated previously. However, it is not known whether the binding interactions between ionizable halogenated alphatic compounds and hTTR also have the same manner. In this study, poly-/perfluorinated chemicals (PFCs) were selected as model compounds and molecular dynamic simulation was performed to investigate the binding mechanisms between PFCs and hTTR. Results show the binding interactions between the halogenated aliphatic compounds and hTTR are related to the chemical forms. The ionized groups of PFCs can form electrostatic interactions with the -NH + 3 groups of Lys 15 residues in hTTR and form hydrogen bonds with the residues of hTTR. By analyzing the molecular orbital energies of PFCs, we also found that the anionic groups (nucleophile) in PFCs could form electron donor - acceptor interactions with the -NH + 3 groups (electrophile) in Lys 15. The aforementioned orientational interactions make the ionized groups of the PFCs point toward the entry port of the binding site. The roles of fluorine atoms in the binding interactions were also explored. The fluorine atoms can influence the binding interactions via inductive effects. Appropriate molecular descriptors were selected to characterize these interactions, and two quantitative structure-activity relationship models were developed. Copyright © 2017 Elsevier Ltd. All rights reserved.

Involvement of Macrophages in the Pathogenesis of Familial Amyloid Polyneuropathy and Efficacy of Human iPS Cell-Derived Macrophages in Its Treatment

PubMed Central

Komohara, Yoshihiro; Takamatsu, Koutaro; Kakuma, Tatsuyuki; Tasaki, Masayoshi; Misumi, Yohei; Ueda, Mitsuharu; Ito, Takaaki; Senju, Satoru; Ando, Yukio

2016-01-01

We hypothesized that tissue-resident macrophages in familial amyloid polyneuropathy (FAP) patients will exhibit qualitative or quantitative abnormalities, that may accelerate transthyretin (TTR)-derived amyloid deposition. To evaluate this, we examined the number and subset of tissue-resident macrophages in heart tissue from amyloid-deposited FAP and control patients. In both FAP and control patients, tissue-resident macrophages in heart tissue were all Iba+/CD163+/CD206+ macrophages. However, the number of macrophages was significantly decreased in FAP patients compared with control patients. Furthermore, the proportion of intracellular TTR in CD14+ monocytes was reduced in peripheral blood compared with healthy donors. Based on these results, we next examined degradation and endocytosis of TTR in human induced pluripotent stem (iPS) cell-derived myeloid lineage cells (MLs), which function like macrophages. iPS-MLs express CD163 and CD206, and belong to the inhibitory macrophage category. In addition, iPS-MLs degrade both native and aggregated TTR in a cell-dependent manner in vitro. Further, iPS-MLs endocytose aggregated, and especially polymerized, TTR. These results suggest that decreased tissue-localized macrophages disrupt clearance of TTR-derived amyloid deposits, leading to progression of a pathological condition in FAP patients. To improve this situation, clinical application of pluripotent stem cell-derived MLs may be useful as an approach for FAP therapy. PMID:27695122

DOE Office of Scientific and Technical Information (OSTI.GOV)

Griffith, Stacy Rene; Agogino, Karen; Li, Jun

Tonopah Test Range (TTR) in Nevada and Kauai Test Facility (KTF) in Hawaii are government-owned, contractor-operated facilities managed and operated by Sandia Corporation (Sandia), a wholly owned subsidiary of Lockheed Martin Corporation. The U.S. Department of Energy (DOE), National Nuclear Security Administration (NNSA), through the Sandia Field Office (SFO), in Albuquerque, New Mexico, administers the contract and oversees contractor operations at TTR and KTF. Sandia manages and conducts operations at TTR in support of the DOE/NNSA’s Weapons Ordnance Program and has operated the site since 1957. Navarro Research and Engineering subcontracts to Sandia in administering most of the environmental programsmore » at TTR. Sandia operates KTF as a rocket preparation launching and tracking facility. This Annual Site Environmental Report summarizes data and the compliance status of the sustainability, environmental protection, and monitoring program at TTR and KTF through Calendar Year 2013. The compliance status of environmental regulations applicable at these sites include state and federal regulations governing air emissions, wastewater effluent, waste management, terrestrial surveillance, Environmental Restoration (ER) cleanup activities, and the National Environmental Policy Act. Sandia is responsible only for those environmental program activities related to its operations. The DOE/NNSA/Nevada Field Office retains responsibility for the cleanup and management of TTR ER sites. Environmental monitoring and surveillance programs are required by DOE Order 231.1B, Environment, Safety, and Health Reporting (DOE 2012).« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Montoya, Amber L.; Wagner, Katrina; Goering, Teresa Lynn

Tonopah Test Range (TTR) in Nevada and Kauai Test Facility (KTF) in Hawaii are government-owned, contractor-operated facilities operated by Sandia Corporation, a subsidiary of Lockheed Martin Corporation. The U.S. Department of Energy (DOE), National Nuclear Security Administration (NNSA), through the Sandia Site Office (SSO), in Albuquerque, NM, manages TTR and KTF's operations. Sandia Corporation conducts operations at TTR in support of DOE/NNSA's Weapons Ordnance Program and has operated the site since 1957. Westinghouse Government Services subcontracts to Sandia Corporation in administering most of the environmental programs at TTR. Sandia Corporation operates KTF as a rocket preparation launching and tracking facility.more » This Annual Site Environmental Report (ASER) summarizes data and the compliance status of the environmental protection and monitoring program at TTR and KTF through Calendar Year (CY) 2004. The compliance status of environmental regulations applicable at these sites include state and federal regulations governing air emissions, wastewater effluent, waste management, terrestrial surveillance, and Environmental Restoration (ER) cleanup activities. Sandia Corporation is responsible only for those environmental program activities related to its operations. The DOE/NNSA, Nevada Site Office (NSO) retains responsibility for the cleanup and management of ER TTR sites. Currently, there are no ER Sites at KTF. Environmental monitoring and surveillance programs are required by DOE Order 450.1, Environmental Protection Program (DOE 2005) and DOE Order 231.1A, Environment, Safety, and Health Reporting (DOE 2004b).« less

Incidence of nonamyloidogenic mutations in the transthyretin gene in patients with autonomic and small fiber neuropathy.

PubMed

Levine, Todd D; Bland, Ruth J

2018-01-01

Mutations of the transthyretin (TTR) gene have been associated with polyneuropathy; the protein product has a tendency to form amyloid deposits in the peripheral nervous system. Patients with small fiber neuropathy (SFN) with or without autonomic symptoms were given skin biopsies to assess nerve fiber density. Any patient with autonomic symptoms was assessed for autonomic neuropathy (AN). If testing revealed no clear cause of neuropathy, the TTR gene was sequenced. Thirty-six percent of patients were found to harbor at least 1 mutation in the TTR gene sequence (variants of unknown significance [VUS]). Of 24 patients diagnosed with SFN, 8% of patients had a point mutation (c76G>A). Of those patients who were diagnosed with both SFN and AN, 68% of patients had a VUS within the TTR gene (c76G>A, c337-18G>C). The results suggest an association between presumed nonamyloidogenic mutations in the TTR gene and the development of AN and SFN. Muscle Nerve 57: 140-142, 2017. © 2017 Wiley Periodicals, Inc.

Serum transthyretin concentration is decreased in dogs with nonthyroidal illness.

PubMed

Piechotta, Marion; Jens, Raila; Rick, Markus; Beyerbach, Martin; Hoppen, Hans-Otto

2012-03-01

Hypothyroidism in dogs is often difficult to diagnose owing to nonspecific clinical signs and laboratory test results that can be mimicked by nonthyroidal illness (NTI). Thyroxine (T4) circulates in blood mainly bound to T4-binding globulin and, to a lesser degree, transthyretin (TTR) and albumin. The concentration of total T4 depends on the concentrations of these binding proteins. We hypothesized that dogs with NTI and decreased serum total T4 concentrations would have decreased serum TTR concentrations. The objective of the study was to measure and compare serum TTR concentrations in healthy dogs, in dogs with NTI and low serum T4 concentrations, and in dogs with hypothyroidism. Assignment of dogs to 3 groups was based on physical examination and serum concentrations of T4 and TSH (mean ± SD): for healthy dogs (n = 13), T4 was 24.8 ± 3.6 nmol/L and TSH was 0.15 ± 0.08 μg/L; for dogs with NTI and low T4 (n = 20), T4 was 3.2 ± 3.0 nmol/L and TSH was 0.18 ± 0.13 μg/L; and for hypothyroid dogs (n = 19), T4 was 5.3 ± 4.3 nmol/L and TSH was 2.33 ± 1.90 μg/L). TTR concentrations in serum were determined semiquantitatively using western blot analysis. Serum TTR concentration (mean ± SD) was decreased in the dogs with NTI (24.8 ± 7.9 mg/L) compared with that of hypothyroid dogs (41.1 ± 21.4 mg/L, P = .0035). Differences were not found between TTR concentrations in clinically healthy dogs (33.3 ± 10.1 mg/L) and hypothyroid dogs or dogs with NTI. Serum TTR concentrations were significantly decreased in dogs with NTI and low T4 compared with concentrations in hypothyroid dogs. Additional studies should be done to determine if TTR concentrations can discriminate between dogs with NTI and low T4 and dogs with primary hypothyroidism. © 2012 American Society for Veterinary Clinical Pathology.

[Comparison of TTR and CMV promoters in vivo and in vitro via a secreted luciferase reporter system].

PubMed

Luo, Shun-Tao; Tian, Wen-Hong; Wang, Gang; Dong, Xiao-Yan; Yang, Li; Wu, Xiao-Bing

2009-11-01

GLuc (Gaussia luciferase) is a secreted luciferase with high sensitivity. In this study, we primarily compared expression character of PTTR with that of PCMV, relied on easy secretion, high sensitivity and simple and fast detection of GLuc. We firstly constructed two plasmids pAAV2-neo-TTR-GLuc and pAAV2-neo-CMV-GLuc. Then, 4 cell lines were transfected with the two plasmids in aid of Lipofectamine 2000, including Huh7 and HepG2, which are derived from liver cells, as well as HEK293 and HeLaS3 cells, which are non-liver cell lines. We monitored the expression of GLuc in the supernatant of these cell cultures at different time points post-transfection. Furthermore, we injected the two plasmids with different doses into BALB/c mice by the means of hydrodynamic delivery and monitored the GLuc expression in vivo with 2.5 microl tail tip blood since 2 h post-injection. The cell assay results suggested that the expression of GLuc driven by CMV promoter was significantly higher than that of GLuc driven by TTR promoter. And, the luciferase activity of GLuc driven by CMV promoter was 50-300 times higher than that of GLuc driven by TTR promoter in HEK293 and HeLaS3 cell lines, but less than 10 times higher than that of GLuc driven by TTR promoter in the HepG2 and Huh7 cell lines, indicating the relative liver-specificity of TTR promoter. In the animal assay, the higher luciferase activity was determined in CMV promoter group than in TTR promoter group at different doses of the two plasmids. But the expression patterns for the two promoters differed obviously. The expression of GLuc driven by CMV promoter reached the maximum 10 hours post-injection and declined rapidly; while the expression of GLuc driven by TTR promoter reached the maximum 48 hours after delivery, and declined very slowly. These results implied that PTTR could keep expression of driven gene in a long time although its expression intensity is lower than PCMV's. Thus, it is more suitable for maintaining longer expression of target genes in liver.

TANKS 18 AND 19-F EQUIPMENT GROUT FILL MATERIAL EVALUATION AND RECOMMENDATIONS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stefanko, D.; Langton, C.

The United States Department of Energy (US DOE) intends to remove Tanks 18-F and 19-F at the Savannah River Site (SRS) from service. The high-level waste (HLW) tanks have been isolated from the F-area Tank Farm (FTF) facilities and will be filled with cementitious grout for the purpose of: (1) physically stabilizing the empty volumes in the tanks, (2) limiting/eliminating vertical pathways from the surface to residual waste on the bottom of the tanks, (3) providing an intruder barrier, and (4) providing an alkaline, chemical reducing environment within the closure boundary to limit solubility of residual radionuclides. Bulk waste andmore » heel waste removal equipment will remain in Tanks 18-F and 19-F when the tanks are closed. This equipment includes: mixer pumps, transfer pumps, transfer jets, equipment support masts, sampling masts and dip tube assemblies. The current Tank 18-F and 19-F closure strategy is to grout the internal void spaces in this equipment to eliminate fast vertical pathways and slow water infiltration to the residual material on the tank floor. This report documents the results of laboratory testing performed to identify a grout formulation for filling the abandoned equipment in Tanks 18-F and 19-F. The objective of this work was to formulate a flowable grout for filling internal voids of equipment that will remain in Tanks 18-F and 19-F during the final closures. This work was requested by V. A. Chander, Tank Farm Closure Engineering, in HLW-TTR-2011-008. The scope for this task is provided in the Task Technical and Quality Assurance Plan (TTQAP), SRNL-RP-2011-00587. The specific objectives of this task were to: (1) Prepare and evaluate the SRR cooling coil grout identified in WSRC-STI-2008-00298 per the TTR for this work. The cooling coil grout is a mixture of BASF MasterFlow{reg_sign} 816 cable grout (67.67 wt. %), Grade 100 ground granulated blast furnace slag (7.52 wt. %) and water (24.81 wt. %); (2) Identify equipment grout placement and performance properties; (3) Design up to 2 additional grout systems for filling the Tank 18-F and Tank 19-F equipment; (4) Prepare samples of candidate grouts and measure fresh properties, thermal properties and cured properties; (5) Recommend a grout for the Tier 1A equipment fill mock up - ADMP 4 foot high mock up, 1 inch and 2 inch pipes; (6) Support procurement of materials for the Tier 1A equipment fill mock up test; (7) Prepare samples of the recommended grout for hydraulic property measurements which can be used for comparison to values used in the F- Tank Farm Performance Assessment (PA); and (8) Document equipment fill grout data and recommendations in a report.« less

ENDEAVOUR: Phase 3 Multicenter Study of Revusiran (ALN-TTRSC) in Patients With Transthyretin (TTR) Mediated Familial Amyloidotic Cardiomyopathy (FAC)

ClinicalTrials.gov

2017-12-08

Transthyretin (TTR) Mediated Familial Amyloidotic Cardiomyopathy (FAC); Amyloidosis, Hereditary; Amyloid Neuropathies, Familial; Amyloid Neuropathies; Amyloidosis, Hereditary, Transthyretin-Related; Familial Transthyretin Cardiac Amyloidosis

Crystal structure of tabtoxin resistance protein complexed with acetyl coenzyme A reveals the mechanism for {beta}-lactam acetylation.

DOE Office of Scientific and Technical Information (OSTI.GOV)

He, H.; Ding, Y.; Bartlam, M.

2003-01-31

Tabtoxin resistance protein (TTR) is an enzyme that renders tabtoxin-producing pathogens, such as Pseudomonas syringae, tolerant to their own phytotoxins. Here, we report the crystal structure of TTR complexed with its natural cofactor, acetyl coenzyme A (AcCoA), to 1.55 {angstrom} resolution. The binary complex forms a characteristic 'V' shape for substrate binding and contains the four motifs conserved in the GCN5-related N-acetyltransferase (GNAT) superfamily, which also includes the histone acetyltransferases (HATs). A single-step mechanism is proposed to explain the function of three conserved residues, Glu92, Asp130 and Tyr141, in catalyzing the acetyl group transfer to its substrate. We also reportmore » that TTR possesses HAT activity and suggest an evolutionary relationship between TTR and other GNAT members.« less

Crystal structure of tabtoxin resistance protein complexed with acetyl coenzyme A reveals the mechanism for beta-lactam acetylation.

PubMed

He, Hongzhen; Ding, Yi; Bartlam, Mark; Sun, Fei; Le, Yi; Qin, Xincheng; Tang, Hong; Zhang, Rongguang; Joachimiak, Andrzej; Liu, Jinyuan; Zhao, Nanming; Rao, Zihe

2003-01-31

Tabtoxin resistance protein (TTR) is an enzyme that renders tabtoxin-producing pathogens, such as Pseudomonas syringae, tolerant to their own phytotoxins. Here, we report the crystal structure of TTR complexed with its natural cofactor, acetyl coenzyme A (AcCoA), to 1.55A resolution. The binary complex forms a characteristic "V" shape for substrate binding and contains the four motifs conserved in the GCN5-related N-acetyltransferase (GNAT) superfamily, which also includes the histone acetyltransferases (HATs). A single-step mechanism is proposed to explain the function of three conserved residues, Glu92, Asp130 and Tyr141, in catalyzing the acetyl group transfer to its substrate. We also report that TTR possesses HAT activity and suggest an evolutionary relationship between TTR and other GNAT members.

Calendar year 2002 annual site environmental report for Tonopah Test Range, Nevada and Kauai Test Facility, Hawaii.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wagner, Katrina; Sanchez, Rebecca V.; Mayeux, Lucie

2003-09-01

Tonopah Test Range (TTR) in Nevada and Kauai Test Facility (KTF) in Hawaii are government-owned, contractor-operated facilities operated by Sandia Corporation, a subsidiary of Lockheed Martin Corporation. The U.S. Department of Energy (DOE), National Nuclear Security Administration (NNSA), through the Sandia Site Office (SSO), in Albuquerque, NM, oversees TTR and KTF's operations. Sandia Corporation conducts operations at TTR in support of DOE/NNSA's Weapons Ordnance Program and has operated the site since 1957. Westinghouse Government Services subcontracts to Sandia Corporation in administering most of the environmental programs at TTR. Sandia Corporation operates KTF as a rocket preparation launching and tracking facility.more » This Annual Site Environmental Report (ASER) summarizes data and the compliance status of the environmental protection and monitoring program at TTR and KTF through Calendar Year (CY) 2002. The compliance status of environmental regulations applicable at these sites include state and federal regulations governing air emissions, wastewater effluent, waste management, terrestrial surveillance, and Environmental Restoration (ER) cleanup activities. Sandia Corporation is responsible only for those environmental program activities related to its operations. The DOE/NNSA, Nevada Site Office (NSO) retains responsibility for the cleanup and management of ER TTR sites. Currently, there are no ER Sites at KTF. Environmental monitoring and surveillance programs are required by DOE Order 5400.1, General Environmental Protection Program (DOE 1990) and DOE Order 231.1, Environment, Safety, and Health Reporting (DOE 1996).« less

Calendar year 2003 : annual site enviromental report for Tonopah Test Range, Nevada and Kauai Test Facility, Hawaii.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wagner, Katrina; Sanchez, Rebecca V.; Mayeux, Lucie

2004-09-01

Tonopah Test Range (TTR) in Nevada and Kauai Test Facility (KTF) in Hawaii are government-owned, contractor-operated facilities operated by Sandia Corporation, a subsidiary of Lockheed Martin Corporation. The U.S. Department of Energy (DOE), National Nuclear Security Administration (NNSA), through the Sandia Site Office (SSO), in Albuquerque, NM, manages TTR and KTF's operations. Sandia Corporation conducts operations at TTR in support of DOE/NNSA's Weapons Ordnance Program and has operated the site since 1957. Westinghouse Government Services subcontracts to Sandia Corporation in administering most of the environmental programs at TTR. Sandia Corporation operates KTF as a rocket preparation launching and tracking facility.more » This Annual Site Environmental Report (ASER) summarizes data and the compliance status of the environmental protection and monitoring program at TTR and KTF through Calendar Year (CY) 2003. The compliance status of environmental regulations applicable at these sites include state and federal regulations governing air emissions, wastewater effluent, waste management, terrestrial surveillance, and Environmental Restoration (ER) cleanup activities. Sandia Corporation is responsible only for those environmental program activities related to its operations. The DOE/NNSA, Nevada Site Office (NSO) retains responsibility for the cleanup and management of ER TTR sites. Currently, there are no ER Sites at KTF. Environmental monitoring and surveillance programs are required by DOE Order 450.1, Environmental Protection Program (DOE 2003) and DOE Order 231.1 Chg 2., Environment, Safety, and Health Reporting (DOE 1996).« less

Comparison of international normalized ratio audit parameters in patients enrolled in GARFIELD-AF and treated with vitamin K antagonists.

PubMed

Fitzmaurice, David A; Accetta, Gabriele; Haas, Sylvia; Kayani, Gloria; Lucas Luciardi, Hector; Misselwitz, Frank; Pieper, Karen; Ten Cate, Hugo; Turpie, Alexander G G; Kakkar, Ajay K

2016-08-01

Vitamin K antagonist (VKA) therapy for stroke prevention in atrial fibrillation (AF) requires monitoring of the international normalized ratio (INR). We evaluated the agreement between two INR audit parameters, frequency in range (FIR) and proportion of time in the therapeutic range (TTR), using data from a global population of patients with newly diagnosed non-valvular AF, the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF). Among 17 168 patients with 1-year follow-up data available at the time of the analysis, 8445 received VKA therapy (±antiplatelet therapy) at enrolment, and of these patients, 5066 with ≥3 INR readings and for whom both FIR and TTR could be calculated were included in the analysis. In total, 70 905 INRs were analysed. At the patient level, TTR showed higher values than FIR (mean, 56·0% vs 49·8%; median, 59·7% vs 50·0%). Although patient-level FIR and TTR values were highly correlated (Pearson correlation coefficient [95% confidence interval; CI], 0·860 [0·852-0·867]), estimates from individuals showed widespread disagreement and variability (Lin's concordance coefficient [95% CI], 0·829 [0·821-0·837]). The difference between FIR and TTR explained 17·4% of the total variability of measurements. These results suggest that FIR and TTR are not equivalent and cannot be used interchangeably. © 2016 John Wiley & Sons Ltd.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Agogino, Karen; Sanchez, Rebecca

Tonopah Test Range (TTR) in Nevada and Kauai Test Facility (KTF) in Hawaii are government-owned, contractor-operated facilities operated by Sandia Corporation (Sandia), a wholly owned subsidiary of Lockheed Martin Corporation. The U.S. Department of Energy (DOE)/National Nuclear Security Administration (NNSA), through the Sandia Site Offi ce (SSO), in Albuquerque, NM, administers the contract and oversees contractor operations at TTR and KTF. Sandia manages and conducts operations at TTR in support of the DOE/NNSA’s Weapons Ordnance Program and has operated the site since 1957. Washington Group International subcontracts to Sandia in administering most of the environmental programs at TTR. Sandia operatesmore » KTF as a rocket preparation launching and tracking facility. This Annual Site Environmental Report (ASER) summarizes data and the compliance status of the environmental protection and monitoring program at TTR and KTF through Calendar Year (CY) 2007. The compliance status of environmental regulations applicable at these sites include state and federal regulations governing air emissions, wastewater effluent, waste management, terrestrial surveillance, and Environmental Restoration (ER) cleanup activities. Sandia is responsible only for those environmental program activities related to its operations. The DOE/NNSA/Nevada Site Offi ce (NSO) retains responsibility for the cleanup and management of ER TTR sites. Currently, there are no ER Sites at KTF. Environmental monitoring and surveillance programs are required by DOE Order 450.1, Environmental Protection Program (DOE 2007a) and DOE Manual 231.1-1A, Environment, Safety, and Health Reporting Manual (DOE 2007).« less

Human TTR conformation altered by rhenium tris-carbonyl derivatives.

PubMed

Ciccone, Lidia; Policar, Clotilde; Stura, Enrico A; Shepard, William

2016-09-01

Transthyretin (TTR) is a 54 kDa homotetrameric serum protein that transports thyroxine (T4) and retinol. TTR is potentially amyloidogenic due to homotetramer dissociation into monomeric intermediates that self-assemble as amyloid deposits and insoluble fibrils. Most crystallographic structures, including those of amyloidogenic variants show the same tetramer without major variations in the monomer-monomer interface nor in the volume of the interdimeric cavity. Soaking TTR crystals in a solution containing rhenium tris-carbonyl derivatives yields a TTR conformer never observed before. Only one of the two monomers of the crystallographic dimer is significantly altered, and the inner part of the T4 binding cavity is expanded at one end and shrunk at the other. The result redefines the mechanism of allosteric communication between the two sites, suggesting that negative cooperativity is a function of dimer asymmetry, which can be induced through internal or external binding. An aspect that remains unexplained is why the conformational changes are ubiquitous throughout the crystal although the heavy metal content of the derivatized crystals is relatively low. The conformational changes observed, which include Leu(82), may represent a form of TTR better at scavenging β-Amyloid. At a resolution of 1.69Å, with excellent refinement statistics and well defined electron density for all parts of the structure, it is possible to envisage answering important questions that range from protein cooperative behavior to heavy atom induced protein conformational modifications that can result in crystallographic non-isomorphism. Copyright © 2016 Elsevier Inc. All rights reserved.

The importance of mean time in therapeutic range for complication rates in warfarin therapy of patients with atrial fibrillation: A systematic review and meta-regression analysis.

PubMed

Vestergaard, Anne Sig; Skjøth, Flemming; Larsen, Torben Bjerregaard; Ehlers, Lars Holger

2017-01-01

\\Anticoagulation is used for stroke prophylaxis in non-valvular atrial fibrillation, amongst other by use of the vitamin K antagonist, warfarin. Quality in warfarin therapy is often summarized by the time patients spend within the therapeutic range (percent time in therapeutic range, TTR). The correlation between TTR and the occurrence of complications during warfarin therapy has been established, but the influence of patient characteristics in that respect remains undetermined. The objective of the present papers was to examine the association between mean TTR and complication rates with adjustment for differences in relevant patient cohort characteristics. A systematic literature search was conducted in MEDLINE and Embase (2005-2015) to identify eligible studies reporting on use of warfarin therapy by patients with non-valvular atrial fibrillation and the occurrence of hemorrhage and thromboembolism. Both randomized controlled trials and observational cohort studies were included. The association between the reported mean TTR and major bleeding and stroke/systemic embolism was analyzed by random-effects meta-regression with and without adjustment for relevant clinical cohort characteristics. In the adjusted meta-regressions, the impact of mean TTR on the occurrence of hemorrhage was adjusted for the mean age and the proportion of populations with prior stroke or transient ischemic attack. In the adjusted analyses on thromboembolism, the proportion of females was, furthermore, included. Of 2169 papers, 35 papers met pre-specified inclusion criteria, holding relevant information on 31 patient cohorts. In univariable meta-regression, increasing mean TTR was significantly associated with a decreased rate of both major bleeding and stroke/systemic embolism. However, after adjustment mean TTR was no longer significantly associated with stroke/systemic embolism. The proportion of residual variance composed by between-study heterogeneity was substantial for all analyses. Although higher mean TTR in warfarin therapy was associated with lower complication rates in atrial fibrillation, the strength of the association was decreased when adjusting for differences in relevant clinical characteristics of the patient cohorts. This study suggests that mainly the safety of warfarin therapy increases with higher mean TTR, whereas effectiveness appears not to be substantially improved. Due to the limitations immanent in the meta-regression methods, the results of the present study should be interpreted with caution. Further research on the association between the quality of warfarin therapy and risk of complications is warranted with adjustment for clinically relevant characteristics.

Plasma Transthyretin as a Biomarker of Lean Body Mass and Catabolic States.

PubMed

Ingenbleek, Yves; Bernstein, Larry H

2015-09-01

Plasma transthyretin (TTR) is a plasma protein secreted by the liver that circulates bound to retinol-binding protein 4 (RBP4) and its retinol ligand. TTR is the sole plasma protein that reveals from birth to old age evolutionary patterns that are closely superimposable to those of lean body mass (LBM) and thus works as the best surrogate analyte of LBM. Any alteration in energy-to-protein balance impairs the accretion of LBM reserves and causes early depression of TTR production. In acute inflammatory states, cytokines induce urinary leakage of nitrogenous catabolites, deplete LBM stores, and cause an abrupt decrease in TTR and RBP4 concentrations. As a result, thyroxine and retinol ligands are released in free form, creating a second frontline that strengthens that primarily initiated by cytokines. Malnutrition and inflammation thus keep in check TTR and RBP4 secretion by using distinct and unrelated physiologic pathways, but they operate in concert to downregulate LBM stores. The biomarker complex integrates these opposite mechanisms at any time and thereby constitutes an ideally suited tool to determine residual LBM resources still available for metabolic responses, hence predicting outcomes of the most interwoven disease conditions. © 2015 American Society for Nutrition.

Quality of warfarin therapy and risk of stroke, bleeding, and mortality among patients with atrial fibrillation: results from the nationwide FinWAF Registry.

PubMed

Lehto, Mika; Niiranen, Jussi; Korhonen, Pasi; Mehtälä, Juha; Khanfir, Houssem; Hoti, Fabian; Lassila, Riitta; Raatikainen, Pekka

2017-06-01

The most important management strategy in atrial fibrillation (AF) patients is preventing stroke with oral anticoagulants. Warfarin is still used as a first-line anticoagulant, although non-vitamin K antagonist oral anticoagulants are currently recommended to manage AF. Using a large, unselected national sample of AF patients, we evaluated the relationships between quality of warfarin therapy and the risks of thromboembolism, bleeding complications, and mortality. The nationwide FinWAF study included 54 568 AF patients taking warfarin. Time in the therapeutic range (TTR) was calculated on a continuous basis using the Rosendaal method and international normalized ratio values over the previous 60 days. Adjusted Cox proportional hazard models were prepared for different TTR levels and major clinical end points. The mean age of patients was 73.1 years (standard deviation 10.8), and 47% were female. The mean follow-up time was 3.2 ± 1.6 years (median 3.4). In the TTR groups of ≤40%, 60-70%, 70-80%, and >80%, the annual risk of stroke was 9.3%, 4.7%, 4.6%, and 3.1%; bleeding events 7.5%, 4.5%, 4.3%, and 2.6%; and overall mortality 20.9%, 8.5%, 6.4%, and 3.1%, respectively. All differences among the TTR groups were highly significant (p < 0.001). The quality of warfarin treatment was strongly associated with the risk of stroke and the prognosis of AF patients. Patient outcomes continued to improve with increasing TTR values up to a TTR ≥80%; therefore, the target for the TTR should exceed 80% instead of the traditional range of at least 60-70%. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Removal mechanisms of benzotriazoles in duckweed Lemna minor wastewater treatment systems.

PubMed

Gatidou, Georgia; Oursouzidou, Maria; Stefanatou, Aimilia; Stasinakis, Athanasios S

2017-10-15

The fate of five benzotriazoles (1H-benzotriazole, BTR; 4-methyl-1H-benzotriazole, 4TTR; 5-methyl-1H-benzotriazole, 5TTR; xylytriazole, XTR and 5-chlorobenzotriazole, CBTR) was studied in batch and continuous-flow Lemna minor systems and the role of different mechanisms on their removal was evaluated. Single and joint toxicity experiments were initially conducted using the Organization for Economic Co-operation and Development (OECD) protocol 221 and no inhibition on specific growth rate of Lemna minor was observed for concentrations up to 200μgL -1 . All tested substances were significantly removed in batch experiments with Lemna minor. Excepting 4TTR, full elimination of CBTR, XTR, 5TTR and BTR was observed up to the end of these experiments (36d), while the half-life values ranged between 1.6±0.3d (CBTR) and 25±3.6d (4-TTR). Calculation of kinetic constants for hydrolysis, photodegradation, and plant uptake revealed that for all BTRs the kinetic constants of plant uptake were by far higher comparing to those of the other mechanisms, reaching 0.394±0.161d -1 for CBTR. The operation of a continuous-flow Lemna minor system consisted of three mini ponds and a total hydraulic residence time of 8.3d showed sufficient removal for most target substances, ranging between 26% (4TTR) and 72% (CBTR). Application of a model for describing micropollutants removal in the examined system showed that plant uptake was the major mechanism governing BTRs removal in Lemna minor systems. Copyright © 2017 Elsevier B.V. All rights reserved.

Pressure calibrants in the hydrothermal diamond-anvil cell

USGS Publications Warehouse

Chou, I.-Ming

2007-01-01

Based on the equation of state of water (EOSW), experimental pressure in the hydrothermal diamond-anvil cell (HDAC) using pure water or dilute aqueous solutions as a pressure medium can be accurately determined at each measured temperature. Consequently, meaningful interpretations can be obtained for observations in the HDAC, which has been widely accepted as a versatile, modern apparatus for hydrothermal experiments. However, this is not true when other pressure media were used because there is no reliable way to determine experimental pressure other than the use of in situ pressure sensors. Most of the available pressure sensors are difficult to apply because they either require expensive facilities to perform the measurements or are unable to provide the accuracy needed for the interpretation of hydrothermal experiments. The only exception is to use the interferometric method to detect the ??-?? quartz transition, although such applications are limited to temperatures above 573??C. In this study, three pressure calibrants were calibrated for applications at lower temperatures, and they were based on visual observation of the ferroelastic phase transitions in BaTiO3 (tetragonal/cubic), Pb3(PO4)2 (monoclinic/trigonal), and PbTiO3 (tetragonal/cubic). For the phase transitions in BaTiO3 and Pb3(PO4)2, the temperature at which twinning disappears during heating was taken as the transition temperature (Ttr); the phase transition pressures (Ptr) can be calculated, respectively, from Ptr (MPa; ??3%) = 0.17 - 21.25 [(Ttr) - 115.3], and Ptr (MPa; ??2%) = 1.00 - 10.62 [(Ttr) - 180.2], where Ttr is in ??C. For the phase transition in PbTiO3, the temperature at which the movement of phase front begins (or ends) on heating (or cooling) was taken as the transition temperature (Ttr,h or Ttr,c), and the phase transition pressures on heating (Ptr,h) and cooling (Ptr,c) can be calculated from Ptr,h (MPa; ??4%) = 7021.7 - 14.235 (Ttr,h), and Ptr,c (MPa; ??4%) = 6831.3 - 14.001 (Ttr,c). Phase transitions for these three pressure calibrants are easy to detect visually, and their P-T phase boundaries have negative slopes and intersect isochors of most of the geologic fluids at high angles and, therefore, are easy to apply. Copyright ?? 2007 by V. H. Winston & Son, Inc. All rights reserved.

Modeling, implementation, and validation of arterial travel time reliability : [summary].

DOT National Transportation Integrated Search

2013-11-01

Travel time reliability (TTR) has been proposed as : a better measure of a facilitys performance than : a statistical measure like peak hour demand. TTR : is based on more information about average traffic : flows and longer time periods, thus inc...

Retrospective study of a TTR FAP cohort to modify NIS+7 for therapeutic trials.

PubMed

Suanprasert, N; Berk, J L; Benson, M D; Dyck, P J B; Klein, C J; Gollob, J A; Bettencourt, B R; Karsten, V; Dyck, P J

2014-09-15

Protein stabilization and oligonucleotide therapies are being tested in transthyretin amyloid polyneuropathy (TTR FAP) trials. From retrospective analysis of 97 untreated TTR FAP patients, we test the adequacy of Neuropathy Impairment Score+7 tests (NIS+7) and modifications to comprehensively score impairments for use in such therapeutic trials. Our data confirms that TTR FAP usually is a sensorimotor polyneuropathy with autonomic features which usually is symmetric, length dependent, lower limb predominant and progressive. NIS+7 adequately assesses weakness and muscle stretch reflexes without ceiling effects but not sensation loss, autonomic dysfunction or nerve conduction abnormalities. Three modifications of NIS+7 are suggested: 1) use of Smart Somatotopic Quantitative Sensation Testing (S ST QSTing); 2) choice of new autonomic assessments, e.g., sudomotor testing of distributed anatomical sites; and 3) use of only compound muscle action potential amplitudes (of ulnar, peroneal and tibial nerves) and sensory nerve action potentials of ulnar and sural nerve - than the previously recommended attributes suggested for the sensitive detection of diabetic sensorimotor polyneuropathy. These modifications of NIS+7 if used in therapeutic trials should improve characterization and quantification of sensation and autonomic impairment in TTR FAP and provide better nerve conduction tests. Copyright © 2014 Elsevier B.V. All rights reserved.

[Quality control of oral anticoagulant therapy in Primary Care in Madrid City, Spain: CHRONOS-TAO study].

PubMed

Alonso Roca, Rafael; Figueroa Guerrero, Carmen Arlene; Mainar de Paz, Victoria; Arribas García, M Paz; Sánchez Perruca, Luis; Rodríguez Barrientos, Ricardo; Casado López, Mariano; Pedraza Flechas, Ana M

2015-09-07

To determine quality control of patients with oral anticoagulant treatment recruited in Primary Care (PC) using the Rosendaal method to estimate time in therapeutic range (TTR) and comparing it with fraction of international normalized ratio (INR) in range and cross-sectional analysis (last INR registred). A retrospective observational study based on electronic medical record in routine clinical practice. PC centers (262) in Madrid. We included all patients with acenocumarol treatment, with an INR therapeutic range established between 2 and 3. We excluded patients with valvular pathology and disrupted clinical follow up in PC (<3 INR determinations in the studied period, a period of>90 days or ≥ 3 periods of>60 days between 2 determinations). The final population was 49,312 patients. The variables considered were all INR values and their respective dates. TTR was calculated by the 3 methods above mentioned. We considered "therapeutic range" INR between 2-3 and "adjusted range" INR between 1.8-3.2. Optimal control for each patient was considered TTR>60%. By using Rosendaal method, TTR was 66.8% (81.7% adjusted), with a percentage of total INR in range was 58.8% (66.5% adjusted), and, with the cross-sectional analysis, it was 70.5% (76.8% adjusted). Mean TTR was 65% (standard deviation 20.3), and the percentage of patients with TTR>60% was 63.3% (88.1% adjusted). The quality control of patients with oral anticoagulants in PC in Madrid is acceptable, similar or higher to other studies and pivotal trials of new anticoagulants. Compared to the Rosendaal method, total fraction of INR underestimates quality control, and cross-sectional analysis slightly overestimates it. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

Transthyretin Ala36Pro mutation in a Chinese pedigree of familial transthyretin amyloidosis with elevated vitreous and serum vascular endothelial growth factor.

PubMed

Zou, Xuan; Dong, Fangtian; Zhang, Shuying; Tian, Rong; Sui, Ruifang

2013-05-01

The familial transthyretin (TTR) amyloidosis (FTA) demonstrates variable penetrance of clinical features associated with mutations in the plasma thyroid hormone-binding protein TTR gene. The purpose of this study was to assess the ocular features, to analyze vitreous and serum vascular endothelial growth factor (VEGF) levels, and to identify the genetic defect in a Chinese family with TTR FTA. The pedigree of interest was a three-generation family with eleven members. The primary ocular signs were vitreous opacities, beginning from the third or fourth decade, accompanied by retinal vasculitis, hemorrhages, and widespread pinpoint deposits in the peripheral retina. Two patients underwent vitrectomy with marked improvement of visual acuity postoperatively. Vitreous and serum samples for VEGF were analyzed with an enzyme-linked immunosorbent assay (ELISA). Forty-eight healthy adult volunteers were enrolled as a control group for the analysis of serum VEGF. Eight subjects who underwent vitrectomy for a macular epiretinal membrane or macular hole were enrolled as control for the analysis of vitreous VEGF. Both serum and vitreous VEGF levels of patients were raised compared to that of controls. Venous blood was collected from family members and the genomic DNA was extracted. All exons and exon-intron boundaries of the TTR gene were sequenced. A previously-described pathogenic transversion in exon 2 (c.G106C, p.Ala36Pro) was identified. Within this family eight individuals were confirmed as affected. In conclusion, a Chinese family with TTR Ala36Pro associated FTA is characterized by early ocular involvement. Widespread pinpoint lesions indicate RPE lesions caused by TTR deposition. FTA is associated with increased VEGF levels, both in serum and vitreous. Copyright © 2013 Elsevier Ltd. All rights reserved.

Post-Closure Inspection Report for the Tonopah Test Range, Nevada: For Calendar Year 2017, Revision 0

DOE Office of Scientific and Technical Information (OSTI.GOV)

Alvarado, Juan; Matthews, Patrick

This report provides the results of the annual post-closure inspections conducted at the closed corrective action units (CAUs) located on the Tonopah Test Range (TTR) and the Nevada Test and Training Range (NTTR). This report covers calendar year 2017 and includes visual inspection and repair activities completed at the following CAUs: CAU 400: Bomblet Pit and Five Points Landfill (TTR) CAU 407: Roller Coaster RadSafe Area (TTR) CAU 424: Area 3 Landfill Complexes (TTR) CAU 453: Area 9 UXO Landfill (TTR) CAU 487: Thunderwell Site (TTR) Visual inspections were conducted according to the post-closure plans in the approved closure reportsmore » and subsequent correspondence with the Nevada Division of Environmental Protection. The annual post-closure inspections were conducted on May 23, 2017. No maintenance or repair issues were noted at CAU 400 and CAU 487. Maintenance items and subsequent repairs include the following: CAU 407: A large animal burrow was observed in the southeast corner of the cover during the inspection. Two additional animal burrows were discovered during repair actions. All cover defects were repaired on January 9, 2018. CAU 424: CAS 03-08-002-A304 (Landfill Cell A3-4): A new monument was installed and the subsidence area was repaired on January 9, 2018. CAU 424: CAS 03-08-002-A308 (Landfill Cell A3-8): Lava rock, used to mark the two eastern monument locations, was noted as missing during the inspection. The lava rock was replaced on January 9, 2018. CAU 453: Five large animal burrows, located near the east–central portion of cover, was noted during the inspection. Eight additional animal burrows were discovered during repair actions. All cover defects were repaired on January 9, 2018.« less

Clinical Prediction Model for Time in Therapeutic Range While on Warfarin in Newly Diagnosed Atrial Fibrillation.

PubMed

Williams, Brent A; Evans, Michael A; Honushefsky, Ashley M; Berger, Peter B

2017-10-12

Though warfarin has historically been the primary oral anticoagulant for stroke prevention in newly diagnosed atrial fibrillation (AF), several new direct oral anticoagulants may be preferred when anticoagulation control with warfarin is expected to be poor. This study developed a prediction model for time in therapeutic range (TTR) among newly diagnosed AF patients on newly initiated warfarin as a tool to assist decision making between warfarin and direct oral anticoagulants. This electronic medical record-based, retrospective study included newly diagnosed, nonvalvular AF patients with no recent warfarin exposure receiving primary care services through a large healthcare system in rural Pennsylvania. TTR was estimated as the percentage of time international normalized ratio measurements were between 2.0 and 3.0 during the first year following warfarin initiation. Candidate predictors of TTR were chosen from data elements collected during usual clinical care. A TTR prediction model was developed and temporally validated and its predictive performance was compared with the SAMe-TT 2 R 2 score (sex, age, medical history, treatment, tobacco, race) using R 2 and c-statistics. A total of 7877 newly diagnosed AF patients met study inclusion criteria. Median (interquartile range) TTR within the first year of starting warfarin was 51% (32, 67). Of 85 candidate predictors evaluated, 15 were included in the final validated model with an R 2 of 15.4%. The proposed model showed better predictive performance than the SAMe-TT 2 R 2 score ( R 2 =3.0%). The proposed prediction model may assist decision making on the proper mode of oral anticoagulant among newly diagnosed AF patients. However, predicting TTR on warfarin remains challenging. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Post-Closure Inspection Report for the Tonopah Test Range, Nevada, for Calendar Year 2013

DOE Office of Scientific and Technical Information (OSTI.GOV)

Silvas, A. J.

2014-03-03

This report provides the results of the annual post-closure inspections conducted at the closed Corrective Action Units (CAUs) located on the Tonopah Test Range (TTR), Nevada. This report covers calendar year 2013 and includes inspection and repair activities completed at the following CAUs: • CAU 400: Bomblet Pit and Five Points Landfill (TTR) • CAU 407: Roller Coaster RadSafe Area (TTR) • CAU 424: Area 3 Landfill Complexes (TTR) • CAU 453: Area 9 UXO Landfill (TTR) • CAU 487: Thunderwell Site (TTR) Inspections were conducted according to the post-closure plans in the approved Closure Reports and subsequent correspondence withmore » the Nevada Division of Environmental Protection. The post-closure inspection plans and subsequent correspondence modifying the requirements for each CAU are included in Appendix B. The inspection checklists are included in Appendix C. Field notes are included in Appendix D. Photographs taken during inspections are included in Appendix E. The annual post-closure inspections were conducted on May 14, 2013. Maintenance was performed at CAU 400, CAU 424, and CAU 453. At CAU 400, animal burrows were backfilled. At CAU 424, erosion repairs were completed at Landfill Cell A3-3, subsidence was repaired at Landfill Cell A3-4, and additional lava rock was placed in high-traffic areas to mark the locations of the surface grade monuments at Landfill Cell A3-3 and Landfill Cell A3-8. At CAU 453, two areas of subsidence were repaired and animal burrows were backfilled. Vegetation monitoring was performed at the CAU 400 Five Points Landfill and CAU 407 in June 2013. The vegetation monitoring report is included in Appendix F.« less

Multi-dose drug dispensing as a tool to improve medication adherence: A study in patients using vitamin K antagonists.

PubMed

van Rein, Nienke; de Geus, Kristel S; Cannegieter, Suzanne C; Reitsma, Pieter H; van der Meer, Felix J M; Lijfering, Willem M

2018-01-01

Multi-dose drug dispensing (MDD) is a dosing aid that provides patients with disposable bags containing all drugs intended for 1 dosing moment. MDD is believed to increase medication adherence, but studies are based on self-reported data, and results may depend on socially desirable answers. Therefore, our purpose was to determine the effect of MDD on medication adherence in non-adherent patients taking vitamin K antagonists (VKAs), and to compare with instructing patients on medication use. We conducted a before-after study in non-adherent patients where MDD was the exposure and change in adherence after MDD initiation was the outcome (within patient comparison). Time in therapeutic range (TTR) was selected as a measure for adherence, as this reflects stability of VKA treatment. To analyze whether MDD improved adherence as compared with standard care (ie, letters or calls from nurses of the anticoagulation clinic), non-adherent patients without MDD were also followed to estimate their TTR change over time (between patient comparison). Eighty-three non-adherent VKA patients started using MDD. The median TTR was 63% before MDD and 73% 6 months after MDD. The within patient TTR increased on average by 13% (95%CI 6% to 21%) within 1 month after starting MDD and remained stable during the next 5 months. The TTR of MDD-patients increased 10% (95%CI 2% to 19%) higher as compared with non-MDD patients within 1 month but was similar after 4 months (TTR difference 3%, 95%CI -2% to 9%). Adherence improved after initiation of MDD. Compared with instructing patients, MDD was associated with better adherence within 1 month but was associated with similar improvement after 4 months. Copyright © 2017 John Wiley & Sons, Ltd.

Transthyretin-Related Familial Amyloid Polyneuropathy (TTR-FAP): A Single-Center Experience in Sicily, an Italian Endemic Area.

PubMed

Mazzeo, Anna; Russo, Massimo; Di Bella, Gianluca; Minutoli, Fabio; Stancanelli, Claudia; Gentile, Luca; Baldari, Sergio; Carerj, Scipione; Toscano, Antonio; Vita, Giuseppe

2015-07-22

Familial amyloid polyneuropathy related to transthyretin gene (TTR-FAP) is a life-threatening disease transmitted as an autosomal dominant trait. Val30Met mutation accounts for the majority of the patients with large endemic foci especially in Portugal, Sweden and Japan. However, more than one hundred other mutations have been described worldwide. A great phenotypic variability among patients with late- and early-onset has been reported. To present a detailed report of TTR-FAP patients diagnosed in our tertiary neuromuscular center, in a 20-year period. Clinical informations were gathered through the database of our center. The study involved 76 individuals carrying a TTR-FAP mutation. Three phenotypes were identified, each corresponding to a different TTR variant, homogeneous within and heterogeneous between each other: i) Glu89Gln mutation, characterised by 5th - 6th decade onset, neuropathy as presenting symptoms, early heart dysfunction, cardiomyopathy as major cause of mortality followed by dysautonomia and cachexia; ii) Phe64Leu mutation, marked by familiarity reported in one-half of cases, late onset, severe peripheral neuropathy, moderate dysautonomia and mild cardiomyopathy, death for wasting syndrome; iii) Thr49Ala mutation, distinguished by onset in the 5th decade, autonomic disturbances as inaugural symptoms which may remain isolated for many years, moderate polyneuropathy, cachexia as major cause of mortality followed by cardiomyopathy. This survey highlighted a prevalence of 8.8/1,000,000 in Sicily Island. Good knowledge of the natural history of the disease according to different TTR mutations allow clinicians to optimise multiprofessional care for patients and to offer carriers a personalized follow-up to reveal first signs of the disease.

Birth of two healthy females after preimplantation genetic diagnosis for familial amyloid polyneuropathy.

PubMed

Almeida, V M; Costa, P M; Moreira, P; Gonçalves, J; Braga, J

2005-05-01

Familial amyloid polyneuropathy (FAP), Portuguese type, is a late onset, high penetrance, autosomal dominant Mendelian disorder caused by a V30M substitution in the transthyretin (TTR) protein. A genetic diagnosis was developed using fluorescent single cell polymerase chain reaction (PCR) on lymphocytes from patients and controls. Ovarian stimulation and oocyte retrieval were carried out using conventional protocols in a couple in whom the female was heterozygous for the mutation TTR V30M. Blastomere biopsy was performed on day 3 after intracytoplasmic sperm injection. PCR was then performed for a segment of the TTR gene encompassing the V30M mutation. The transfer of three embryos at day 4 resulted in a twin pregnancy, confirmed as healthy females by amniocentesis at 16 weeks of gestation; the birth took place at 37 weeks of gestation. With this report, FAP, TTR related, joins the lengthening list of genetic conditions for which preimplantation genetic diagnosis has been successfully carried out.

Transthyretin Interferes with Aβ Amyloid Formation by Redirecting Oligomeric Nuclei into Non-Amyloid Aggregates.

PubMed

Nilsson, Lina; Pamrén, Annelie; Islam, Tohidul; Brännström, Kristoffer; Golchin, Solmaz A; Pettersson, Nina; Iakovleva, Irina; Sandblad, Linda; Gharibyan, Anna L; Olofsson, Anders

2018-06-08

The pathological Aβ aggregates associated with Alzheimer's disease follow a nucleation-dependent path of formation. A nucleus represents an oligomeric assembly of Aβ peptides that acts as a template for subsequent incorporation of monomers to form a fibrillar structure. Nuclei can form de novo or via surface-catalyzed secondary nucleation, and the combined rates of elongation and nucleation control the overall rate of fibril formation. Transthyretin (TTR) obstructs Aβ fibril formation in favor of alternative non-fibrillar assemblies, but the mechanism behind this activity is not fully understood. This study shows that TTR does not significantly disturb fibril elongation; rather, it effectively interferes with the formation of oligomeric nuclei. We demonstrate that this interference can be modulated by altering the relative contribution of elongation and nucleation, and we show how TTR's effects can range from being essentially ineffective to almost complete inhibition of fibril formation without changing the concentration of TTR or monomeric Aβ. Copyright © 2018. Published by Elsevier Ltd.

Modulation of the fibrillogenesis inhibition properties of two transthyretin ligands by halogenation.

PubMed

Cotrina, Ellen Y; Pinto, Marta; Bosch, Lluís; Vilà, Marta; Blasi, Daniel; Quintana, Jordi; Centeno, Nuria B; Arsequell, Gemma; Planas, Antoni; Valencia, Gregorio

2013-11-27

The amyloidogenic protein transthyretin (TTR) is thought to aggregate into amyloid fibrils by tetramer dissociation which can be inhibited by a number of small molecule compounds. Our analysis of a series of crystallographic protein-inhibitor complexes has shown no clear correlation between the observed molecular interactions and the in vitro activity of the inhibitors. From this analysis, it emerged that halogen bonding (XB) could be mediating some key interactions. Analysis of the halogenated derivatives of two well-known TTR inhibitors has shown that while flufenamic acid affinity for TTR was unchanged by halogenation, diflunisal gradually improves binding up to 1 order of magnitude after iodination through interactions that can be interpreted as a suboptimal XB (carbonyl Thr106: I...O distance 3.96-4.05 Å; C-I...O angle 152-156°) or as rather optimized van der Waals contacts or as a mixture of both. These results illustrate the potential of halogenation strategies in designing and optimizing TTR fibrillogenesis inhibitors.

Design and development of split-parallel through-the road retrofit hybrid electric vehicle with in-wheel motors

NASA Astrophysics Data System (ADS)

Zulkifli, S. A.; Syaifuddin Mohd, M.; Maharun, M.; Bakar, N. S. A.; Idris, S.; Samsudin, S. H.; Firmansyah; Adz, J. J.; Misbahulmunir, M.; Abidin, E. Z. Z.; Syafiq Mohd, M.; Saad, N.; Aziz, A. R. A.

2015-12-01

One configuration of the hybrid electric vehicle (HEV) is the split-axle parallel hybrid, in which an internal combustion engine (ICE) and an electric motor provide propulsion power to different axles. A particular sub-type of the split-parallel hybrid does not have the electric motor installed on board the vehicle; instead, two electric motors are placed in the hubs of the non-driven wheels, called ‘hub motor’ or ‘in-wheel motor’ (IWM). Since propulsion power from the ICE and IWM is coupled through the vehicle itself, its wheels and the road on which it moves, this particular configuration is termed ‘through-the-road’ (TTR) hybrid. TTR configuration enables existing ICE-powered vehicles to be retrofitted into an HEV with minimal physical modification. This work describes design of a retrofit- conversion TTR-IWM hybrid vehicle - its sub-systems and development work. Operating modes and power flow of the TTR hybrid, its torque coupling and resultant traction profiles are initially discussed.

White matter microstructural properties correlate with sensorimotor synchronization abilities.

PubMed

Blecher, Tal; Tal, Idan; Ben-Shachar, Michal

2016-09-01

Sensorimotor synchronization (SMS) to an external auditory rhythm is a developed ability in humans, particularly evident in dancing and singing. This ability is typically measured in the lab via a simple task of finger tapping to an auditory beat. While simplistic, there is some evidence that poor performance on this task could be related to impaired phonological and reading abilities in children. Auditory-motor synchronization is hypothesized to rely on a tight coupling between auditory and motor neural systems, but the specific pathways that mediate this coupling have not been identified yet. In this study, we test this hypothesis and examine the contribution of fronto-temporal and callosal connections to specific measures of rhythmic synchronization. Twenty participants went through SMS and diffusion magnetic resonance imaging (dMRI) measurements. We quantified the mean asynchrony between an auditory beat and participants' finger taps, as well as the time to resynchronize (TTR) with an altered meter, and examined the correlations between these behavioral measures and diffusivity in a small set of predefined pathways. We found significant correlations between asynchrony and fractional anisotropy (FA) in the left (but not right) arcuate fasciculus and in the temporal segment of the corpus callosum. On the other hand, TTR correlated with FA in the precentral segment of the callosum. To our knowledge, this is the first demonstration that relates these particular white matter tracts with performance on an auditory-motor rhythmic synchronization task. We propose that left fronto-temporal and temporal-callosal fibers are involved in prediction and constant comparison between auditory inputs and motor commands, while inter-hemispheric connections between the motor/premotor cortices contribute to successful resynchronization of motor responses with a new external rhythm, perhaps via inhibition of tapping to the previous rhythm. Our results indicate that auditory-motor synchronization skills are associated with anatomical pathways that have been previously related to phonological awareness, thus offering a possible anatomical basis for the behavioral covariance between these abilities. Copyright © 2016 Elsevier Inc. All rights reserved.

Development and Initial Testing of the Tiltrotor Test Rig

NASA Technical Reports Server (NTRS)

Acree, C. W., Jr.; Sheikman, A. L.

2018-01-01

The NASA Tiltrotor Test Rig (TTR) is a new, large-scale proprotor test system, developed jointly with the U.S. Army and Air Force, to develop a new, large-scale proprotor test system for the National Full-Scale Aerodynamics Complex (NFAC). The TTR is designed to test advanced proprotors up to 26 feet in diameter at speeds up to 300 knots, and even larger rotors at lower airspeeds. This combination of size and speed is unprecedented and is necessary for research into 21st-century tiltrotors and other advanced rotorcraft concepts. The TTR will provide critical data for validation of state-of-the-art design and analysis tools.

Quality of oral anticoagulation with phenprocoumon in regular medical care and its potential for improvement in a telemedicine-based coagulation service--results from the prospective, multi-center, observational cohort study thrombEVAL.

PubMed

Prochaska, Jürgen H; Göbel, Sebastian; Keller, Karsten; Coldewey, Meike; Ullmann, Alexander; Lamparter, Heidrun; Jünger, Claus; Al-Bayati, Zaid; Baer, Christina; Walter, Ulrich; Bickel, Christoph; ten Cate, Hugo; Münzel, Thomas; Wild, Philipp S

2015-01-23

The majority of studies on quality of oral anticoagulation (OAC) therapy with vitamin K-antagonists are performed with short-acting warfarin. Data on long-acting phenprocoumon, which is frequently used in Europe for OAC therapy and is considered to enable more stable therapy adjustment, are scarce. In this study, we aimed to assess quality of OAC therapy with phenprocoumon in regular medical care and to evaluate its potential for optimization in a telemedicine-based coagulation service. In the prospective observational cohort study program thrombEVAL we investigated 2,011 patients from regular medical care in a multi-center cohort study and 760 patients from a telemedicine-based coagulation service in a single-center cohort study. Data were obtained from self-reported data, computer-assisted personal interviews, and laboratory measurements according to standard operating procedures with detailed quality control. Time in therapeutic range (TTR) was calculated by linear interpolation method to assess quality of OAC therapy. Study monitoring was carried out by an independent institution. Overall, 15,377 treatment years and 48,955 international normalized ratio (INR) measurements were analyzed. Quality of anticoagulation, as measured by median TTR, was 66.3% (interquartile range (IQR) 47.8/81.9) in regular medical care and 75.5% (IQR 64.2/84.4) in the coagulation service (P <0.001). Stable anticoagulation control within therapeutic range was achieved in 63.8% of patients in regular medical care with TTR at 72.1% (IQR 58.3/84.7) as compared to 96.4% of patients in the coagulation service with TTR at 76.2% [(IQR 65.6/84.7); P = 0.001)]. Prospective follow-up of coagulation service patients with pretreatment in regular medical care showed an improvement of the TTR from 66.2% (IQR 49.0/83.6) to 74.5% (IQR 62.9/84.2; P <0.0001) in the coagulation service. Treatment in the coagulation service contributed to an optimization of the profile of time outside therapeutic range, a 2.2-fold increase of stabile INR adjustment and a significant decrease in TTR variability by 36% (P <0.001). Quality of anticoagulation with phenprocoumon was comparably high in this real-world sample of regular medical care. Treatment in a telemedicine-based coagulation service substantially improved quality of OAC therapy with regard to TTR level, frequency of stable anticoagulation control, and TTR variability. ClinicalTrials.gov, unique identifier NCT01809015, March 8, 2013.

Synovial deposition of wild-type transthyretin-derived amyloid in knee joint osteoarthritis patients.

PubMed

Takanashi, Tetsuo; Matsuda, Masayuki; Yazaki, Masahide; Yamazaki, Hideshi; Nawata, Masashi; Katagiri, Yoshiki; Ikeda, Shu-Ichi

2013-09-01

To investigate histological features of deposited amyloid in the synovial tissue and its clinical significance in knee joint osteoarthritis (OA) patients. We prospectively enrolled 232 consecutive patients who underwent arthroplasty or total replacement of the knee joint for treatment of OA. Congo red staining and immunohistochemistry were performed in the synovial tissue obtained at surgery. When transthyretin (TTR)-derived amyloid was positive, we analyzed all 4 exons of the TTR gene using the direct DNA sequencing method in order to detect mutations. We analyzed 322 specimens in this study. Twenty-six specimens (8.1%) obtained from 21 patients (5 men and 16 women; mean, 79.0 ± 4.6 years) showed deposition of amyloid, which was positively stained with the anti-TTR antibody. Eighteen patients showed inhomogeneous accumulations of amyloid in the loose connective tissue under the synovial epithelia sometimes with nodule formation, while in the remaining three, small vessels in the adipose tissue were involved. Medical records of these patients revealed nothing remarkable in the clinical course, laboratory data or macroscopic intraarticular findings at surgery. No mutations were detectable in the TTR gene analysis. Wild-type TTR-derived amyloid may affect the synovial tissue as a result of long-term mechanical stress or as a part of senile systemic amyloidosis in approximately 8% of knee joint OA patients. No obvious clinical significance was found in synovial deposition of amyloid.

Downsizing of lean body mass is a key determinant of Alzheimer's disease.

PubMed

Ingenbleek, Yves; Bernstein, Larry H

2015-01-01

Lean body mass (LBM) encompasses all metabolically active organs distributed into visceral and structural tissue compartments and collecting the bulk of N and K stores of the human body. Transthyretin (TTR) is a plasma protein mainly secreted by the liver within a trimolecular TTR-RBP-retinol complex revealing from birth to old age strikingly similar evolutionary patterns with LBM in health and disease. TTR is also synthesized by the choroid plexus along distinct regulatory pathways. Chronic dietary methionine (Met) deprivation or cytokine-induced inflammatory disorders generates LBM downsizing following differentiated physiopathological processes. Met-restricted regimens downregulate the transsulfuration cascade causing upstream elevation of homocysteine (Hcy) safeguarding Met homeostasis and downstream drop of hydrogen sulfide (H2S) impairing anti-oxidative capacities. Elderly persons constitute a vulnerable population group exposed to increasing Hcy burden and declining H2S protection, notably in plant-eating communities or in the course of inflammatory illnesses. Appropriate correction of defective protein status and eradication of inflammatory processes may restore an appropriate LBM size allowing the hepatic production of the retinol circulating complex to resume, in contrast with the refractory choroidal TTR secretory process. As a result of improved health status, augmented concentrations of plasma-derived TTR and retinol may reach the cerebrospinal fluid and dismantle senile amyloid plaques, contributing to the prevention or the delay of the onset of neurodegenerative events in elderly subjects at risk of Alzheimer's disease.

Establishing and validating the fluorescent amyloid ligand h-FTAA (heptamer formyl thiophene acetic acid) to identify transthyretin amyloid deposits in carpal tunnel syndrome.

PubMed

Hahn, Katharina; Nilsson, K Peter R; Hammarström, Per; Urban, Peter; Meliss, Rolf Rüdiger; Behrens, Hans-Michael; Krüger, Sandra; Röcken, Christoph

2017-06-01

Transthyretin-derived (ATTR) amyloidosis is a frequent finding in carpal tunnel syndrome. We tested the following hypotheses: the novel fluorescent amyloid ligand heptameric formic thiophene acetic acid (h-FTAA) has a superior sensitivity for the detection of amyloid compared with Congo red-staining; Amyloid load correlates with patient gender and/or patient age. We retrieved 208 resection specimens obtained from 184 patients with ATTR amyloid in the carpal tunnel. Serial sections were stained with Congo red, h-FTAA and an antibody directed against transthyretin (TTR). Stained sections were digitalized and forwarded to computational analyses. The amount of amyloid was correlated with patient demographics. Amyloid stained intensely with h-FTAA and an anti-TTR-antibody. Congo red-staining combined with fluorescence microscopy was significantly less sensitive than h-FTAA-fluorescence and TTR-immunostaining: the highest percentage area was found in TTR-immunostained sections, followed by h-FTAA and Congo red. The Pearson correlation coefficient was .8 (Congo red vs. h-FTAA) and .9 (TTR vs. h-FTAA). Amyloid load correlated with patient gender, anatomical site and patient age. h-FTAA is a highly sensitive method to detect even small amounts of ATTR amyloid in the carpal tunnel. The staining protocol is easy and h-FTAA may be a much more sensitive procedure to detect amyloid at an earlier stage.

Characterisation of serum transthyretin by electrospray ionisation-ion mobility mass spectrometry: Application to familial amyloidotic polyneuropathy type I (FAP-I).

PubMed

Pont, Laura; Benavente, Fernando; Vilaseca, Marta; Giménez, Estela; Sanz-Nebot, Victoria

2015-11-01

Transthyretin (TTR) is a homotetrameric protein which is known to misfold and aggregate causing different types of amyloidosis, such as familial amyloidotic polyneuropathy type I (FAP-I). FAP-I is associated with a specific TTR mutant variant (TTR (Met30)) that can be easily detected analysing the monomeric forms of the mutant protein. Meanwhile, the mechanism of protein aggregation onset, which could be triggered by structural changes on the native tetrameric protein complex, remains uncertain. We developed and described herein a new sample pretreatment based on immunoprecipitation (IP) to purify TTR from serum under non-denaturing conditions. Later, a nano-electrospray ionization-ion mobility mass spectrometry (nano-ESI-IM-MS or IM-MS) method was optimised to analyse the protein complexes in serum samples from healthy controls and FAP-I patients. IM-MS allowed separation and characterisation of tetrameric, trimeric and dimeric TTR gas ions due to their differential drift time, which is related to ion size and charge. The tetramer-to-dimer abundance ratio was differential between healthy controls and FAP-I patients (asymptomatic, symptomatic and an iatrogenic patient originally without the mutation who received a liver transplant from an FAP-I patient), and was also indicative of the effectiveness of liver transplantation as a treatment for FAP-I. Copyright © 2015 Elsevier B.V. All rights reserved.

Alternate Reductant Cold Cap Evaluation Furnace Phase II Testing

DOE Office of Scientific and Technical Information (OSTI.GOV)

Johnson, F. C.; Stone, M. E.; Miller, D. H.

2014-09-03

Savannah River Remediation (SRR) conducted a Systems Engineering Evaluation (SEE) to determine the optimum alternate reductant flowsheet for the Defense Waste Processing Facility (DWPF). Specifically, two proposed flowsheets (nitric–formic–glycolic and nitric–formic–sugar) were evaluated based upon results from preliminary testing. Comparison of the two flowsheets among evaluation criteria indicated a preference towards the nitric–formic–glycolic flowsheet. Further research and development of this flowsheet eliminated the formic acid, and as a result, the nitric–glycolic flowsheet was recommended for further testing. Based on the development of a roadmap for the nitric–glycolic acid flowsheet, Waste Solidification Engineering (WS-E) issued a Technical Task Request (TTR) tomore » address flammability issues that may impact the implementation of this flowsheet. Melter testing was requested in order to define the DWPF flammability envelope for the nitric-glycolic acid flowsheet. The Savannah River National Laboratory (SRNL) Cold Cap Evaluation Furnace (CEF), a 1/12 th scale DWPF melter, was selected by the SRR Alternate Reductant project team as the melter platform for this testing. The overall scope was divided into the following sub-tasks as discussed in the Task Technical and Quality Assurance Plan (TTQAP): Phase I - A nitric–formic acid flowsheet melter test (unbubbled) to baseline the CEF cold cap and vapor space data to the benchmark melter flammability models; Phase II - A nitric–glycolic acid flowsheet melter test (unbubbled and bubbled) to: Define new cold cap reactions and global kinetic parameters in support of the melter flammability model development; Quantify off-gas surging potential of the feed; Characterize off-gas condensate for complete organic and inorganic carbon species. After charging the CEF with cullet from Phase I CEF testing, the melter was slurry-fed with glycolic flowsheet based SB6-Frit 418 melter feed at 36% waste loading and was operated continuously for 25 days. Process data was collected throughout testing and included melter operation parameters and off-gas chemistry. In order to generate off-gas data in support of the flammability model development for the nitric-glycolic flowsheet, vapor space steady state testing in the range of ~300-750°C was conducted under the following conditions, (i) 100% (nominal and excess antifoam levels) and 125% stoichiometry feed and (ii) with and without argon bubbling. Adjustments to feed rate, heater outputs and purge air flow were necessary in order to achieve vapor space temperatures in this range. Surge testing was also completed under nominal conditions for four days with argon bubbling and one day without argon bubbling.« less

Corrective action investigation plan for CAU Number 453: Area 9 Landfill, Tonopah Test Range

DOE Office of Scientific and Technical Information (OSTI.GOV)

NONE

This Corrective Action Investigation Plan (CAIP) contains the environmental sample collection objectives and criteria for conducting site investigation activities at the Area 9 Landfill, Corrective Action Unit (CAU) 453/Corrective Action (CAS) 09-55-001-0952, which is located at the Tonopah Test Range (TTR). The TTR, included in the Nellis Air Force Range, is approximately 255 kilometers (140 miles) northwest of Las Vegas, Nevada. The Area 9 Landfill is located northwest of Area 9 on the TTR. The landfill cells associated with CAU 453 were excavated to receive waste generated from the daily operations conducted at Area 9 and from range cleanup whichmore » occurred after test activities.« less

Study on the binding characteristics of hydroxylated polybrominated diphenyl ethers and thyroid transporters using the multispectral technique and computational simulation.

PubMed

Wei, Yuchen; Yi, Zhongsheng; Xu, Jie; Yang, Wu; Yang, Lulu; Liu, Hongyan

2018-04-24

Hydroxylated polybrominated diphenyl ethers (OH-PBDEs) are a class of toxic environmental pollutants that are persistent, bioaccumulative, and difficult to degrade. Their structure is very similar to the thyroid hormone (T4) and uses the body's thyroid transporter (TTR) binding to interfere with the endocrine balance, disrupting the body's normal physiological activity. According to Fourier transform infrared spectroscopy and dynamics simulation of do_dssp module analysis, there are three kinds of OH-PBDEs that can induce TTR secondary structural changes. Fluorescence spectra and UV-Vis spectra show that for the three kinds of OH-PBDEs for TTR, the main methods of quenching are static quenching and non-radiative energy transfer. According to thermodynamic analysis, ΔG < 0, ΔH > 0, and ΔS > 0 combine to show that the hydrophobic interaction is the main driving force of the combination. From the molecular docking analysis, it was found that 4'-hydroxy-2,2',4,5'- tetrabromodiphenyl ether (4'-OH-BDE49) and 4 hydroxy-2,2',3,4',5,6,6'- heptabromodiphenyl ether (4-OH-BDE188) had a cationic-π interaction with TTR, whereas 4 hydroxy-2,2',3,4,5,5',6- heptabromodiphenyl ether (4-OH-BDE187) was bonded to TTR by hydrogen bonds to form stable complexes. In this paper, we highlight the consistency of spectroscopic experiments and computer simulations so as to provide a reliable analytical method for the toxicological properties of small molecule contaminants.

2016 Annual Site Environmental report Sandia National Laboratories Tonopah Test Range Nevada & Kaua'i Test Facility Hawai'i.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Salas, Angela Maria; Griffith, Stacy R.

Sandia National Laboratories (SNL) is a multimission laboratory managed and operated by National Technology & Engineering Solutions of Sandia, LLC, a wholly owned subsidiary of Honeywell International Inc., for the U.S. Department of Energy’s (DOE’s), National Nuclear Security Administration (NNSA) under contract DE-NA0003525. The DOE/NNSA Sandia Field Office administers the contract and oversees contractor operations at the SNL, Tonopah Test Range (SNL/TTR) in Nevada and the SNL, Kaua‘i Test Facility (SNL/KTF) in Hawai‘i. SNL personnel manage and conduct operations at SNL/TTR in support of the DOE/NNSA’s Weapons Ordnance Program and have operated the site since 1957. Navarro Research and Engineeringmore » personnel perform most of the environmental programs activities at SNL/TTR. The DOE/NNSA/Nevada Field Office retains responsibility for cleanup and management of SNL/TTR Environmental Restoration sites. SNL personnel operate SNL/KTF as a rocket preparation launching and tracking facility. This Annual Site Environmental Report (ASER) summarizes data and the compliance status of sustainability, environmental protection, and monitoring programs at SNL/TTR and SNL/KTF during calendar year 2016. Major environmental programs include air quality, water quality, groundwater protection, terrestrial and biological surveillance, waste management, pollution prevention, environmental restoration, oil and chemical spill prevention, and implementation of the National Environmental Policy Act. This ASER is prepared in accordance with and as required by DOE O 231.1B, Admin Change 1, Environment, Safety, and Health Reporting.« less

Post-Closure Inspection Report for the Tonopah Test Range, Nevada, For Calendar Year 2011

DOE Office of Scientific and Technical Information (OSTI.GOV)

NSTec Environmental Restoration

This report provides the results of the annual post-closure inspections conducted at the closed Corrective Action Units (CAUs) located on the Tonopah Test Range (TTR), Nevada. This report covers calendar year 2011 and includes inspection and repair activities completed at the following CAUs: (1) CAU 400: Bomblet Pit and Five Points Landfill (TTR); (2) CAU 407: Roller Coaster RadSafe Area (TTR); (3) CAU 424: Area 3 Landfill Complexes (TTR); (4) CAU 453: Area 9 UXO Landfill (TTR); and (5) CAU 487: Thunderwell Site (TTR) Inspections were conducted according to the post-closure plans in the approved Closure Reports. The post-closure inspectionmore » plan for each CAU is included in Appendix B. The inspection checklists are included in Appendix C, field notes are included in Appendix D, and photographs taken during inspections are included in Appendix E. The annual post-closure inspections were conducted May 3 and 4, 2011. Maintenance was performed at CAU 424, CAU 453, and CAU 487. At CAU 424, two surface grade monuments at Landfill Cell A3-3 could not be located during the inspection. The two monuments were located and marked with lava rock on July 13, 2011. At CAU 453, there was evidence of animal burrowing. Animal burrows were backfilled on July 13, 2011. At CAU 487, one use restriction warning sign was missing, and wording was faded on the remaining signs. A large animal burrow was also present. The signs were replaced, and the animal burrow was backfilled on July 12, 2011. As a best management practice, the use restriction warning signs at CAU 407 were replaced with standard Federal Facility Agreement and Consent Order signs on July 13, 2011. Vegetation monitoring was performed at the CAU 400 Five Points Landfill and CAU 407 in June 2011, and the vegetation monitoring report is included in Appendix F.« less

Matrix Metalloproteinases and their Tissue Inhibitors in Cardiac Amyloidosis: Relationship to Structural, Functional Myocardial Changes and to Light Chain Amyloid Deposition

PubMed Central

Biolo, Andreia; Ramamurthy, Sujata; Connors, Lawreen H.; O'Hara, Carl J.; Meier-Ewert, Hans K.; Hoo, Pamela T. Soo; Sawyer, Douglas B.; Seldin, David S.; Sam, Flora

2009-01-01

Background Cardiac amyloidosis is characterized by amyloid infiltration resulting in extracellular matrix (ECM) disruption. Amyloid cardiomyopathy due to immunoglobulin light chain protein (AL-CMP) deposition, has an accelerated clinical course and a worse prognosis compared to non-light chain cardiac amyloidoses i.e., forms associated with wild-type or mutated transthyretin (TTR). We therefore tested the hypothesis that determinants of proteolytic activity of the ECM, the matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), would have distinct patterns and contribute to the pathogenesis of AL-CMP vs. TTR. Methods / Results We studied 40 patients with systemic amyloidosis: 10 AL-CMP patients, 20 patients with TTR-associated forms of cardiac amyloidosis, i.e. senile systemic amyloidois (SSA, involving wild-type TTR) or mutant TTR (ATTR), and 10 patients with AL amyloidosis without cardiac involvement. Serum MMP-2 and −9, TIMP-1, −2 and −4, brain natriuretic peptide (BNP) values and echocardiography were determined. AL-CMP and SSA-ATTR groups had similar degrees of increased left ventricular wall thickness (LVWT). However, BNP, MMP-9 and TIMP-1 levels were distinctly elevated accompanied by marked diastolic dysfunction in the AL-CMP group vs. no or minimal increases in the SSA-ATTR group. BNP, MMPs and TIMPs were not correlated with the degree of LVWT but were correlated to each other and to measures of diastolic dysfunction. Immunostaining of human endomyocardial biopsies showed diffuse expression of MMP-9 and TIMP-1 in AL-CMP and limited expression in SSA or ATTR hearts. Conclusions Despite comparable LVWT with TTR-related cardiac amyloidosis, AL-CMP patients have higher BNP, MMPs and TIMPs, which correlated with diastolic dysfunction. These findings suggest a relationship between light chains and ECM proteolytic activation that may play an important role in the functional and clinical manifestations of AL-CMP, distinct from the other non-light chain cardiac amyloidoses. PMID:19808299

Is Lutein a Physiologically Important Ligand for Transthyretin in Humans?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Liwei

Lutein and zeaxanthin are the only carotenoids accumulated in the macula of the human retina and are known as the macular pigments (MP). These pigments account for the yellow color of the macula and appear to play an important role in protecting against age-related macular degeneration (AMD). The uptake of lutein and zeaxanthin in human eyes is remarkably specific. It is likely that specific transport or binding proteins are involved. The objective is to determine whether transthyretin (TTR) is a transport protein in human plasma and could thus deliver lutein from the blood to the retina. In this study, theymore » used a biosynthetic 13C-lutein tracer and gas chromatography-combustion interfaced-isotope ratio mass spectrometry (GCC-IRMS) to gain the requisite sensitivity to detect the minute amounts of lutein expected as a physiological ligand for human transthyretin. The biosynthetic 13C-labeled lutein tracer was purified from algae. Healthy women (n = 4) each ingested 1 mg of 13C-labeled lutein daily for 3 days and a blood sample was collected 24 hours after the final dose. Plasma TTR was isolated by retinol-binding protein (RBP)-sepharose affinity chromatography and extracted with chloroform. The 13C/ 12C ratio in the TTR extract was measured by GCC-IRMS. There was no 13C-lutein enrichment in the pure TTR extract. This result indicated that lutein is not associated with TTR in human plasma after ingestion in physiological amounts. Some hydrophobic compounds with yellow color may bind to human TTR in the plasma. However, this association needs to be further proved by showing specificity. The study provides a new approach for carotenoid-binding protein studies using a stable isotope tracer method combined with the high precision of GCC-IRMS. The mechanism of selective transport, uptake, and accumulation of lutein in human macula remain to be determined.« less

A moderate elevation of circulating levels of IGF-I does not alter ErbB2 induced mammary tumorigenesis

PubMed Central

2011-01-01

Background Epidemiological evidence suggests that moderately elevated levels of circulating insulin-like growth factor-I (IGF-I) are associated with increased risk of breast cancer in women. How circulating IGF-I may promote breast cancer incidence is unknown, however, increased IGF-I signaling is linked to trastuzumab resistance in ErbB2 positive breast cancer. Few models have directly examined the effect of moderately high levels of circulating IGF-I on breast cancer initiation and progression. The purpose of this study was to assess the ability of circulating IGF-I to independently initiate mammary tumorigenesis and/or accelerate the progression of ErbB2 mediated mammary tumor growth. Methods We crossed heterozygous TTR-IGF-I mice with heterozygous MMTV-ErbB2 mice to generate 4 different genotypes: TTR-IGF-I/MMTV-ErbB2 (bigenic), TTR-IGF-I only, MMTV-ErbB2 only, and wild type (wt). Virgin females were palpated twice a week and harvested when tumors reached 1000 mm3. For study of normal development, blood and tissue were harvested at 4, 6 and 9 weeks of age in TTR-IGF-I and wt mice. Results TTR-IGF-I and TTR-IGF-I/ErbB2 bigenic mice showed a moderate 35% increase in circulating total IGF-I compared to ErbB2 and wt control mice. Elevation of circulating IGF-I had no effect upon pubertal mammary gland development. The transgenic increase in IGF-I alone wasn't sufficient to initiate mammary tumorigenesis. Elevated circulating IGF-I had no effect upon ErbB2-induced mammary tumorigenesis or metastasis, with median time to tumor formation being 30 wks and 33 wks in TTR-IGF-I/ErbB2 bigenic and ErbB2 mice respectively (p = 0.65). Levels of IGF-I in lysates from ErbB2/TTR-IGF-I tumors compared to ErbB2 was elevated in a similar manner to the circulating IGF-I, however, there was no effect on the rate of tumor growth (p = 0.23). There were no morphological differences in tumor type (solid adenocarcinomas) between bigenic and ErbB2 mammary glands. Conclusion Using the first transgenic animal model to elevate circulating levels of IGF-I to those comparable to women at increased risk of breast cancer, we showed that moderately high levels of systemic IGF-I have no effect on pubertal mammary gland development, initiating mammary tumorigenesis or promoting ErbB2 driven mammary carcinogenesis. Our work suggests that ErbB2-induced mammary tumorigenesis is independent of the normal variation in circulating levels of IGF-I. PMID:21867536

SLURRY MIX EVAPORATOR BATCH ACCEPTABILITY AND TEST CASES OF THE PRODUCT COMPOSITION CONTROL SYSTEM WITH THORIUM AS A REPORTABLE ELEMENT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Edwards, T.

2010-10-07

The Defense Waste Processing Facility (DWPF), which is operated by Savannah River Remediation, LLC (SRR), has recently begun processing Sludge Batch 6 (SB6) by combining it with Frit 418 at a nominal waste loading (WL) of 36%. A unique feature of the SB6/Frit 418 glass system, as compared to the previous glass systems processed in DWPF, is that thorium will be a reportable element (i.e., concentrations of elemental thorium in the final glass product greater than 0.5 weight percent (wt%)) for the resulting wasteform. Several activities were initiated based upon this unique aspect of SB6. One of these was anmore » investigation into the impact of thorium on the models utilized in DWPF's Product Composition and Control System (PCCS). While the PCCS is described in more detail below, for now note that it is utilized by Waste Solidification Engineering (WSE) to evaluate the acceptability of each batch of material in the Slurry Mix Evaporator (SME) before this material is passed on to the melter. The evaluation employs models that predict properties associated with processability and product quality from the composition of vitrified samples of the SME material. The investigation of the impact of thorium on these models was conducted by Peeler and Edwards [1] and led to a recommendation that DWPF can process the SB6/Frit 418 glass system with ThO{sub 2} concentrations up to 1.8 wt% in glass. Questions also arose regarding the handling of thorium in the SME batch acceptability process as documented by Brown, Postles, and Edwards [2]. Specifically, that document is the technical bases of PCCS, and while Peeler and Edwards confirmed the reliability of the models, there is a need to confirm that the current implementation of DWPF's PCCS appropriately handles thorium as a reportable element. Realization of this need led to a Technical Task Request (TTR) prepared by Bricker [3] that identified some specific SME-related activities that the Savannah River National Laboratory (SRNL) was requested to conduct. SRNL issued a Task Technical and Quality Assurance (TT&QA) plan [4] in response to the SRR request. The conclusions provided in this report are that no changes need to be made to the SME acceptability process (i.e., no modifications to WSRC-TR-95-00364, Revision 5, are needed) and no changes need to be made to the Product Composition Control System (PCCS) itself (i.e. the spreadsheet utilized by Waste Solidification Engineering (WSE) for acceptability decisions does not require modification) in response to thorium becoming a reportable element for DWPF operations. In addition, the inputs and results for the two test cases requested by WSE for use in confirming the successful activation of thorium as a reportable element for DWPF operations during the processing of SB6 are presented in this report.« less

Genetic differences in the serum proteome of horses, donkeys and mules are detectable by protein profiling.

PubMed

Henze, Andrea; Aumer, Franziska; Grabner, Arthur; Raila, Jens; Schweigert, Florian J

2011-10-01

Although horses and donkeys belong to the same genus, their genetic characteristics probably result in specific proteomes and post-translational modifications (PTM) of proteins. Since PTM can alter protein properties, specific PTM may contribute to species-specific characteristics. Therefore, the aim of the present study was to analyse differences in serum protein profiles of horses and donkeys as well as mules, which combine the genetic backgrounds of both species. Additionally, changes in PTM of the protein transthyretin (TTR) were analysed. Serum protein profiles of each species (five animals per species) were determined using strong anion exchanger ProteinChips® (Bio-Rad, Munich, Germany) in combination with surface-enhanced laser desorption ionisation-time of flight MS. The PTM of TTR were analysed subsequently by immunoprecipitation in combination with matrix-assisted laser desorption ionisation-time of flight MS. Protein profiling revealed species-specific differences in the proteome, with some protein peaks present in all three species as well as protein peaks that were unique for donkeys and mules, horses and mules or for horses alone. The molecular weight of TTR of horses and donkeys differed by 30 Da, and both species revealed several modified forms of TTR besides the native form. The mass spectra of mules represented a merging of TTR spectra of horses and donkeys. In summary, the present study indicated that there are substantial differences in the proteome of horses and donkeys. Additionally, the results probably indicate that the proteome of mules reveal a higher similarity to donkeys than to horses.

Teledermatology as a means to improve access to inpatient dermatology care.

PubMed

Sharma, Priyank; Kovarik, Carrie L; Lipoff, Jules B

2016-07-01

Many hospitals have limited inpatient dermatology consultation access. Most dermatologists are outpatient-based and may find the distance and time to complete inpatient consultations prohibitive. Teledermatology may improve access to inpatient dermatology care by reducing barriers of distance and time. We conducted a prospective two-phase pilot study at two academic hospitals comparing time needed to complete inpatient consultations after resident dermatologists initially evaluated patients, called average handling time (AHT), and time needed to respond to the primary team, called time to response (TTR), with and without teledermatology with surveys to capture changes in dermatologist opinion on teledermatology. Teledermatology was only used in the study phase, and patients were seen in-person in both study phases. Teledermatology alone sufficiently answered consultations in 10 of 25 study consultations. The mean AHT in the study phase (sAHT) was 26.9 min compared to the baseline phase (bAHT) of 43.5 min, a 16.6 min reduction (p = 0.004). The 10 study cases where teledermatology alone was sufficient had mean study TTR (sTTR) of 273.3 min compared to a baseline TTR (bTTR) of 405.7 min, a 132.4 min reduction (p = 0.032). Teledermatology reduces the time required for an attending dermatologist to respond and the time required for a primary team to receive a response for an inpatient dermatology consultation in a subset of cases. These findings suggest teledermatology can be used as a tool to improve access to inpatient dermatology care. © The Author(s) 2015.

Identification of prognostic markers in transthyretin and AL cardiac amyloidosis.

PubMed

Damy, Thibaud; Jaccard, Arnaud; Guellich, Aziz; Lavergne, David; Galat, Arnault; Deux, Jean-François; Hittinger, Luc; Dupuis, Jehan; Frenkel, Valérie; Rigaud, Charlotte; Plante-Bordeneuve, Violaine; Bodez, Diane; Mohty, Dania

2016-09-01

The prognosis of amyloidosis is known to depend heavily on cardiac function and may be improved by identifying patients at highest risk for adverse cardiac events. Identify predictors of mortality in patients with cardiac light-chain amyloidosis (AL), hereditary transthyretin amyloidosis (m-TTR), or wild-type transthyretin amyloidosis (WT-TTR) to prompt physician to refer these patients to dedicated centers. Observational study. About 266 patients referred for suspected cardiac amyloidosis (CA) in two French university centers were included. About 198 patients had CA (AL = 118, m-TTR = 57, and WT-TTR = 23). Their median (25th-75th percentile) age, NT-proBNP left ventricular ejection fraction were, respectively, 68 years (59-76), 2339 pg mL -1 (424-5974), and 60% (48-66). About 31% were in NYHA class III-IV. Interventricular septal thickness was greater in the m-TTR and WT-TTR groups than in the AL group (p < 0.0001). Median follow-up in survivor was 26 months (15-44) and 87 (44%) patients died. By multivariate analysis, independent predictors of mortality for AL amyloidosis were the following: age, cardiac output and NT-proBNP; for TTR amyloidosis was: NT-proBNP. When all amyloidosis were combined NT-proBNP, low cardiac output and pericardial effusion were independently associated with mortality. NT-proBNP is a strong prognosticator in the three types of cardiac amyloidosis. High NT-proBNP, low cardiac output, and pericardial effusion at the time of screening should prompt physician to refer the patients to amyloidosis referral center.

On-line immunoaffinity solid-phase extraction capillary electrophoresis mass spectrometry using Fab´antibody fragments for the analysis of serum transthyretin.

PubMed

Pont, Laura; Benavente, Fernando; Barbosa, José; Sanz-Nebot, Victoria

2017-08-01

This paper describes an on-line immunoaffinity solid-phase extraction capillary electrophoresis mass spectrometry (IA-SPE-CE-MS) method using an immunoaffinity sorbent with Fab' antibody fragments (Fab'-IA) for the analysis of serum transthyretin (TTR), a homotetrameric protein (M r ~56,000) involved in different types of amyloidosis. The IA sorbent was prepared by covalent attachment of Fab' fragments obtained from a polyclonal IgG antibody against TTR to succinimidyl silica particles. The Fab'-IA-SPE-CE-MS methodology was first established analyzing TTR standard solutions. Under optimized conditions, repeatability and reproducibility were acceptable, the method was linear between 1 and 25µgmL -1 , limits of detection (LODs) were around 0.5µgmL -1 (50-fold lower than by CE-MS, ~25µgmL -1 ) and different TTR conformations were observed (folded and unfolded). The applicability of the developed method to screen for familial amyloidotic polyneuropathy type I (FAP-I), which is the most common hereditary systemic amyloidosis, was evaluated analyzing serum samples from healthy controls and FAP-I patients. For the analysis of sera, the most abundant proteins were precipitated with 5% (v/v) of phenol before Fab'-IA-SPE-CE-MS. The current method enhanced our previous results for the analysis of TTR using intact antibodies immobilized on magnetic beads. It allowed a slight improvement on LODs (2-fold), the detection of proteoforms found at lower concentrations and the preparation of microcartridges with extended durability. Copyright © 2017. Published by Elsevier B.V.

The business case for quality improvement: oral anticoagulation for atrial fibrillation.

PubMed

Rose, Adam J; Berlowitz, Dan R; Ash, Arlene S; Ozonoff, Al; Hylek, Elaine M; Goldhaber-Fiebert, Jeremy D

2011-07-01

The potential to save money within a short time frame provides a more compelling "business case" for quality improvement than merely demonstrating cost-effectiveness. Our objective was to demonstrate the potential for cost savings from improved control in patients anticoagulated for atrial fibrillation. Our population consisted of 67 077 Veterans Health Administration patients anticoagulated for atrial fibrillation between October 1, 2006, and September 30, 2008. We simulated the number of adverse events and their associated costs and utilities, both before and after various degrees of improvement in percent time in therapeutic range (TTR). The simulation had a 2-year time horizon, and costs were calculated from the perspective of the payer. In the base-case analysis, improving TTR by 5% prevented 1114 adverse events, including 662 deaths; it gained 863 quality-adjusted life-years and saved $15.9 million compared with the status quo, not accounting for the cost of the quality improvement program. Improving TTR by 10% prevented 2087 events, gained 1606 quality-adjusted life-years, and saved $29.7 million. In sensitivity analyses, costs were most sensitive to the estimated risk of stroke and the expected stroke reduction from improved TTR. Utilities were most sensitive to the estimated risk of death and the expected mortality benefit from improved TTR. A quality improvement program to improve anticoagulation control probably would be cost-saving for the payer, even if it were only modestly effective in improving control and even without considering the value of improved health. This study demonstrates how to make a business case for a quality improvement initiative.

A homozygous transthyretin variant associated with senile systemic amyloidosis: evidence for a late-onset disease of genetic etiology.

PubMed Central

Jacobson, D R; Gorevic, P D; Buxbaum, J N

1990-01-01

Senile systemic amyloidosis (SSA) is a late-onset disease characterized by deposition of amyloid fibrils containing transthyretin (TTR). Amino acid sequencing of protein isolated from the amyloid fibrils of a patient with SSA identified TTR containing a position - 122 isoleucine-for-valine substitution. This change led to the prediction of a genomic G-to-A transition, destroying an MaeIII restriction site. We confirmed the presence of the variant DNA fragment both by Southern blotting and by visualization of MaeIII digests of DNA amplified around codon 122, by using the polymerase chain reaction. The patient's DNA was entirely resistant to MaeIII cleavage; therefore, only the mutant sequence was present. DNA from none of either 24 controls or six other SSA patients contained the variant. Quantitative Southern blotting demonstrated that the patient's DNA contained two copies of the TTR gene per genome; the mutation was therefore homozygous rather than hemizygous. In the present case, the homozygous mutation TTR (122 Val----Ile) is associated with SSA, a finding which is consistent with autosomal recessive inheritance of this condition. Images Figure 2 Figure 4 Figure 5 Figure 6 Figure 7 PMID:2349941

Evolving landscape in the management of transthyretin amyloidosis

PubMed Central

Hawkins, Philip N.; Ando, Yukio; Dispenzeri, Angela; Gonzalez-Duarte, Alejandra; Adams, David; Suhr, Ole B.

2015-01-01

Transthyretin (TTR) amyloidosis (ATTR amyloidosis) is a multisystemic, multigenotypic disease resulting from deposition of insoluble ATTR amyloid fibrils in various organs and tissues. Although considered rare, the prevalence of this serious disease is likely underestimated because symptoms can be non-specific and diagnosis largely relies on amyloid detection in tissue biopsies. Treatment is guided by which tissues/organs are involved, although therapeutic options are limited for patients with late-stage disease. Indeed, enthusiasm for liver transplantation for familial ATTR amyloidosis with polyneuropathy was dampened by poor outcomes among patients with significant neurological deficits or cardiac involvement. Hence, there remains an unmet medical need for new therapies. The TTR stabilizers tafamidis and diflunisal slow disease progression in some patients with ATTR amyloidosis with polyneuropathy, and the postulated synergistic effect of doxycycline and tauroursodeoxycholic acid on dissolution of amyloid is under investigation. Another therapeutic approach is to reduce production of the amyloidogenic protein, TTR. Plasma TTR concentration can be significantly reduced with ISIS-TTRRx, an investigational antisense oligonucleotide-based drug, or with patisiran and revusiran, which are investigational RNA interference-based therapeutics that target the liver. The evolving treatment landscape for ATTR amyloidosis brings hope for further improvements in clinical outcomes for patients with this debilitating disease. PMID:26611723

Nevada National Security Site Environmental Report 2010

DOE Office of Scientific and Technical Information (OSTI.GOV)

C. Wills, ed.

2011-09-13

This NNSSER was prepared to satisfy DOE Order DOE O 231.1B, “Environment, Safety and Health Reporting.” Its purpose is to (1) report compliance status with environmental standards and requirements, (2) present results of environmental monitoring of radiological and nonradiological effluents, (3) report estimated radiological doses to the public from releases of radioactive material, (4) summarize environmental incidents of noncompliance and actions taken in response to them, (5) describe the NNSA/NSO Environmental Management System and characterize its performance, and (6) highlight significant environmental programs and efforts. This NNSSER summarizes data and compliance status for calendar year 2010 at the Nevada Nationalmore » Security Site (NNSS) (formerly the Nevada Test Site) and its two support facilities, the North Las Vegas Facility (NLVF) and the Remote Sensing Laboratory–Nellis (RSL-Nellis). It also addresses environmental restoration (ER) projects conducted at the Tonopah Test Range (TTR). Through a Memorandum of Agreement, NNSA/NSO is responsible for the oversight of TTR ER projects, and the Sandia Site Office of NNSA (NNSA/SSO) has oversight of all other TTR activities. NNSA/SSO produces the TTR annual environmental report available at http://www.sandia.gov/news/publications/environmental/index.html.« less

Serum proteomic analysis reveals potential serum biomarkers for occupational medicamentosa-like dermatitis caused by trichloroethylene.

PubMed

Huang, Peiwu; Ren, Xiaohu; Huang, Zhijun; Yang, Xifei; Hong, Wenxu; Zhang, Yanfang; Zhang, Hang; Liu, Wei; Huang, Haiyan; Huang, Xinfeng; Wu, Desheng; Yang, Linqing; Tang, Haiyan; Zhou, Li; Li, Xuan; Liu, Jianjun

2014-08-17

Trichloroethylene (TCE) is an industrial solvent with widespread occupational exposure and also a major environmental contaminant. Occupational medicamentosa-like dermatitis induced by trichloroethylene (OMLDT) is an autoimmune disease and it has become one major hazard in China. In this study, sera from 3 healthy controls and 3 OMLDT patients at different disease stages were used for a screening study by 2D-DIGE and MALDI-TOF-MS/MS. Eight proteins including transthyretin (TTR), retinol binding protein 4 (RBP4), haptoglobin, clusterin, serum amyloid A protein (SAA), apolipoprotein A-I, apolipoprotein C-III and apolipoprotein C-II were found to be significantly altered among the healthy, acute-stage, healing-stage and healed-stage groups. Specifically, the altered expression of TTR, RBP4 and haptoglobin were further validated by Western blot analysis and ELISA. Our data not only suggested that TTR, RBP4 and haptoglobin could serve as potential serum biomarkers of OMLDT, but also indicated that measurement of TTR, RBP4 and haptoglobin or their combination could help aid in the diagnosis, monitoring the progression and therapy of the disease. Copyright © 2014. Published by Elsevier Ireland Ltd.

Status of endangered and threatened plant species on Tonopah Test Range: a survey

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rhoads, W.A.; Cochrane, S.A.; Williams, M.P.

From intensive field investigation in 1978, six species under consideration by the US Fish and Wildlife Service (FWS) for endangered or threatened status were found on or near the Tonopah Test Range (TTR) in southern central Nevada. Based on recognized threats to these species, their overall distribution, rarity, and other factors, status recommendations were prepared for Sandia Corporation. The single species originally listed for endangered status by FWS, Asclepias eastwoodiana, is herein recommended for threatened status. Of the five other species suggested for threatened status, we propose three as meriting this status: Astragalus pseudoiodanthus, Coryphantha vivipara var. rosea, and Sclerocactusmore » polyancistrus. Gilia nyensis should have further monitoring but appears to require no formal protection at this time. The fifth, Phacelia mustelina, does not require any monitoring or protective actions. Astragalus pseudoiodanthus has yet to be found on TTR, although it is to be expected in the northwest region of the Range and was included in the report for that reason. In addition, ten species that occur in the vicinity of TTR, and which may yet be found on TTR, are discussed in brief. Each species is discussed in relation to distribution, rarity, taxonomy, habitat requirements, endangerment, assessment of status, and proposed protection and monitoring needs. Habitats suggested for protection are recommended for the species warranting threatened status, and are delineated on a composite USGS topographic map. Construction activities and off-road vehicle travel are the most prominent man-caused threats to species on TTR; habitat destruction by trampling and overgrazing by feral horses and non-permit cattle significantly modifies habitats of certain species. 41 refs., 23 figs.« less

[Evaluation of the quality control of anticoagulation in patients with atrial fibrillation in a Primary Health Care Area of Madrid].

PubMed

Habashneh Sánchez, S; Abad Díaz, I; Tinajero Valle, C P; Cortés Palmero, A; Lobón Agúndez, M C; Muñoz Fernández, C

2016-01-01

To calculate the time in therapeutic range (TTR), as well as the scores on the CHADS2 scale in anticoagulated patients with non-valvular atrial fibrillation, attending the Primary Care Health Centre of Aravaca. Basic health area of Aravaca (Madrid). Retrospective observational study. The Community of Madrid provides a list of patients with non-valvular atrial fibrillation and on anticoagulant therapy in the centre. Excluding those with less than 8 INRs, who began treatment after January 2011, interrupted by inter-current treatment or had cancer or coagulopathy. The study period is from 1 January 2012 to 1 January 2013. The TTR (fraction of INRs in range) was the primary endpoint. The score was also calculated on the CHADS2 scale. A value of 56.28% TTR (59.5-53.1) was obtained from a sample of 963 INRs. Just over half (52%) of patients had a TTR<60%. There were 65 patients with a mean age of 80±7.5 years. The distribution of risk factors for the CHADS2 scale was: Heart failure 18.5%; hypertension 80%; diabetes 29.2%, and embolic events 18.5%. The results of our sample TTR is suboptimal (<60%), which implies an increased risk for embolic episodes and increased likelihood of bleeding. We need to incorporate into our clinical practice an objective measure of the quality of anticoagulation in order to identify poorly controlled patients and introduce corrective measures. Copyright © 2014 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España, S.L.U. All rights reserved.

Health literacy and warfarin therapy at two anticoagulation clinics in Brazil

PubMed Central

Martins, Maria Auxiliadora Parreiras; Costa, Josiane Moreira; Mambrini, Juliana Vaz de Melo; Ribeiro, Antonio Luiz Pinho; Benjamin, Emelia J; Brant, Luisa Campos Caldeira; Paasche-Orlow, Michael K; Magnani, Jared W

2017-01-01

Objective Health literacy has been related to health-related conditions and health outcomes. Studies examining the association of health literacy and anticoagulation have had variable results. We sought to investigate the relations of health literacy and percentage of time in therapeutic range (TTR) in a vulnerable Brazilian cohort at two hospital-based anticoagulation clinics. Methods We measured health literacy with the Short Assessment of Health Literacy for Portuguese-speaking Adults (SAHLPA-18) in 2015–2016. We identified the demographic and clinical characteristics associated with health literacy and related health literacy to TTR. Results We enrolled 422 adults prescribed chronic warfarin therapy in our observational study (median age 62.1 years; 58.8% women; monthly income $200.00). The prevalence of inadequate health literacy (score 0–14 points) was 72.3% with a median score of 12 (quartiles, Q1=10; Q3=15) on the SAHLPA-18. The median TTR was 66.1%. In the multivariable logistic analysis, cognitive impairment and assistance with taking warfarin were associated with inadequate health literacy. Prosthetic heart valves and more school years were associated with adequate health literacy. Our analyses showed no significant relation between health literacy and TTR, analysing health literacy as a categorical (adjusted OR 1.05; 95% CI 0.65 to 1.70) or continuous variable (Spearman’s coefficient 0.02; p=0.70). Conclusions Inadequate health literacy was highly prevalent in this impoverished Brazilian cohort receiving anticoagulation with warfarin. However, we did not identify an association between health literacy and TTR. Future investigations may consider the systemic factors that contribute towards successful anticoagulation outcomes for vulnerable patient cohorts with inadequate health literacy. PMID:28258243

Health literacy and warfarin therapy at two anticoagulation clinics in Brazil.

PubMed

Martins, Maria Auxiliadora Parreiras; Costa, Josiane Moreira; Mambrini, Juliana Vaz de Melo; Ribeiro, Antonio Luiz Pinho; Benjamin, Emelia J; Brant, Luisa Campos Caldeira; Paasche-Orlow, Michael K; Magnani, Jared W

2017-07-01

Health literacy has been related to health-related conditions and health outcomes. Studies examining the association of health literacy and anticoagulation have had variable results. We sought to investigate the relations of health literacy and percentage of time in therapeutic range (TTR) in a vulnerable Brazilian cohort at two hospital-based anticoagulation clinics. We measured health literacy with the Short Assessment of Health Literacy for Portuguese-speaking Adults (SAHLPA-18) in 2015-2016. We identified the demographic and clinical characteristics associated with health literacy and related health literacy to TTR. We enrolled 422 adults prescribed chronic warfarin therapy in our observational study (median age 62.1 years; 58.8% women; monthly income $200.00). The prevalence of inadequate health literacy (score 0-14 points) was 72.3% with a median score of 12 (quartiles, Q1=10; Q3=15) on the SAHLPA-18. The median TTR was 66.1%. In the multivariable logistic analysis, cognitive impairment and assistance with taking warfarin were associated with inadequate health literacy. Prosthetic heart valves and more school years were associated with adequate health literacy. Our analyses showed no significant relation between health literacy and TTR, analysing health literacy as a categorical (adjusted OR 1.05; 95% CI 0.65 to 1.70) or continuous variable (Spearman's coefficient 0.02; p=0.70). Inadequate health literacy was highly prevalent in this impoverished Brazilian cohort receiving anticoagulation with warfarin. However, we did not identify an association between health literacy and TTR. Future investigations may consider the systemic factors that contribute towards successful anticoagulation outcomes for vulnerable patient cohorts with inadequate health literacy. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Bleeding complications and mortality in warfarin-treated VTE patients, dependence of INR variability and iTTR.

PubMed

Sandén, Per; Renlund, Henrik; Svensson, Peter J; Själander, Anders

2017-01-05

High quality of warfarin treatment is important to prevent recurrence of venous thromboembolism (VTE) without bleeding complications. The aim of this study was to examine the effect of individual time in therapeutic range (iTTR) and International Normalised Ratio (INR) variability on bleeding risk and mortality in a large cohort of well-managed patients with warfarin due to VTE. A cohort of 16612 patients corresponding to 19502 treatment periods with warfarin due to VTE between January 1, 2006 and December 31, 2011 was retrieved from the Swedish national quality register AuriculA and matched with the Swedish National Patient Register for bleeding complications and background characteristics and the Cause of death register for occurrence and date of death. The rate of bleeding was 1.79 (confidence interval (CI) 95 % 1.66-1.93) per 100 treatment years among all patients. Those with poor warfarin treatment quality had a higher rate of clinically relevant bleeding, both when measured as iTTR below 70 %, 2.91 (CI 95 % 2.61-3.21) or as INR variability over the mean value 0.85, 2.61 (CI 95 % 2.36-2.86). Among those with both high INR variability and low iTTR the risk of clinically relevant bleeding was clearly increased hazard ratio (HR) 3.47 (CI 95 % 2.89-4.17). A similar result was found for all-cause mortality with a HR of 3.67 (CI 95 % 3.02-4.47). Both a low iTTR and a high INR variability increase the risk of bleeding complications or mortality. When combining the two treatment quality indicators patients at particular high risk of bleeding or death can be identified.

Ecological studies of small vertebrates in Pu-contaminated study areas of NTS and TTR

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bradley, W.G.; Moor, K.S.; White, M.G.

Ecological studies of vertebrates in plutonium-contaminated areas of the Nevada Test Site (NTS) were initiated in March 1972, and have continued to date. In September 1973, standard census methods were also employed to derive a qualitative and quantitative inventory of vertebrate biota of four Nevada Applied Ecology Group (NAEG) study areas of the Tonopah Test Range (TTR). A checklist of vertebrates of NAEG study areas of NTS and TTR is presented. Data are presented on vertebrate composition, relative abundance, and seasonal status in the study areas. Concentrations of $sup 239$Pu and $sup 241$Am were determined in pelt or skin, GImore » tract, and carcass of 13 lizards and 16 mammals resident on Clean Slate 2, TTR, and Area 11, NTS. A total of 71 animals were collected for radioanalysis. However, the data were not available at the time this report was written. Pu tissue burdens were highest in lizards from Area 11 GZ. Maximum values obtained in nCi/g ash were 30.9, 42.2, and 0.43 for the pelt, GI tract, and carcass, respectively. Maximum $sup 239$Pu values in tissues of small rodents from Area 11 (not from GZ) were 11.4, 6.49, and 0.20 nCi/g ash for pelt, GI tract, and carcass, respectively. Pu/Am ratios were relatively consistent in tissue samples of lizards and small mammals from Area 11 (approximately 6:1, Pu/Am). Pu/Am ratios were not consistent in vertebrates of Clean Slate 2, TTR, and appeared to be lower in carcass (28:1, Pu/Am in mammals) than GI tract (9:1, Pu/Am in mammals). Although this trend was more conspicuous in mammals, it was also evident in reptiles. (auth)« less

APOLLO I: Anticoagulation control in atrial fibrillation.

PubMed

Pinho-Costa, Luís; Moreira, Sónia; Azevedo, Cristiana; Azevedo, Pedro; Castro, Elisabete; Sousa, Hélder; Melo, Miguel

2015-05-01

Anticoagulation control as assessed by time in therapeutic range (TTR) correlates positively with the safety and efficacy of thromboprophylaxis in atrial fibrillation. We set out to assess TTR in our unit and to investigate determinants of better control. This was a case series study of atrial fibrillation patients anticoagulated with warfarin or acenocoumarol at the Family Health Unit of Fânzeres. Sociodemographic and clinical data were collected and TTR was calculated by the Rosendaal method, based on international normalized ratio tests performed in external laboratories in the preceding six months. SPSS 21.0 was used for the statistical analysis, with descriptive statistics, Spearman's correlation, and the Mann-Whitney U and Kruskal-Wallis tests. Of the 106 eligible patients, 70% participated in the study. Median TTR was 65.3% (P25=48.3%, P75=86.8%). We found a positive association between this variable and duration of atrial fibrillation (ρ=0.477, p<0.001, r(2)=0.116) and with duration of anticoagulation (ρ=0.5, p<0.001, r(2)=0.087). No association was found with age, gender, educational level or existence of a caregiver (p>0.05). Median TTR in our unit is similar to that in southern European countries and close to the good control threshold (70%) proposed by the European Society of Cardiology. The duration of atrial fibrillation and of anticoagulation explains only a small part of the measure's variability. Other determinants of anticoagulation control must be investigated in future studies and comparative studies should be carried out in family health units monitoring anticoagulation on the premises. Copyright © 2014 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.

Advanced Rotorcraft Transmission Program

DTIC Science & Technology

1990-05-21

600 a/c, 25 year, 420 FH per year.] Sikorskya Boeing MDHC Bell (ACA) (FAR-TTR) (FAR) (FAR-TTR) Transmission weight, lb 7879 (-27%) 1359(-25%) 1344(-25...LII " IVI NI I V f NWlY - f Nj Ii ( 1111 Cl AI 111011 CANIAL RAI P) IOW~I~t N*S SP-I - I CMl’ l A NI S I AR Il VIA.Ill j I~~)J Nil VI ~ IAI AANY

Hereditary cardiac amyloidosis associated with the transthyretin Ile122 mutation in a white man.

PubMed

Gillmore, J D; Booth, D R; Pepys, M B; Hawkins, P N

1999-09-01

An 83 year old white man with atrial fibrillation was admitted to hospital after a cerebral infarct. Echocardiography was characteristic of cardiac amyloid deposition and subsequent tests confirmed amyloidosis of transthyretin (TTR) type, in association with the Ile122 mutation of the TTR gene; this has only been reported previously in African Americans in whom it occurs with an allele frequency of 2%. Haplotype analysis did not suggest a different founder than for the African Ile122 mutation. Cardiac amyloidosis should be considered among elderly patients presenting with cardiac failure and/or arrhythmia, particularly if they are resistant to conventional treatment; if confirmed, it should be followed by precise characterisation of amyloid fibril type. The prevalence of autosomal dominant cardiac TTR amyloidosis in elderly white people is unknown but early diagnosis and supportive treatment may prevent complications among affected family members.

76 FR 54258 - Request for Comments-Fiscal Oversight Task Force Report and Recommendations

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-31

... LEGAL SERVICES CORPORATION Request for Comments--Fiscal Oversight Task Force Report and... Fiscal Oversight Task Force, which reviewed and made recommendations regarding how LSC conducts fiscal... territories. By Resolution adopted on July 21, 2010, the Board established the Fiscal Oversight Task Force...

Detection and Characterization of Aggregates, Prefibrillar Amyloidogenic Oligomers, and Protofibrils Using Fluorescence Spectroscopy

PubMed Central

Lindgren, Mikael; Sörgjerd, Karin; Hammarström, Per

2005-01-01

Transthyretin (TTR) is a protein linked to a number of different amyloid diseases including senile systemic amyloidosis and familial amyloidotic polyneuropathy. The transient nature of oligomeric intermediates of misfolded TTR that later mature into fibrillar aggregates makes them hard to study, and methods to study these species are sparse. In this work we explore a novel pathway for generation of prefibrillar aggregates of TTR, which provides important insight into TTR misfolding. Prefibrillar amyloidogenic oligomers and protofibrils of misfolded TTR were generated in vitro through induction of the molten globule type A-state from acid unfolded TTR through the addition of NaCl. The aggregation process produced fairly monodisperse oligomers (300–500 kD) within 2 h that matured after 20 h into larger spherical clusters (30–50 nm in diameter) and protofibrils as shown by transmission electron microscopy. Further maturation of the aggregates showed shrinkage of the spheres as the fibrils grew in length, suggesting a conformational change of the spheres into more rigid structures. The structural and physicochemical characteristics of the aggregates were investigated using fluorescence, circular dichroism, chemical cross-linking, and transmission electron microscopy. The fluorescent dyes 1-anilinonaphthalene-8-sulfonate (ANS), 4-4-bis-1-phenylamino-8-naphthalene sulfonate (Bis-ANS), 4-(dicyanovinyl)-julolidine (DCVJ), and thioflavin T (ThT) were employed in both static and kinetic assays to characterize these oligomeric and protofibrillar states using both steady-state and time-resolved fluorescence techniques. DCVJ, a molecular rotor, was employed for the first time for studies of an amyloidogenic process and is shown useful for detection of the early steps of the oligomerization process. DCVJ bound to the early prefibrillar oligomers (300–500 kD) with an apparent dissociation constant of 1.6 μM, which was slightly better than for ThT (6.8 μM). Time-resolved fluorescence anisotropy decay of ANS was shown to be a useful tool for giving further structural and kinetic information of the oligomeric aggregates. ThT dramatically increases its fluorescence quantum yield when bound to amyloid fibrils; however, the mechanism behind this property is unknown. Data from this work suggest that unbound ThT is also intrinsically quenched and functions similarly to a molecular rotor, which in combination with its environmental dependence provides a blue shift to the characteristic 482 nm wavelength when bound to amyloid fibrils. PMID:15764666

Prevalence, Severity, and Prognostic Value of Sleep Apnea Syndromes in Cardiac Amyloidosis

PubMed Central

Bodez, Diane; Guellich, Aziz; Kharoubi, Mounira; Covali-Noroc, Ala; Tissot, Claire-Marie; Guendouz, Soulef; Hittinger, Luc; Dubois-Randé, Jean-Luc; Lefaucheur, Jean-Pascal; Planté-Bordeneuve, Violaine; Adnot, Serge; Boyer, Laurent; Damy, Thibaud

2016-01-01

Study Objectives: To assess prevalence, severity, and prognostic value of sleep-disordered breathing (SDB), in the three main cardiac amyloidosis (CA) types, i.e., light-chain (AL), transthyretin-related familial (m-TTR), or senile (WT-TTR). Methods: Patients consecutively referred for CA diagnosis work-up underwent cardiac assessment and nocturnal polygraphy. SDB was defined as apnea-hypopnea index (AHI) ≥ 5/h. Multivariate analysis was used to identify predictors of a major adverse cardiac event (MACE) defined as death, heart transplantation and acute heart failure. Results: Seventy CA patients were included (31 AL, 22 m-TTR, 17 WT-TTR). The mean ± standard deviation age and left ventricular ejection fraction were 71 ± 12 years and 49% ± 13% and median (interquartile range) N terminal pro brain natriuretic peptide (NT-proBNP) was 3,932 (1,607; 7,028) pg/mL. The prevalence of SDB was 90% without difference between amyloidosis types. SDB was central in 27% and obstructive in 73%. AL had less frequent severe SDB compared to m-TTR and WT-TTR (P = 0.015) but longer time with peripheral capillary oxygen saturation (SpO2) < 90% (P = 0.037). After a median follow-up of 7.5 (2.8; 14.9) months, 49% patients experienced MACE. Time with nocturnal SpO2 < 90% was the only independent predictor of MACE. The best-identified threshold was 30 min. Values > 30 min were associated with bad prognosis (Log-rank χ2: 8.01, P value = 0.005). Using binomial logistic regression, determinants of time with nocturnal SpO2 < 90% were New York Heart Association class (P = 0.011), and log-NT-proBNP (P = 0.04) but not AHI. Conclusions: In CA population, prevalence of SDB is high (90%) and dominated by the obstructive pattern. Bad prognosis in this population was driven by nocturnal desaturation, reflecting heart failure severity and respiratory involvement. Citation: Bodez D, Guellich A, Kharoubi M, Covali-Noroc A, Tissot CM, Guendouz S, Hittinger L, Dubois-Randé JL, Lefaucheur JP, Planté-Bordeneuve V, Adnot S, Boyer L, Damy T. Prevalence, severity, and prognostic value of sleep apnea syndromes in cardiac amyloidosis. SLEEP 2016;39(7):1333–1341. PMID:27091529

Regulation of DNA Replication Timing on Human Chromosome by a Cell-Type Specific DNA Binding Protein SATB1

PubMed Central

Oda, Masako; Kanoh, Yutaka; Watanabe, Yoshihisa; Masai, Hisao

2012-01-01

Background Replication timing of metazoan DNA during S-phase may be determined by many factors including chromosome structures, nuclear positioning, patterns of histone modifications, and transcriptional activity. It may be determined by Mb-domain structures, termed as “replication domains”, and recent findings indicate that replication timing is under developmental and cell type-specific regulation. Methodology/Principal Findings We examined replication timing on the human 5q23/31 3.5-Mb segment in T cells and non-T cells. We used two independent methods to determine replication timing. One is quantification of nascent replicating DNA in cell cycle-fractionated stage-specific S phase populations. The other is FISH analyses of replication foci. Although the locations of early- and late-replicating domains were common between the two cell lines, the timing transition region (TTR) between early and late domains were offset by 200-kb. We show that Special AT-rich sequence Binding protein 1 (SATB1), specifically expressed in T-cells, binds to the early domain immediately adjacent to TTR and delays the replication timing of the TTR. Measurement of the chromosome copy number along the TTR during synchronized S phase suggests that the fork movement may be slowed down by SATB1. Conclusions Our results reveal a novel role of SATB1 in cell type-specific regulation of replication timing along the chromosome. PMID:22879953

Regulation of DNA replication timing on human chromosome by a cell-type specific DNA binding protein SATB1.

PubMed

Oda, Masako; Kanoh, Yutaka; Watanabe, Yoshihisa; Masai, Hisao

2012-01-01

Replication timing of metazoan DNA during S-phase may be determined by many factors including chromosome structures, nuclear positioning, patterns of histone modifications, and transcriptional activity. It may be determined by Mb-domain structures, termed as "replication domains", and recent findings indicate that replication timing is under developmental and cell type-specific regulation. We examined replication timing on the human 5q23/31 3.5-Mb segment in T cells and non-T cells. We used two independent methods to determine replication timing. One is quantification of nascent replicating DNA in cell cycle-fractionated stage-specific S phase populations. The other is FISH analyses of replication foci. Although the locations of early- and late-replicating domains were common between the two cell lines, the timing transition region (TTR) between early and late domains were offset by 200-kb. We show that Special AT-rich sequence Binding protein 1 (SATB1), specifically expressed in T-cells, binds to the early domain immediately adjacent to TTR and delays the replication timing of the TTR. Measurement of the chromosome copy number along the TTR during synchronized S phase suggests that the fork movement may be slowed down by SATB1. Our results reveal a novel role of SATB1 in cell type-specific regulation of replication timing along the chromosome.

Thromboembolic and Major Bleeding Events With Rivaroxaban Versus Warfarin Use in a Real-World Setting.

PubMed

Russo-Alvarez, Giavanna; Martinez, Kathryn A; Valente, Megan; Bena, James; Hu, Bo; Luxenburg, Jennifer; Chaitoff, Alexander; Ituarte, Catherine; Brateanu, Andrei; Rothberg, Michael B

2018-01-01

Although randomized trials demonstrate the noninferiority of rivaroxaban compared with warfarin in the context of nonvalvular atrial fibrillation (AF), little is known about how these drugs compare in practice. To assess the relative effectiveness and safety of rivaroxaban versus warfarin in a large health system and to evaluate this association by time in therapeutic range (TTR). We conducted a retrospective cohort study with propensity matching in the Cleveland Clinic Health System. The study included patients initiated on warfarin or rivaroxaban for thromboembolic prevention in nonvalvular AF between January 2012 and July 2016. The main outcomes were thromboembolic events and major bleeds. Analyses were stratified by warfarin patients' TTR. The cohort consisted of 472 propensity-matched pairs. The mean age was 73.6 years (SD = 11.7), and the mean CHADS 2 score was 1.8. The median TTR for warfarin patients was 64%. In the propensity-matched analysis, there was no significant difference in thromboembolic or major bleeding events between groups. Among warfarin patients with a TTR <64% and their matched rivaroxaban pairs, there was also no significant difference in thromboembolic or major bleeding events. Under real-world conditions, warfarin and rivaroxaban were associated with similar safety and effectiveness, even among those with suboptimal therapeutic control. Individualized decision making, taking into account the nontherapeutic tradeoffs associated with these medications (eg, monitoring, half-life, cost) is warranted.

Effect-directed analysis to explore the polar bear exposome: identification of thyroid hormone disrupting compounds in plasma.

PubMed

Simon, Eszter; van Velzen, Martin; Brandsma, Sicco H; Lie, Elisabeth; Løken, Katharina; de Boer, Jacob; Bytingsvik, Jenny; Jenssen, Bjørn M; Aars, Jon; Hamers, Timo; Lamoree, Marja H

2013-08-06

Compounds with transthyretin (TTR)-binding potency in the blood plasma of polar bear cubs were identified with effect-directed analysis (EDA). This approach contributes to the understanding of the thyroid disrupting exposome of polar bears. The selection of these samples for in-depth EDA was based on the difference between the observed TTR-binding potency on the one hand and the calculated potency (based on known concentrations of TTR-binding compounds and their relative potencies) on the other. A library-based identification was applied to the liquid chromatography-time-of-flight-mass spectrometry (LC-ToF-MS) data by screening for matches between compound lists and the LC-ToF-MS data regarding accurate mass and isotope pattern. Then, isotope cluster analysis (ICA) was applied to the LC-ToF-MS data allowing specific screening for halogen isotope patterns. The presence of linear and branched nonylphenol (NP) was observed for the first time in polar bears. Furthermore, the presence of one di- and two monohydroxylated octachlorinated biphenyls (octaCBs) was revealed in the extracts. Linear and branched NP, 4'-OH-CB201 and 4,4'-OH-CB202 could be successfully confirmed with respect to their retention time in the analytical system. In addition, branched NP, mono- and dihydroxylated-octaCBs showed TTR-binding potencies and could explain another 32 ± 2% of the total measured activities in the extracts.

Retinol Binding Protein 4 in children with Inflammatory Bowel Disease: a negative correlation with the disease activity.

PubMed

Roma, E; Krini, M; Hantzi, E; Sakka, S; Panayiotou, I; Margeli, A; Papassotiriou, I; Kanaka-Gantenbein, C

2012-10-01

Retinol Binding Protein-4 (RBP-4), the action of which was initially thought to be only the transport of vitamin A, is a major circulating adipocytokine involved in the inflammation. We evaluated the serum RBP-4 levels in children with inflammatory bowel disease (IBD) and correlated them with transthyretin (TTR), inflammation markers, disease activity, and body mass index (BMI). In 41 children of mean age 11.9 ± 3.6 years (range 5-17.7 y) with IBD (19 with Crohn's disease (CD) and 22 with Ulcerative colitis (UC) serum RBP-4, TTR, Amyloid A (SAA), C-Reactive Protein (CRP), Erythrocyte Sedimentation Rate (ESR), disease activity and BMI were prospectively determined and compared with those of 42 matched controls. No difference in the RBP-4 and TTR serum levels, between patients and controls as well as between active and remission state of the disease was noticed. A negative correlation of serum RBP-4 with the disease activity, SAA and ESR and a positive correlation with TTR was found, but no significant correlation with CRP or BMI was found. Inflammation markers were significantly increased in patients compared to controls and had a positive correlation with the disease activity. RBP-4 negatively correlated with disease activity of children with IBD probably indicating a protective anti-inflammatory mechanism of action in addition to transport of vitamin A.

The evaluation of preoperative nutritional status in patients undergoing thoracic surgery.

PubMed

Trufă, D I; Arhire, Lidia Iuliana; Niţă, Otilia; Gherasim, Andreea; Niţă, G; Graur, Mariana

2014-01-01

The aim of this study was to assess the preoperative nutritional status of patients undergoing thoracic surgery using different nutritional tools. . We conducted a prospective study on a sample of 43 thoracic patients, including 23 with neoplasms and 20 with non-neoplastic pathology who underwent thoracic surgery procedures between July-September 2011, in the Thoracic Surgery Clinic in Iaşi. Weight and height were measured and body mass index (BMI) was calculated. WHO classification for BMI categories was used. Preoperative serum level of transthyretin (TTR) and demographic data (gender, age) were also assessed. All patients were examined by the Subjective Global Assessment (SGA) and the Nutritional Risk Screening 2002 (NRS 2002). After performing SGA, 67.9% of the patients were well-nourished, 21.4% were moderately or suspected of being malnourished and 10.7% were severely malnourished. The level of TTR was significantly lower in the moderately or severely malnourished group, compared to those considered well-nourished. According to NRS-2002, 42.9% of the patients were considered at nutritional risk. The level of TTR of these patients was lower than the level of TTR of the patients without nutritional risk, but without statistical significance. Subjective Global Assessment (SGA) and the Nutritional Risk Screening 2002 (NRS 2002) are useful in identifying patients with nutritional risk, so that appropriate nutritional management could be initialised even before surgery.

Assessment of the binding of hydroxylated polybrominated diphenyl ethers to thyroid hormone transport proteins using a site-specific fluorescence probe.

PubMed

Ren, Xiao M; Guo, Liang-Hong

2012-04-17

Polybrominated diphenyl ethers (PBDEs) have been shown to disrupt thyroid hormone (TH) functions on experimental animals, and one of the proposed disruption mechanisms is the competitive binding of PBDE metabolites to TH transport proteins. In this report, a nonradioactive, site-specific fluorescein-thyroxine (F-T4) conjugate was designed and synthesized as a fluorescence probe to study the binding interaction of hydroxylated PBDEs to thyroxine-binding globulin (TBG) and transthyretin (TTR), two major TH transport proteins in human plasma. Compared with free F-T4, the fluorescence intensity of TTR-bound conjugate was enhanced by as much as 2-fold, and the fluorescence polarization value of TBG-bound conjugate increased by more than 20-fold. These changes provide signal modulation mechanisms for F-T4 as a fluorescence probe. Based on fluorescence quantum yield and lifetime measurements, the fluorescence intensity enhancement was likely due to the elimination of intramolecular fluorescence quenching of fluorescein by T4 after F-T4 was bound to TTR. In circular dichroism and intrinsic tryptophan fluorescence measurements, F-T4 induced similar spectroscopic changes of the proteins as T4 did, suggesting that F-T4 bound to the proteins at the T4 binding site. By using F-T4 as the fluorescence probe in competitive binding assays, 11 OH-PBDEs with different levels of bromination and different hydroxylation positions were assessed for their binding affinity with TBG and TTR, respectively. The results indicate that the binding affinity generally increased with bromine number and OH position also played an important role. 3-OH-BDE-47 and 3'-OH-BDE-154 bound to TTR and TBG even stronger, respectively, than T4. With rising environmental level and high bioaccumulation capability, PBDEs have the potential to disrupt thyroid homeostasis by competitive binding with TH transport proteins.

Diagnostic pitfalls in sporadic transthyretin familial amyloid polyneuropathy (TTR-FAP).

PubMed

Planté-Bordeneuve, V; Ferreira, A; Lalu, T; Zaros, C; Lacroix, C; Adams, D; Said, G

2007-08-14

Transthyretin familial amyloid polyneuropathies (TTR-FAPs) are autosomal dominant neuropathies of fatal outcome within 10 years after inaugural symptoms. Late diagnosis in patients who present as nonfamilial cases delays adequate management and genetic counseling. Clinical data of the 90 patients who presented as nonfamilial cases of the 300 patients of our cohort of patients with TTR-FAP were reviewed. They were 21 women and 69 men with a mean age at onset of 61 (extremes: 38 to 78 years) and 17 different mutations of the TTR gene including Val30Met (38 cases), Ser77Tyr (16 cases), Ile107Val (15 cases), and Ser77Phe (5 cases). Initial manifestations included mainly limb paresthesias (49 patients) or pain (17 patients). Walking difficulty and weakness (five patients) and cardiac or gastrointestinal manifestations (five patients), were less common at onset. Mean interval to diagnosis was 4 years (range 1 to 10 years); 18 cases were mistaken for chronic inflammatory demyelinating polyneuropathy, which was the most common diagnostic error. At referral a length-dependent sensory loss affected the lower limbs in 2, all four limbs in 20, and four limbs and anterior trunk in 77 patients. All sensations were affected in 60 patients (67%), while small fiber dysfunction predominated in the others. Severe dysautonomia affected 80 patients (90%), with postural hypotension in 52, gastrointestinal dysfunction in 50, impotence in 58 of 69 men, and sphincter disturbance in 31. Twelve patients required a cardiac pacemaker. Nerve biopsy was diagnostic in 54 of 65 patients and salivary gland biopsy in 20 of 30. Decreased nerve conduction velocity, increased CSF protein, negative biopsy findings, and false immunolabeling of amyloid deposits were the main causes of diagnostic errors. We conclude that DNA testing, which is the most reliable test for TTR-FAP, should be performed in patients with a progressive length-dependent small fiber polyneuropathy of unknown origin, especially when associated with autonomic dysfunction.

Stroke and Bleeding Risk Associated With Antithrombotic Therapy for Patients With Nonvalvular Atrial Fibrillation in Clinical Practice

PubMed Central

An, JaeJin; Niu, Fang; Lang, Daniel T; Jazdzewski, Kristin P; Le, Paul T; Rashid, Nazia; Meissner, Brian; Mendes, Robert; Dills, Diana G; Aranda, Gustavus; Bruno, Amanda

2015-01-01

Background The quality of antithrombotic therapy for patients with nonvalvular atrial fibrillation during routine medical care is often suboptimal. Evidence linking stroke and bleeding risk with antithrombotic treatment is limited. The purpose of this study was to evaluate the associations between antithrombotic treatment episodes and outcomes. Methods and Results A retrospective longitudinal observational cohort study was conducted using patients newly diagnosed with nonvalvular atrial fibrillation with 1 or more stroke risk factors (CHADS2 ≥1) in Kaiser Permanente Southern California between January 1, 2006 and December 31, 2011. A total of 1782 stroke and systemic embolism (SE) and 3528 major bleed events were identified from 23 297 patients during the 60 021 person-years of follow-up. The lowest stroke/SE rates and major bleed rates were observed in warfarin time in therapeutic range (TTR) ≥55% episodes (stroke/SE: 0.87 [0.71 to 1.04]; major bleed: 4.91 [4.53 to 5.28] per 100 person-years), which was similar to the bleed rate in aspirin episodes (4.95 [4.58 to 5.32] per 100 person-years). The warfarin TTR ≥55% episodes were associated with a 77% lower risk of stroke/SE (relative risk=0.23 [0.18 to 0.28]) compared to never on therapy; and the warfarin TTR <55% and on-aspirin episodes were associated with a 20% lower and with a 26% lower risk of stroke/SE compared to never on therapy, respectively. The warfarin TTR <55% episodes were associated with nearly double the risk of a major bleed compared to never on therapy (relative risk=1.93 [1.74 to 2.14]). Conclusions Continuation of antithrombotic therapy as well as maintaining an adequate level of TTR is beneficial to prevent strokes while minimizing bleeding events. PMID:26187996

The Sex, Age, Medical History, Treatment, Tobacco Use, Race Risk (SAMe TT2R2) Score Predicts Warfarin Control in a Singaporean Population.

PubMed

Bernaitis, Nijole; Ching, Chi Keong; Chen, Liping; Hon, Jin Shing; Teo, Siew Chong; Davey, Andrew K; Anoopkumar-Dukie, Shailendra

2017-01-01

Warfarin reduces stroke risk in atrial fibrillation (AF) patients but requires ongoing monitoring. Time in therapeutic range (TTR) is used as a measure of warfarin control, with a TTR less than 60% associated with adverse patient outcomes. The Sex, Age, Medical history, Treatment, Tobacco use, Race (SAMe-TT 2 R 2 ) score has been identified as a model able to predict warfarin control, but this has been tested in mainly Caucasian populations. Therefore, the aim of this study was to determine the ability of the SAMe-TT 2 R 2 score to predict warfarin control in a Singaporean population consisting of Chinese, Malay, and Indian race. Retrospective data were collected from the National Heart Centre Singapore for AF patients receiving warfarin between January and June 2014. The TTR and the SAMe-TT 2 R 2 score were calculated for each patient. The 1137 non-valvular AF patients had a mean TTR of 58.0 ± 34.3% and a median SAMe-TT 2 R 2 score of 3. The categorized SAMe-TT 2 R 2 scores (2 versus >2) showed a significant reduction in mean TTR for the entire population (63.2% versus 55.8%, P = .0004) and also when categorized according to race for Chinese (62.7% versus 56.9%, P = .0075) and Malay (68.4% versus 50.6%, P = .0131) populations. The SAMe-TT 2 R 2 tool is effective in predicting warfarin control in a Singaporean population as patients with a score greater than 2 had poor control. The minimum score for non-Caucasian patients is 2; thus, in these patients, the presence of any additional risk factors identified in the SAMe-TT 2 R 2 tool categorizes them as unlikely to achieve adequate warfarin control and possible candidates for alternative anticoagulants. Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Performance Assessment of Hazardous Air Pollutant (HAP)Free Chemical Paint Strippers on Military Coatings for Validation to Federal Specification TT-R-2918A

DTIC Science & Technology

2016-03-01

ARL-TN-0742 ● MAR 2016 US Army Research Laboratory Performance Assessment of Hazardous Air Pollutant (HAP)–Free Chemical Paint ...Free Chemical Paint Strippers on Military Coatings for Validation to Federal Specification TT-R-2918A by Lindsey Blohm Oak Ridge Institute for...COVERED (From - To) 1–30 April 2014 4. TITLE AND SUBTITLE Performance Assessment of Hazardous Air Pollutant (HAP)–Free Chemical Paint Strippers

Modulating inhibitors of transthyretin fibrillogenesis via sulfation: polychlorinated biphenyl sulfates as models.

PubMed

Grimm, Fabian A; Lehmler, Hans-Joachim; He, Xianran; Robertson, Larry W; Duffel, Michael W

2015-02-25

Small molecules that bind with high affinity to thyroxine (T4) binding sites on transthyretin (TTR) kinetically stabilize the protein's tetrameric structure, thereby efficiently decreasing the rate of tetramer dissociation in TTR related amyloidoses. Current research efforts aim to optimize the amyloid inhibiting properties of known inhibitors, such as derivatives of biphenyls, dibenzofurans and benzooxazoles, by chemical modification. In order to test the hypothesis that sulfate group substituents can improve the efficiencies of such inhibitors, we evaluated the potential of six polychlorinated biphenyl sulfates to inhibit TTR amyloid fibril formation in vitro. In addition, we determined their binding orientations and molecular interactions within the T4 binding site by molecular docking simulations. Utilizing this combined experimental and computational approach, we demonstrated that sulfation significantly improves the amyloid inhibiting properties as compared to both parent and hydroxylated PCBs. Importantly, several PCB sulfates were of equal or higher potency than some of the most effective previously described inhibitors. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Modulating Inhibitors of Transthyretin Fibrillogenesis via Sulfation: Polychlorinated Biphenyl Sulfates as Models1

PubMed Central

Grimm, Fabian A.; Lehmler, Hans-Joachim; He, Xianran; Robertson, Larry W.; Duffel, Michael W.

2015-01-01

Small molecules that bind with high affinity to thyroxine (T4) binding sites on transthyretin (TTR) kinetically stabilize the protein’s tetrameric structure, thereby efficiently decreasing the rate of tetramer dissociation in TTR related amyloidoses. Current research efforts aim to optimize the amyloid inhibiting properties of known inhibitors, such as derivatives of biphenyls, dibenzofurans and benzooxazoles, by chemical modification. In order to test the hypothesis that sulfate group substituents can improve the efficiencies of such inhibitors, we evaluated the potential of six polychlorinated biphenyl sulfates to inhibit TTR amyloid fibril formation in vitro. In addition, we determined their binding orientations and molecular interactions within the T4 binding site by molecular docking simulations. Utilizing this combined experimental and computational approach, we demonstrated that sulfation significantly improves the amyloid inhibiting properties as compared to both parent and hydroxylated PCBs. Importantly, several PCB sulfates were of equal or higher potency than some of the most effective previously described inhibitors. PMID:25595224

Anatomy of an amyloidogenic intermediate: conversion of beta-sheet to alpha-sheet structure in transthyretin at acidic pH.

PubMed

Armen, Roger S; Alonso, Darwin O V; Daggett, Valerie

2004-10-01

The homotetramer of transthyretin (TTR) dissociates into a monomeric amyloidogenic intermediate that self-assembles into amyloid fibrils at low pH. We have performed molecular dynamics simulations of monomeric TTR at neutral and low pH at physiological (310 K) and very elevated temperature (498 K). In the low-pH simulations at both temperatures, one of the two beta-sheets (strands CBEF) becomes disrupted, and alpha-sheet structure forms in the other sheet (strands DAGH). alpha-sheet is formed by alternating alphaL and alphaR residues, and it was first proposed by Pauling and Corey. Overall, the simulations are in agreement with the available experimental observations, including solid-state NMR results for a TTR-peptide amyloid. In addition, they provide a unique explanation for the results of hydrogen exchange experiments of the amyloidogenic intermediate-results that are difficult to explain with beta-structure. We propose that alpha-sheet may represent a key pathological conformation during amyloidogenesis. Copyright 2004 Elsevier Ltd.

DETERMINATION OF REPORTABLE RADIONUCLIDES FOR DWPF SLUDGE BATCH 7B (MACROBATCH 9)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Crawford, C. L.; Diprete, D. P.

The Waste Acceptance Product Specifications (WAPS) 1.2 require that “The Producer shall report the inventory of radionuclides (in Curies) that have half-lives longer than 10 years and that are, or will be, present in concentrations greater than 0.05 percent of the total inventory for each waste type indexed to the years 2015 and 3115”. As part of the strategy to comply with WAPS 1.2, the Defense Waste Processing Facility (DWPF) will report for each waste type, all radionuclides (with half-lives greater than 10 years) that have concentrations greater than 0.01 percent of the total inventory from time of production throughmore » the 1100 year period from 2015 through 3115. The initial listing of radionuclides to be included is based on the design-basis glass as identified in the Waste Form Compliance Plan (WCP) and Waste Form Qualification Report (WQR). However, it is required that this list be expanded if other radionuclides with half-lives greater than 10 years are identified that may meet the greater than 0.01% criterion for Curie content. Specification 1.6 of the WAPS, International Atomic Energy Agency (IAEA) Safeguards Reporting for High Level Waste (HLW), requires that the ratio by weights of the following uranium and plutonium isotopes be reported: U-233, U-234, U-235, U-236, U-238, Pu-238, Pu-239, Pu-240, Pu-241, and Pu- 242. Therefore, the complete set of reportable radionuclides must also include this set of U and Pu isotopes. The DWPF is receiving radioactive sludge slurry from HLW Tank 40. The radioactive sludge slurry in Tank 40 is a blend of the heel from Sludge Batch 7a (SB7a) and Sludge Batch 7b (SB7b) that was transferred to Tank 40 from Tank 51. The blend of sludge in Tank 40 is also referred to as Macrobatch 9 (MB9). This report develops the list of reportable radionuclides and associated activities as a function of time. The DWPF will use this list and the activities as one of the inputs for the development of the Production Records that relate to radionuclide inventory. This work was initiated through Technical Task Request (TTR) HLW-DWPF-TTR-2011-0004; Rev. 0 entitled Sludge Batch 7b Qualification Studies. Specifically, this report details results from performing Subtask II, Item 2 of the TTR and, in part, meets Deliverable 6 of the TTR. The work was performed following the Task Technical and Quality Assurance Plan (TTQAP), SRNL-RP-2011-00247, Rev. 0 and Analytical Study Plan (ASP), SRNL-RP-2011-00248, Rev. 0. In order to determine the reportable radionuclides for SB7b (MB9), a list of radioisotopes that may meet the criteria as specified by the Department of Energy’s (DOE) WAPS was developed. All radioactive U- 235 fission products and all radioactive activation products that could be in the SRS HLW were considered. In addition, all U and Pu isotopes identified in WAPS 1.6 were included in the list. This list was then evaluated and some isotopes were excluded from the projection calculations. Based on measurements and analytical detection limits, 27 radionuclides have been identified as reportable for DWPF SB7b as specified by WAPS 1.2. The WCP and WQR require that all of the radionuclides present in the Design Basis glass be considered as the initial set of reportable radionuclides. For SB7b, all of the radionuclides in the Design Basis glass are reportable except for three radionuclides: Pd-107, Cs-135, and Th-230. At no time during the 1100- year period between 2015 and 3115 did any of these three radionuclides contribute to more than 0.01% of the radioactivity on a Curie basis. Two additional uranium isotopes (U-235 and -236) must be added to the list of reportable radionuclides in order to meet WAPS 1.6. All of the Pu isotopes (Pu-238, -239, -240, -241, and -242) and other U isotopes (U-233, -234, and -238) identified in WAPS 1.6 were already determined to be reportable according to WAPS 1.2 This brings the total number of reportable radionuclides for SB7b to 29. The radionuclide measurements made for SB7b are similar to those performed in the previous SB7a MB8 work. Some method development/refinement occurred during the conduct of these measurements, leading to lower detection limits and more accurate measurement of some isotopes than was previously possible. Improvement in the analytical measurements will likely continue, and this in turn should lead to improved detection limit values for some radionuclides and actual measurements for still others.« less

Determination Of Reportable Radionuclides For DWPF Sludge Batch 7B (Macrobatch 9)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Crawford, C. L.; DiPrete, D. P.

The Waste Acceptance Product Specifications (WAPS) 1.2 require that “The Producer shall report the inventory of radionuclides (in Curies) that have half-lives longer than 10 years and that are, or will be, present in concentrations greater than 0.05 percent of the total inventory for each waste type indexed to the years 2015 and 3115”. As part of the strategy to comply with WAPS 1.2, the Defense Waste Processing Facility (DWPF) will report for each waste type, all radionuclides (with half-lives greater than 10 years) that have concentrations greater than 0.01 percent of the total inventory from time of production throughmore » the 1100 year period from 2015 through 3115. The initial listing of radionuclides to be included is based on the design-basis glass as identified in the Waste Form Compliance Plan (WCP) and Waste Form Qualification Report (WQR). However, it is required that this list be expanded if other radionuclides with half-lives greater than 10 years are identified that may meet the greater than 0.01% criterion for Curie content. Specification 1.6 of the WAPS, International Atomic Energy Agency (IAEA) Safeguards Reporting for High Level Waste (HLW), requires that the ratio by weights of the following uranium and plutonium isotopes be reported: U-233, U-234, U-235, U-236, U-238, Pu-238, Pu-239, Pu-240, Pu-241, and Pu-242. Therefore, the complete set of reportable radionuclides must also include this set of U and Pu isotopes. The DWPF is receiving radioactive sludge slurry from HLW Tank 40. The radioactive sludge slurry in Tank 40 is a blend of the heel from Sludge Batch 7a (SB7a) and Sludge Batch 7b (SB7b) that was transferred to Tank 40 from Tank 51. The blend of sludge in Tank 40 is also referred to as Macrobatch 9 (MB9). This report develops the list of reportable radionuclides and associated activities as a function of time. The DWPF will use this list and the activities as one of the inputs for the development of the Production Records that relate to radionuclide inventory. This work was initiated through Technical Task Request (TTR) HLW-DWPF-TTR-2011-0004; Rev. 0 entitled Sludge Batch 7b Qualification Studies. Specifically, this report details results from performing Subtask II, Item 2 of the TTR and, in part, meets Deliverable 6 of the TTR. The work was performed following the Task Technical and Quality Assurance Plan (TTQAP), SRNL-RP-2011-00247, Rev. 0 and Analytical Study Plan (ASP), SRNL-RP-2011-00248, Rev. 0. In order to determine the reportable radionuclides for SB7b (MB9), a list of radioisotopes that may meet the criteria as specified by the Department of Energy’s (DOE) WAPS was developed. All radioactive U-235 fission products and all radioactive activation products that could be in the SRS HLW were considered. In addition, all U and Pu isotopes identified in WAPS 1.6 were included in the list. This list was then evaluated and some isotopes were excluded from the projection calculations. Based on measurements and analytical detection limits, 27 radionuclides have been identified as reportable for DWPF SB7b as specified by WAPS 1.2. The WCP and WQR require that all of the radionuclides present in the Design Basis glass be considered as the initial set of reportable radionuclides. For SB7b, all of the radionuclides in the Design Basis glass are reportable except for three radionuclides: Pd-107, Cs-135, and Th-230. At no time during the 1100-year period between 2015 and 3115 did any of these three radionuclides contribute to more than 0.01% of the radioactivity on a Curie basis. Two additional uranium isotopes (U-235 and -236) must be added to the list of reportable radionuclides in order to meet WAPS 1.6. All of the Pu isotopes (Pu-238, -239, -240, -241, and -242) and other U isotopes (U-233, -234, and -238) identified in WAPS 1.6 were already determined to be reportable according to WAPS 1.2 This brings the total number of reportable radionuclides for SB7b to 29. The radionuclide measurements made for SB7b are similar to those performed in the previous SB7a MB8 work. Some method development/refinement occurred during the conduct of these measurements, leading to lower detection limits and more accurate measurement of some isotopes than was previously possible. Improvement in the analytical measurements will likely continue, and this in turn should lead to improved detection limit values for some radionuclides and actual measurements for still others.« less

Teaching Children with Autism to Request Help with Difficult Tasks

ERIC Educational Resources Information Center

Rodriguez, Nicole M.; Levesque, Megan A.; Cohrs, Victoria L.; Niemeier, Jessica J.

2017-01-01

We taught three children diagnosed with autism spectrum disorder to request help using an interrupted chain procedure during which we manipulated task materials such that the child was either incapable or capable of independently completing a link of a behavior chain. We initially observed undesirable generalization of requests for help during…

78 FR 9928 - Food and Drug Administration Drug Shortages Task Force and Strategic Plan; Request for Comments

Federal Register 2010, 2011, 2012, 2013, 2014

2013-02-12

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2013-N-0124] Food and Drug Administration Drug Shortages Task Force and Strategic Plan; Request for Comments AGENCY: Food and Drug Administration, HHS. ACTION: Notice; request for comments. SUMMARY: To assist the Food...

32 CFR 1901.22 - Action and determination(s) by originator(s) or any interested party.

Code of Federal Regulations, 2012 CFR

2012-07-01

... for access. CIA components tasked pursuant to a Privacy Act access request shall search all relevant... any). (b) Initial action for amendment. CIA components tasked pursuant to a Privacy Act amendment... amendment request. If the CIA component records manager declines to make the requested amendment or declines...

32 CFR 1901.22 - Action and determination(s) by originator(s) or any interested party.

Code of Federal Regulations, 2014 CFR

2014-07-01

... for access. CIA components tasked pursuant to a Privacy Act access request shall search all relevant... any). (b) Initial action for amendment. CIA components tasked pursuant to a Privacy Act amendment... amendment request. If the CIA component records manager declines to make the requested amendment or declines...

32 CFR 1901.22 - Action and determination(s) by originator(s) or any interested party.

Code of Federal Regulations, 2010 CFR

2010-07-01

... for access. CIA components tasked pursuant to a Privacy Act access request shall search all relevant... any). (b) Initial action for amendment. CIA components tasked pursuant to a Privacy Act amendment... amendment request. If the CIA component records manager declines to make the requested amendment or declines...

Gene structure and evolution of transthyretin in the order Chiroptera.

PubMed

Khwanmunee, Jiraporn; Leelawatwattana, Ladda; Prapunpoj, Porntip

2016-02-01

Bats are mammals in the order Chiroptera. Although many extensive morphologic and molecular genetics analyses have been attempted, phylogenetic relationships of bats has not been completely resolved. The paraphyly of microbats is of particular controversy that needs to be confirmed. In this study, we attempted to use the nucleotide sequence of transthyretin (TTR) intron 1 to resolve the relationship among bats. To explore its utility, the complete sequences of TTR gene and intron 1 region of bats in Vespertilionidae: genus Eptesicus (Eptesicus fuscus) and genus Myotis (Myotis brandtii, Myotis davidii, and Myotis lucifugus), and Pteropodidae (Pteropus alecto and Pteropus vampyrus) were extracted from the retrieved sequences, whereas those of Rhinoluphus affinis and Scotophilus kuhlii were amplified and sequenced. The derived overall amino sequences of bat TTRs were found to be very similar to those in other eutherians but differed from those in other classes of vertebrates. However, missing of amino acids from N-terminal or C-terminal region was observed. The phylogenetic analysis of amino acid sequences suggested bat and other eutherian TTRs lineal descent from a single most recent common ancestor which differed from those of non-placental mammals and the other classes of vertebrates. The splicing of bat TTR precursor mRNAs was similar to those of other eutherian but different from those of marsupial, bird, reptile and amphibian. Based on TTR intron 1 sequence, the inferred evolutionary relationship within Chiroptera revealed more closely relatedness of R. affinis to megabats than to microbats. Accordingly, the paraphyly of microbats was suggested.

Tear dynamics in healthy and dry eyes.

PubMed

Cerretani, Colin F; Radke, C J

2014-06-01

Dry-eye disease, an increasingly prevalent ocular-surface disorder, significantly alters tear physiology. Understanding the basic physics of tear dynamics in healthy and dry eyes benefits both diagnosis and treatment of dry eye. We present a physiological-based model to describe tear dynamics during blinking. Tears are compartmentalized over the ocular surface; the blink cycle is divided into three repeating phases. Conservation laws quantify the tear volume and tear osmolarity of each compartment during each blink phase. Lacrimal-supply and tear-evaporation rates are varied to reveal the dependence of tear dynamics on dry-eye conditions, specifically tear osmolarity, tear volume, tear-turnover rate (TTR), and osmotic water flow. Predicted periodic-steady tear-meniscus osmolarity is 309 and 321 mOsM in normal and dry eyes, respectively. Tear osmolarity, volume, and TTR all match available clinical measurements. Osmotic water flow through the cornea and conjunctiva contribute 10 and 50% to the total tear supply in healthy and dry-eye conditions, respectively. TTR in aqueous-deficient dry eye (ADDE) is only half that in evaporative dry eye (EDE). The compartmental periodic-steady tear-dynamics model accurately predicts tear behavior in normal and dry eyes. Inclusion of osmotic water flow is crucial to match measured tear osmolarity. Tear-dynamics predictions corroborate the use of TTR as a clinical discriminator between ADDE and EDE. The proposed model is readily extended to predict the dynamics of aqueous solutes such as drugs or fluorescent tags.

Distinct Annular Oligomers Captured along the Assembly and Disassembly Pathways of Transthyretin Amyloid Protofibrils

PubMed Central

Pires, Ricardo H.; Karsai, Árpád; Saraiva, Maria J.; Damas, Ana M.; Kellermayer, Miklós S. Z.

2012-01-01

Background Defects in protein folding may lead to severe degenerative diseases characterized by the appearance of amyloid fibril deposits. Cytotoxicity in amyloidoses has been linked to poration of the cell membrane that may involve interactions with amyloid intermediates of annular shape. Although annular oligomers have been detected in many amyloidogenic systems, their universality, function and molecular mechanisms of appearance are debated. Methodology/Principal Findings We investigated with high-resolution in situ atomic force microscopy the assembly and disassembly of transthyretin (TTR) amyloid protofibrils formed of the native protein by pH shift. Annular oligomers were the first morphologically distinct intermediates observed in the TTR aggregation pathway. Morphological analysis suggests that they can assemble into a double-stack of octameric rings with a 16±2 nm diameter, and displaying the tendency to form linear structures. According to light scattering data coupled to AFM imaging, annular oligomers appeared to undergo a collapse type of structural transition into spheroid oligomers containing 8–16 monomers. Disassembly of TTR amyloid protofibrils also resulted in the rapid appearance of annular oligomers but with a morphology quite distinct from that observed in the assembly pathway. Conclusions/Significance Our observations indicate that annular oligomers are key dynamic intermediates not only in the assembly but also in the disassembly of TTR protofibrils. The balance between annular and more compact forms of aggregation could be relevant for cytotoxicity in amyloidogenic disorders. PMID:22984597

78 FR 10127 - Request for Nominations to the Agricultural Air Quality Task Force

Federal Register 2010, 2011, 2012, 2013, 2014

2013-02-13

... Conservation Service Request for Nominations to the Agricultural Air Quality Task Force AGENCY: Natural... Nominations to the Agricultural Air Quality Task Force. SUMMARY: The Secretary of Agriculture invites... Force (AAQTF) which was established by the Federal Agriculture Improvement and Reform Act of 1996 to...

NESHAP Annual Report for CY 2015 Sandia National Laboratories Tonopah Test Range

DOE Office of Scientific and Technical Information (OSTI.GOV)

Evelo, Stacie

2016-05-01

This National Emission Standards for Hazardous Air Pollutants (NESHAP) Annual Report has been prepared in a format to comply with the reporting requirements of 40 CFR 61.94 and the April 5, 1995 Memorandum of Agreement (MOA) between the Department of Energy (DOE) and the Environmental Protection Agency (EPA). According to the EPA approved NESHAP Monitoring Plan for the Tonopah Test Range (TTR), 40 CFR 61, subpart H, and the MOA, no additional monitoring or measurements are required at TTR in order to demonstrate compliance with the NESHAP regulation.

Relation of quality of anticoagulation control with different management systems among patients with atrial fibrillation: Data from FANTASIIA Registry.

PubMed

Roldán Rabadán, Inmaculada; Esteve-Pastor, María Asunción; Anguita-Sánchez, Manuel; Muñiz, Javier; Camacho Siles, José; Quesada, María Angustias; Ruiz Ortiz, Martín; Marín, Francisco; Martínez Sellés, Manuel; Bertomeu, Vicente; Lip, Gregory Y H; Cequier Fillat, Angel; Badimón, Lina

2018-05-01

Anticoagulation control in patients with atrial fibrillation (AF) has a multidisciplinary approach although is usually managed by general practitioners (GP) or haematologists. The aim of our study was to assess the quality of anticoagulation control with vitamin K antagonists (VKAs) in relation to the responsible specialist in a "real-world" AF population. We consecutively enrolled VKA anticoagulated patients included in the FANTASIIA Registry from 2013 to 2015. We analysed demographical, clinical characteristics and the quality of anticoagulation control according to the specialist responsible (ie GPs or haematologists). Data on 1584 patients were included (42.5% females, mean age 74.0 ± 9.4 years): 977 (61.7%) patients were controlled by GPs and 607 (38.3%) by haematologists. Patients managed by GPs had higher previous heart disease (53.2% vs 43.3%, P < .001), heart failure (32.9% vs 26.5%, P < .008) and dilated cardiomyopathy (15.2% vs 8.7%, P < .001) with better renal function (69.3 ± 24.7 vs 63.1 ± 21.4 mL/min, P < .001) compared to patients managed by haematologists. There was no difference between groups in the type of AF, CHA 2 DS 2 -VASc or HAS-BLED scores, but patients with electrical cardioversion were more prevalent in GP group. The overall mean time in therapeutic range (TTR) assessed by Rosendaal method was 61.5 ± 24.9%; 52.6% of patients had TTR<65% and 60% of patients had TTR<70%. TTR was significantly lower in patients controlled by haematologists than by GPs (63 ± 24.4 vs 59.2 ± 25.6, P < .005). About 60% of AF patients anticoagulated with VKAs had poor anticoagulation control (ie TTR<70%), and their management was only slightly better than when it is managed by general practitioners. © 2018 Stichting European Society for Clinical Investigation Journal Foundation.

The Impact of Residual Disease After Preoperative Systemic Therapy on Clinical Outcomes in Patients with Inflammatory Breast Cancer.

PubMed

Nakhlis, Faina; Regan, Meredith M; Warren, Laura E; Bellon, Jennifer R; Hirshfield-Bartek, Judith; Duggan, Margaret M; Dominici, Laura S; Golshan, Mehra; Jacene, Heather A; Yeh, Eren D; Mullaney, Erin E; Overmoyer, Beth

2017-09-01

Inflammatory breast cancer (IBC) is a rare and aggressive disease treated with multimodality therapy: preoperative systemic therapy (PST) followed by modified radical mastectomy (MRM), chest wall and regional nodal radiotherapy, and adjuvant biologic therapy and/or endocrine therapy when appropriate. In non-IBC, the degree of pathologic response to PST has been shown to correlate with time to recurrence (TTR) and overall survival (OS). We sought to determine if pathologic response correlates with oncologic outcomes of IBC patients. Following review of IBC patients' records (1997-2014), we identified 258 stage III IBC patients; 181 received PST followed by MRM and radiotherapy and were subsequently analyzed. Pathologic complete response (pCR) to PST, hormone receptor and human epidermal growth factor receptor 2 (HER2) status, grade, and histology were evaluated as predictors of TTR and OS by Cox model. Overall, 95/181 (52%) patients experienced recurrence; 93/95 (98%) were distant metastases (median TTR 3.2 years). Seventy-three patients (40%) died (median OS 6.9 years). pCR was associated with improved TTR (hazard ratio [HR] 0.20, 95% confidence interval [CI] 0.09-0.46, p < 0.01, univariate; HR 0.17, 95% CI 0.07-0.41, p < 0.0001, multivariate) and improved OS (HR 0.26, 95% CI 0.11-0.65, p < 0.01, univariate). In patients with pCR, grade III (HR 1.91, 95% CI 1.16-3.13, p = 0.01), and triple-negative phenotype (HR 3.54, 95% CI 1.79-6.98, p = 0.0003) were associated with shorter TTR, while residual ductal carcinoma in situ was not (HR 0.85, 95% CI 0.53-1.35, p = 0.48, multivariate). In stage III IBC, pCR was associated with prognosis, further influenced by grade, hormone receptor, and HER2 status. Investigating mechanisms that contribute to better response to PST could help improve oncologic outcomes in IBC.

Analysis of normal and truncated holo- and apo-retinol-binding protein (RBP) in human serum: altered ratios in chronic renal failure.

PubMed

Jaconi, S; Saurat, J H; Siegenthaler, G

1996-05-01

Retinol, the precursor of the retinoic acid hormone, is transported in the serum by a specific carrier, the retinol-binding protein (RBP). Compared to serum of healthy controls, the serum of patients with chronic renal failure (CRF) contains markedly increased levels of the RBP form truncated at the C terminal, des(182Leu-183Leu), (RBP2), which suggests that RBP2 is cleared by the kidney in healthy people but accumulates in serum of CRF patients (Jaconi S, et al. J Lipid Res 1995:36:1247-53). To understand better the mechanism of retinol transport, we have developed a new analytical strategy to analyze the various forms of RBP that circulate in the blood: RBP with and without retinol (holo- and apo-RBP, respectively), RBP bound or not to transthyretin (TTR) and to determine in which of these forms RBP2 circulates. We confirm, but now by direct measurement, that holo-RBP and, to a larger extent, apo-RBP are increased in CRF serum compared to normal serum. We also show that almost all apo-RBP and about 50% of total holo-RBP, corresponding to RBP excess in CRF serum, circulate free and are not complexed to TTR, the remaining 50% being complexed to TTR. This observation suggests that the high levels of free holo-RBP, not bound to TTR, which correspond to the increase in total RBPs measured in CRF serum, may alter the tissue uptake of retinol and be responsible for the signs of hypervitaminosis A observed in these patients. Secondly, we found that the truncation resulting in RBP2 does not alter its binding properties for retinol nor those of holo-RBP2 for TTR. We observed that the high amounts of free holo-RBP2 and holo-RBP in sera of CRF patients were low in normal serum, suggesting that these forms are cleared by the kidney in normal conditions. The possible role of free holo-RBPs is discussed in the context of retinol recycling.

Educational intervention improves anticoagulation control in atrial fibrillation patients: the TREAT randomised trial.

PubMed

Clarkesmith, Danielle E; Pattison, Helen M; Lip, Gregory Y H; Lane, Deirdre A

2013-01-01

Stroke prevention in atrial fibrillation (AF), most commonly with warfarin, requires maintenance of a narrow therapeutic target (INR 2.0 to 3.0) and is often poorly controlled in practice. Poor patient-understanding surrounding AF and its treatment may contribute to the patient's willingness to adhere to recommendations. A theory-driven intervention, developed using patient interviews and focus groups, consisting of a one-off group session (1-6 patients) utilising an "expert-patient" focussed DVD, educational booklet, self-monitoring diary and worksheet, was compared in a randomised controlled trial (ISRCTN93952605) against usual care, with patient postal follow-ups at 1, 2, 6, and 12-months. Ninety-seven warfarin-naïve AF patients were randomised to intervention (n=46, mean age (SD) 72.0 (8.2), 67.4% men), or usual care (n=51, mean age (SD) 73.7 (8.1), 62.7% men), stratified by age, sex, and recruitment centre. Primary endpoint was time within therapeutic range (TTR); secondary endpoints included knowledge, quality of life, anxiety/depression, beliefs about medication, and illness perceptions. Intervention patients had significantly higher TTR than usual care at 6-months (76.2% vs. 71.3%; p=0.035); at 12-months these differences were not significant (76.0% vs. 70.0%; p=0.44). Knowledge increased significantly across time (F (3, 47) = 6.4; p<0.01), but there were no differences between groups (F (1, 47) = 3.3; p = 0.07). At 6-months, knowledge scores predicted TTR (r=0.245; p=0.04). Patients' scores on subscales representing their perception of the general harm and overuse of medication, as well as the perceived necessity of their AF specific medications predicted TTR at 6- and 12-months. A theory-driven educational intervention significantly improves TTR in AF patients initiating warfarin during the first 6-months. Adverse clinical outcomes may potentially be reduced by improving patients' understanding of the necessity of warfarin and reducing their perception of treatment harm. Improving education provision for AF patients is essential to ensure efficacious and safe treatment. The trial is registered with Current Controlled Trials, ISRCTN93952605, and details are available at www.controlled-trials.com/ISRCTN93952605.

Tafamidis for transthyretin familial amyloid polyneuropathy

PubMed Central

Maia, Luis F.; Martins da Silva, Ana; Waddington Cruz, Marcia; Planté-Bordeneuve, Violaine; Lozeron, Pierre; Suhr, Ole B.; Campistol, Josep M.; Conceição, Isabel Maria; Schmidt, Hartmut H.-J.; Trigo, Pedro; Kelly, Jeffery W.; Labaudinière, Richard; Chan, Jason; Packman, Jeff; Wilson, Amy; Grogan, Donna R.

2012-01-01

Objectives: To evaluate the efficacy and safety of 18 months of tafamidis treatment in patients with early-stage V30M transthyretin familial amyloid polyneuropathy (TTR-FAP). Methods: In this randomized, double-blind trial, patients received tafamidis 20 mg QD or placebo. Coprimary endpoints were the Neuropathy Impairment Score–Lower Limbs (NIS-LL) responder analysis (<2-point worsening) and treatment-group difference in the mean change from baseline in Norfolk Quality of Life–Diabetic Neuropathy total score (TQOL) in the intent-to-treat (ITT) population (n = 125). These endpoints were also evaluated in the efficacy-evaluable (EE; n = 87) population. Secondary endpoints, including changes in neurologic function, nutritional status, and TTR stabilization, were analyzed in the ITT population. Results: There was a higher-than-anticipated liver transplantation dropout rate. No differences were observed between the tafamidis and placebo groups for the coprimary endpoints, NIS-LL responder analysis (45.3% vs 29.5% responders; p = 0.068) and change in TQOL (2.0 vs 7.2; p = 0.116) in the ITT population. In the EE population, significantly more tafamidis patients than placebo patients were NIS-LL responders (60.0% vs 38.1%; p = 0.041), and tafamidis patients had better-preserved TQOL (0.1 vs 8.9; p = 0.045). Significant differences in most secondary endpoints favored tafamidis. TTR was stabilized in 98% of tafamidis and 0% of placebo patients (p < 0.0001). Adverse events were similar between groups. Conclusions: Although the coprimary endpoints were not met in the ITT population, tafamidis was associated with no trend toward more NIS-LL responders and a significant reduction in worsening of most neurologic variables, supporting the hypothesis that preventing TTR dissociation can delay peripheral neurologic impairment. Classification of evidence: This study provides Class II evidence that 20 mg tafamidis QD was associated with no difference in clinical progression in patients with TTR-FAP, as measured by the NIS-LL and the Norfolk QOL-DN score. Secondary outcomes demonstrated a significant delay in peripheral neurologic impairment with tafamidis, which was well tolerated over 18 months. PMID:22843282

Results of a Regional Effort to Improve Warfarin Management.

PubMed

Rose, Adam J; Park, Angela; Gillespie, Christopher; Van Deusen Lukas, Carol; Ozonoff, Al; Petrakis, Beth Ann; Reisman, Joel I; Borzecki, Ann M; Benedict, Ashley J; Lukesh, William N; Schmoke, Timothy J; Jones, Ellen A; Morreale, Anthony P; Ourth, Heather L; Schlosser, James E; Mayo-Smith, Michael F; Allen, Arthur L; Witt, Daniel M; Helfrich, Christian D; McCullough, Megan B

2017-05-01

Improved anticoagulation control with warfarin reduces adverse events and represents a target for quality improvement. No previous study has described an effort to improve anticoagulation control across a health system. To describe the results of an effort to improve anticoagulation control in the New England region of the Veterans Health Administration (VA). Our intervention encompassed 8 VA sites managing warfarin for more than 5000 patients in New England (Veterans Integrated Service Network 1 [VISN 1]). We provided sites with a system to measure processes of care, along with targeted audit and feedback. We focused on processes of care associated with site-level anticoagulation control, including prompt follow-up after out-of-range international normalized ratio (INR) values, minimizing loss to follow-up, and use of guideline-concordant INR target ranges. We used a difference-in-differences (DID) model to examine changes in anticoagulation control, measured as percentage time in therapeutic range (TTR), as well as process measures and compared VISN 1 sites with 116 VA sites located outside VISN 1. VISN 1 sites improved on TTR, our main indicator of quality, from 66.4% to 69.2%, whereas sites outside VISN 1 improved from 65.9% to 66.4% (DID 2.3%, P < 0.001). Improvement in TTR correlated strongly with the extent of improvement on process-of-care measures, which varied widely across VISN 1 sites. A regional quality improvement initiative, using performance measurement with audit and feedback, improved TTR by 2.3% more than control sites, which is a clinically important difference. Improving relevant processes of care can improve outcomes for patients receiving warfarin.

Levels and distributions of organic pollutants in subtidal sediments from the Loire estuary: Are there any relationships with TTR-binding activity?

NASA Astrophysics Data System (ADS)

Couderc, M.; Gandolfi, F.; Zalouk-Vergnoux, A.; Beyeler, N.; Malleret, L.; Ambidina, I.; Kamari, A.; Blanchet-Letrouvé, I.; Mouneyrac, C.; Hamers, T.; Poirier, L.

2016-12-01

The Loire estuary runs through important urban sites with shipping, industrial and agricultural activities, being the receptacle of diffusive pollutants comprising, a mixture of contaminants such as persistent organic pollutants (POPs). This work was set out to evaluate the occurrence of thyroid endocrine disruptors in sediments of this estuary. Sediments were collected in September 2012 and April 2013, in subtidal zones along the estuary. Targeted chemical analyses of five classes of pollutants, i.e. polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), polycyclic aromatic hydrocarbons (PAHs), alkylphenols (APs), and bisphenol A (BPA) were performed in sediment extracts. Extracts were further tested for their thyroid hormone (TH) disrupting potency to compete with TH for binding to its transporter protein transthyretin (TTR). The Haute-Indre site was characterized by a significant PAH contamination whereas Saint-Nazaire, Bellevue and Rezé would be particularly contaminated by PCBs. These observations could be linked to the different type of anthropogenic activities taking place close to these sites. Donges, Mindin and Paimboeuf were the sampling sites displaying the lowest contamination in PAHs, APs, PCBs and PBDEs. No inter-site difference could be observed for TTR-binding activity, which should be attributed to different compounds than the chemically analyzed compounds, as confirmed by PCA analyses. Furthermore, the TTR-binding potencies of the extracts were relatively low compared to data from literature. More investigations on the quantification of PCB and PBDE hydroxylated metabolites and other known endocrine disruptors such as pesticides or perfluorinated compounds could be considered, as well as bioassays highlighting other endocrine disrupting effects.

The interval between prothrombin time tests and the quality of oral anticoagulants treatment in patients with chronic atrial fibrillation.

PubMed

Shalev, Varda; Rogowski, Ori; Shimron, Orit; Sheinberg, Bracha; Shapira, Itzhak; Seligsohn, Uri; Berliner, Shlomo; Misgav, Mudi

2007-01-01

The incidence of stroke in patients with atrial fibrillation (AF) can be significantly reduced with warfarin therapy especially if optimally controlled. To evaluate the effect of the interval between consecutive prothrombin time measurements on the time in therapeutic range (INR 2-3) in a cohort of patients with AF on chronic warfarin treatment in the community. All INR measurements available from a relatively large cohort of patients with chronic AF were reviewed and the mean interval between consecutive INR tests of each patient was correlated with the time in therapeutic range (TTR). Altogether 251,916 INR measurements performed in 4408 patients over a period of seven years were reviewed. Sixty percent of patients had their INR measured on average every 2 to 3 weeks and most others were followed at intervals of 4 weeks or longer. A small proportion (3.6%) had their INR measured on average every week. A significant decline in the time in therapeutic range was observed as the intervals between tests increased. At one to three weeks interval the TTR was 48%, at 4 weeks interval 45% and at 5 weeks 41% (P<0.0005). A five percent increment in TTR was observed if more tests were performed at multiplications of exactly 7 days (43% vs 48% P<0.0001). A better control with an increase in the TTR was observed in patients with atrial fibrillation if prothrombin time tests are performed at regular intervals of no longer than 3 weeks.

An evaluation of the transition temperature range of super-elastic orthodontic NiTi springs using differential scanning calorimetry.

PubMed

Barwart, O; Rollinger, J M; Burger, A

1999-10-01

Differential scanning calorimetry (DSC) was used to determine the transition temperature ranges (TTR) of four types of super-elastic orthodontic nickel-titanium coil springs (Sentalloy). A knowledge of the TTR provides information on the temperature at which a NiTi wire or spring can assume superelastic properties and when this quality disappears. The spring types in this study can be distinguished from each other by their characteristic TTR during cooling and heating. For each tested spring type a characteristic TTR during heating (austenite transformation) and cooling (martensite transformation) was evaluated. The hysteresis of the transition temperature, found between cooling and heating, was 3.4-5.2 K. Depending on the spring type the austenite transformation started (As) at 9.7-17.1 degrees C and finished (Af) at 29.2-37 degrees C. The martensite transformation starting temperature (Ms) was evaluated at 32.6-25.4 degrees C, while Mf (martensite transformation finishing temperature) was 12.7-6.5 degrees C. The results show that the springs become super-elastic when the temperature increases and As is reached. They undergo a loss of super-elastic properties and a rapid decrease in force delivery when they are cooled to Mf. For the tested springs, Mf and As were found to be below room temperature. Thus, at room temperature and some degrees lower, all the tested springs exert super-elastic properties. For orthodontic treatment this means the maintenance of super-elastic behaviour, even when mouth temperature decreases to about room temperature as can occur, for example, during meals.

Air Monitoring Network at Tonopah Test Range: Network Description and Capabilities

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jeffrey Tappen; George Nikolich; Ken Giles

2010-05-18

During the period April to June 2008, at the behest of the U.S. Department of Energy (DOE) National Nuclear Security Administration, Nevada Site Office (NNSA/NSO); the Desert Research Institute (DRI) constructed and deployed two portable environmental monitoring stations at the Tonopah Test Range (TTR) as part of the Environmental Restoration Project Soils Sub-Project. The TTR is located within the boundaries of the Nevada Test and Training Range (NTTR) near the northern edge, and covers an area of approximately 725.20 km2 (179,200 acres). The primary objective of the monitoring stations is to evaluate whether and under what conditions there is windmore » transport of radiological contaminants from one of the three Soil Sub-Project Corrective Action Units (CAUs) associated with Operation Roller Coaster on TTR. Operation Roller Coaster was a series of tests, conducted in 1963, designed to examine the stability and dispersal of plutonium in storage and transportation accidents. These tests did not result in any nuclear explosive yield. However, the tests did result in the dispersal of plutonium and contamination of surface soils in the surrounding area.« less

Sandia National Laboratories, Tonopah Test Range Fire Control Bunker (Building 09-51): Photographs and Written Historical and Descriptive Data

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ullrich, Rebecca A.

The Fire Control Bunker (Building 09-51) is a contributing element to the Sandia National Laboratories (SNL) Tonopah Test Range (TTR) Historic District. The SNL TTR Historic District played a significant role in U.S. Cold War history in the areas of stockpile surveillance and non-nuclear field testing of nuclear weapons design. The district covers approximately 179,200 acres and illustrates Cold War development testing of nuclear weapons components and systems. This report includes historical information, architectural information, sources of information, project information, maps, blueprints, and photographs.

Sandia National Laboratories, Tonopah Test Range Assembly Building 9B (Building 09-54): Photographs and Written Historical and Descriptive Data

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ullrich, Rebecca A.

Assembly Building 9B (Building 09-54) is a contributing element to the Sandia National Laboratories (SNL) Tonopah Test Range (TTR) Historic District. The SNL TTR Historic District played a significant role in U.S. Cold War history in the areas of stockpile surveillance and non-nuclear field testing of nuclear weapons designs. The district covers approximately 179,200 acres and illustrates Cold War development testing of nuclear weapons components and systems. This report includes historical information, architectural information, sources of information, project information, maps, blueprints, and photographs.

Potential Role of In Vivo Confocal Microscopy for Imaging Corneal Nerves in Transthyretin Familial Amyloid Polyneuropathy.

PubMed

Rousseau, Antoine; Cauquil, Cecile; Dupas, Benedicte; Labbé, Antoine; Baudouin, Christophe; Barreau, Emmanuel; Théaudin, Marie; Lacroix, Catherine; Guiochon-Mantel, Anne; Benmalek, Anouar; Labetoulle, Marc; Adams, David

2016-09-01

Small fiber neuropathy (SFN) is an important feature of transthyretin familial amyloid polyneuropathy (TTR-FAP). A practical and objective method for the clinical evaluation of SFN is needed to improve the management of this disease. In vivo confocal microscopy (IVCM) of the corneal nerves, a rapid noninvasive technique, may be used as a surrogate marker of SFN. To determine the correlation of SFN with IVCM in patients with TTR-FAP. A prospective, single-center, cross-sectional controlled study was conducted at the French National Reference Center for TTR-FAP from June 1, 2013, to June 30, 2014. Fifteen patients with TTR-FAP underwent a complete neurologic examination, including Neuropathy Impairment Score of the Lower Limbs, hand grip strength, and evaluation of vegetative dysfunction, as well as electrophysiologic studies (nerve conduction and electrochemical skin conductance) and intraepidermal nerve fiber density quantification. Patients and 15 controls (matched for age and sex) underwent ophthalmologic assessments, including corneal esthesiometry and IVCM. Correlation of corneal nerve fiber length (CNFL) with the severity of SFN. Of the 15 patients enrolled in the study, 6 were women (40%); mean (SD) age was 54.4 [13.7] years. The CNFL was shorter in the patients than in controls (13.08 vs 17.57 mm/mm2; difference of 4.49 [95% CI, 0.72 to 8.27]; P = .02). The patients' CNFL correlated with the severity of both autonomic neuropathy assessed by the Compound Autonomic Dysfunction Test (rs = 0.66 [95% CI, 0.22 to 0.87]; P = .008) or electrochemical skin conductance (rs = 0.80 [95% CI, 0.50 to 0.93]; P < .001) and sensorimotor neuropathy assessed using the Neuropathy Impairment Score of the Lower Limbs (rs = -0.58 [95% CI, -0.84 to -0.11]; P = .02). Patients with altered sensory nerve action potentials and intraepidermal nerve fiber density had a shorter CNFL (P = .04 and P = .02, respectively). The CNFL could be measured in all patients compared with sensory nerve action potentials (11 patients [73%; 95% CI, 44% to 92%]; P < .001) and intraepidermal nerve fiber density (4 patients [27%; 95% CI, 8% to 55%]; P < .001). In these 15 patients with TTR-FAP, IVCM measurement permitted rapid, noninvasive evaluation of small-fiber alterations in patients and could be used to assess SFN in this setting. The CNFL could be measured in all patients, thus avoiding the floor effect seen with other neuropathy measures. Longitudinal studies with more cases evaluated are needed to define the place of IVCM in monitoring patients with TTR-FAP.

SAMe-TT2R2 Score in the Outpatient Anticoagulation Clinic to Predict Time in Therapeutic Range and Adverse Events.

PubMed

Pivatto Junior, Fernando; Scheffel, Rafael Selbach; Ries, Lucas; Wolkind, Ricardo Roitman; Marobin, Roberta; Barkan, Sabrina Sigal; Amon, Luís Carlos; Biolo, Andréia

2017-04-01

The SAMe-TT2R2 score was developed to predict which patients on oral anticoagulation with vitamin K antagonists (VKAs) will reach an adequate time in therapeutic range (TTR) (> 65%-70%). Studies have reported a relationship between this score and the occurrence of adverse events. To describe the TTR according to the score, in addition to relating the score obtained with the occurrence of adverse events in patients with nonvalvular atrial fibrillation (AF) on oral anticoagulation with VKAs. Retrospective cohort study including patients with nonvalvular AF attending an outpatient anticoagulation clinic of a tertiary hospital. Visits to the outpatient clinic and emergency, as well as hospital admissions to the institution, during 2014 were evaluated. The TTR was calculated through the Rosendaal´s method. We analyzed 263 patients (median TTR, 62.5%). The low-risk group (score 0-1) had a better median TTR as compared with the high-risk group (score ≥ 2): 69.2% vs. 56.3%, p = 0.002. Similarly, the percentage of patients with TTR ≥ 60%, 65% or 70% was higher in the low-risk group (p < 0.001, p = 0.001 and p = 0.003, respectively). The high-risk group had a higher percentage of adverse events (11.2% vs. 7.2%), although not significant (p = 0.369). The SAMe-TT2R2 score proved to be effective to predict patients with a better TTR, but was not associated with adverse events. O escore SAMe-TT2R2 foi desenvolvido visando predizer quais pacientes em anticoagulação oral com antagonistas da vitamina K (AVKs) atingirão um tempo na faixa terapêutica (TFT) adequado (> 65%-70%) no seguimento. Estudos também o relacionaram com a ocorrência de eventos adversos. Descrever o TFT de acordo com o escore, além de relacionar a pontuação obtida com a ocorrência de eventos adversos adversos em pacientes com fibrilação atrial (FA) não valvar em anticoagulação oral com AVKs. Estudo de coorte retrospectivo incluindo pacientes com FA não valvar em acompanhamento em ambulatório de anticoagulação de um hospital terciário. Foi realizada uma avaliação retrospectiva de consultas ambulatoriais, visitas a emergência e internações hospitalares na instituição no período de janeiro-dezembro/2014. O TFT foi calculado aplicando-se o método de Rosendaal. Foram analisados 263 pacientes com TFT mediano de 62,5%. O grupo de baixo risco (0-1 ponto) obteve um TFT mediano maior em comparação com o grupo de alto risco (≥ 2 pontos): 69,2% vs. 56,3%, p = 0,002. Da mesma forma, o percentual de pacientes com TFT ≥ 60%, 65% ou 70% foi superior nos pacientes de baixo risco (p < 0,001, p = 0,001 e p = 0,003, respectivamente). Os pacientes de alto risco tiveram um percentual maior de eventos adversos (11,2% vs. 7,2%), embora não significativo (p = 0,369). O escore SAMe-TT2R2 foi uma ferramenta eficaz na predição do TFT em pacientes com FA em uso de AVKs para anticoagulação, porém não se associou à ocorrência de eventos adversos.

Fluorodeoxyglucose positron emission tomography for detection of tumor recurrence following radiofrequency ablation in retrospective cohort of stage I lung cancer.

PubMed

Wang, Yingbing; Lanuti, Michael; Bernheim, Adam; Shepard, Jo-Anne O; Sharma, Amita

2018-05-03

The goal of this study was to define patterns for tumor recurrence on PET following RFA, compare time to imaging recurrence by PET versus CT, evaluate whether pre-treatment tumor uptake predicts recurrence and propose an optimal post-RFA surveillance strategy. A retrospective cohort study was performed of biopsy confirmed primary stage I lung cancers treated with RFA. FDG PET and near contemporaneous diagnostic CT imaging pre-ablation, within 30 days post-ablation, and beyond 6 months were independently and retrospectively evaluated for features supportive of recurrence. Time to imaging recurrence by PET (TTR_PET) and by CT (TTR_CT) were determined and compared. FDG avidity of untreated tumors was compared between recurrent and non-recurrent groups. Thirteen recurrences after 72 RFA treatments were confirmed by diagnostic CT. All recurrences were associated with focally intense and increasing FDG uptake beyond 6 months (sensitivity 100%; specificity 98.5%). Mean TTR_PET was 14 months compared to mean TTR_CT of 17 months (not statistically significant). Normalized SUVmax and total lesions glycolysis of lung cancers that recurred after RFA was 4.0 and 6.0, respectively compared to 2.8 and 5.0, respectively for cancers that did not recur (p = .068). A pattern of focally intense and increasing FDG PET uptake has high sensitivity and specificity for detecting recurrent lung cancer following RFA. Surveillance after RFA should include a contrast enhanced diagnostic CT at 1 month to diagnose procedural complications, PET at 6 months as a post-treatment metabolic baseline (with diagnostic CT if PET is abnormal) and alternating diagnostic CTs or PET every 6 months for 2 years.

Nevada National Security Site Environmental Report 2011

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cathy Wills, ed

2012-09-12

This report was prepared to meet the information needs of the public and the requirements and guidelines of the U.S. Department of Energy (DOE) for annual site environmental reports. It was prepared by National Security Technologies, LLC (NSTec), for the U.S. Department of Energy, National Nuclear Security Administration Nevada Site Office (NNSA/NSO). This and previous years reports, called Annual Site Environmental Reports (ASERs), Nevada Test Site Environmental Reports (NTSERs), and, beginning in 2010, Nevada National Security Site Environmental Reports (NNSSERs), are posted on the NNSA/NSO website at http://www.nv.energy.gov/library/publications/aser.aspx. This NNSSER was prepared to satisfy DOE Order DOE O 231.1B, 'Environment,more » Safety and Health Reporting.' Its purpose is to (1) report compliance status with environmental standards and requirements, (2) present results of environmental monitoring of radiological and nonradiological effluents, (3) report estimated radiological doses to the public from releases of radioactive material, (4) summarize environmental incidents of noncompliance and actions taken in response to them, (5) describe the NNSA/NSO Environmental Management System and characterize its performance, and (6) highlight significant environmental programs and efforts. This NNSSER summarizes data and compliance status for calendar year 2011 at the Nevada National Security Site (NNSS) (formerly the Nevada Test Site) and its two support facilities, the North Las Vegas Facility (NLVF) and the Remote Sensing Laboratory-Nellis (RSL-Nellis). It also addresses environmental restoration (ER) projects conducted at the Tonopah Test Range (TTR). Through a Memorandum of Agreement, NNSA/NSO is responsible for the oversight of TTR ER projects, and the Sandia Site Office of NNSA (NNSA/SSO) has oversight of all other TTR activities. NNSA/SSO produces the TTR annual environmental report available at http://www.sandia.gov/news/publications/environmental/index.html.« less

Nevada Test Site Environmental Report 2009

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cathy Wills, ed.

2010-09-13

The Nevada Test Site Environmental Report 2009 was prepared to meet the information needs of the public and the requirements and guidelines of the U.S. Department of Energy (DOE) for annual site environmental reports. It was prepared by National Security Technologies, LLC (NSTec), for the U.S. Department of Energy, National Nuclear Security Administration Nevada Site Office (NNSA/NSO). This and previous years’ Nevada Test Site Environmental Reports (NTSERs) are posted on the NNSA/NSO website at http://www.nv.doe.gov/library/publications/aser.aspx. This NTSER was prepared to satisfy DOE Order DOE O 231.1A, “Environment, Safety and Health Reporting.” Its purpose is to (1) report compliance status withmore » environmental standards and requirements, (2) present results of environmental monitoring of radiological and nonradiological effluents, (3) report estimated radiological doses to the public from releases of radioactive material, (4) summarize environmental incidents of noncompliance and actions taken in response to them, (5) describe the NNSA/NSO Environmental Management System and characterize its performance, and (6) highlight significant environmental programs and efforts. This NTSER summarizes data and compliance status for calendar year 2009 at the Nevada Test Site (NTS) and its two support facilities, the North Las Vegas Facility (NLVF) and the Remote Sensing Laboratory (RSL)-Nellis. It also addresses environmental restoration (ER) projects conducted at the Tonopah Test Range (TTR). Through a Memorandum of Agreement, NNSA/NSO is responsible for the oversight of TTR ER projects, and the Sandia Site Office of NNSA (NNSA/SSO) has oversight of all other TTR activities. NNSA/SSO produces the TTR annual environmental report available at http://www.sandia.gov/news/publications/environmental/index.html.« less

Methane related authigenic carbonates, chimneys and crusts from the Gulf of Cadiz

NASA Astrophysics Data System (ADS)

Magalhães, V.; Vasconcelos, C.; Gaspar, L.; Monteiro, H.; Pinheiro, L.; Ivanov, M.; Díaz-del-Río, V.; Somoza, L.

2003-04-01

During the TTR 11 and TTR 12 cruises (2001 and 2002), the area south and southwest of the Guadalquivir Diapiric Ridge was intensely surveyed with seismics, side scan sonar (MAK), underwater TV and sampling. This area is characterized by a very strong backscatter on the available side scan sonar images and a very irregular seafloor, with morphological and sedimentological features evidencing fluid escape structures (mud diapirs and mud volcanoes); and sedimentary structures associated with the outflow of the Mediterranean water (MOW). Based on the data and samples collected during the TTR11 and TTR12 cruises, complemented with data from the ANASTYA 2000 and 2001 cruises, it seems that this area corresponds to a large field of carbonate chimneys and crusts. Dredge profiles on the Iberico dome and west of this structure, on the main channel of the MOW, yielded a large amount of carbonate slabs and chimneys. These consist essentially of intrapelbiomicrite. Petrographic and XRD shows that their mineralogical composition consists mainly of dolomite, high magnesium calcite, quartz, feldspar and clays. Bioclasts of plantonic foraminifera (globigerinoids), ostracods and peletts are observed. Iron and manganese oxides are present and the cement is essentially biomicrite. In different samples from the same chimney a variation on the dolomite/calcite ratio is observed from the interior to the external part of the chimney. Values of dolomite show a variation from 47% in the interior to 17 % in the exterior. As regards Si02 (19-16%), Al2O3 (4-3%) and Fe2O3 (5-7%), the variations observed are not significant. Stable isotopic analysis of Carbon shown low d13C values (down to -46.88 per mil vs. PDB) and d18O up to + 4.90 per mil vs.

Initial reactive sticking coefficient of O 2 on Si(111)-7 × 7 at elevated temperatures

NASA Astrophysics Data System (ADS)

Shklyaev, A. A.; Suzuki, Takanori

1996-05-01

Kinetics of the initial stage of oxide growth in the reaction of oxygen with Si(111)-7 × 7 at temperatures from room temperature to Ttr, and pressures from 5 × 10 -9 to 2 × 10 -7 Torr are investigated with optical second-harmonic generation, here temperature from oxide growth to Si etching without oxide growth. At a fixed pressure, the initial reactive sticking coefficient ( S0), obtained from the rate of oxide growth, decreases with increasing temperature to S0=0 at Ttr. We have found that the initial reacti sticking coefficient depends on the O 2 pressure. At temperatures above 320°C, the whole temperature dependence of S0 is situated in the region of higher temperatures for higher O 2 pressures ( Pox). Moreover, an additional bend in the temperature dependence of S0 is observed for Pox>1 × 10 -8 Torr near Ttr. A precursor-mediated adsorption model involving the reaction of formation is considered. The parameters of this model, obtained from the best fits to the experimental data, show that oxide growth rate constant increases and volatile SiO formation rate constant decreases as a function of O 2 pressure. At zero oxide coverage, the pressure dependence of the reaction rate constants is suggested to originate from interaction in the layer of the chemisorbed precursor species, whose coverage depends on the O 2 pressure. The volatile SiO formation is described by a three-step sequential two-channel process through the chemisorbed O 2 precursor species, whereas one of the channels with a larger activation energy is suggested to induce the additional bend in S0( T) near Ttr at higher O 2 pressures.

Patient-Specific Tailored Intervention Improves INR Time in Therapeutic Range and INR Variability in Heart Failure Patients.

PubMed

Gotsman, Israel; Ezra, Orly; Hirsh Raccah, Bruria; Admon, Dan; Lotan, Chaim; Dekeyser Ganz, Freda

2017-08-01

Many patients with heart failure need anticoagulants, including warfarin. Good control is particularly challenging in heart failure patients, with <60% of international normalized ratio (INR) measurements in the therapeutic range, thereby increasing the risk of complications. This study aimed to evaluate the effect of a patient-specific tailored intervention on anticoagulation control in patients with heart failure. Patients with heart failure taking warfarin therapy (n = 145) were randomized to either standard care or a 1-time intervention assessing potential risk factors for lability of INR, in which they received patient-specific instructions. Time in therapeutic range (TTR) using Rosendaal's linear model was assessed 3 months before and after the intervention. The patient-tailored intervention significantly increased anticoagulation control. The median TTR levels before intervention were suboptimal in the interventional and control groups (53% vs 45%, P = .14). After intervention the median TTR increased significantly in the interventional group compared with the control group (80% [interquartile range, 62%-93%] vs 44% [29%-61%], P <.0001). The intervention resulted in a significant improvement in the interventional group before versus after intervention (53% vs 80%, P <.0001) but not in the control group (45% vs 44%, P = .95). The percentage of patients with a TTR ≥60%, considered therapeutic, was substantially higher in the interventional group: 79% versus 25% (P <.0001). The INR variability (standard deviation of each patient's INR measurements) decreased significantly in the interventional group, from 0.53 to 0.32 (P <.0001) after intervention but not in the control group. Patient-specific tailored intervention significantly improves anticoagulation therapy in patients with heart failure. Copyright © 2017 Elsevier Inc. All rights reserved.

DEVELOPMENT OF AN ANTIFOAM TRACKING SYSTEM AS AN OPTION TO SUPPORT THE MELTER OFF-GAS FLAMMABILITY CONTROL STRATEGY AT THE DWPF

DOE Office of Scientific and Technical Information (OSTI.GOV)

Edwards, T.; Lambert, D.

The Savannah River National Laboratory (SRNL) has been working with the Savannah River Remediation (SRR) Defense Waste Processing Facility (DWPF) in the development and implementation of an additional strategy for confidently satisfying the flammability controls for DWPF’s melter operation. An initial strategy for implementing the operational constraints associated with flammability control in DWPF was based upon an analytically determined carbon concentration from antifoam. Due to the conservative error structure associated with the analytical approach, its implementation has significantly reduced the operating window for processing and has led to recurrent Slurry Mix Evaporator (SME) and Melter Feed Tank (MFT) remediation. Tomore » address the adverse operating impact of the current implementation strategy, SRR issued a Technical Task Request (TTR) to SRNL requesting the development and documentation of an alternate strategy for evaluating the carbon contribution from antifoam. The proposed strategy presented in this report was developed under the guidance of a Task Technical and Quality Assurance Plan (TTQAP) and involves calculating the carbon concentration from antifoam based upon the actual mass of antifoam added to the process assuming 100% retention. The mass of antifoam in the Additive Mix Feed Tank (AMFT), in the Sludge Receipt and Adjustment Tank (SRAT), and in the SME is tracked by mass balance as part of this strategy. As these quantities are monitored, the random and bias uncertainties affecting their values are also maintained and accounted for. This report documents: 1) the development of an alternate implementation strategy and associated equations describing the carbon concentration from antifoam in each SME batch derived from the actual amount of antifoam introduced into the AMFT, SRAT, and SME during the processing of the batch. 2) the equations and error structure for incorporating the proposed strategy into melter off-gas flammability assessments. Sample calculations of the system are also included in this report. Please note that the system developed and documented in this report is intended as an alternative to the current, analytically-driven system being utilized by DWPF; the proposed system is not intended to eliminate the current system. Also note that the system developed in this report to track antifoam mass in the AMFT, SRAT, and SME will be applicable beyond just Sludge Batch 8. While the model used to determine acceptability of the SME product with respect to melter off-gas flammability controls must be reassessed for each change in sludge batch, the antifoam mass tracking methodology is independent of sludge batch composition and as such will be transferable to future sludge batches.« less

Task Management for Firefighters: A Practical Approach to Task Management.

ERIC Educational Resources Information Center

Roberts, Stephen S.

1979-01-01

A project management system for organizing requests from multiple departments and controlling the workload of the development/maintenance computer staff is described. Practical solutions to deciding project priorities, determining time estimates, creating positive peer pressure among programing staff, and formalizing information requests are…

Timing of gazes in child dialogues: a time-course analysis of requests and back channelling in referential communication.

PubMed

Sandgren, Olof; Andersson, Richard; van de Weijer, Joost; Hansson, Kristina; Sahlén, Birgitta

2012-01-01

This study investigates gaze behaviour in child dialogues. In earlier studies the authors have investigated the use of requests for clarification and responses in order to study the co-creation of understanding in a referential communication task. By adding eye tracking, this line of research is now expanded to include non-verbal contributions in conversation. To investigate the timing of gazes in face-to-face interaction and to relate the gaze behaviour to the use of requests for clarification. Eight conversational pairs of typically developing 10-15 year olds participated. The pairs (director and executor) performed a referential communication task requiring the description of faces. During the dialogues both participants wore head-mounted eye trackers. All gazes were recorded and categorized according to the area fixated (Task, Face, Off). The verbal context for all instances of gaze at the partner's face was identified and categorized using time-course analysis. The results showed that the executor spends almost 90% of the time fixating the gaze on the task, 10% on the director's face and less than 0.5% elsewhere. Turn shift, primarily requests for clarification, and back channelling significantly predicted the executors' gaze to the face of the task director. The distribution of types of requests showed that requests for previously unmentioned information were significantly more likely to be associated with gaze at the director. The study shows that the executors' gaze at the director accompanies important dynamic shifts in the dialogue. The association with requests for clarification indicates that gaze at the director can be used to monitor the response with two modalities. Furthermore, the significantly higher association with requests for previously unmentioned information indicates that gaze may be used to emphasize the verbal content. The results will be used as a reference for studies of gaze behaviour in clinical populations with hearing and language impairments. © 2012 Royal College of Speech and Language Therapists.

Impact of Aspirin on Warfarin Control as Measured by Time in Therapeutic Range.

PubMed

Boyce, Michelle L; Zayac, Alexa; Davis, Arie; Badrick, Tony; Anoopkumar-Dukie, Shailendra; Bernaitis, Nijole

2018-05-12

Warfarin is an oral anticoagulant widely prescribed for a variety of thromboembolic indications including venous thromboembolism (VTE) deep vein thrombosis (DVT) and the prevention of stroke associated for atrial fibrillation (AF). 1 Warfarin requires ongoing monitoring of Internationalised Normalised Ratio (INR) due to a narrow therapeutic index and interactions with numerous drugs. 2 The time in therapeutic range (TTR) is often used to indicate the quality of warfarin therapy due to the established correlation between higher mean TTR and reduced complications such as bleeding and thromboembolism. 3 This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Transition temperature range of thermally activated nickel-titanium archwires

PubMed Central

SPINI, Tatiana Sobottka; VALARELLI, Fabrício Pinelli; CANÇADO, Rodrigo Hermont; de FREITAS, Karina Maria Salvatore; VILLARINHO, Denis Jardim

2014-01-01

Objectives The shape memory resulting from the superelasticity and thermoelastic effect is the main characteristic of thermally activated NiTi archwires and is closely related to the transition temperature range (TTR). The aim of this study was to evaluate the TTR of thermally activated NiTi archwires commercially available. Material and Methods Seven different brands of 0.019"x0.025" thermally activated nickel-titanium archwires were tested as received by differential scanning calorimetry (DSC) over the temperature range from -100°C to 150°C at 10°C/min. Results All thermally activated NiTi archwires analyzed presented stage transformation during thermal scanning with final austenitic temperature (Af) ranging from 20.39°C to 45.42°C. Three brands of NiTi archwires presented Af close to the room temperature and, this way, do not present properties of shape memory and pseudoelasticity that are desirable in clinical applications. Conclusions The thermally activated NiTi archwires present great variability in the TTR and the elastic parameters of each NiTi archwire should be provided by the manufacturers, to allow achievement of the best clinical performance possible. PMID:24676581

Air Monitoring Network at Tonopah Test Range: Network Description, Capabilities, and Analytical Results

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hartwell, William T.; Daniels, Jeffrey; Nikolich, George

2012-01-01

During the period April to June 2008, at the behest of the Department of Energy (DOE), National Nuclear Security Administration, Nevada Site Office (NNSA/NSO); the Desert Research Institute (DRI) constructed and deployed two portable environmental monitoring stations at the Tonopah Test Range (TTR) as part of the Environmental Restoration Project Soils Activity. DRI has operated these stations since that time. A third station was deployed in the period May to September 2011. The TTR is located within the northwest corner of the Nevada Test and Training Range (NTTR), and covers an area of approximately 725.20 km2 (280 mi2). The primarymore » objective of the monitoring stations is to evaluate whether and under what conditions there is wind transport of radiological contaminants from Soils Corrective Action Units (CAUs) associated with Operation Roller Coaster on TTR. Operation Roller Coaster was a series of tests, conducted in 1963, designed to examine the stability and dispersal of plutonium in storage and transportation accidents. These tests did not result in any nuclear explosive yield. However, the tests did result in the dispersal of plutonium and contamination of surface soils in the surrounding area.« less

Improving the management of warfarin in aged-care facilities utilising innovative technology: a proof-of-concept study.

PubMed

Bereznicki, Luke R E; Jackson, Shane L; Kromdijk, Wiete; Gee, Peter; Fitzmaurice, Kimbra; Bereznicki, Bonnie J; Peterson, Gregory M

2014-02-01

In aged-care facilities (ACFs) monitoring of warfarin can be logistically challenging and International Normalised Ratio (INR control) is often suboptimal. We aimed to determine whether an integrated information and communications technology system and the use of point-of-care (POC) monitors by nursing staff could improve the INR control of aged-care facility residents who take warfarin. Nursing staff identified residents who were prescribed warfarin in participating ACFs. A computer program (MedePOC) was developed to store and transmit INR results from the ACFs to general practitioners (GPs) for dosage adjustment. Nursing staff received training in the use of the CoaguChek XS point-of-care INR monitor and the MedePOC software. Following a run-in phase, eligible patients were monitored weekly for up to 12 weeks. The primary outcome was the change in the time in therapeutic range (TTR) in the intervention phase compared to the TTR in the 12 months preceding the study. All GPs, nursing staff and patients were surveyed for their experiences and opinions of the project. Twenty-four patients and 19 GPs completed the trial across six ACFs. The mean TTR for all patients improved non-significantly from 58.9 to 60.6% (P=0.79) and the proportion of INR tests in range improved non-significantly from 57.1 to 64.1% (P=0.21). The mean TTR improved in 14 patients (58%) and in these patients the mean absolute improvement in TTR was 23.1%. A post hoc analysis of the INR data using modified therapeutic INR ranges to reflect the dosage adjustment practices of GPs suggested that the intervention did lead to improved INR control. The MedePOC program and POC monitoring was well received by nursing staff. Weekly POC INR monitoring conducted in ACFs and electronic communication of the results and warfarin doses resulted in non-significant improvements in INR control in a small cohort of elderly residents. Further research involving modification to the communication strategy and a longer follow-up period is warranted to investigate whether this strategy can improve INR control and clinical outcomes in this vulnerable population. © 2013 The Authors. IJPP © 2013 Royal Pharmaceutical Society.

75 FR 12493 - Task Force on Childhood Obesity: Request for Information

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-16

... Force on Childhood Obesity: Request for Information AGENCY: U.S. Department of Agriculture, U.S.... SUMMARY: Across the country, childhood obesity has reached epidemic rates. On February 9, 2010, President Obama signed a Presidential Memo establishing a Task Force on Childhood Obesity that directs Federal...

What drives the 'August effect'? A observational study of the effect of junior doctor changeover on out of hours work.

PubMed

Blakey, John D; Fearn, Andrew; Shaw, Dominick E

2013-01-01

To investigate whether measurements of junior doctor on-call workload and performance can clarify the mechanisms underlying the increase in morbidity and mortality seen after junior doctor changeover: the 'August effect'. Quantitative retrospective observational study of routinely collected data on junior doctor workload. Two large teaching hospitals in England. Task level data from a wireless out of hours system (n = 29,885 requests) used by medical staff, nurses, and allied health professionals. Number and type of tasks requested by nurses, time to completion of tasks by junior doctors. There was no overall change in the number of tasks requested by nurses out of hours around the August changeover (median requests per hour 15 before and 14 after, p = 0.46). However, the number of tasks classified as urgent was greater (p = 0.016) equating to five more urgent tasks per day. After changeover, doctors took less time to complete tasks overall due to a reduction in time taken for routine tasks (median 74 vs. 66 min; p = 3.9 × 10(-9)). This study suggests that the 'August effect' is not due to new junior doctors completing tasks more slowly or having a greater workload. Further studies are required to investigate the causes of the increased number of urgent tasks seen, but likely factors are errors, omissions, and poor prioritization. Thus, improved training and quality control has the potential to address this increased duration of unresolved patient risk. The study also highlights the potential of newer technologies to facilitate quantitative study of clinical activity.

TANKS 18 AND 19-F STRUCTURAL FLOWABLE GROUT FILL MATERIAL EVALUATION AND RECOMMENDATIONS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stefanko, D.; Langton, C.

2011-11-01

Cementitious grout will be used to close Tanks 18-F and 19-F. The functions of the grout are to: (1) physically stabilize the final landfill by filling the empty volume in the tanks with a non compressible material; (2) provide a barrier for inadvertent intrusion into the tank; (3) reduce contaminant mobility by (a) limiting the hydraulic conductivity of the closed tank and (b) reducing contact between the residual waste and infiltrating water; and (4) providing an alkaline, chemically reducing environment in the closed tank to control speciation and solubility of selected radionuclides. The objective of this work was to identifymore » a single (all-in-one) grout to stabilize and isolate the residual radionuclides in the tank, provide structural stability of the closed tank and serve as an inadvertent intruder barrier. This work was requested by V. A. Chander, High Level Waste (HLW) Tank Engineering, in HLW-TTR-2011-008. The complete task scope is provided in the Task Technical and QA Plan, SRNL-RP-2011-00587 Revision 0. The specific objectives of this task were to: (1) Identify new admixtures and dosages for formulating a zero bleed flowable tank fill material selected by HLW Tank Closure Project personnel based on earlier tank fill studies performed in 2007. The chemical admixtures used for adjusting the flow properties needed to be updated because the original admixture products are no longer available. Also, the sources of cement and fly ash have changed, and Portland cements currently available contain up to 5 wt. % limestone (calcium carbonate). (2) Prepare and evaluate the placement, compressive strength, and thermal properties of the selected formulation with new admixture dosages. (3) Identify opportunities for improving the mix selected by HLW Closure Project personnel and prepare and evaluate two potentially improved zero bleed flowable fill design concepts; one based on the reactor fill grout and the other based on a shrinkage compensating flowable fill mix design. (4) Prepare samples for hydraulic property measurements for comparison to the values in the F and H- Tank Farm Performance Assessments (PAs). (5) Identify a grout mix for the Tanks 18-F and 19-F Grout Procurement Specification [Forty, 2011 a, b, c]. Results for two flowable zero bleed structural fill concepts containing 3/8 inch gravel (70070 Series and LP-8 Series) and a sand only mix (SO Series) are provided in this report. Tank Farm Engineering and SRNL Project Management selected the 70070 mix as the base case for inclusion in Revision 0 of the Tanks 18-F and 19-F grout procurement specification [Forty 2011 a] and requested admixture recommendations and property confirmation for this formulation [Forty, 2011 b]. Lower cementitious paste mixes were formulated because the 70070 mix is over designed with respect to strength and generates more heat from hydration reactions than is desirable for mass pour application. Work was also initiated on a modification of the recommended mix which included shrinkage compensation to mitigate fast pathways caused by shrinkage cracking and poor physical bonding to the tank and ancillary equipment. Testing of this option was postponed to FY12.« less

Coherent two-dimensional terahertz-terahertz-Raman spectroscopy.

PubMed

Finneran, Ian A; Welsch, Ralph; Allodi, Marco A; Miller, Thomas F; Blake, Geoffrey A

2016-06-21

We present 2D terahertz-terahertz-Raman (2D TTR) spectroscopy, the first technique, to our knowledge, to interrogate a liquid with multiple pulses of terahertz (THz) light. This hybrid approach isolates nonlinear signatures in isotropic media, and is sensitive to the coupling and anharmonicity of thermally activated THz modes that play a central role in liquid-phase chemistry. Specifically, by varying the timing between two intense THz pulses, we control the orientational alignment of molecules in a liquid, and nonlinearly excite vibrational coherences. A comparison of experimental and simulated 2D TTR spectra of bromoform (CHBr3), carbon tetrachloride (CCl4), and dibromodichloromethane (CBr2Cl2) shows previously unobserved off-diagonal anharmonic coupling between thermally populated vibrational modes.

21 CFR 20.50 - Nonspecific and overly burdensome requests.

Code of Federal Regulations, 2010 CFR

2010-04-01

... policy reasons justifying the requests. A decision on the processing of such a request for information... PUBLIC INFORMATION Procedures and Fees § 20.50 Nonspecific and overly burdensome requests. The Food and... taking into account the staff-hours required, the tasks from which these resources must be diverted, the...

Hsf-1 affects podocyte markers NPHS1, NPHS2 and WT1 in a transgenic mouse model of TTRVal30Met-related amyloidosis.

PubMed

Petrakis, Ioannis; Mavroeidi, Vasiliki; Stylianou, Kostas; Andronikidi, Eva; Lioudaki, Eirini; Perakis, Kostas; Stratigis, Spyridon; Vardaki, Eleftheria; Zafeiri, Maria; Giannakakis, Kostantinos; Plaitakis, Andreas; Amoiridis, George; Saraiva, Maria Joao; Daphnis, Eugene

2013-09-01

Familial amyloid polyneuropathy is characterized by transthyretin (TTR) deposition in various tissues, including the kidneys. While deposition induces organ dysfunction, renal involvement in TTR-related amyloidosis could manifest from proteinuria to end-stage kidney failure. As proteinuria is considered result of glomerular filtration barrier injury we investigated whether TTR deposition affects either glomerular basement membrane (GBM) or podocytes. Immunohistochemistry, immunoblot and gene expression studies for nephrin, podocin and WT1 were run on renal tissue from human-TTRV30M transgenic mice hemizygous or homozygous for heat shock factor one (Hsf-1). Transmission electron microscopy was used for evaluation of podocyte foot process width (PFW) and GBM thickness in Hsf-1 hemizygous mice with or without TTRV30M or amyloid deposition. Glomeruli of hsf-1 hemizygous transgenic mice showed lower nephrin and podocin protein levels but an increased podocyte number when compared to Hsf-1 homozygous transgenic mice. Nephrin, podocin and WT1 gene expression levels were unaffected by the Hsf-1 carrier status. TTRV30M deposition was associated with increased PFW and GBM thickness. Under the effect of Hsf-1 hemizygosity, TTRV30M deposition has deleterious effects on GBM thickness, PFW and slit diaphragm composition, without affecting nephrin and podocin gene expression.

Different disease-causing mutations in transthyretin trigger the same conformational conversion.

PubMed

Steward, Robert E; Armen, Roger S; Daggett, Valerie

2008-03-01

Transthyretin (TTR)-containing amyloid fibrils are deposited in cardiac tissue as a natural consequence of aging. A large number of inherited mutations lead to amyloid diseases by accelerating TTR deposition in other organs. Amyloid formation is preceded by a disruption of the quaternary structure of TTR and conformational changes in the monomer. To study conformational changes preceding the formation of amyloid, we performed molecular dynamics simulations of the wild-type monomer, amyloidogenic variants (V30M, L55P, V122I) and a protective variant (T119M) at neutral and low pH. At low pH, the D strand dissociated from the beta-sheet to expose the A strand, consistent with experimental studies. In amyloidogenic variants and in the wild-type at low pH, there was a conformational change in the beta-sheets into alpha-sheet via peptide bond flips that was not observed at neutral pH in the wild-type monomer. The same residues participated in conversion in each amyloidogenic variant simulation, originating in the G strand between residues 106 and 109, with accelerated conversion at low pH. The T119M protective variant changed the local conformation of the H strand and suppressed the conversion observed in amyloidogenic variants.

Amyloid Formation by Human Carboxypeptidase D Transthyretin-like Domain under Physiological Conditions*

PubMed Central

Garcia-Pardo, Javier; Graña-Montes, Ricardo; Fernandez-Mendez, Marc; Ruyra, Angels; Roher, Nerea; Aviles, Francesc X.; Lorenzo, Julia; Ventura, Salvador

2014-01-01

Protein aggregation is linked to a growing list of diseases, but it is also an intrinsic property of polypeptides, because the formation of functional globular proteins comes at the expense of an inherent aggregation propensity. Certain proteins can access aggregation-prone states from native-like conformations without the need to cross the energy barrier for unfolding. This is the case of transthyretin (TTR), a homotetrameric protein whose dissociation into its monomers initiates the aggregation cascade. Domains with structural homology to TTR exist in a number of proteins, including the M14B subfamily carboxypeptidases. We show here that the monomeric transthyretin-like domain of human carboxypeptidase D aggregates under close to physiological conditions into amyloid structures, with the population of folded but aggregation-prone states being controlled by the conformational stability of the domain. We thus confirm that the TTR fold keeps a generic residual aggregation propensity upon folding, resulting from the presence of preformed amyloidogenic β-strands in the native state. These structural elements should serve for functional/structural purposes, because they have not been purged out by evolution, but at the same time they put proteins like carboxypeptidase D at risk of aggregation in biological environments and thus can potentially lead to deposition diseases. PMID:25294878

Serum ferritin as a new prognostic factor in hepatocellular carcinoma patients treated with radiofrequency ablation.

PubMed

Facciorusso, Antonio; Del Prete, Valentina; Antonino, Matteo; Neve, Viviana; Crucinio, Nicola; Di Leo, Alfredo; Carr, Brian I; Barone, Michele

2014-11-01

Hepatic iron accumulation is considered to be a cofactor that influences liver injury and hepatocarcinogenesis. Aim of this study is to determine whether serum ferritin (SF) levels relate to overall survival (OS) and time to recurrence (TTR) in hepatocellular carcinoma (HCC) patients treated with percutaneous radiofrequency ablation (RFA). We measured SF levels in 103 HCC patients (median age 70, M/F = 82.5%/17.5%) who underwent RFA between 2005 and 2010. Correlation between SF and other prognostic factors at baseline was analyzed. SF levels were entered into a Cox model and their influence on OS and TTR was evaluated in univariate and multivariate analyses. SF did not correlate with α-fetoprotein (rho: -0.12, P = 0.22), neutrophil/lymphocyte ratio (rho: -0.1020, P = 0.30), Model for End-Stage Liver Disease (rho: 0.18, P = 0.06), Child-Pugh score (P = 0.5), or Barcelona Cancer of the Liver Clinic stage (P = 0.16). A log-rank test found the value of 244 ng/mL as the optimal prognostic cut-off point for SF. Median OS was 62 months (54-78) and survival rate was 97%, 65%, and 52% at 1, 4, and 5 years, respectively. Performance status and SF were the only predictors of OS at multivariate analysis. Median TTR was 38 months (34-49) with a recurrence-free survival rate of 82.5%, 26.2%, and 23.3% at 1, 4, and 5 years, respectively, while SF and age were the only predictors of TTR. SF level, possibly reflecting the degree of hepatic inflammation and fibrosis, is a negative risk factor for survival and recurrence after percutaneous RFA in HCC patients. © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

Anticoagulant and antiplatelet therapy in patients with atrial fibrillation undergoing percutaneous coronary intervention.

PubMed

Goto, Koji; Nakai, Kentaro; Shizuta, Satoshi; Morimoto, Takeshi; Shiomi, Hiroki; Natsuaki, Masahiro; Yahata, Mitsuhiko; Ota, Chihiro; Ono, Koh; Makiyama, Takeru; Nakagawa, Yoshihisa; Furukawa, Yutaka; Kadota, Kazushige; Takatsu, Yoshiki; Tamura, Takashi; Takizawa, Akinori; Inada, Tsukasa; Doi, Osamu; Nohara, Ryuji; Matsuda, Mitsuo; Takeda, Teruki; Kato, Masayuki; Shirotani, Manabu; Eizawa, Hiroshi; Ishii, Katsuhisa; Lee, Jong-Dae; Takahashi, Masaaki; Horie, Minoru; Takahashi, Mamoru; Miki, Shinji; Aoyama, Takeshi; Suwa, Satoru; Hamasaki, Shuichi; Ogawa, Hisao; Mitsudo, Kazuaki; Nobuyoshi, Masakiyo; Kita, Toru; Kimura, Takeshi

2014-07-01

The prevalence, intensity, safety, and efficacy of oral anticoagulation (OAC) in addition to dual antiplatelet therapy (DAPT) in "real-world" patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) have not yet been fully evaluated. In the Coronary REvascularization Demonstrating Outcome Study in Kyoto registry cohort-2, a total of 1,057 patients with AF (8.3%) were identified among 12,716 patients undergoing first PCI. Cumulative 5-year incidence of stroke was higher in patients with AF than in no-AF patients (12.8% vs 5.8%, p <0.0001). Although most patients with AF had CHADS2 score ≥2 (75.2%), only 506 patients (47.9%) received OAC with warfarin at hospital discharge. Cumulative 5-year incidence of stroke in the OAC group was not different from that in the no-OAC group (13.8% vs 11.8%, p = 0.49). Time in therapeutic range (TTR) was only 52.6% with an international normalized ratio of 1.6 to 2.6, and only 154 of 409 patients (37.7%) with international normalized ratio data had TTR ≥65%. Cumulative 5-year incidence of stroke in patients with TTR ≥65% was markedly lower than that in patients with TTR <65% (6.9% vs 15.1%, p = 0.01). In a 4-month landmark analysis in the OAC group, there was a trend for higher cumulative incidences of stroke and major bleeding in the on-DAPT (n = 286) than in the off-DAPT (n = 173) groups (15.1% vs 6.7%, p = 0.052 and 14.7% vs 8.7%, p = 0.10, respectively). In conclusion, OAC was underused and its intensity was mostly suboptimal in real-world patients with AF undergoing PCI, which lead to inadequate stroke prevention. Long-term DAPT in patients receiving OAC did not reduce stroke incidence. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Smad4 Loss in Esophageal Adenocarcinoma Is Associated With an Increased Propensity for Disease Recurrence and Poor Survival

PubMed Central

Singhi, Aatur D.; Foxwell, Tyler J.; Nason, Katie; Cressman, Kristi L.; McGrath, Kevin M.; Sun, Weijing; Bahary, Nathan; Zeh, Herbert J.; Levy, Ryan M.; Luketich, James D.; Davison, Jon M.

2015-01-01

Previously regarded as a rare neoplasm, the incidence of esophageal adenocarcinoma has risen rapidly in recent decades. It is often discovered late in the disease process and has a dismal prognosis. Current prognostic markers including clinical, radiographic, and histopathologic findings have limited utility and do not consider the biology of this deadly disease. Genome-wide analyses have identified SMAD4 inactivation in a subset of tumors. Although Smad4 has been extensively studied in other gastrointestinal malignancies, its role in esophageal adenocarcinoma remains to be defined. Herein, we show, in a large cohort of esophageal adenocarcinomas, Smad4 loss by immunohistochemistry in 21 of 205 (10%) tumors and that Smad4 loss correlated with increased postoperative recurrence (P=0.040). Further, patients whose tumors lacked Smad4 had shorter time to recurrence (TTR) (P=0.007) and poor overall survival (OS) (P=0.011). The median TTR and OS of patients with Smad4-negative tumors was 13 and 16 months, respectively, as compared with 23 and 22 months, respectively, among patients with Smad4-positive tumors. In multivariate analyses, Smad4 loss was a prognostic factor for both TTR and OS, independent of histologic grade, lymphovascular invasion, perineural invasion, tumor stage, and lymph node status. Considering Smad4 loss correlated with postoperative locoregional and/or distant metastases, Smad4 was also assessed in a separate cohort of 5 locoregional recurrences and 43 metastatic esophageal adenocarcinomas. In contrast to primary tumors, a higher prevalence of Smad4 loss was observed in metastatic disease (44% vs. 10%). In summary, loss of Smad4 protein expression is an independent prognostic factor for TTR and OS that correlates with increased propensity for disease recurrence and poor survival in patients with esophageal adenocarcinoma after surgical resection. PMID:25634752

Factors associated with survival after relapse in patients with low-risk endometrial cancer treated with surgery alone

PubMed Central

2017-01-01

Objective To determine factors influencing overall survival following recurrence (OSFR) in women with low-risk endometrial cancer (EC) treated with surgery alone. Methods A multicenter, retrospective department database review was performed to identify patients with recurrent “low-risk EC” (patients having less than 50% myometrial invasion [MMI] with grade 1 or 2 endometrioid EC) at 10 gynecologic oncology centers in Turkey. Demographic, clinicopathological, and survival data were collected. Results We identified 67 patients who developed recurrence of their EC after initially being diagnosed and treated for low-risk EC. For the entire study cohort, the median time to recurrence (TTR) was 23 months (95% confidence interval [CI]=11.5–34.5; standard error [SE]=5.8) and the median OSFR was 59 months (95% CI=12.7–105.2; SE=23.5). We observed 32 (47.8%) isolated vaginal recurrences, 6 (9%) nodal failures, 19 (28.4%) peritoneal failures, and 10 (14.9%) hematogenous disseminations. Overall, 45 relapses (67.2%) were loco-regional whereas 22 (32.8%) were extrapelvic. According to the Gynecologic Oncology Group (GOG) Trial-99, 7 (10.4%) out of 67 women with recurrent low-risk EC were qualified as high-intermediate risk (HIR). The 5-year OSFR rate was significantly higher for patients with TTR ≥36 months compared to those with TTR <36 months (74.3% compared to 33%, p=0.001). On multivariate analysis for OSFR, TTR <36 months (hazard ratio [HR]=8.46; 95% CI=1.65–43.36; p=0.010) and presence of HIR criteria (HR=4.62; 95% CI=1.69–12.58; p=0.003) were significant predictors. Conclusion Low-risk EC patients recurring earlier than 36 months and those carrying HIR criteria seem more likely to succumb to their tumors after recurrence. PMID:28657226

Vaccination with live attenuated simian immunodeficiency virus causes dynamic changes in intestinal CD4+CCR5+ T cells

PubMed Central

2011-01-01

Background Vaccination with live attenuated SIV can protect against detectable infection with wild-type virus. We have investigated whether target cell depletion contributes to the protection observed. Following vaccination with live attenuated SIV the frequency of intestinal CD4+CCR5+ T cells, an early target of wild-type SIV infection and destruction, was determined at days 3, 7, 10, 21 and 125 post inoculation. Results In naive controls, modest frequencies of intestinal CD4+CCR5+ T cells were predominantly found within the LPL TTrM-1 and IEL TTrM-2 subsets. At day 3, LPL and IEL CD4+CCR5+ TEM cells were dramatically increased whilst less differentiated subsets were greatly reduced, consistent with activation-induced maturation. CCR5 expression remained high at day 7, although there was a shift in subset balance from CD4+CCR5+ TEM to less differentiated TTrM-2 cells. This increase in intestinal CD4+CCR5+ T cells preceded the peak of SIV RNA plasma loads measured at day 10. Greater than 65.9% depletion of intestinal CD4+CCR5+ T cells followed at day 10, but overall CD4+ T cell homeostasis was maintained by increased CD4+CCR5- T cells. At days 21 and 125, high numbers of intestinal CD4+CCR5- naive TN cells were detected concurrent with greatly increased CD4+CCR5+ LPL TTrM-2 and IEL TEM cells at day 125, yet SIV RNA plasma loads remained low. Conclusions This increase in intestinal CD4+CCR5+ T cells, following vaccination with live attenuated SIV, does not correlate with target cell depletion as a mechanism of protection. Instead, increased intestinal CD4+CCR5+ T cells may correlate with or contribute to the protection conferred by vaccination with live attenuated SIV. PMID:21291552

A team-based approach to warfarin management in long term care: A feasibility study of the MEDeINR electronic decision support system

PubMed Central

2010-01-01

Background Previous studies in long-term care (LTC) have demonstrated that warfarin management is suboptimal with preventable adverse events often occurring as a result of poor International Normalized Ratio (INR) control. To assist LTC teams with the challenge of maintaining residents on warfarin in the therapeutic range (INR of 2.0 to 3.0), we developed an electronic decision support system that was based on a validated algorithm for warfarin dosing. We evaluated the MEDeINR system in a pre-post implementation design by examining the impact on INR control, testing frequency, and experiences of staff in using the system. Methods For this feasibility study, we piloted the MEDeINR system in six LTC homes in Ontario, Canada. All128 residents (without a prosthetic valve) who were taking warfarin were included. Three-months of INR data prior to MEDeINR was collected via a retrospective chart audit, and three-months of INR data after implementation of MEDeINR was captured in the central computer database. The primary outcomes compared in a pre-post design were time in therapeutic range (TTR) and time in sub/supratherapeutic ranges based on all INR measures for every resident on warfarin. Secondary measures included the number of monthly INR tests/resident and survey/focus-group feedback from the LTC teams. Results LTC homes in our study had TTR's that were higher than past reports prior to the intervention. Overall, the TTR increased during the MEDeINR phase (65 to 69%), but was only significantly increased for one home (62% to 71%, p < 0.05). The percentage of time in supratherapeutic decreased from 14% to 11%, p = 0.08); there was little change for the subtherapeutic range (21% to 20%, p = 0.66). Overall, the average number of INR tests/30 days decreased from 4.2 to 3.1 (p < 0.0001) per resident after implementation of MEDeINR. Feedback received from LTC clinicians and staff was that the program decreased the work-load, improved confidence in management and decisions, and was generally easy to use. Conclusion Although LTC homes in our sample had TTR's that were relatively high prior to the intervention, the MEDeINR program represented a useful tool to promote optimal TTR, decrease INR venipunctures, streamline processes, and increase nurse and physician confidence around warfarin management. We have demonstrated that MEDeINR was a practical, usable clinical information system that can be incorporated into the LTC environment. PMID:20537178

High-Preference Strategies and Other Interspersal Procedures for Learners with Disabilities: A Review of the Literature

ERIC Educational Resources Information Center

Clinton, Elias; Clees, Tom J.

2015-01-01

Interspersal Procedures (IP) represent a group of interventions that imbed, at varying ratios, requests for individuals to exhibit mastered skills before or within sequences of requests for target skills. Interspersal Procedures include numerous strategies, such as high-probability request sequences, pre-task requests, and high-preference…

78 FR 1918 - Public-Private Partnerships Public Meeting and Request for Comment

Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-09

... complexities in P3 agreements, tasked the USDOT, via the Moving Ahead for Progress in the 21st Century Act (MAP...), DOT. ACTION: Public meeting notice; request for comment. SUMMARY: The USDOT/FHWA is tasked by MAP-21... be conducted on Wednesday, January 16, 2013, from 12:00 p.m. to 4:00 p.m., e.t. ADDRESSES: Comment...

SLUDGE WASHING AND DEMONSTRATION OF THE DWPF FLOWSHEET IN THE SRNL SHIELDED CELLS FOR SLUDGE BATCH 7A QUALIFICATION

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pareizs, J.; Billings, A.; Click, D.

2011-07-08

Waste Solidification Engineering (WSE) has requested that characterization and a radioactive demonstration of the next batch of sludge slurry (Sludge Batch 7a*) be completed in the Shielded Cells Facility of the Savannah River National Laboratory (SRNL) via a Technical Task Request (TTR). This characterization and demonstration, or sludge batch qualification process, is required prior to transfer of the sludge from Tank 51 to the Defense Waste Processing Facility (DWPF) feed tank (Tank 40). The current WSE practice is to prepare sludge batches in Tank 51 by transferring sludge from other tanks. Discharges of nuclear materials from H Canyon are oftenmore » added to Tank 51 during sludge batch preparation. The sludge is washed and transferred to Tank 40, the current DWPF feed tank. Prior to transfer of Tank 51 to Tank 40, SRNL simulates the Tank Farm and DWPF processes with a Tank 51 sample (referred to as the qualification sample). Sludge Batch 7a (SB7a) is composed of portions of Tanks 4, 7, and 12; the Sludge Batch 6 heel in Tank 51; and a plutonium stream from H Canyon. SRNL received the Tank 51 qualification sample (sample ID HTF-51-10-125) following sludge additions to Tank 51. This report documents: (1) The washing (addition of water to dilute the sludge supernate) and concentration (decanting of supernate) of the SB7a - Tank 51 qualification sample to adjust sodium content and weight percent insoluble solids to Tank Farm projections. (2) The performance of a DWPF Chemical Process Cell (CPC) simulation using the washed Tank 51 sample. The simulation included a Sludge Receipt and Adjustment Tank (SRAT) cycle, where acid was added to the sludge to destroy nitrite and reduce mercury, and a Slurry Mix Evaporator (SME) cycle, where glass frit was added to the sludge in preparation for vitrification. The SME cycle also included replication of five canister decontamination additions and concentrations. Processing parameters were based on work with a non-radioactive simulant. (3) Vitrification of a portion of the SME product and characterization and durability testing (as measured by the Product Consistency Test (PCT)) of the resulting glass. (4) Rheology measurements of the initial slurry samples and samples after each phase of CPC processing. This program was controlled by a Task Technical and Quality Assurance Plan (TTQAP), and analyses were guided by an Analytical Study Plan. This work is Technical Baseline Research and Development (R&D) for the DWPF. It should be noted that much of the data in this document has been published in interoffice memoranda. The intent of this technical report is bring all of the SB7a related data together in a single permanent record and to discuss the overall aspects of SB7a processing.« less

The future distribution of the savannah biome: model-based and biogeographic contingency

PubMed Central

Scheiter, Simon; Langan, Liam; Trabucco, Antonio; Higgins, Steven I.

2016-01-01

The extent of the savannah biome is expected to be profoundly altered by climatic change and increasing atmospheric CO2 concentrations. Contrasting projections are given when using different modelling approaches to estimate future distributions. Furthermore, biogeographic variation within savannahs in plant function and structure is expected to lead to divergent responses to global change. Hence the use of a single model with a single savannah tree type will likely lead to biased projections. Here we compare and contrast projections of South American, African and Australian savannah distributions from the physiologically based Thornley transport resistance statistical distribution model (TTR-SDM)—and three versions of a dynamic vegetation model (DVM) designed and parametrized separately for specific continents. We show that attempting to extrapolate any continent-specific model globally biases projections. By 2070, all DVMs generally project a decrease in the extent of savannahs at their boundary with forests, whereas the TTR-SDM projects a decrease in savannahs at their boundary with aridlands and grasslands. This difference is driven by forest and woodland expansion in response to rising atmospheric CO2 concentrations in DVMs, unaccounted for by the TTR-SDM. We suggest that the most suitable models of the savannah biome for future development are individual-based dynamic vegetation models designed for specific biogeographic regions. This article is part of the themed issue ‘Tropical grassy biomes: linking ecology, human use and conservation’. PMID:27502376

The future distribution of the savannah biome: model-based and biogeographic contingency.

PubMed

Moncrieff, Glenn R; Scheiter, Simon; Langan, Liam; Trabucco, Antonio; Higgins, Steven I

2016-09-19

The extent of the savannah biome is expected to be profoundly altered by climatic change and increasing atmospheric CO2 concentrations. Contrasting projections are given when using different modelling approaches to estimate future distributions. Furthermore, biogeographic variation within savannahs in plant function and structure is expected to lead to divergent responses to global change. Hence the use of a single model with a single savannah tree type will likely lead to biased projections. Here we compare and contrast projections of South American, African and Australian savannah distributions from the physiologically based Thornley transport resistance statistical distribution model (TTR-SDM)-and three versions of a dynamic vegetation model (DVM) designed and parametrized separately for specific continents. We show that attempting to extrapolate any continent-specific model globally biases projections. By 2070, all DVMs generally project a decrease in the extent of savannahs at their boundary with forests, whereas the TTR-SDM projects a decrease in savannahs at their boundary with aridlands and grasslands. This difference is driven by forest and woodland expansion in response to rising atmospheric CO2 concentrations in DVMs, unaccounted for by the TTR-SDM. We suggest that the most suitable models of the savannah biome for future development are individual-based dynamic vegetation models designed for specific biogeographic regions.This article is part of the themed issue 'Tropical grassy biomes: linking ecology, human use and conservation'. © 2016 The Author(s).

Transthyretin V122I (pV142I)* cardiac amyloidosis: an age-dependent autosomal dominant cardiomyopathy too common to be overlooked as a cause of significant heart disease in elderly African Americans

PubMed Central

Buxbaum, Joel N.; Ruberg, Frederick L.

2017-01-01

Since the identification of a valine-to-isoleucine substitution at position 122 (TTR V122I; pV142I) in the transthyretin (TTR)-derived fibrils extracted from the heart of a patient with late-onset cardiac amyloidosis, it has become clear that the amyloidogenic mutation and the disease occur almost exclusively in individuals of identifiable African descent. In the United States, the amyloidogenic allele frequency is 0.0173 and is carried by 3.5% of community-dwelling African Americans. Genotyping across Africa indicates that the origin of the allele is in the West African countries that were the major source of the slave trade to North America. At autopsy, the allele was found to be associated with cardiac TTR amyloid deposition in all the carriers after age 65 years; however, the clinical penetrance varies, resulting in substantial heart disease in some carriers and few symptoms in others. The allele has been found in 10% of African Americans older than age 65 with severe congestive heart failure. At this time there are potential forms of therapy in clinical trials. The combination of a highly accurate genetic test and the potential for specific therapy demands a greater awareness of this autosomal dominant, age-dependent cardiac disease in the cardiology community. PMID:28102864

A Pilot Study to Evaluate Effectiveness of INR Self-Testing in Elderly Patients.

PubMed

Pogge, Elizabeth

2015-12-01

To determine if international normalized ratio (INR) patient self-testing (PST) resulted in an increased time in therapeutic range (TTR) in an elderly population when compared with clinic testing over a six-month period. A pilot study and retrospective chart review from August 2010 to August 2014. Ambulatory, anticoagulation clinic with two locations in Sun City West and Peoria, Arizona. Of 91 patients, the data of 20 patients who were 65 years of age or older and had at least six months of pre- and post-PST INR data were extracted and analyzed. The primary outcome evaluated improvement of TTR during post-PST in elderly patients compared with clinic management over a six-month period. Secondary outcomes assessed patients' satisfaction with PST and identified barriers to PST. The post-PST mean TTR significantly increased to 73% from 63.6% for the first six months of PST (P = 0.04). Participants were satisfied with PST, with an average score ranging from 4.6 to 5 on a Likert scale of 1 to 5 on 10 satisfaction survey questions. Cost was identified as the most common barrier to PST, with 43% of patients not participating in PST because of financial burden. With appropriate screening and training, PST is associated with improved TTRs and higher patient satisfaction in elderly patients when compared with clinic testing. Barriers identified to PST include cost, the complex process, and noncompliance.

Promoting Task-Based Pragmatics Instruction in EFL Classroom Contexts: The Role of Task Complexity

ERIC Educational Resources Information Center

Kim, Youjin; Taguchi, Naoko

2015-01-01

Robinson's (2001) Cognition Hypothesis claims that more complex tasks promote interaction and language development. This study examined the effect of task complexity in the learning of request-making expressions. Task complexity was operationalized as [+/- reasoning] following Robinson's framework. The study employed a pretest-posttest research…

Anaphylaxis

MedlinePlus

... Library ▸ Anaphylaxis TTR Share | Anaphylaxis Anaphylaxis (an–a–fi–LAK–sis) is a serious allergic reaction that ... Immunology 555 East Wells Street Suite 1100, Milwaukee , WI 53202-3823 (414) 272-6071 Additional Contact Information ...

The roles of the trading time risks on stock investment return and risks in stock price crashes

NASA Astrophysics Data System (ADS)

Li, Jiang-Cheng; Dong, Zhi-Wei; Yang, Guo-Hui; Long, Chao

2017-03-01

The roles of the trading time risks (TTRs) on stock investment return and risks are investigated in the condition of stock price crashes with Hushen300 data (CSI300) and Dow Jones Industrial Average (ˆDJI), respectively. In order to describe the TTR, we employ the escape time that the stock price drops from the maximum to minimum value in a data window length (DWL). After theoretical and empirical research on probability density function of return, the results in both ˆDJI and CSI300 indicate that: (i) As increasing DWL, the expectation of returns and its stability are weakened. (ii) An optimal TTR is related to a maximum return and minimum risk of stock investment in stock price crashes.

Educational and behavioural interventions for anticoagulant therapy in patients with atrial fibrillation.

PubMed

Clarkesmith, Danielle E; Pattison, Helen M; Khaing, Phyo H; Lane, Deirdre A

2017-04-05

Current guidelines recommend oral anticoagulation therapy for patients with atrial fibrillation (AF) with one or more risk factors for stroke; however, anticoagulation control (time in therapeutic range (TTR)) with vitamin K antagonists (VKAs) is dependent on many factors. Educational and behavioural interventions may impact patients' ability to maintain their international normalised ratio (INR) control. This is an updated version of the original review first published in 2013. To evaluate the effects of educational and behavioural interventions for oral anticoagulation therapy (OAT) on TTR in patients with AF. We updated searches from the previous review by searching the Cochrane Central Register of Controlled Trials (CENTRAL) and the Database of Abstracts of Reviews of Effects (DARE) in The Cochrane Library (January 2016, Issue 1), MEDLINE Ovid (1949 to February week 1 2016), EMBASE Classic + EMBASE Ovid (1980 to Week 7 2016), PsycINFO Ovid (1806 to Week 1 February 2016) and CINAHL Plus with Full Text EBSCO (1937 to 16/02/2016). We applied no language restrictions. We included randomised controlled trials evaluating the effect of any educational and behavioural intervention compared with usual care, no intervention, or intervention in combination with other self-management techniques among adults with AF who were eligible for, or currently receiving, OAT. Two of the review authors independently selected studies and extracted data. Risk of bias was assessed using the Cochrane 'Risk of bias' tool. We included outcome data on TTR, decision conflict (patient's uncertainty in making health-related decisions), percentage of INRs in the therapeutic range, major bleeding, stroke and thromboembolic events, patient knowledge, patient satisfaction, quality of life (QoL), beliefs about medication, illness perceptions, and anxiety and depression. We pooled data for three outcomes - TTR, anxiety and depression, and decision conflict - and reported mean differences (MD). Where insufficient data were present to conduct a meta-analysis, we reported effect sizes and confidence intervals (CI) from the included studies. We evaluated the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. Eleven trials with a total of 2246 AF patients (ranging from 14 to 712 by study) were included within the review. Studies included education, decision aids, and self-monitoring plus education interventions. The effect of self-monitoring plus education on TTR was uncertain compared with usual care (MD 6.31, 95% CI -5.63 to 18.25, I 2 = 0%, 2 trials, 69 participants, very low-quality evidence). We found small but positive effects of education on anxiety (MD -0.62, 95% CI -1.21 to -0.04, I 2 = 0%, 2 trials, 587 participants, low-quality evidence) and depression (MD -0.74, 95% CI -1.34 to -0.14, I 2 = 0%, 2 trials, 587 participants, low-quality evidence) compared with usual care. The effect of decision aids on decision conflict favoured usual care (MD -0.1, 95% CI -0.17 to -0.02, I 2 = 0%, 2 trials, 721 participants, low-quality evidence). This review demonstrates that there is insufficient evidence to draw definitive conclusions regarding the impact of educational or behavioural interventions on TTR in AF patients receiving OAT. Thus, more trials are needed to examine the impact of interventions on anticoagulation control in AF patients and the mechanisms by which they are successful. It is also important to explore the psychological implications for patients suffering from this long-term chronic condition.

Tanks 18 And 19-F Structural Flowable Grout Fill Material Evaluation And Recommendations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Langton, C. A.; Stefanko, D. B.

2013-04-23

Cementitious grout will be used to close Tanks 18-F and 19-F. The functions of the grout are to: 1) physically stabilize the final landfill by filling the empty volume in the tanks with a non-compressible material; 2) provide a barrier for inadvertent intrusion into the tank; 3) reduce contaminant mobility by a) limiting the hydraulic conductivity of the closed tank and b) reducing contact between the residual waste and infiltrating water; and 4) providing an alkaline, chemically reducing environment in the closed tank to control speciation and solubility of selected radionuclides. The objective of this work was to identify amore » single (all-in-one) grout to stabilize and isolate the residual radionuclides in the tank, provide structural stability of the closed tank and serve as an inadvertent intruder barrier. This work was requested by V. A. Chander, High Level Waste (HLW) Tank Engineering, in HLW-TTR-2011-008. The complete task scope is provided in the Task Technical and QA Plan, SRNL-RP-2011-00587 Revision 0. The specific objectives of this task were to: 1) Identify new admixtures and dosages for formulating a zero bleed flowable tank fill material selected by HLW Tank Closure Project personnel based on earlier tank fill studies performed in 2007. The chemical admixtures used for adjusting the flow properties needed to be updated because the original admixture products are no longer available. Also, the sources of cement and fly ash have changed, and Portland cements currently available contain up to 5 wt. % limestone (calcium carbonate). 2) Prepare and evaluate the placement, compressive strength, and thermal properties of the selected formulation with new admixture dosages. 3) Identify opportunities for improving the mix selected by HLW Closure Project personnel and prepare and evaluate two potentially improved zero bleed flowable fill design concepts; one based on the reactor fill grout and the other based on a shrinkage compensating flowable fill mix design. 4) Prepare samples for hydraulic property measurements for comparison to the values in the F and H- Tank Farm Performance Assessments (PAs). 5) Identify a grout mix for the Tanks 18-F and 19-F Grout Procurement Specification [Forty, 2011 a, b, c]. Results for two flowable zero bleed structural fill concepts containing 3/8 inch gravel (70070 Series and LP#8 Series) and a sand only mix (SO Series) are provided in this report. Tank Farm Engineering and SRNL Project Management selected the 70070 mix as the base case for inclusion in Revision 0 of the Tanks 18-F and 19-F grout procurement specification [Forty 2011 a] and requested admixture recommendations and property confirmation for this formulation [Forty, 2011 b]. Lower cementitious paste mixes were formulated because the 70070 mix is over designed with respect to strength and generates more heat from hydration reactions than is desirable for mass pour application. Work was also initiated on a modification of the recommended mix which included shrinkage compensation to mitigate fast pathways caused by shrinkage cracking and poor physical bonding to the tank and ancillary equipment. Testing of this option was postponed to FY12. Mix, LP#8-16 is recommended for inclusion in the specification for furnishing and delivering tank closure grout for Tanks 18-F and 19-F [Forty, 2011 c]. A shrinkage compensating variation of this mix, LP#16C, has not been fully developed and characterized at this time.« less

Genetic and Non-Genetic Factors Affecting the Quality of Anticoagulation Control and Vascular Events in Atrial Fibrillation.

PubMed

Park, Yun Kyung; Lee, Mi Ji; Kim, Jae Ha; Lee, Jin Soo; Park, Rae Woong; Kim, Gyeong-Moon; Chung, Chin-Sang; Lee, Kwang Ho; Kim, June Soo; Lee, Soo-Youn; Bang, Oh Young

2017-06-01

Warfarin has a narrow therapeutic window. We hypothesized that genetic factors related to warfarin metabolism (CYP2C9) and activity (VKORC1) would show stronger associations than modifiable factors with the quality of anticoagulation control and risks for thromboembolism and hemorrhage. In this retrospective cohort analysis, clinical and genetic data were collected from 380 patients with atrial fibrillation (AF) who were followed for an average observation period of 4 years. We evaluated the factors associated with time in therapeutic range (TTR, international normalized ratio [INR]: 2-3) and vascular events (either thromboembolic or hemorrhagic), including both genetic (CYP2C9 and VKORC1 genotype) and modifiable factors (anticoagulation service and warfarin dose assessment interval). The genotypic frequency of CYP2C9*3 (rs1057910) was 9.5% and that of VKORC1 1173C>T (rs9934438) was 16.3%. TTR showed dependence on VKORC1 polymorphism: TTR was higher in carriers of the VKORC1 1173C>T than of the VKORC1 TT genotype (61.7 ± 16.0% versus 56.7 ± 17.4%, P = .031). Multivariate testing showed that the VKORC1 genotype and anticoagulation service were independently related to labile INRs (TTR <65%). Vascular events were observed in 66 patients (18.4%) during the study period. A Cox proportional hazard model showed that the use of anticoagulation service and patients' characteristics, such as AF-thromboembolic risk (CHA 2 DS 2 -VASc score: Congestive heart failure, Hypertension, Age 75 years or older, Diabetes mellitus, previous Stroke or transient ischemic attack, Vascular disease, Age 65 to 74 years, female) and consequence (neurologic disability), but not genetic factors, were independently associated with vascular events. Both genetic factor (VKORC1 genotype) and clinical efforts (anticoagulation service) influenced the quality of anticoagulation control. However, clinical events were more strongly associated with patient characteristics and clinical efforts than with genetic factors. Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.

[Prevalence of oral anticoagulation and quality of its management in primary healthcare: A study by the Health Sentinel Network of the Region of Valencia (Spain)].

PubMed

Boned-Ombuena, Ana; Pérez-Panadés, Jordi; López-Maside, Aurora; Miralles-Espí, Maite; Guardiola Vilarroig, Sandra; Adam Ruiz, Desamparados; Zurriaga, Oscar

2017-11-01

To estimate the prevalence of patients with oral anticoagulant therapy (OAT) in the Region of Valencia and to evaluate the quality of management of OAT with vitaminK antagonists (VKA) carried out in primary healthcare. Observational cross-sectional study conducted through the Health Sentinel Network of the Region of Valencia, which includes a survey and the retrospective analysis of OAT monitoring. Primary healthcare, Region of Valencia, Spain. All patients aged 18years or older on OAT who consulted during the year 2014. The population covered by the 59 doctors of the Health Sentinel Network constitutes 2.2% of the adult population of the Region of Valencia, and it is representative of it. Demographic, socioeconomic and health data as well as information concerning OAT. Quality of OAT management with VKA was assessed by means of the percentage of time in therapeutic range (TTR), computed using the Rosendaal method. A total of 1,144 patients were recorded (mean age 74.5±11 years; 49.7% women). Prevalence of OAT in the Region of Valencia is 1.3 cases per 100 population. The characteristic profile of these patients is an old person, with several comorbidities and a low level of education, who lives accompanied. Atrial fibrillation is the most common indication. 82.8% of patients on OAT with VKA were monitored in primary healthcare. The average TTR was 65.0%, and 53.9% of patients had a TTR ≥65%. Among inadequately controlled patients, 74.4% were perceived as well-controlled by their primary care doctor. Prevalence of OAT is high, and it is expected to increase. The degree of control achieved meets the generally accepted quality standard (mean TTR ≥65%), and it is comparable to that observed in other national and international studies. However, there is wide scope for improvement. It is crucial to optimize the management of this therapy in the most effective and cost-effective way. Among other measures, access of physicians to their patients' clinical information should be improved. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

Tonopah Test Range Air Monitoring: CY2016 Meteorological, Radiological, and Wind Transported Particulate Observations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chapman, Jenny; Nikolich, George; Shadel, Craig

In 1963, the U.S. Department of Energy (DOE) (formerly the Atomic Energy Commission [AEC]), implemented Operation Roller Coaster on the Tonopah Test Range (TTR) and an adjacent area of the Nevada Test and Training Range (NTTR) (formerly the Nellis Air Force Range). This operation resulted in radionuclide-contaminated soils at the Clean Slate I, II, and III sites. This report documents observations made during ongoing monitoring of radiological, meteorological, and dust conditions at stations installed adjacent to Clean Slate I and Clean Slate III, and at the TTR Sandia National Laboratories (SNL) Range Operations Control (ROC) center. The primary objective ofmore » the monitoring effort is to determine if wind blowing across the Clean Slate sites is transporting particles of radionuclide-contaminated soil beyond the physical and administrative boundaries of the sites.« less

Structural and functional analysis of PucM, a hydrolase in the ureide pathway and a member of the transthyretin-related protein family

PubMed Central

Jung, Du-Kyo; Lee, Youra; Park, Sung Goo; Park, Byoung Chul; Kim, Ghyung-Hwa; Rhee, Sangkee

2006-01-01

The ureide pathway, which produces ureides from uric acid, is an essential purine catabolic process for storing and transporting the nitrogen fixed in leguminous plants and some bacteria. PucM from Bacillus subtilis was recently characterized and found to catalyze the second reaction of the pathway, hydrolyzing 5-hydroxyisourate (HIU), a product of uricase in the first step. PucM has 121 amino acid residues and shows high sequence similarity to the functionally unrelated protein transthyretin (TTR), a thyroid hormone-binding protein. Therefore, PucM belongs to the TTR-related proteins (TRP) family. The crystal structures of PucM at 2.0 Å and its complexes with the substrate analogs 8-azaxanthine and 5,6-diaminouracil reveal that even with their overall structure similarity, homotetrameric PucM and TTR are completely different, both in their electrostatic potential and in the size of the active sites located at the dimeric interface. Nevertheless, the absolutely conserved residues across the TRP family, including His-14, Arg-49, His-105, and the C-terminal Tyr-118–Arg-119–Gly-120–Ser-121, indeed form the active site of PucM. Based on the results of site-directed mutagenesis of these residues, we propose a possible mechanism for HIU hydrolysis. The PucM structure determined for the TRP family leads to the conclusion that diverse members of the TRP family would function similarly to PucM as HIU hydrolase. PMID:16782815

Rapid progression of familial amyloidotic polyneuropathy

PubMed Central

Coelho, Teresa; Obici, Laura; Merlini, Giampaolo; Mincheva, Zoia; Suanprasert, Narupat; Bettencourt, Brian R.; Gollob, Jared A.; Gandhi, Pritesh J.; Litchy, William J.; Dyck, Peter J.

2015-01-01

Objectives: To assess the association between severity of neuropathy and disease stage, and estimate the rate of neuropathy progression in a retrospective cross-sectional analysis of a multinational population of patients with familial amyloidotic polyneuropathy (FAP). Methods: We characterize neuropathy severity and rate of progression in available patients with FAP in France, the United States, Portugal, and Italy. Neuropathy Impairment Scores (NIS), time from symptom onset to NIS measurement, polyneuropathy disability (PND) scores, FAP disease stage, and manual grip strength data were collected. We estimated neuropathy progression using Loess Fit and Gompertz Fit models. Results: For the 283 patients studied (mean age, 56.4 years), intercountry genotypic variation in the transthyretin (TTR) mutation was observed, with the majority of patients in Portugal (92%) having early-onset Val30Met-FAP. There was also marked intercountry variation in PND score, FAP stage, and TTR stabilizer use. NIS was associated with PND score (NIS 10 and 99 for scores I and IV, respectively; p < 0.0001) and FAP stage (NIS 14 and 99 for stages 1 and 3, respectively; p < 0.0001). In addition, there was an association between NIS and TTR genotype. The estimated rate of NIS progression for a population with a median NIS of 32 was 14.3 points/year; the corresponding estimated rate for the modified NIS+7 is 17.8 points/year. Conclusions: In a multinational population of patients with FAP, rapid neuropathic progression is observed and the severity of neuropathy is associated with functional scales of locomotion. PMID:26208957

Social motivation in prospective memory: higher importance ratings and reported performance rates for social tasks.

PubMed

Penningroth, Suzanna L; Scott, Walter D; Freuen, Margaret

2011-03-01

Few studies have addressed social motivation in prospective memory (PM). In a pilot study and two main studies, we examined whether social PM tasks possess a motivational advantage over nonsocial PM tasks. In the pilot study and Study 1, participants listed their real-life important and less important PM tasks. Independent raters categorized the PM tasks as social or nonsocial. Results from both studies showed a higher proportion of tasks rated as social when important tasks were requested than when less important tasks were requested. In Study 1, participants also reported whether they had remembered to perform each PM task. Reported performance rates were higher for tasks rated as social than for those rated as nonsocial. Finally, in Study 2, participants rated the importance of two hypothetical PM tasks, one social and one nonsocial. The social PM task was rated higher in importance. Overall, these findings suggest that social PM tasks are viewed as more important than nonsocial PM tasks and they are more likely to be performed. We propose that consideration of the social relevance of PM will lead to a more complete and ecologically valid theoretical description of PM performance. (PsycINFO Database Record (c) 2011 APA, all rights reserved).

Teaching an Individual with Severe Intellectual Delay to Request Assistance Conditionally

ERIC Educational Resources Information Center

Reichle, Joe; McComas, Jennifer; Dahl, Norm; Solberg, Gina; Pierce, Sarah; Smith, David

2005-01-01

The purpose of this study was to evaluate intervention procedures to teach conditional use of a communicative request for assistance and independent task performance. A 40-year-old man with autism and severe mental retardation with a history of escape-related problems was taught to use a graphic symbol to request assistance and to engage…

Anaphylaxis

MedlinePlus

... Menu Search Main navigation Skip to content Conditions & Treatments Allergies Asthma Primary Immunodeficiency Disease Related Conditions Drug Guide ... Expert Search Search AAAAI Breadcrumb navigation Home ▸ Conditions & Treatments ▸ Library ▸ Allergy Library ▸ Anaphylaxis TTR Share | Anaphylaxis Anaphylaxis (an–a– ...

Latex Allergy

MedlinePlus

... Menu Search Main navigation Skip to content Conditions & Treatments Allergies Asthma Primary Immunodeficiency Disease Related Conditions Drug Guide ... Expert Search Search AAAAI Breadcrumb navigation Home ▸ Conditions & Treatments ▸ Library ▸ Allergy Library ▸ Latex allergy TTR Share | Latex Allergy This ...

Food Allergy

MedlinePlus

... Menu Search Main navigation Skip to content Conditions & Treatments Allergies Asthma Primary Immunodeficiency Disease Related Conditions Drug Guide ... Expert Search Search AAAAI Breadcrumb navigation Home ▸ Conditions & Treatments ▸ Library ▸ Allergy Library ▸ Food allergy TTR Share | Food Allergy For ...

Automated Neuropsychological Assessment Metrics Version 4 (ANAM4): Select Psychometric Properties and Administration Procedures

DTIC Science & Technology

2013-12-01

review Task 22 Preparation of Project Final Report 6 A request for a 12 month no- cost extension for this study was approved on 7 November 2012...extending study activities through December 2013. A modified statement of work, approved as part of the no- cost extension, is presented in Table 6. Table...6: MODIFIED SOW for remaining PROJECT Tasks and STUDY TIMETABLE (Nov 2012) A request for an additional 12 month no- cost extension for this study

75 FR 16577 - Gulf War Veterans' Illnesses Task Force

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-01

... DEPARTMENT OF VETERANS AFFAIRS Gulf War Veterans' Illnesses Task Force AGENCY: Department of Veterans Affairs (VA). ACTION: Notice with request for comments. SUMMARY: The Secretary Department of Veterans Affairs (VA) established the Gulf War Veterans' Illnesses Task Force (GWVI-TF) in August 2009 to...

78 FR 28292 - Gulf War Veterans' Illnesses Task Force

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-14

... DEPARTMENT OF VETERANS AFFAIRS Gulf War Veterans' Illnesses Task Force AGENCY: Department of Veterans Affairs (VA). ACTION: Notice with request for comments. SUMMARY: The Secretary, Department of Veterans Affairs (VA) established the Gulf War Veterans' Illnesses Task Force (GWVI-TF) in August 2009 to...

76 FR 65321 - Gulf War Veterans' Illnesses Task Force

Federal Register 2010, 2011, 2012, 2013, 2014

2011-10-20

... DEPARTMENT OF VETERANS AFFAIRS Gulf War Veterans' Illnesses Task Force AGENCY: Department of Veterans Affairs (VA). ACTION: Notice with request for comments. SUMMARY: The Secretary, Department of Veterans Affairs (VA) established the Gulf War Veterans' Illnesses Task Force (GWVI-TF) in August 2009 to...

Biosensor-based microRNA detection: techniques, design, performance, and challenges.

PubMed

Johnson, Blake N; Mutharasan, Raj

2014-04-07

The current state of biosensor-based techniques for amplification-free microRNA (miRNA) detection is critically reviewed. Comparison with non-sensor and amplification-based molecular techniques (MTs), such as polymerase-based methods, is made in terms of transduction mechanism, associated protocol, and sensitivity. Challenges associated with miRNA hybridization thermodynamics which affect assay selectivity and amplification bias are briefly discussed. Electrochemical, electromechanical, and optical classes of miRNA biosensors are reviewed in terms of transduction mechanism, limit of detection (LOD), time-to-results (TTR), multiplexing potential, and measurement robustness. Current trends suggest that biosensor-based techniques (BTs) for miRNA assay will complement MTs due to the advantages of amplification-free detection, LOD being femtomolar (fM)-attomolar (aM), short TTR, multiplexing capability, and minimal sample preparation requirement. Areas of future importance in miRNA BT development are presented which include focus on achieving high measurement confidence and multiplexing capabilities.

78 FR 2447 - Proposed Information Collection Request (ICR) for the Worker Classification Survey; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-11

... ANNUALIZED Cost to Respondents:......... $93,670 * Includes sixty (60) pre-test cases. ** U.S. Department of... status. The primary tasks of the survey include: (1) design and cognitively test survey questions to be...

Parenteral nutrition improves nutritional status, autonomic symptoms and quality of life in transthyretin amyloid polyneuropathy.

PubMed

Russo, Massimo; Vita, Gian Luca; Stancanelli, Claudia; Mazzeo, Anna; Vita, Giuseppe; Messina, Sonia

2016-06-01

Transthyretin familial amyloid polyneuropathy (TTR-FAP) is an inherited amyloidosis, leading to death in about ten years in most cases due to cardiac failure or wasting syndrome. Previous studies showed that modified body mass index was related to time before death, duration of gastrointestinal disturbances, malabsorption and functional capacity. We report two patients in whom nutritional status worsened despite diet modification, hypercaloric supplement and two relevant therapeutic approaches such as liver transplant and tafamidis meglumine, respectively. The first patient, a 52-year-old lady carrying Thr49Ala mutation, had a disease duration of twelve years and had lost weight up to 35 kg because of daily diarrhea. The second patient, a 63-year-old man with Glu89Gln mutation and a disease duration of fifteen years, was in the New York Heart Association (NYHA) Functional Classification class III and his weight was 39 kg. In both cases, a peripherally inserted central catheter was placed for parenteral nutrition. It allowed to improve their nutritional status and clinical conditions, with body weight gains of 11 and 8 kg in a one year follow-up, respectively. Moreover, reduction of autonomic symptoms including postural hypotension, nausea and diarrhoea was recorded with ameliorated quality of life. Our experience suggests that parenteral nutrition may be useful in reducing complications and disabilities in TTR-FAP patients, even when all dietary adjustments have been ineffective. Reasonably, the improvement in nutritional status may prolong survival in TTR-FAP patients. Copyright © 2016 Elsevier B.V. All rights reserved.

Biomarkers in volunteers exposed to mobile phone radiation.

PubMed

Söderqvist, Fredrik; Carlberg, Michael; Hardell, Lennart

2015-06-01

For some time it has been investigated whether low-intensity non-thermal microwave radiation from mobile phones adversely affects the mammalian blood-brain barrier (BBB). All such studies except one have been either in vitro or experimental animal studies. The one carried out on humans showed a statistically significant increase in serum transthyretin (TTR) 60 min after finishing of a 30-min microwave exposure session. The aim of the present study was to follow up on the finding of the previous one using a better study design. Using biomarkers analyzed in blood serum before and after the exposure this single blinded randomized counterbalanced study, including 24 healthy subjects aged 18-30 years that all underwent three exposure conditions (SAR(10G)=2 W/kg, SAR(10G)=0.2 W/kg, sham), tested whether microwaves from an 890-MHz phone-like signal give acute effects on the integrity of brain-shielding barriers. Over time, statistically significant variations were found for two of the three biomarkers (TTR; β-trace protein); however, no such difference was found between the different exposure conditions nor was there any interaction between exposure condition and time of blood sampling. In conclusion this study failed to show any acute clinically or statistically significant effect of short term microwave exposure on the serum levels of S100β, TTR and β-trace protein with a follow up limited to two hours. The study was hampered by the fact that all study persons were regular wireless phone users and thus not naïve as to microwave exposure. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Contemporary Patterns of Multiple Organ Dysfunction in Trauma.

PubMed

Shepherd, Joanna M; Cole, Elaine; Brohi, Karim

2017-04-01

Multiple organ dysfunction syndrome (MODS) is associated with poor outcomes for trauma patients. Different forms of MODS may exist and have different consequences. The ability to distinguish them clinically may have implications for prognosis and treatment. We wished to study whether prolonged MODS (PRMODS) could be observed as a distinct clinical entity to early resolving MODS (ERMODS) in critically injured patients. Adult major trauma patients recruited to a prospective observational study at a single major trauma center were eligible for inclusion. MODS was defined as Sequential Organ Failure Assessment (SOFA) score >5; and PRMODS as lasting >7 days. Time to recovery (TTR) was calculated as the number of days before the SOFA fell below the MODS threshold (≤5). Five hundred ninety-five patients were enrolled of whom 285 developed ERMODS (48%) and 184 (31%) PRMODS. Organ dysfunction was more severe and protracted in PRMODS, especially in patients without brain injury (mean SOFA 11 vs. 6, Day 2, P < 0.001; TTR 17 vs. 3 days, P < 0.001). PRMODS exhibited higher rates of hepatic and renal dysfunction (84% vs. 56%; and 78% vs. 47%, P≤0.001). Patterns of recovery were distinct in hepatic, renal, and neurological systems (TTR 15 vs. 4; 20 vs. 3; and 28 vs. 7 days, P < 0.01). PRMODS was associated with higher infection and mortality rates (91% vs. 41%; and 22% vs. 7%, P < 0.001). PRMODS appears common, a distinct clinical entity, and associated with worse patient outcomes. PRMODS may represent an important endpoint for studies evaluating outcomes following trauma.

Biosensor discovery of thyroxine transport disrupting chemicals

DOE Office of Scientific and Technical Information (OSTI.GOV)

Marchesini, Gerardo R.; Meimaridou, Anastasia; Haasnoot, Willem

2008-10-01

Ubiquitous chemicals may interfere with the thyroid system that is essential in the development and physiology of vertebrates. We applied a surface plasmon resonance (SPR) biosensor-based screening method for the fast screening of chemicals with thyroxine (T4) transport disrupting activity. Two inhibition assays using the main thyroid hormone transport proteins, T4 binding globulin (TBG) and transthyretin (TTR), in combination with a T4-coated biosensor chip were optimized and automated for screening chemical libraries. The transport protein-based biosensor assays were rapid, high throughput and bioeffect-related. A library of 62 chemicals including the natural hormones, polychlorinated biphenyls (PCBs), polybrominated diphenylethers (PBDEs) and metabolites,more » halogenated bisphenol A (BPA), halogenated phenols, pharmaceuticals, pesticides and other potential environmentally relevant chemicals was tested with the two assays. We discovered ten new active compounds with moderate to high affinity for TBG with the TBG assay. Strikingly, the most potent binding was observed with hydroxylated metabolites of the brominated diphenyl ethers (BDEs) BDE 47, BDE 49 and BDE 99, that are commonly found in human plasma. The TTR assay confirmed the activity of previously identified hydroxylated metabolites of PCBs and PBDEs, halogenated BPA and genistein. These results show that the hydroxylated metabolites of the ubiquitous PBDEs not only target the T4 transport at the TTR level, but also, and to a great extent, at the TBG level where most of the T4 in humans is circulating. The optimized SPR biosensor-based transport protein assay is a suitable method for high throughput screening of large libraries for potential thyroid hormone disrupting compounds.« less

Expression of Serum Retinol Binding Protein and Transthyretin within Mouse Gastric Ghrelin Cells

PubMed Central

Walker, Angela K.; Gong, Zhi; Park, Won-Mee

2013-01-01

Ghrelin is an orexigenic peptide hormone produced mainly by a distinct group of dispersed endocrine cells located within the gastric oxyntic mucosa. Besides secreted gene products derived from the preproghrelin gene, which include acyl-ghrelin, desacyl-ghrelin and obestatin, ghrelin cells also synthesize the secreted protein nesfatin-1. The main goal of the current study was to identify other proteins secreted from ghrelin cells. An initial gene chip screen using mRNAs derived from highly enriched pools of mouse gastric ghrelin cells demonstrated high levels of serum retinol-binding protein (RBP4) and transthyretin (TTR), both of which are known to circulate in the bloodstream bound to each other. This high expression was confirmed by quantitative RT-PCR using as template mRNA derived from the enriched gastric ghrelin cell pools and from two ghrelin-producing cell lines (SG-1 and PG-1). RBP4 protein also was shown to be secreted into the culture medium of ghrelin cell lines. Neither acute nor chronic caloric restriction had a significant effect on RBP4 mRNA levels within stomachs of C57BL/6J mice, although both manipulations significantly decreased stomach TTR mRNA levels. In vitro studies using PG-1 cells showed no effect on RBP4 release of octanoic acid, epinephrine or norepinephrine, all of which are known to act directly on ghrelin cells to stimulate ghrelin secretion. These data provide new insights into ghrelin cell physiology, and given the known functions of RBP4 and TTR, support an emerging role for the ghrelin cell in blood glucose handling and metabolism. PMID:23840311

Effects of Regional Differences in Asia on Efficacy and Safety of Edoxaban Compared With Warfarin--Insights From the ENGAGE AF-TIMI 48 Trial.

PubMed

Shimada, Yuichi J; Yamashita, Takeshi; Koretsune, Yukihiro; Kimura, Tetsuya; Abe, Kenji; Sasaki, Shunichi; Mercuri, Michele; Ruff, Christian T; Giugliano, Robert P

2015-01-01

In 21,105 patients with atrial fibrillation in the ENGAGE AF-TIMI 48 trial, edoxaban was non-inferior to warfarin in preventing thromboembolic events while reducing bleeding. We compared results in Japan with the rest of East Asia (EA), including China, Korea, and Taiwan. We compared baseline characteristics, time-in-therapeutic range (TTR) for warfarin, and outcomes (efficacy: stroke or systemic embolic events [SEE], safety: major bleeding). Interaction P values were used to assess for effect modification of treatment (higher-dose edoxaban [HDE, 60 mg/30 mg] vs. warfarin; lower-dose edoxaban [LDE, 30 mg/15 mg] vs. warfarin) by region with adjustments for baseline characteristics. Fewer patients in Japan (n=1,010) were female, taking aspirin or amiodarone, naïve to warfarin (P<0.001 for each), had a history of stroke or transient ischemic attack (P=0.02), and more patients needed dose reduction (P<0.001) compared with EA (n=933). The mean TTR was higher in Japan (70% vs. 56%, P<0.001). Evidence for statistical interactions was observed for HDE vs. warfarin by region for stroke/SEE (adjusted P-int=0.052) and major bleeding (adjusted P-int=0.048) with greater relative efficacy and safety with HDE in EA compared with Japan. No interactions were observed for LDE vs. warfarin after adjustment. HDE had a greater relative efficacy and safety in EA compared with Japan that was only partially explained by differences in baseline characteristics and TTR.

EFFECTS ON HEPATIC GENE EXPRESSION IN MALE RATS ADMINISTERED PBDES IN HOUSEHOLD DUST

EPA Science Inventory

Studies show that polybrominated diphenyl ethers (PBDEs) decrease thyroid hormone concentrations via induction of hepatic uridinediphosphate-glucoronosyltransferase (UGTs) and transthyretin (Ttr) binding. Because PBDEs exhibit endocrine disrupting properties and are present in h...

Effect of medication timing on anticoagulation stability in users of warfarin (the INRange RCT): study protocol for a randomized controlled trial.

PubMed

Heran, Balraj S; Allan, G Michael; Green, Lee; Korownyk, Christina; Kolber, Michael; Olivier, Nicole; Flesher, Mary; Garrison, Scott

2016-08-04

Warfarin is an oral anticoagulant medication that disrupts the liver's production of clotting factors. While this medication is highly effective for the prevention of thromboembolic events, it also has a narrow therapeutic range and a vulnerability to interactions with other drugs and vitamin K-containing foods. Warfarin is commonly ingested at dinnertime, the same time of day that dietary vitamin K consumption (found largely in green leafy vegetables) is most variable. While the long half-life of warfarin might make this irrelevant, the ultra short half-life of vitamin K and the possibility of a hepatic first-pass effect for warfarin make it worth evaluating whether morning ingestion of warfarin, when vitamin K levels are consistently low, leads to greater stability of its anticoagulant effect. An examination of the timing of administration on the effectiveness of warfarin has never before been conducted. This is a 7-month Prospective Randomized Open Blinded End-point (PROBE) study in which established evening warfarin users (primary care managed Canadian outpatients in the provinces of British Columbia and Alberta) will be randomized to either switch to morning ingestion of warfarin (the intervention) or to continue with evening use (the control). The primary outcome is the percent change in the proportion of time spent outside the therapeutic range of the international normalized ratio (INR) blood test. Secondary outcomes include change in proportion of time spent within the therapeutic INR range (TTR), percentage of patients with TTR >75 %, percentage of patients with TTR <60 %, and major warfarin-related cardiovascular events (including all-cause mortality, hospitalization for stroke, hospitalization for GI bleeding, and deep venous thrombosis/pulmonary embolism). We will also compare whether day-to-day variability in the consumption of high vitamin K-containing foods at baseline affects the baseline TTR in this cohort of evening warfarin users. This study addresses whether the timing of warfarin ingestion influences the stability of its anticoagulant effect. Should morning ingestion prove superior, the safety and effectiveness of this medication, and hence the prevention of stroke, pulmonary embolus, and major hemorrhage, could potentially be improved with no added cost or inconvenience to the patient. ClinicalTrials.gov: NCT02376803 . Registered on 25 February 2015.

75 FR 47624 - U.S. Coral Reef Task Force Public Meeting and Public Comment

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-06

... DEPARTMENT OF THE INTERIOR Fish and Wildlife Service U.S. Coral Reef Task Force Public Meeting and... (Service), announce a public meeting of the U.S. Coral Reef Task Force (USCRTF) and a request for written.... Coral Reef Task Force Department of the Interior Liaison, U.S. Department of the Interior, MS-3530-MIB...

Beads task vs. box task: The specificity of the jumping to conclusions bias.

PubMed

Balzan, Ryan P; Ephraums, Rachel; Delfabbro, Paul; Andreou, Christina

2017-09-01

Previous research involving the probabilistic reasoning 'beads task' has consistently demonstrated a jumping-to-conclusions (JTC) bias, where individuals with delusions make decisions based on limited evidence. However, recent studies have suggested that miscomprehension may be confounding the beads task. The current study aimed to test the conventional beads task against a conceptually simpler probabilistic reasoning "box task" METHODS: One hundred non-clinical participants completed both the beads task and the box task, and the Peters et al. Delusions Inventory (PDI) to assess for delusion-proneness. The number of 'draws to decision' was assessed for both tasks. Additionally, the total amount of on-screen evidence was manipulated for the box task, and two new box task measures were assessed (i.e., 'proportion of evidence requested' and 'deviation from optimal solution'). Despite being conceptually similar, the two tasks did not correlate, and participants requested significantly less information on the beads task relative to the box task. High-delusion-prone participants did not demonstrate hastier decisions on either task; in fact, for box task, this group was observed to be significantly more conservative than low-delusion-prone group. Neither task was incentivized; results need replication with a clinical sample. Participants, and particularly those identified as high-delusion-prone, displayed a more conservative style of responding on the novel box task, relative to the beads task. The two tasks, whilst conceptually similar, appear to be tapping different cognitive processes. The implications of these results are discussed in relation to the JTC bias and the theoretical mechanisms thought to underlie it. Copyright © 2016 Elsevier Ltd. All rights reserved.

Advanced Thermal Emission Imaging Systems Definition and Development

NASA Technical Reports Server (NTRS)

Blasius, Karl; Nava, David (Technical Monitor)

2002-01-01

Santa Barbara Remote Sensing (SBRS), Raytheon Company, is pleased to submit this quarterly progress report of the work performed in the third quarter of Year 2 of the Advanced THEMIS Project, July through September 2002. We review here progress in the proposed tasks. During July through September 2002 progress was made in two major tasks, Spectral Response Characterization and Flight Instrument Definition. Because of staffing problems and technical problems earlier in the program we have refocused the remaining time and budget on the key technical tasks. Current technical problems with a central piece of test equipment has lead us to request a 1 quarter extension to the period of performance. This request is being made through a separate letter independent of this report.

In Health-Related Tasks, Where Does the School Nurse Function?

ERIC Educational Resources Information Center

Berg, Beryl; And Others

1973-01-01

The study provided a composite picture of health-related tasks performed in one school district. Nurses were able to evaluate their current practices and recommend specific improvements in nursing actions. Other school districts seeking a profile of their involvement in health-related tasks may request copies of the questionnaire or the entire…

78 FR 49217 - Airworthiness Directives; the Boeing Company Airplanes

Federal Register 2010, 2011, 2012, 2013, 2014

2013-08-13

... Airworthiness Limitations Boeing requested that we add ALI Task 28-AWL-18, ``Fuel Quantity Indicating System... Control Limitation (CDCCL) Task 28-AWL-19, ``Fuel Quantity Indicating System (FQIS)--Out- Tank Wiring... of the airplane. [[Page 49220

Establishment of Symbolic Communication in Persons with Severe Retardation.

ERIC Educational Resources Information Center

Romski, Mary Ann; And Others

1988-01-01

Three of four severely retarded adolescents and young adults learned to use computer-based lexigrams to request foods and, subsequently, objects. Additional request experience with lexigrams resulted in consistent improvement on labeling and comprehension tasks, emergence of subject-initiated lexigram communications, and facilitation of spoken…

Towards data warehousing and mining of protein unfolding simulation data.

PubMed

Berrar, Daniel; Stahl, Frederic; Silva, Candida; Rodrigues, J Rui; Brito, Rui M M; Dubitzky, Werner

2005-10-01

The prediction of protein structure and the precise understanding of protein folding and unfolding processes remains one of the greatest challenges in structural biology and bioinformatics. Computer simulations based on molecular dynamics (MD) are at the forefront of the effort to gain a deeper understanding of these complex processes. Currently, these MD simulations are usually on the order of tens of nanoseconds, generate a large amount of conformational data and are computationally expensive. More and more groups run such simulations and generate a myriad of data, which raises new challenges in managing and analyzing these data. Because the vast range of proteins researchers want to study and simulate, the computational effort needed to generate data, the large data volumes involved, and the different types of analyses scientists need to perform, it is desirable to provide a public repository allowing researchers to pool and share protein unfolding data. To adequately organize, manage, and analyze the data generated by unfolding simulation studies, we designed a data warehouse system that is embedded in a grid environment to facilitate the seamless sharing of available computer resources and thus enable many groups to share complex molecular dynamics simulations on a more regular basis. To gain insight into the conformational fluctuations and stability of the monomeric forms of the amyloidogenic protein transthyretin (TTR), molecular dynamics unfolding simulations of the monomer of human TTR have been conducted. Trajectory data and meta-data of the wild-type (WT) protein and the highly amyloidogenic variant L55P-TTR represent the test case for the data warehouse. Web and grid services, especially pre-defined data mining services that can run on or 'near' the data repository of the data warehouse, are likely to play a pivotal role in the analysis of molecular dynamics unfolding data.

Suboptimal Anticoagulant Management in Japanese Patients with Nonvalvular Atrial Fibrillation Receiving Warfarin for Stroke Prevention.

PubMed

Hirano, Teruyuki; Kaneko, Hirokazu; Mishina, Sari; Wang, Feng; Morita, Satoshi

2017-10-01

Atrial fibrillation (AF) is the most common cardiac arrhythmia, with increasing prevalence in Japan. Although prothrombin time-international normalized ratio (PT-INR) targets for monitoring warfarin therapy in patients with nonvalvular AF (NVAF) are well defined, real-world patient characteristics and PT-INR levels remain unknown among Japanese patients with NVAF who initiate and continue warfarin (warfarin maintainers) versus those who switch from warfarin to direct oral anticoagulants (DOACs; warfarin switchers). Patients with NVAF receiving oral anticoagulants between February 2013 and June 2015 were identified using a nationwide electronic medical record (EMR) database from 69 hospitals in Japan. Demographics and characteristics of patients, PT-INR, time in therapeutic range (TTR), and frequency in range (FIR) of PT-INR between warfarin maintainers and warfarin switchers were assessed. A total of 1705 patients met inclusion criteria and were examined (1501 warfarin maintainers versus 204 warfarin switchers). CHADS 2 , CHA 2 DS 2 -VASc, and HAS-BLED scores were comparable between groups. However, these scores were significantly higher among warfarin switchers at the time of switching than at the time of warfarin initiation. Furthermore, TTR and FIR of PT-INR were lower in warfarin switchers than in maintainers. Nevertheless, TTR and FIR were below 50% (PT-INR, 1.6-2.6) in both patient groups. In this EMR-based clinical study, patients who switched to DOACs had both poor or inadequate PT-INR control and higher risk factors of stroke. Many patients receiving warfarin did not achieve sufficient PT-INR therapeutic range. DOACs could be recommended in Japanese patients with NVAF with inadequate PT-INR control and increased risk of stroke. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Randomized controlled trial of supervised patient self-testing of warfarin therapy using an internet-based expert system.

PubMed

Ryan, F; Byrne, S; O'Shea, S

2009-08-01

Increased frequency of prothrombin time testing, facilitated by patient self-testing (PST) of the International Normalized Ratio (INR) can improve the clinical outcomes of oral anticoagulation therapy (OAT). However, oversight of this type of management is often difficult and time-consuming for healthcare professionals. This study reports the first randomized controlled trial of an automated direct-to-patient expert system, enabling remote and effective management of patients on OAT. A prospective, randomized controlled cross-over study was performed to test the hypothesis that supervised PST using an internet-based, direct-to-patient expert system could provide improved anticoagulation control as compared with that provided by an anticoagulation management service (AMS). During the 6 months of supervised PST, patients measured their INR at home using a portable meter and entered this result, along with other information, onto the internet web page. Patients received instant feedback from the system as to what dose to take and when the next test was due. During the routine care arm, patients attended the AMS at least every 4-6 weeks and were dosed by the anticoagulation pharmacist or physician. The primary outcome variable was the difference in the time in therapeutic range (TTR) between both arms. One hundred and sixty-two patients were enrolled (male 61.6%, mean age 58.7 years), and 132 patients (81.5%) completed both arms. TTR was significantly higher during PST management than during AMS management (median TTR 74% vs 58.6%; z=5.67, P < 0.001). The use of an internet-based, direct-to-patient expert system for the management of PST improves the control of OAT as compared with AMS management.

Bronchoconstriction induced by increasing airway temperature in ovalbumin-sensitized rats: role of tachykinins.

PubMed

Hsu, Chun-Chun; Lin, Ruei-Lung; Lin, You Shuei; Lee, Lu-Yuan

2013-09-01

This study was carried out to determine the effect of allergic inflammation on the airway response to increasing airway temperature. Our results showed the following: 1) In Brown-Norway rats actively sensitized by ovalbumin (Ova), isocapnic hyperventilation with humidified warm air (HWA) for 2 min raised tracheal temperature (Ttr) from 33.4 ± 0.6°C to 40.6 ± 0.1°C, which induced an immediate and sustained (>10 min) increase in total pulmonary resistance (Rl) from 0.128 ± 0.004 to 0.212 ± 0.013 cmH2O·ml(-1)·s (n = 6, P < 0.01). In sharp contrast, the HWA challenge caused the same increase in Ttr but did not generate any increase in Rl in control rats. 2) The increase in Rl in sensitized rats was reproducible when the same HWA challenge was repeated 60-90 min later. 3) This bronchoconstrictive effect was temperature dependent: a slightly smaller increase in peak Ttr (39.6 ± 0.2°C) generated a significant but smaller increase in Rl in sensitized rats. 4) The HWA-induced bronchoconstriction was not generated by the humidity delivered by the HWA challenge alone, because the same water content delivered by saline aerosol at room temperature had no effect. 5) The HWA-evoked increase in Rl in sensitized rats was not blocked by atropine but was completely prevented by pretreatment either with a combination of neurokinin (NK)-1 and NK-2 antagonists or with formoterol, a β2 agonist, before the HWA challenge. This study showed that increasing airway temperature evoked a pronounced and reversible increase in airway resistance in sensitized rats and that tachykinins released from the vagal bronchopulmonary C-fiber endings were primarily responsible.

Roles and potential mechanisms of selenium in countering thyrotoxicity of DEHP.

PubMed

Zhang, Pei; Guan, Xie; Yang, Min; Zeng, Li; Liu, Changjiang

2018-04-01

Di-(2-ethylhexyl) phthalate (DEHP) as a ubiquitous environmental contaminant could disturb thyroid hormone (TH) homeostasis. Selenium as an essential trace element has protective effects on thyroids. To verify roles of selenium in countering thyrotoxicity of DEHP and elucidate potential mechanisms, Sprague-Dawley rats and Nthy-ori 3-1 cells were treated with DEHP or/and selenomethionine (SeMet). Results showed that selenium supplementation elevated plasma free thyroxine (FT4) that was decreased by DEHP, and free triiodothyronine (FT3) and thyroid stimulating hormone (TSH) levels were also partially recovered. DEHP-caused histopathologic changes were ameliorated after selenium supplementation, as indicated by recovered thyroid follicular epithelial cell numbers and cavity diameters. DEHP disrupted the redox equilibrium, causing depletions of SOD, GPx1, GPx3, and TxnRd, and accumulations of MDA. Nevertheless, selenium supplementation effectively improved the redox status. DEHP affected biosynthesis, biotransformation, biotransport, and metabolism of THs, as well as thyrotropin releasing hormone receptor (TRHr) levels. Plasma selenium, thyroid peroxidase (TPO), deiodinase 1 (Dio1), and transthyretin (TTR) were downregulated, while Dio3, Ugt1a1, Sult1e1, CYP2b1, CYP3a1, and TRHr were upregulated by DEHP. However, selenium supplementation led to elevations of selenium, Dio1 and TTR, and reductions of Ugt1a1, Sult1e1, CYP2b1, and TRHr. TPO, Dio3, and CYP3a1 were not significantly affected by selenium supplementation. Taken together, selenium could ameliorate DEHP-caused TH dyshomeostasis via modulations of the redox status, Dio1, TTR, TRHr, and hepatic enzymes. Copyright © 2017 Elsevier B.V. All rights reserved.

CpG Island Methylator Phenotype Positive Tumors in the Absence of MLH1 Methylation Constitute a Distinct Subset of Duodenal Adenocarcinomas and Are Associated with Poor Prognosis

PubMed Central

Fu, Tao; Pappou, Emmanouil P.; Guzzetta, Angela A.; Jeschke, Jana; Kwak, Ruby; Dave, Pujan; Hooker, Craig M.; Morgan, Richard; Baylin, Stephen B.; Iacobuzio-Donahue, Christine A.; Wolfgang, Christopher L.; Ahuja, Nita

2012-01-01

Purpose Little information is available on genetic and epigenetic changes in duodenal adenocarcinomas. The purpose was to identify possible subsets of duodenal adenocarcinomas based on microsatellite instability (MSI), DNA methylation, mutations in the KRAS and BRAF genes, clinicopathologic features, and prognosis. Experimental Design Demographics, tumor characteristics and survival were available for 99 duodenal adenocarcinoma patients. Testing for KRAS and BRAF mutations, MSI, MLH1 methylation and CpG island methylator phenotype (CIMP) status was performed. A Cox proportional hazard model was built to predict survival. Results CIMP+ was detected in 27 of 99 (27.3%) duodenal adenocarcinomas, and was associated with MSI (P = 0.011) and MLH1 methylation (P < 0.001), but not with KRAS mutations (P = 0.114), as compared to CIMP− tumors. No BRAF V600E mutation was detected. Among the CIMP+ tumors, 15 (55.6%) were CIMP+/MLH1-unmethylated (MLH1-U). Kaplan-Meier analysis showed tumors classified by CIMP, CIMP/MLH1 methylation status or CIMP/MSI status could predict overall survival (OS; P = 0.047, 0.002, and 0.002, respectively), while CIMP/MLH1 methylation status could also predict time-to-recurrence (TTR; P = 0.016). In multivariate analysis, CIMP/MLH1 methylation status showed a significant prognostic value regarding both OS (P < 0.001) and TTR (P = 0.023). Patients with CIMP+/MLH1-U tumors had the worst OS and TTR. Conclusions Our results demonstrate existence of CIMP in duodenal adenocarcinomas. The combination of CIMP+/MLH1-U appears to be independently associated with poor prognosis in patients with duodenal adenocarcinomas. This study also suggests that BRAF mutations are not involved in duodenal tumorigenesis, MSI or CIMP development. PMID:22825585

Pattern of myocardial 99mTc-HMDP uptake and impact on myocardial function in patients with transthyretin cardiac amyloidosis.

PubMed

Pradel, Sarah; Brun, Stéphanie; Victor, Gérard; Pascal, Pierre; Fournier, Pauline; Ribes, David; Lavie-Badie, Yoan; Galinier, Michel; Carrié, Didier; Berry, Isabelle; Lairez, Olivier

2018-06-07

The purpose of the study was to describe the pattern of 99m Tc-labeled phosphate agents myocardial uptake by scintigraphy and explore its impact on left ventricular (LV) functions in transthyretin cardiac amyloidosis (TTR-CA). Fifty patients with TTR-CA underwent 99m Tc- hydroxymethylene-diphosphonate ( 99m Tc-HMDP) scintigraphy and echocardiography with measure of LV thickness, longitudinal strain (LS), systolic and diastolic functions. Cardiac retention by scintigraphy was assessed by visual scoring and the heart/whole body (H/WB) ratio was calculated by dividing counts in the heart by counts in late whole-body images. The mean population age was 79 ± 10 years. Mean H/WB ratio was 12 ± 7. Myocardial 99m Tc-HMDP uptake on segments 5, 6, 7, 8, 11, 12, 13, 14, 16, and 17 was correlated with H/WB ratio. Mean LVEF and global LS were 51 ± 10% and - 10 ± 3%, respectively. H/WB ratio was correlated with global LS (R = 0.408, P = .003), Ea (R = - 0.566, P < .001) and mean left ventricular wall thickness (R = 0.476, P < .001) but not with LVEF (R = - 0.109, P = .453). Segmental myocardial uptake was slightly correlated with segmental LS (R = 0.152, P < .001). H/WB ratio was not correlated with NT-proBNP levels (R = 0.219, P = .148) neither E/Ea ratio (R = 0.204, P = .184). These findings show the relationship between bone tracer myocardial uptake and LV functions in patients with TTR cardiac amyloidosis.

High-resolution molecular structure of a peptide in an amyloid fibril determined by magic angle spinning NMR spectroscopy

NASA Astrophysics Data System (ADS)

Jaroniec, Christopher P.; Macphee, Cait E.; Bajaj, Vikram S.; McMahon, Michael T.; Dobson, Christopher M.; Griffin, Robert G.

2004-01-01

Amyloid fibrils are self-assembled filamentous structures associated with protein deposition conditions including Alzheimer's disease and the transmissible spongiform encephalopathies. Despite the immense medical importance of amyloid fibrils, no atomic-resolution structures are available for these materials, because the intact fibrils are insoluble and do not form diffraction-quality 3D crystals. Here we report the high-resolution structure of a peptide fragment of the amyloidogenic protein transthyretin, TTR(105-115), in its fibrillar form, determined by magic angle spinning NMR spectroscopy. The structure resolves not only the backbone fold but also the precise conformation of the side chains. Nearly complete 13C and 15N resonance assignments for TTR(105-115) formed the basis for the extraction of a set of distance and dihedral angle restraints. A total of 76 self-consistent experimental measurements, including 41 restraints on 19 backbone dihedral angles and 35 13C-15N distances between 3 and 6 Å were obtained from 2D and 3D NMR spectra recorded on three fibril samples uniformly 13C, 15N-labeled in consecutive stretches of four amino acids and used to calculate an ensemble of peptide structures. Our results indicate that TTR(105-115) adopts an extended -strand conformation in the amyloid fibrils such that both the main- and side-chain torsion angles are close to their optimal values. Moreover, the structure of this peptide in the fibrillar form has a degree of long-range order that is generally associated only with crystalline materials. These findings provide an explanation of the unusual stability and characteristic properties of this form of polypeptide assembly.

Feasibility of investigating differential proteomic expression in depression: implications for biomarker development in mood disorders

PubMed Central

Frye, M A; Nassan, M; Jenkins, G D; Kung, S; Veldic, M; Palmer, B A; Feeder, S E; Tye, S J; Choi, D S; Biernacka, J M

2015-01-01

The objective of this study was to determine whether proteomic profiling in serum samples can be utilized in identifying and differentiating mood disorders. A consecutive sample of patients with a confirmed diagnosis of unipolar (UP n=52) or bipolar depression (BP-I n=46, BP-II n=49) and controls (n=141) were recruited. A 7.5-ml blood sample was drawn for proteomic multiplex profiling of 320 proteins utilizing the Myriad RBM Discovery Multi-Analyte Profiling platform. After correcting for multiple testing and adjusting for covariates, growth differentiation factor 15 (GDF-15), hemopexin (HPX), hepsin (HPN), matrix metalloproteinase-7 (MMP-7), retinol-binding protein 4 (RBP-4) and transthyretin (TTR) all showed statistically significant differences among groups. In a series of three post hoc analyses correcting for multiple testing, MMP-7 was significantly different in mood disorder (BP-I+BP-II+UP) vs controls, MMP-7, GDF-15, HPN were significantly different in bipolar cases (BP-I+BP-II) vs controls, and GDF-15, HPX, HPN, RBP-4 and TTR proteins were all significantly different in BP-I vs controls. Good diagnostic accuracy (ROC-AUC⩾0.8) was obtained most notably for GDF-15, RBP-4 and TTR when comparing BP-I vs controls. While based on a small sample not adjusted for medication state, this discovery sample with a conservative method of correction suggests feasibility in using proteomic panels to assist in identifying and distinguishing mood disorders, in particular bipolar I disorder. Replication studies for confirmation, consideration of state vs trait serial assays to delineate proteomic expression of bipolar depression vs previous mania, and utility studies to assess proteomic expression profiling as an advanced decision making tool or companion diagnostic are encouraged. PMID:26645624

Cost effectiveness of novel oral anticoagulants for stroke prevention in atrial fibrillation depending on the quality of warfarin anticoagulation control.

PubMed

Janzic, Andrej; Kos, Mitja

2015-04-01

Vitamin K antagonists, such as warfarin, are standard treatments for stroke prophylaxis in patients with atrial fibrillation. Patient outcomes depend on quality of warfarin management, which includes regular monitoring and dose adjustments. Recently, novel oral anticoagulants (NOACs) that do not require regular monitoring offer an alternative to warfarin. The aim of this study was to evaluate whether cost effectiveness of NOACs for stroke prevention in atrial fibrillation depends on the quality of warfarin control. We developed a Markov decision model to simulate warfarin treatment outcomes in relation to the quality of anticoagulation control, expressed as percentage of time in the therapeutic range (TTR). Standard treatment with adjusted-dose warfarin and improved anticoagulation control by genotype-guided dosing were compared with dabigatran, rivaroxaban, apixaban and edoxaban. The analysis was performed from the Slovenian healthcare payer perspective using 2014 costs. In the base case, the incremental cost-effectiveness ratio for apixaban, dabigatran and edoxaban was below the threshold of €25,000 per quality-adjusted life-years compared with adjusted-dose warfarin with a TTR of 60%. The probability that warfarin was a cost-effective option was around 1%. This percentage rises as the quality of anticoagulation control improves. At a TTR of 70%, warfarin was the preferred treatment in half the iterations. The cost effectiveness of NOACs for stroke prevention in patients with nonvalvular atrial fibrillation who are at increased risk for stroke is highly sensitive to warfarin anticoagulation control. NOACs are more likely to be cost-effective options in settings with poor warfarin management than in settings with better anticoagulation control, where they may not represent good value for money.

The Effects of Increasing Ocular Surface Stimulation on Blinking and Tear Secretion

PubMed Central

Wu, Ziwei; Begley, Carolyn G.; Port, Nicholas; Bradley, Arthur; Braun, Richard; King-Smith, Ewen

2015-01-01

Purpose. To investigate the effect of varying levels of ocular surface stimulation on the timing and amplitude of the blink and tear secretion. Methods. Following instillation of fluorescein dye, increasing levels of air flow were directed toward the central corneas of 10 healthy subjects. Interblink interval (IBI), tear meniscus height (TMH), and fluorescence intensity were measured simultaneously. Because blinking can obscure changes in TMH, we developed novel measures of tear secretion by calculating tear meniscus fluorescein concentration (TMFC) from intensity using a mathematical model. The change of TMH and TMFC over trials and the slope of the TMFC within each IBI (IBI-TTR) were further calculated. Results. The mean IBI was decreased by 8.08 ± 8.54 seconds from baseline to maximum air stimulation. The TMH increase was highly variable (0.41 ± 0.39 mm) among subjects, compared to the fluorescence tear turnover metrics: decrease in TMFC of 2.84 ± 0.98 natural logarithm or ln(%) and IBI-TTR of 0.065 ± 0.032 ln(%)/sec. Ocular surface stimulation was highly correlated with the TMFC and IBI-TTR, but less so with TMH (Pearson's r = 0.71, 0.69, and 0.40, P < 0.01, respectively). Blinking and tearing were significantly correlated with each other (Pearson's r = 0.56, P < 0.01), but tearing lagged behind by an average of 6.54 ± 4.07 seconds. Conclusions. Blinking and tearing share a common origin with sensory stimulation at the ocular surface. Both showed a dose–response increase with surface stimulation and were correlated with each other. These methods can potentially be used to understand alterations in ocular surface sensory function and associated protective responses in dry eye and other disorders of the ocular surface. PMID:26132780

The Effects of Increasing Ocular Surface Stimulation on Blinking and Tear Secretion.

PubMed

Wu, Ziwei; Begley, Carolyn G; Port, Nicholas; Bradley, Arthur; Braun, Richard; King-Smith, Ewen

2015-07-01

To investigate the effect of varying levels of ocular surface stimulation on the timing and amplitude of the blink and tear secretion. Following instillation of fluorescein dye, increasing levels of air flow were directed toward the central corneas of 10 healthy subjects. Interblink interval (IBI), tear meniscus height (TMH), and fluorescence intensity were measured simultaneously. Because blinking can obscure changes in TMH, we developed novel measures of tear secretion by calculating tear meniscus fluorescein concentration (TMFC) from intensity using a mathematical model. The change of TMH and TMFC over trials and the slope of the TMFC within each IBI (IBI-TTR) were further calculated. The mean IBI was decreased by 8.08 ± 8.54 seconds from baseline to maximum air stimulation. The TMH increase was highly variable (0.41 ± 0.39 mm) among subjects, compared to the fluorescence tear turnover metrics: decrease in TMFC of 2.84 ± 0.98 natural logarithm or ln(%) and IBI-TTR of 0.065 ± 0.032 ln(%)/sec. Ocular surface stimulation was highly correlated with the TMFC and IBI-TTR, but less so with TMH (Pearson's r = 0.71, 0.69, and 0.40, P < 0.01, respectively). Blinking and tearing were significantly correlated with each other (Pearson's r = 0.56, P < 0.01), but tearing lagged behind by an average of 6.54 ± 4.07 seconds. Blinking and tearing share a common origin with sensory stimulation at the ocular surface. Both showed a dose-response increase with surface stimulation and were correlated with each other. These methods can potentially be used to understand alterations in ocular surface sensory function and associated protective responses in dry eye and other disorders of the ocular surface.

Risk stratification and stroke prevention therapy care gaps in Canadian atrial fibrillation patients (from the Co-ordinated National Network to Engage Physicians in the Care and Treatment of Patients With Atrial Fibrillation chart audit).

PubMed

Patel, Ashish D; Tan, Mary K; Angaran, Paul; Bell, Alan D; Berall, Murray; Bucci, Claudia; Demchuk, Andrew M; Essebag, Vidal; Goldin, Lianne; Green, Martin S; Gregoire, Jean C; Gross, Peter L; Heilbron, Brett; Lin, Peter J; Ramanathan, Krishnan; Skanes, Allan; Wheeler, Bruce H; Goodman, Shaun G

2015-03-01

The objectives of this national chart audit (January to June 2013) of 6,346 patients with atrial fibrillation (AF; ≥18 years without a significant heart valve disorder) from 647 primary care physicians were to (1) describe the frequency of stroke and bleed risk assessments in patients with nonvalvular AF by primary care physicians, including the accuracy of these assessments relative to established predictive indexes; (2) outline contemporary methods of anticoagulation used; and (3) report the time in the therapeutic range among patients prescribed warfarin. An annual stroke risk assessment was not undertaken in 15% and estimated without a formal risk tool in 33%; agreement with CHADS2 score estimation was seen in 87% of patients. Major bleeding risk assessment was not undertaken in 25% and estimated without a formal risk tool in 47%; agreement with HAS-BLED score estimation was observed in 64% with physician overestimation in 26% of patients. Antithrombotic therapy included warfarin (58%), dabigatran (22%), rivaroxaban (14%), and apixaban (<1%). Among warfarin-treated patients, the median international normalized ratio was 2.4 and time in therapeutic range (TTR) was 73%; however, the TTR was <50% in 845 (25%), 50% to 69% in 674 (20%), and ≥70% in 1,827 (55%) patients. In conclusion, we describe a contemporary real-world elderly population with AF at important risk for stroke. There is apparent overestimation of bleeding risk in many patients. Warfarin was the dominant stroke prevention treatment; however, the suggested TTR target was achieved in only 55% of these patients. Copyright © 2015 Elsevier Inc. All rights reserved.

Million Hearts 2022: Understanding the Links between Environmental Pollutant Exposure and Cardiovascular and Cerebrovascular Events - Justus-Warren Heart Disease and Stroke Prevention Task Force

EPA Science Inventory

The webinar was requested by the Justus-Warren Heart Disease and Stroke Prevention Task Force. From their website, “The task force was established in 1995 in North Carolina to provide statewide leadership for the prevention and management of cardiovascular disease. Meetings are...

Metrology for Information Technology

DTIC Science & Technology

1997-05-01

Technology (IT) MEL/ITL Task Group on Metrology for Information Technology (IT) U.S. DEPARTMENT OF COMMERCE Technology Administration National Institute of...NIST management requested a white paper on metrology for information technology (IT). A task group was formed to develop this white paper with...representatives from the Manufacturing Engineering Laboratory (MEL), the Information Technology Laboratory (ITL), and Technology Services (TS). The task

32 CFR 1900.21 - Processing of requests for records.

Code of Federal Regulations, 2010 CFR

2010-07-01

... Information Act Amendments of 1996. (b) Database of “officially released information.” As an alternative to extensive tasking and as an accommodation to many requesters, the Agency maintains a database of “officially released information” which contains copies of documents released by this Agency. Searches of this database...

A Cost Analysis of Forward Positioning Material in the Fifth Fleet Area of Responsibility

DTIC Science & Technology

2014-12-01

CTF combined task force CY calendar year DDC defense distribution center DDNB Defense Depot Navy Detachment, Bahrain DHL DHL Airways DLA...items from Bahrain to the requesting unit.  Defense Distribution Center ( DDC )– DDC is concerned with getting the requested national item

Drug Information Requests at the Philadelphia College of Pharmacy and Science.

ERIC Educational Resources Information Center

Snow, Bonnie

1979-01-01

Analysis of requests received at the Pharmaceutical Information Center of the Philadelphia College of Pharmacy and Science contributes to: (1) the task of educational planning for health-science professionals, (2) identification of pharmaceutical literature retrieval skills needed, and (3) identification of sources which contain information…

77 FR 34355 - Proposed Collection; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-11

..., training conditions, technological environment, types of jobs and tasks, types of programs needed, and... information on organizational goals (e.g., desired performance), training conditions (e.g., technological environment), specific jobs and tasks, types of programs needed, and target audience. Evaluation respondents...

Solid-State NMR Studies Reveal Native-like β-Sheet Structures in Transthyretin Amyloid

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lim, Kwang Hun; Dasari, Anvesh K. R.; Hung, Ivan

Structural characterization of amyloid rich in cross-β structures is crucial for unraveling the molecular basis of protein misfolding and amyloid formation associated with a wide range of human disorders. Elucidation of the β-sheet structure in noncrystalline amyloid has, however, remained an enormous challenge. Here we report structural analyses of the β-sheet structure in a full-length transthyretin amyloid using solid-state NMR spectroscopy. Magic-angle-spinning (MAS) solid-state NMR was employed to investigate native-like β-sheet structures in the amyloid state using selective labeling schemes for more efficient solid-state NMR studies. Analyses of extensive long-range 13 C- 13 C correlation MAS spectra obtained with selectivelymore » 13 CO- and 13 Cα-labeled TTR reveal that the two main β-structures in the native state, the CBEF and DAGH β-sheets, remain intact after amyloid formation. The tertiary structural information would be of great use for examining the quaternary structure of TTR amyloid.« less

Solid-State NMR Studies Reveal Native-like β-Sheet Structures in Transthyretin Amyloid

DOE PAGES

Lim, Kwang Hun; Dasari, Anvesh K. R.; Hung, Ivan; ...

2016-09-02

Structural characterization of amyloid rich in cross-β structures is crucial for unraveling the molecular basis of protein misfolding and amyloid formation associated with a wide range of human disorders. Elucidation of the β-sheet structure in noncrystalline amyloid has, however, remained an enormous challenge. Here we report structural analyses of the β-sheet structure in a full-length transthyretin amyloid using solid-state NMR spectroscopy. Magic-angle-spinning (MAS) solid-state NMR was employed to investigate native-like β-sheet structures in the amyloid state using selective labeling schemes for more efficient solid-state NMR studies. Analyses of extensive long-range 13 C- 13 C correlation MAS spectra obtained with selectivelymore » 13 CO- and 13 Cα-labeled TTR reveal that the two main β-structures in the native state, the CBEF and DAGH β-sheets, remain intact after amyloid formation. The tertiary structural information would be of great use for examining the quaternary structure of TTR amyloid.« less

Quality of anticoagulation control: do race and language matter?

PubMed

Bhandari, Vijay Kumar; Wang, Frances; Bindman, Andrew B; Schillinger, Dean

2008-02-01

No studies have evaluated the quality of anticoagulation control among populations characterized by low socioeconomic status, diverse racial and ethnic backgrounds, or limited English proficiency. We conducted a retrospective cohort study to evaluate the effects of race/ethnicity and language on anticoagulation outcomes among patients (N=864) receiving continuous anticoagulation services at a university-affiliated public hospital. White/non-Hispanic patients made up 24%, Asian/Pacific Islanders 33%, Hispanics 22%, African Americans 18%. English (63%), Spanish, (14%), and Cantonese (13%) were the most common languages. Mean time in therapeutic range (TTR) was 43%. After adjustment, TTR was lower for African Americans than for Whites (absolute difference, -8.7%, p< .001) and for Spanish-speaking than for English-speaking Hispanics (absolute difference, -7.2%, p< .05). There were no differences between Asian/Pacific Islanders and Whites, nor between Cantonese-speaking and English-speaking Asian/Pacific Islanders. Future research should examine mechanisms by which race/ethnicity and language affect quality of anticoagulation and evaluate programs to improve treatment in diverse communities.

Kinetic assay for high-throughput screening of in vitro transthyretin amyloid fibrillogenesis inhibitors.

PubMed

Dolado, Ignacio; Nieto, Joan; Saraiva, Maria João M; Arsequell, Gemma; Valencia, Gregori; Planas, Antoni

2005-01-01

Stabilization of tetrameric transthyretin (TTR) by binding of small ligands is a current strategy aimed at inhibiting amyloid fibrillogenesis in transthyretin-associated pathologies, such as senile systemic amyloidosis (SSA) and familial amyloidotic polyneuropathy (FAP). A kinetic assay is developed for rapid evaluation of compounds as potential in vitro inhibitors in a high-throughput screening format. It is based on monitoring the time-dependent increase of absorbance due to turbidity occurring by acid-induced protein aggregation. The method uses the highly amyloidogenic Y78F mutant of human transthyretin (heterogously expressed in Escherichia coli cells). Initial rates of protein aggregation at different inhibitor concentrations follow a monoexponential dose-response curve from which inhibition parameters are calculated. For the assay development, thyroid hormones and nonsteroidal antiinflamatory drugs were chosen among other reference compounds. Some of them are already known to be in vitro inhibitors of TTR amyloidogenesis. Analysis time is optimized to last 1.5 h, and the method is implemented in microtiter plates for screening of libraries of potential fibrillogenesis inhibitors.

GPS Moving Vehicle Experiment

NASA Technical Reports Server (NTRS)

Oaks, O. J.; Reid, Wilson; Wright, James; Duffey, Christopher; Williams, Charles; Warren, Hugh; Zeh, Tom; Buisson, James

1996-01-01

The Naval Research Laboratory (NRL) in the development of timing systems for remote locations, had a technical requirement for a Y code (SA/AS) Global Positioning System (GPS) precise time transfer receiver (TTR) which could be used both in a stationary mode or mobile mode. A contract was awarded to the Stanford Telecommunication Corporation (STEL) to build such a device. The Eastern Range (ER) als had a requirement for such a receiver and entered into the contract with NRL for the procurement of additional receivers. The Moving Vehicle Experiment (MVE) described in this paper is the first in situ test of the STEL Model 5401C Time Transfer System in both stationary and mobile operations. The primary objective of the MVE was to test the timing accuracy of the newly developed GPS TTR aboard a moving vessel. To accomplish this objective, a joint experiment was performed with personnel from NRL and the er at the Atlantic Undersea Test and Evaluation Center (AUTEC) test range at Andros Island. Results and discussion of the test are presented in this paper.

Closure Report for Corrective Action Unit 408: Bomblet Target Area Tonopah Test Range (TTR), Nevada, Revision 0

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mark Krauss

2010-09-01

This Closure Report (CR) presents information supporting the closure of Corrective Action Unit (CAU) 408: Bomblet Target Area (TTR), Tonopah Test Range, Nevada. This CR complies with the requirements of the Federal Facility Agreement and Consent Order that was agreed to by the State of Nevada; U.S. Department of Energy (DOE), Environmental Management; U.S. Department of Defense; and DOE, Legacy Management. Corrective Action Unit 408 is located at the Tonopah Test Range, Nevada, and consists of Corrective Action Site (CAS) TA-55-002-TAB2, Bomblet Target Areas. This CAS includes the following seven target areas: • Mid Target • Flightline Bomblet Location •more » Strategic Air Command (SAC) Target Location 1 • SAC Target Location 2 • South Antelope Lake • Tomahawk Location 1 • Tomahawk Location 2 The purpose of this CR is to provide documentation supporting the completed corrective actions and data confirming that the closure objectives for the CAS within CAU 408 were met. To achieve this, the following actions were performed: • Review the current site conditions, including the concentration and extent of contamination. • Implement any corrective actions necessary to protect human health and the environment. • Properly dispose of corrective action and investigation wastes. • Document Notice of Completion and closure of CAU 408 issued by the Nevada Division of Environmental Protection. From July 2009 through August 2010, closure activities were performed as set forth in the Streamlined Approach for Environmental Restoration Plan for CAU 408: Bomblet Target Area, Tonopah Test Range (TTR), Nevada. The purposes of the activities as defined during the data quality objectives process were as follows: • Identify and remove munitions of explosive concern (MEC) associated with DOE activities. • Investigate potential disposal pit locations. • Remove depleted uranium-contaminated fragments and soil. • Determine whether contaminants of concern (COCs) are present. • If COCs are present, determine their nature and extent, implement appropriate corrective actions, and properly dispose of wastes. Analytes detected during the closure activities were evaluated against final action levels to determine COCs for CAU 408. Assessment of the data indicated COCs are not present at CAS TA-55-002-TAB2; therefore, no corrective action is necessary. No use restrictions are required to be placed on this CAU because the investigation showed no evidence of remaining soil contamination or remaining debris/waste upon completion of all investigation activities. The MEC was successfully removed and dispositioned as planned using current best available technologies. As MEC guidance and general MEC standards acknowledge that MEC response actions cannot determine with 100 percent certainty that all MEC and unexploded ordnance (UXO) are removed, the clean closure of CAU 408 will implement a best management practice of posting UXO hazard warning signs near the seven target areas. The signs will warn future land users of the potential for encountering residual UXO hazards. The DOE, National Nuclear Security Administration Nevada Site Office, provides the following recommendations: • A Notice of Completion to the DOE, National Nuclear Security Administration Nevada Site Office, is requested from the Nevada Division of Environmental Protection for closure of CAU 408. • Corrective Action Unit 408 should be moved from Appendix III to Appendix IV of the Federal Facility Agreement and Consent Order.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Raszewski, F; Tommy Edwards, T; David Peeler, D

Sludge Batch 4 (SB4) is currently being processed in the Defense Waste Processing Facility (DWPF) using Frit 510. The slurry pumps in Tank 40 are experiencing in-leakage of bearing water, which is causing the sludge slurry feed in Tank 40 to become dilute at a rapid rate. Currently, the DWPF is removing this dilution water by performing caustic boiling during the Sludge Receipt and Adjustment Tank (SRAT) cycle. In order to alleviate prolonged SRAT cycle times that may eventually impact canister production rates, decant scenarios of 100, 150, and 200 kilogallons of supernate were proposed for Tank 40 during themore » DWPF March outage. Based on the results of the preliminary assessment issued by the Savannah River National Laboratory (SRNL), the Liquid Waste Organization (LWO) issued a Technical Task Request (TTR) for SRNL to (1) perform a more detailed evaluation using updated SB4 compositional information and (2) assess the viability of Frit 510 and determine any potential impacts on the SB4 system. As defined in the TTR, LWO requested that SRNL validate the sludge--only SB4 flowsheet and the coupled operations flowsheet using the 100K gallon decant volume as well as the addition of 3 wt% sodium on a calcined oxide basis. Approximately 12 historical glasses were identified during a search of the ComProTM database that are located within at least one of the five glass regions defined by the proposed SB4 flowsheet options. While these glasses meet the requirements of a variability study there was some concern that the compositional coverage did not adequately bound all cases. Therefore, SRNL recommended that a supplemental experimental variability study be performed to support the various SB4 flowsheet options that may be implemented for future SB4 operations in DWPF. Eighteen glasses were selected based on nominal sludge projections representing the current as well as the proposed flowsheets over a WL interval of interest to DWPF (32-42%). The intent of the experimental portion of the variability study is to demonstrate that the glasses of the Frit 510-modified SB4 compositional region (Cases No.1-5) are both acceptable relative to the Environmental Assessment (EA) reference glass and predictable by the current DWPF process control models for durability. Frit 510 is a viable option for the processing of SB4 after a Tank 40 decant and the addition of products from the Actinide Removal Process (ARP). The addition of ARP did not have any negative impacts on the acceptability and predictability of the variability study glasses. The results of the variability study indicate that all of the study glasses (both quenched and centerline canister cooled (ccc)) have normalized releases for boron that are well below the reference EA glass (16.695 g/L). The durabilities of all of the study glasses are predictable using the current Product Composition Control System (PCCS) durability models with the exception of SB4VAR24ccc (Case No.2 at 41%). PCCS is not applicable to non-homogeneous glasses (i.e. glasses containing crystals such as acmite and nepheline), thus SB4VAR24ccc should not be predictable as it contains nepheline. The presence of nepheline has been confirmed in both SB4VAR13ccc and SB4VAR24ccc by X-ray diffraction (XRD). These two glasses are the first results which indicate that the current nepheline discriminator value of 0.62 is not conservative. The nepheline discriminator was implemented into PCCS for SB4 based on the fact that all of the historical glasses evaluated with nepheline values of 0.62 or greater did not contain nepheline via XRD analysis. Although these two glasses do cause some concern over the use of the 0.62 nepheline value for future DWPF glass systems, the impact to the current SB4 system is of little concern. More specifically, the formation of nepheline was observed in glasses targeting 41 or 42% WL. Current processing of the Frit 510-SB4 system in DWPF has nominally targeted 34% WL. For the SB4 variability study glasses targeting these lower WLs, nepheline formation was not observed and the minimal difference in PCT response between quenched and ccc versions supported its absence.« less

A study of the influence of task familiarity on user behaviors and performance with a MeSH term suggestion interface for PubMed bibliographic search.

PubMed

Tang, Muh-Chyun; Liu, Ying-Hsang; Wu, Wan-Ching

2013-09-01

Previous research has shown that information seekers in biomedical domain need more support in formulating their queries. A user study was conducted to evaluate the effectiveness of a metadata based query suggestion interface for PubMed bibliographic search. The study also investigated the impact of search task familiarity on search behaviors and the effectiveness of the interface. A real user, user search request and real system approach was used for the study. Unlike tradition IR evaluation, where assigned tasks were used, the participants were asked to search requests of their own. Forty-four researchers in Health Sciences participated in the evaluation - each conducted two research requests of their own, alternately with the proposed interface and the PubMed baseline. Several performance criteria were measured to assess the potential benefits of the experimental interface, including users' assessment of their original and eventual queries, the perceived usefulness of the interfaces, satisfaction with the search results, and the average relevance score of the saved records. The results show that, when searching for an unfamiliar topic, users were more likely to change their queries, indicating the effect of familiarity on search behaviors. The results also show that the interface scored higher on several of the performance criteria, such as the "goodness" of the queries, perceived usefulness, and user satisfaction. Furthermore, in line with our hypothesis, the proposed interface was relatively more effective when less familiar search requests were attempted. Results indicate that there is a selective compatibility between search familiarity and search interface. One implication of the research for system evaluation is the importance of taking into consideration task familiarity when assessing the effectiveness of interactive IR systems. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

The approach to engineering tasks composition on knowledge portals

NASA Astrophysics Data System (ADS)

Novogrudska, Rina; Globa, Larysa; Schill, Alexsander; Romaniuk, Ryszard; Wójcik, Waldemar; Karnakova, Gaini; Kalizhanova, Aliya

2017-08-01

The paper presents an approach to engineering tasks composition on engineering knowledge portals. The specific features of engineering tasks are highlighted, their analysis makes the basis for partial engineering tasks integration. The formal algebraic system for engineering tasks composition is proposed, allowing to set the context-independent formal structures for engineering tasks elements' description. The method of engineering tasks composition is developed that allows to integrate partial calculation tasks into general calculation tasks on engineering portals, performed on user request demand. The real world scenario «Calculation of the strength for the power components of magnetic systems» is represented, approving the applicability and efficiency of proposed approach.

76 FR 622 - Agency Information Collection Activities: Request for Comments for a New Information Collection

Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-05

... and simulator driving tasks will require 4\\1/2\\ hours of the participant's time, spread over the four... persons will participate, divided across the three regions. 10 weeks will be needed to complete the 4... the 4\\1/2\\ hours for the simulator tasks, the other choice tasks, and questionnaires, and the one hour...

75 FR 54416 - Agency Information Collection Activities: Notice of Request for Approval of a New Information...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-07

... the 4\\1/2\\ hours for the simulator tasks, the other choice tasks, and questionnaires, and the one hour..., questionnaires and simulator driving tasks will require four and one half hours of the participant's time, spread... from the device to a computer. Sensitive data, such as the home and work locations of the drivers, will...

77 FR 30560 - Proposed Generic Communication; Generic Letter on Seismic Risk Evaluations for Operating Reactors

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-23

... the Fukushima Near-Term Task Force Recommendations 2.1 and 2.3. The request for information letters... addressing the Fukushima Near-Term Task Force Recommendations 2.1 and 2.3. The memorandum is available... Fukushima Near-Term Task Force Recommendations 2.1 and 2.3 (ADAMS Accession Number ML12056A046), as...

Evaluation and Preliminary Results of the New USNO PPS Timing Receiver

DTIC Science & Technology

2000-11-01

timing receiver, one may currently obtain raw pseudorange and carrier-phase data by periodically downloading such data from a flashcard . Several...preliminary experiments have been performed using data collected from the prototype TTR- 12 receivers’ flashcards and geodetic GPS carrier-phase techniques

75 FR 11893 - Food and Drug Administration Transparency Task Force; Request for Comments

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-12

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2009-N-0247... Administration, HHS. ACTION: Notice; request for comments. SUMMARY: The Food and Drug Administration (FDA) is soliciting comments from interested persons on ways in which FDA can increase transparency between FDA and...

What Lies Beneath?: Verbal Report in Interlanguage Requests in English

ERIC Educational Resources Information Center

Woodfield, Helen

2010-01-01

The present study investigates the role of concurrent and retrospective verbal report in exploring the cognitive processes of six pairs of advanced ESL learners engaged on a written discourse completion task eliciting status-unequal requests in English. Qualitative analysis of the concurrent data indicate that (i) social contextual aspects of the…

[Insurance medical consultation in private health insurance - which insurance medical questions are put to the medical consultant?].

PubMed

Hakimi, R; Herre, K; Seyffer, R

2015-03-01

This study deals with the task areas of the medical consultant in private health insurance. Although insurance medical consultation for the insurance business originated in the 19th century, the tasks and competencies of the medical consultants are still mostly unknown. This study is a complete inventory count of all insurance medical consultation requests for the year 2013. All of the 5493 insurance medical consultation requests have been evaluated. Most of the consultation requests concern the medical necessity for medical drugs, followed by the medical consultation of alternative medicine and the classification of cure and rehabilitation measures of hospital medical treatments. The need for insurance medical consultation on lifestyle drugs, cosmetic operations and artificial insemination has increased significantly in the past 10 years. Since 2009, moreover, the need for medical consultation on the subject of "Ruhensleistungen" with regard to non-payers and "Notlagentarif" has strongly increased.

Managing the space sciences

NASA Technical Reports Server (NTRS)

1995-01-01

In April 1994 the National Research Council received a request from NASA that the NRC's Space Studies Board provide guidance on questions relating to the management of NASA's programs in the space sciences. The issues raised in the request closely reflect questions posed in the agency's fiscal year 1994 Senate appropriations report. These questions included the following: Should all the NASA space science programs be gathered into a 'National Institute for Space Science'? What other organizational changes might be made to improve the coordination and oversight of NASA space science programs? What processes should be used for establishing interdisciplinary science priorities based on scientific merit and other criteria, while ensuring opportunities for newer fields and disciplines to emerge? And what steps could be taken to improve utilization of advanced technologies in future space scienc missions? This report details the findings of the Committee on the Future of Space Science (FOSS) and its three task groups: the Task Group on Alternative Organizations, Task Group on Research Prioritization, and the Task Group on Technology.

The effects of echolalia on acquisition and generalization of receptive labeling in autistic children.

PubMed Central

Charlop, M H

1983-01-01

This investigation, consisting of two experiments, was designed to assess the effects of autistic immediate echolalia on acquisition and generalization of receptive labeling tasks. Experiment 1 addressed whether autistic children could use their echolalia to facilitate acquisition. The results indicated that incorporating echolalia (echo of the requested object's label) into the task before manual response (handing the requested object to the experimenter) facilitated receptive labeling. Experiment 2 was designed to determine the effects of incorporating echolalia into task response on acquisition and subsequent generalization. These results indicated that echolalia facilitated generalization for echolalic autistic children but not for functionally mute autistic children. The results of the experiments are discussed in terms of stimulus control. Additionally, it is proposed that perhaps in certain cases, echolalia should not be eliminated, but used to advantage in receptive responding. PMID:6833164

The effects of echolalia on acquisition and generalization of receptive labeling in autistic children.

PubMed

Charlop, M H

1983-01-01

This investigation, consisting of two experiments, was designed to assess the effects of autistic immediate echolalia on acquisition and generalization of receptive labeling tasks. Experiment 1 addressed whether autistic children could use their echolalia to facilitate acquisition. The results indicated that incorporating echolalia (echo of the requested object's label) into the task before manual response (handing the requested object to the experimenter) facilitated receptive labeling. Experiment 2 was designed to determine the effects of incorporating echolalia into task response on acquisition and subsequent generalization. These results indicated that echolalia facilitated generalization for echolalic autistic children but not for functionally mute autistic children. The results of the experiments are discussed in terms of stimulus control. Additionally, it is proposed that perhaps in certain cases, echolalia should not be eliminated, but used to advantage in receptive responding.

Anticoagulation Quality Assessment in Patients with Nonvalvular Atrial Fibrillation (NVAF) and Comparison with Major Trials of Direct-Acting Oral Anticoagulants

DTIC Science & Technology

2016-04-22

Purpose: The benefits of warfarin anticoagulation therapy are strongly correlated with the ability to maintain patients’ INR goal, known as the time...Rosendaal). Differences in TTR calculations could alter perceptions about the effectiveness of warfarin therapy.

Freedom of Information Act Requests: Six Keys to Handling Them

DTIC Science & Technology

2016-01-01

Defense AT&L: January–February 2016 50 Freedom of Information Act Requests Six Keys to Handling Them Michael A. Rodgers Rodgers is a professor of...crucial mission tasks. Understanding and using the six steps and keys provided above will free you from FOIA-induced distractions. The author can be contacted at michael.rodgers@dau.mil.

75 FR 71131 - Submission for OMB Review; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-22

... impacts. To complete this task with scientific rigor, it will be necessary to collect high quality survey... instruments, methodologies, procedures, and analytical techniques for this task. Moreover, they have been pilot tested in 11 States. The tools and techniques were submitted for review, and were approved, by...

Development of Physical Employment Standards for the Royal Australian Navy: Validation of Identified Whole-of-ship Tasks

DTIC Science & Technology

2014-11-01

to determining individual CS tasks, this partially satisfied Navy’s request to quantify the physical demands of the course in order to draw parity ...will enable comparison between task demands on the course and during on-board duties. These data will be used to determine whether there is parity ...between the physical and physiological demands of the ACSC (or components of it) and CS tasks performed on-board each platform. If parity is drawn

Investigation of Performance Improvements Including Application of Inlet Guide Vanes to a Cross-flow Fan

DTIC Science & Technology

2009-09-01

25 Figure 17. IGV Cut Out from Fluid Domain...Figure 22. Installed IGVS as Viewed from the CFF Inlet.................................................30 Figure 23. Schematic of Turbine Test Rig (TTR...44 Figure 28. Close In View of Velocity Vector Plot Near IGVS for 6IGV Model..............45 Figure 29

Common presentation of rare diseases: Left ventricular hypertrophy and diastolic dysfunction.

PubMed

Linhart, Ales; Cecchi, Franco

2018-04-15

Left ventricular hypertrophy may be a consequence of a hemodynamic overload or a manifestation of several diseases affecting different structural and functional proteins of cardiomyocytes. Among these, sarcomeric hypertrophic cardiomyopathy (HCM) represents the most frequent cause. In addition, several metabolic diseases lead to myocardial thickening, either due to intracellular storage (glycogen storage and lysosomal diseases), extracellular deposition (TTR and AL amyloidosis) or due to abnormal energy metabolism (mitochondrial diseases). The recognition of these rare causes of myocardial hypertrophy is important for family screening strategies, risk assessment, and treatment. Moreover, as there are specific therapies for some forms of HCM including enzyme substitution and chaperone therapies and specific treatments for TTR amyloidosis, a differential diagnosis should be sought in all patients with unexplained left ventricular hypertrophy. Diastolic dysfunction is a key feature of HCM and its phenocopies. Its assessment is complex and requires evaluation of several functional parameters and structural changes. Severe diastolic dysfunction carries a negative prognostic implication and its value in differential diagnosis is limited. Copyright © 2018 Elsevier B.V. All rights reserved.

Corrective action investigation plan for Corrective Action Unit Number 423: Building 03-60 Underground Discharge Point, Tonopah Test Range, Nevada

DOE Office of Scientific and Technical Information (OSTI.GOV)

NONE

1997-10-27

This Corrective Action Investigation Plan (CAIP) contains the environmental sample collection objectives and the criteria for conducting site investigation activities at Corrective Action Unit (CAU) Number 423, the Building 03-60 Underground Discharge Point (UDP), which is located in Area 3 at the Tonopah Test Range (TTR). The TTR, part of the Nellis Air Force Range, is approximately 225 kilometers (140 miles) northwest of Las Vegas, Nevada. CAU Number 423 is comprised of only one Corrective Action Site (CAS) which includes the Building 03-60 UDP and an associated discharge line extending from Building 03-60 to a point approximately 73 meters (240more » feet) northwest. The UDP was used between approximately 1965 and 1990 to dispose of waste fluids from the Building 03-60 automotive maintenance shop. It is likely that soils surrounding the UDP have been impacted by oil, grease, cleaning supplies and solvents as well as waste motor oil and other automotive fluids released from the UDP.« less

Length of stay of stroke rehabilitation inpatients: prediction through the functional independence measure.

PubMed

Franchignoni, F; Tesio, L; Martino, M T; Benevolo, E; Castagna, M

1998-01-01

A model for prediction of length of stay (LOS, in days) of stroke rehabilitation inpatients was developed, based on patients' age (years) and function at admission (scored on the Functional Independence Measure, FIMSM). One hundred and twenty-nine cases, consecutively admitted to three free-standing rehabilitation centres in Italy, were analyzed. A multiple linear regression using forward stepwise selection procedure was adopted. Median admission and discharge scores were: 57 and 75 for the total FIM score, 29 and 48 for the 13-item motor FIM subscore, 29 and 30 for the 5-item cognitive FIM subscore (potential range: 18-126, 13-91, 5-35, respectively). Median LOS was 44 days (interquartile range 30-62). The logLOS predictive model included three FIM items ("toilet transfer", TTr; "social interaction"; "expression") and patient's age (R2 = 0.48). TTr alone explained 31.3% of the variance of logLOS. These results are consistent with previous American studies, showing that FIM scores at admission are strong predictors of patients' LOS, with the transfer items having the greatest predictive power.

Experimental Model for Successful Liver Cell Therapy by Lenti TTR-YapERT2 Transduced Hepatocytes with Tamoxifen Control of Yap Subcellular Location

PubMed Central

Yovchev, Mladen; Jaber, Fadi L.; Lu, Zhonglei; Patel, Shachi; Locker, Joseph; Rogler, Leslie E.; Murray, John W.; Sudol, Marius; Dabeva, Mariana D.; Zhu, Liang; Shafritz, David A.

2016-01-01

Liver repopulation by transplanted hepatocytes has not been achieved previously in a normal liver microenvironment. Here we report that adult rat hepatocytes transduced ex vivo with a lentivirus expressing a human YapERT2 fusion protein (hYapERT2) under control of the hepatocyte-specific transthyretin (TTR) promoter repopulate normal rat liver in a tamoxifen-dependent manner. Transplanted hepatocytes expand very slowly but progressively to produce 10% repopulation at 6 months, showing clusters of mature hepatocytes that are fully integrated into hepatic parenchyma, with no evidence for dedifferentiation, dysplasia or malignant transformation. Thus, we have developed the first vector designed to regulate the growth control properties of Yap that renders it capable of producing effective cell therapy. The level of liver repopulation achieved has significant translational implications, as it is 2-3x the level required to cure many monogenic disorders of liver function that have no underlying hepatic pathology and is potentially applicable to diseases of other tissues and organs. PMID:26763940

The role of fibrinogen glycation in ATTR: evidence for chaperone activity loss in disease.

PubMed

Fonseca, Daniel; Gilberto, Samuel; Ribeiro-Silva, Cristina; Ribeiro, Raquel; Guinote, Inês Batista; Saraiva, Susana; Gomes, Ricardo A; Mateus, Élia; Viana, Ana; Barroso, Eduardo; Freire, Ana Ponces; Freire, Patrick; Cordeiro, Carlos; da Costa, Gonçalo

2016-07-15

Transthyretin amyloidosis (ATTR) belongs to a class of disorders caused by protein misfolding and aggregation. ATTR is a disabling disorder of autosomal dominant trait, where transthyretin (TTR) forms amyloid deposits in different organs, causing dysfunction of the peripheral nervous system. We previously discovered that amyloid fibrils from ATTR patients are glycated by methylglyoxal. Even though no consensus has been reached about the actual role of methylglyoxal-derived advanced glycation end-products in amyloid diseases, evidence collected so far points to a role for protein glycation in conformational abnormalities, being ubiquitously found in amyloid deposits in Alzheimer's disease, dialysis-related amyloidosis and Parkinson's diseases. Human fibrinogen, an extracellular chaperone, was reported to specifically interact with a wide spectrum of stressed proteins and suppress their aggregation, being an interacting protein with TTR. Fibrinogen is differentially glycated in ATTR, leading to its chaperone activity loss. Here we show the existence of a proteostasis imbalance in ATTR linked to fibrinogen glycation by methylglyoxal. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

Timing of Gazes in Child Dialogues: A Time-Course Analysis of Requests and Back Channelling in Referential Communication

ERIC Educational Resources Information Center

Sandgren, Olof; Andersson, Richard; van de Weijer, Joost; Hansson, Kristina; Sahlen, Birgitta

2012-01-01

Background: This study investigates gaze behaviour in child dialogues. In earlier studies the authors have investigated the use of requests for clarification and responses in order to study the co-creation of understanding in a referential communication task. By adding eye tracking, this line of research is now expanded to include non-verbal…

"I Just Need More Time": A Study of Native and Non-Native Students' Requests to Faculty for an Extension

ERIC Educational Resources Information Center

Woodfield, Helen; Economidou-Kogetsidis, Maria

2010-01-01

This paper examines the status-unequal requests of 89 advanced mixed-L1 learners and 87 British English native speakers elicited by a written discourse completion task. Significant differences were observed in all three dimensions analysed: internal and external modification, and perspective. The data demonstrate learners' overuse of zero marking…

Cruciferous vegetable supplementation in a controlled diet study alters the serum peptidome in a GSTM1-genotype dependent manner

PubMed Central

2011-01-01

Background Cruciferous vegetable intake is inversely associated with the risk of several cancers. Isothiocyanates (ITC) are hypothesized to be the major bioactive constituents contributing to these cancer-preventive effects. The polymorphic glutathione-S-transferase (GST) gene family encodes several enzymes which catalyze ITC degradation in vivo. Methods We utilized high throughput proteomics methods to examine how human serum peptides (the "peptidome") change in response to cruciferous vegetable feeding in individuals of different GSTM1 genotypes. In two randomized, crossover, controlled feeding studies (EAT and 2EAT) participants consumed a fruit- and vegetable-free basal diet and the basal diet supplemented with cruciferous vegetables. Serum samples collected at the end of the feeding period were fractionated and matrix assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry spectra were obtained. Peak identification/alignment computer algorithms and mixed effects models were used to analyze the data. Results After analysis of spectra from EAT participants, 24 distinct peaks showed statistically significant differences associated with cruciferous vegetable intake. Twenty of these peaks were driven by their GSTM1 genotype (i.e., GSTM1+ or GSTM1- null). When data from EAT and 2EAT participants were compared by joint processing of spectra to align a common set, 6 peaks showed consistent changes in both studies in a genotype-dependent manner. The peaks at 6700 m/z and 9565 m/z were identified as an isoform of transthyretin (TTR) and a fragment of zinc α2-glycoprotein (ZAG), respectively. Conclusions Cruciferous vegetable intake in GSTM1+ individuals led to changes in circulating levels of several peptides/proteins, including TTR and a fragment of ZAG. TTR is a known marker of nutritional status and ZAG is an adipokine that plays a role in lipid mobilization. The results of this study present evidence that the GSTM1-genotype modulates the physiological response to cruciferous vegetable intake. PMID:21272319

Inflammation, negative nitrogen balance, and outcome after aneurysmal subarachnoid hemorrhage.

PubMed

Badjatia, Neeraj; Monahan, Aimee; Carpenter, Amanda; Zimmerman, Jacqueline; Schmidt, J Michael; Claassen, Jan; Connolly, E Sander; Mayer, Stephan A; Karmally, Wahida; Seres, David

2015-02-17

To analyze the impact of inflammation and negative nitrogen balance (NBAL) on nutritional status and outcomes after subarachnoid hemorrhage (SAH). This was a prospective observational study of SAH patients admitted between May 2008 and June 2012. Measurements of C-reactive protein (CRP), transthyretin (TTR), resting energy expenditure (REE), and NBAL (g/day) were performed over 4 preset time periods during the first 14 postbleed days (PBD) in addition to daily caloric intake. Factors associated with REE and NBAL were analyzed with multivariable linear regression. Hospital-acquired infections (HAI) were tracked daily for time-to-event analyses. Poor outcome at 3 months was defined as a modified Rankin Scale score ≥ 4 and assessed by multivariable logistic regression. There were 229 patients with an average age of 55 ± 15 years. Higher REE was associated with younger age (p = 0.02), male sex (p < 0.001), higher Hunt Hess grade (p = 0.001), and higher modified Fisher score (p = 0.01). Negative NBAL was associated with lower caloric intake (p < 0.001), higher body mass index (p < 0.001), aneurysm clipping (p = 0.03), and higher CRP:TTR ratio (p = 0.03). HAIs developed in 53 (23%) patients on mean PBD 8 ± 3. Older age (p = 0.002), higher Hunt Hess (p < 0.001), lower caloric intake (p = 0.001), and negative NBAL (p = 0.04) predicted time to first HAI. Poor outcome at 3 months was associated with higher Hunt Hess grade (p < 0.001), older age (p < 0.001), negative NBAL (p = 0.01), HAI (p = 0.03), higher CRP:TTR ratio (p = 0.04), higher body mass index (p = 0.03), and delayed cerebral ischemia (p = 0.04). Negative NBAL after SAH is influenced by inflammation and associated with an increased risk of HAI and poor outcome. Underfeeding and systemic inflammation are potential modifiable risk factors for negative NBAL and poor outcome after SAH. © 2015 American Academy of Neurology.

Closure Report for Corrective Action Unit 412: Clean Slate I Plutonium Dispersion (TTR) Tonopah Test Range, Nevada, Revision 0

DOE Office of Scientific and Technical Information (OSTI.GOV)

Matthews, Patrick

This Closure Report (CR) presents information supporting the clean closure of Corrective Action Unit (CAU) 412: Clean Slate I Plutonium Dispersion (TTR), located on the Tonopah Test Range, Nevada. CAU 412 consists of a release of radionuclides to the surrounding soil from a storage–transportation test conducted on May 25, 1963. Corrective action investigation (CAI) activities were performed in April and May 2015, as set forth in the Streamlined Approach for Environmental Restoration (SAFER) Plan for Corrective Action Unit 412: Clean Slate I Plutonium Dispersion (TTR), Tonopah Test Range, Nevada; and in accordance with the Soils Activity Quality Assurance Plan. Themore » purpose of the CAI was to fulfill data needs as defined during the data quality objectives process. The CAU 412 dataset of investigation results was evaluated based on a data quality assessment. This assessment demonstrated the dataset is complete and acceptable for use in fulfilling the data needs identified by the data quality objectives process. This CR provides documentation and justification for the clean closure of CAU 412 under the FFACO without further corrective action. This justification is based on historical knowledge of the site, previous site investigations, implementation of the 1997 interim corrective action, and the results of the CAI. The corrective action of clean closure was confirmed as appropriate for closure of CAU 412 based on achievement of the following closure objectives: Radiological contamination at the site is less than the final action level using the ground troops exposure scenario (i.e., the radiological dose is less than the final action level): Removable alpha contamination is less than the high contamination area criterion: No potential source material is present at the site, and any impacted soil associated with potential source material has been removed so that remaining soil contains contaminants at concentrations less than the final action levels: and There is sufficient information to characterize investigation and remediation waste for disposal.« less

Effects of the soya isoflavone genistein in early life stages of the Senegalese sole, Solea senegalensis: Thyroid, estrogenic and metabolic biomarkers.

PubMed

Sarasquete, Carmen; Úbeda-Manzanaro, Maria; Ortiz-Delgado, Juan Bosco

2017-09-01

This study examines the effects induced by environmentally relevant concentrations of the isoflavone genistein (3mg/L and 10mg/L) during early life stages of the Senegalese sole. Throughout the hypothalamus-pituitary-thyroid (HPT) axis, several neurohormonal regulatory thyroid signalling patterns (thyroglobulin/Tg, thyroid peroxidase/TPO, transthyretin/TTR, thyroid receptors/TRβ, and iodothrynonine deiodinases, Dio2 and Dio3) were analysed. Furthermore, the expression patterns of estrogen receptor ERβ and haemoprotein Cyp1a were also evaluated. In the control larvae, progressive increases of constitutive hormonal signalling pathways have been evidenced from the pre-metamorphosis phase onwards, reaching the highest expression basal levels at the metamorphosis (Tg, TPO, Dio2) and/or during post-metamorphosis (TTR, TRβ, ERβ). When the early larvae were exposed to both genistein concentrations (3mg/L and 10mg/L), a statistically significant down-regulation of TPO, TTR and Tg mRNA levels was clearly detected at the metamorphic stages. In addition, the Dio2 and Dio3 transcript expression levels were also down and up-regulated when exposed to both genistein concentrations. In the larvae exposed to genistein, no statistically significant responses were recorded for the TRβ expression patterns. Nevertheless, the ERβ and Cyp1a transcript levels were up-regulated at the middle metamorphic stage (S2, at 16 dph) in the larvae exposed to high genistein concentrations and, only the ERβ was down-regulated (S1, at 12dph) at the lower doses. Finally, all these pointed out imbalances were only temporarily disrupted by exposure to genistein, since most of the modulated transcriptional signals (i.e. up or down-regulation) were quickly restored to the baseline levels. Additionally, the control and genistein-exposed Senegalese sole specimens showed characteristic ontogenetic patterns and completely suitable for an optimal development, metamorphosis, and growth. Copyright © 2017. Published by Elsevier Inc.

Antipsychotic medications for the treatment of delirium: a systematic review and meta-analysis of randomised controlled trials.

PubMed

Kishi, Taro; Hirota, Tomoya; Matsunaga, Shinji; Iwata, Nakao

2016-07-01

We performed an updated meta-analysis of antipsychotic treatment in patients with delirium, based on a previous meta-analysis published in 2007. Included in this study were randomised, placebo-controlled or usual care (UC) controlled trials of antipsychotics in adult patients with delirium. Our primary outcome measure was response rate at the study end point. The secondary outcome measures included improvement of severity of delirium, Clinical Global Impression-Severity Scale (CGI-S), time to response (TTR), discontinuation rate and individual adverse effects. The risk ratio (RR), the number-needed-to-treat/harm (NNT/NNH), 95% CIs and standardised mean difference (SMD), were calculated. We identified 15 studies (mean duration: 9.8 days) for the systematic review (total n=949, amisulpride=20, aripiprazole=8, chlorpromazine=13, haloperidol=316, intramuscular olanzapine or haloperidol injection=62, olanzapine=144, placebo=75, quetiapine=125, risperidone=124, UC=30 and ziprasidone=32), 4 of which were conference abstracts and unpublished. When pooled as a group, antipsychotics were superior to placebo/UC in terms of response rate (RR=0.22, NNT=2), delirium severity scales scores (SMD=-1.27), CGI-S scores (SMD=-1.57) and TTR (SMD=-1.22). The pooled antipsychotic group was associated with a higher incidence of dry mouth (RR=13.0, NNH=5) and sedation (RR=4.59, NNH=5) compared with placebo/UC. Pooled second-generation antipsychotics (SGAs) were associated with shorter TTR (SMD=-0.27) and a lower incidence of extrapyramidal symptoms (RR=0.31, NNH=7) compared with haloperidol. Our results suggested that SGAs have a benefit for the treatment of delirium with regard to efficacy and safety compared with haloperidol. However, further study using larger samples is required. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Applying an artificial neural network model for developing a severity score for patients with hereditary amyloid polyneuropathy.

PubMed

Novis, Shenia; Machado, Felipe; Costa, Victor B; Foguel, Debora; Cruz, Marcia W; de Seixas, José Manoel

2017-09-01

Hereditary (familial) amyloid polyneuropathy (FAP) is a systemic disease that includes a sensorimotor polyneuropathy related to transthyretin (TTR) mutations. So far, a scale designed to classify the severity of this disease has not yet been validated. This work proposes the implementation of an artificial neural network (ANN) in order to develop a severity scale for monitoring the disease progression in FAP patients. In order to achieve this goal, relevant symptoms and laboratory findings were collected from 98 Brazilian patients included in THAOS - the Transthyretin Amyloidosis Outcomes Survey. Ninety-three percent of them bore Val30Met, the most prevalent variant of TTR worldwide; 63 were symptomatic and 35 were asymptomatic. These data were numerically codified for the purpose of constructing a Self-Organizing Map (SOM), which maps data onto a grid of artificial neurons. Mapped data could be clustered by similarity into five groups, based on increasing FAP severity (from Groups 1 to 5). Most symptoms were virtually absent from patients who mapped to Group 1, which also includes the asymptomatic patients. Group 2 encompasses the patients bearing symptoms considered to be initial markers of FAP, such as first signs of walking disabilities and lack of sensitivity to temperature and pain. Interestingly, the patients with cardiac symptoms, which also carry cardiac-associated mutations of the TTR gene (such as Val112Ile and Ala19Asp), were concentrated in Group 3. Symptoms such as urinary and fecal incontinence and diarrhea characterized particularly Groups 4 and 5. Renal impairment was found almost exclusively in Group 5. Model validation was accomplished by considering the symptoms from a sample with 48 additional Brazilian patients. The severity scores proposed here not only identify the current stage of a patient's disease but also offer to the physician an easy-to-read, 2D map that makes it possible to track disease progression.

Inflammation, negative nitrogen balance, and outcome after aneurysmal subarachnoid hemorrhage

PubMed Central

Monahan, Aimee; Carpenter, Amanda; Zimmerman, Jacqueline; Schmidt, J. Michael; Claassen, Jan; Connolly, E. Sander; Mayer, Stephan A.; Karmally, Wahida; Seres, David

2015-01-01

Objective: To analyze the impact of inflammation and negative nitrogen balance (NBAL) on nutritional status and outcomes after subarachnoid hemorrhage (SAH). Methods: This was a prospective observational study of SAH patients admitted between May 2008 and June 2012. Measurements of C-reactive protein (CRP), transthyretin (TTR), resting energy expenditure (REE), and NBAL (g/day) were performed over 4 preset time periods during the first 14 postbleed days (PBD) in addition to daily caloric intake. Factors associated with REE and NBAL were analyzed with multivariable linear regression. Hospital-acquired infections (HAI) were tracked daily for time-to-event analyses. Poor outcome at 3 months was defined as a modified Rankin Scale score ≥4 and assessed by multivariable logistic regression. Results: There were 229 patients with an average age of 55 ± 15 years. Higher REE was associated with younger age (p = 0.02), male sex (p < 0.001), higher Hunt Hess grade (p = 0.001), and higher modified Fisher score (p = 0.01). Negative NBAL was associated with lower caloric intake (p < 0.001), higher body mass index (p < 0.001), aneurysm clipping (p = 0.03), and higher CRP:TTR ratio (p = 0.03). HAIs developed in 53 (23%) patients on mean PBD 8 ± 3. Older age (p = 0.002), higher Hunt Hess (p < 0.001), lower caloric intake (p = 0.001), and negative NBAL (p = 0.04) predicted time to first HAI. Poor outcome at 3 months was associated with higher Hunt Hess grade (p < 0.001), older age (p < 0.001), negative NBAL (p = 0.01), HAI (p = 0.03), higher CRP:TTR ratio (p = 0.04), higher body mass index (p = 0.03), and delayed cerebral ischemia (p = 0.04). Conclusions: Negative NBAL after SAH is influenced by inflammation and associated with an increased risk of HAI and poor outcome. Underfeeding and systemic inflammation are potential modifiable risk factors for negative NBAL and poor outcome after SAH. PMID:25596503

77 FR 58143 - Interagency Task Force on Antimicrobial Resistance (ITFAR): An Update of A Public Health Action...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-09-19

...-2012-0011] Interagency Task Force on Antimicrobial Resistance (ITFAR): An Update of A Public Health...), Department of Health and Human Services (HHS). ACTION: Notice of public meeting and request for comments... Federal agencies in accomplishing activities outlined in ``A Public Health Action Plan to Combat...

Report of the Task Force on De-Regulation Initiatives.

ERIC Educational Resources Information Center

Fishbein, Estelle A.; Blumer, Dennis H.

In response to a request by the Presidential Task Force on Regulatory Relief, this report offers specific recommendations for reform of federal regulations. A cover letter explains the constraints imposed by the recommended format: that the report is unable to address adequately the area of federal regulatory activity generating the most adverse…

Cultural Influences on Toddlers' Prosocial Behavior: How Maternal Task Assignment Relates to Helping Others

ERIC Educational Resources Information Center

Köster, Moritz; Cavalcante, Lilia; Vera Cruz de Carvalho, Rafael; Dôgo Resende, Briseida; Kärtner, Joscha

2016-01-01

This cross-cultural study investigates how maternal task assignment relates to toddlers' requested behavior and helping between 18 and 30 months. One hundred seven mother-child dyads were assessed in three different cultural contexts (rural Brazil, urban Germany, and urban Brazil). Brazilian mothers showed assertive scaffolding (serious and…

The Effect of Configuration on VSWM Performance of Down Syndrome Individuals

ERIC Educational Resources Information Center

Carretti, B.; Lanfranchi, S.

2010-01-01

Background: Recent studies have demonstrated that individuals with Down syndrome (DS) are poorer than controls in spatial-simultaneous tasks, but not in spatial-sequential tasks. To explain this finding, it has been suggested that the simultaneous visuo-spatial working memory deficit of individuals with DS could be due to the request for…

The WorkQueue project - a task queue for the CMS workload management system

NASA Astrophysics Data System (ADS)

Ryu, S.; Wakefield, S.

2012-12-01

We present the development and first experience of a new component (termed WorkQueue) in the CMS workload management system. This component provides a link between a global request system (Request Manager) and agents (WMAgents) which process requests at compute and storage resources (known as sites). These requests typically consist of creation or processing of a data sample (possibly terabytes in size). Unlike the standard concept of a task queue, the WorkQueue does not contain fully resolved work units (known typically as jobs in HEP). This would require the WorkQueue to run computationally heavy algorithms that are better suited to run in the WMAgents. Instead the request specifies an algorithm that the WorkQueue uses to split the request into reasonable size chunks (known as elements). An advantage of performing lazy evaluation of an element is that expanding datasets can be accommodated by having job details resolved as late as possible. The WorkQueue architecture consists of a global WorkQueue which obtains requests from the request system, expands them and forms an element ordering based on the request priority. Each WMAgent contains a local WorkQueue which buffers work close to the agent, this overcomes temporary unavailability of the global WorkQueue and reduces latency for an agent to begin processing. Elements are pulled from the global WorkQueue to the local WorkQueue and into the WMAgent based on the estimate of the amount of work within the element and the resources available to the agent. WorkQueue is based on CouchDB, a document oriented NoSQL database. The WorkQueue uses the features of CouchDB (map/reduce views and bi-directional replication between distributed instances) to provide a scalable distributed system for managing large queues of work. The project described here represents an improvement over the old approach to workload management in CMS which involved individual operators feeding requests into agents. This new approach allows for a system where individual WMAgents are transient and can be added or removed from the system as needed.

Examination of Learner and Situation Level Variables: Choice of Speech Act and Request Strategy by Spanish L2 Learners

ERIC Educational Resources Information Center

Kuriscak, Lisa

2015-01-01

This study focuses on variation within a group of learners of Spanish (N = 253) who produced requests and complaints via a written discourse completion task. It examines the effects of learner and situational variables on production--the effect of proficiency and addressee-gender on speech-act choice and the effect of perception of imposition on…

75 FR 6635 - Foreign-Trade Zone 33-Pittsburgh, Pennsylvania, Expansion of Manufacturing Authority, Subzone 33E...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-02-10

...-81u), and the regulations of the Board (15 CFR part 400). It was formally filed on February 4, 2010. Subzone 33E (123 employees, 360 million square meters coating capacity) currently has authority for the... the production of monochrome TTR printer rolls (some 336 million square meters capacity), using...

Environmental Effects on Materials for Space Applications.

DTIC Science & Technology

1983-03-01

o;t tnut wthicni was 6.own fby the elet -nlt,ttr t- I -w~v tool I!.- for .hoolt a f :rther 2 ritt:s,:t. Pihtogtaphs taker-. fo-r erosof 3d seontis...Luigi BALIS CREMA. Renato BARBONI, Antonio CASTELI.ANI Istituto di Tecnologia Aerospaziale Via ’udossiana, 16 -- 00184 Roma - Italy SUMMARY A. series of

U.S. EPA, Pesticide Product Label, SECURITY POWERTOX COTTON SPRAY, 12/16/1983

EPA Pesticide Factsheets

2011-04-14

... NI.'D" end only 'or tlloN u_ covered by II .• Certilled Aula lIor ... J,' !)~1 .·.Y"· e'.El" d"~1 ... a~ tt')r VI>;, nc.oj_st.ri\\tiC"I. ~~o. 7GY-J7C'1 cL ...

Using Xbox kinect motion capture technology to improve clinical rehabilitation outcomes for balance and cardiovascular health in an individual with chronic TBI.

PubMed

Chanpimol, Shane; Seamon, Bryant; Hernandez, Haniel; Harris-Love, Michael; Blackman, Marc R

2017-01-01

Motion capture virtual reality-based rehabilitation has become more common. However, therapists face challenges to the implementation of virtual reality (VR) in clinical settings. Use of motion capture technology such as the Xbox Kinect may provide a useful rehabilitation tool for the treatment of postural instability and cardiovascular deconditioning in individuals with chronic severe traumatic brain injury (TBI). The primary purpose of this study was to evaluate the effects of a Kinect-based VR intervention using commercially available motion capture games on balance outcomes for an individual with chronic TBI. The secondary purpose was to assess the feasibility of this intervention for eliciting cardiovascular adaptations. A single system experimental design ( n = 1) was utilized, which included baseline, intervention, and retention phases. Repeated measures were used to evaluate the effects of an 8-week supervised exercise intervention using two Xbox One Kinect games. Balance was characterized using the dynamic gait index (DGI), functional reach test (FRT), and Limits of Stability (LOS) test on the NeuroCom Balance Master. The LOS assesses end-point excursion (EPE), maximal excursion (MXE), and directional control (DCL) during weight-shifting tasks. Cardiovascular and activity measures were characterized by heart rate at the end of exercise (HRe), total gameplay time (TAT), and time spent in a therapeutic heart rate (TTR) during the Kinect intervention. Chi-square and ANOVA testing were used to analyze the data. Dynamic balance, characterized by the DGI, increased during the intervention phase χ 2 (1, N = 12) = 12, p = .001. Static balance, characterized by the FRT showed no significant changes. The EPE increased during the intervention phase in the backward direction χ 2 (1, N = 12) = 5.6, p = .02, and notable improvements of DCL were demonstrated in all directions. HRe ( F (2,174) = 29.65, p = < .001) and time in a TTR ( F (2, 12) = 4.19, p = .04) decreased over the course of the intervention phase. Use of a supervised Kinect-based program that incorporated commercial games improved dynamic balance for an individual post severe TBI. Additionally, moderate cardiovascular activity was achieved through motion capture gaming. Further studies appear warranted to determine the potential therapeutic utility of commercial VR games in this patient population. Clinicaltrial.gov ID - NCT02889289.

Hydrocarbon gases in Baikal bottom sediments: preliminary results of the Second international Class@Baikal cruise

NASA Astrophysics Data System (ADS)

Vidischeva, Olesya; Akhmanov, Grigorii; Khlystov, Oleg; Giliazetdinova, Dina

2016-04-01

In July 2015 the research cruise in the waters of Lake Baikal was carried out onboard RV "G.Yu. Vereshchagin". The expedition was organized by Lomonosov Moscow State University and Limnological Institute of Russian Academy of Sciences. The main purpose of the expedition was to study the modern sedimentation and natural geological processes on the bottom of Lake Baikal. One of the tasks of the cruise was to conduct gas-geochemical survey of bottom sediments. The samples of hydrocarbon gases were collected during the cruise. Subsequent study of the composition and origin of the sampled gas was carried out in the laboratories of Moscow State University. 708 samples from 61 bottom sampling stations were studied. Analyzed samples are from seven different areas located in the southern and central depressions of the lake: (1) "Goloustnoe" seepage area; (2) Bolshoy mud volcano; (3) Elovskiy Area; (4) "Krasny Yar" Seep; (5) "St. Petersburg" Seep; (6) Khuray deep-water depositional system; and (7) Kukuy Griva (Ridge) area. The results of molecular composition analysis indicate that hydrocarbon gases in bottom sediments from almost all sampling stations are represented mostly by pure methane. Ethane was detected only in some places within "Krasny Yar", "Goloustnoe" and "St. Petersburg" seepage areas. The highest concentrations of methane were registered in the sediments from the "Krasny Yar" area - 14 457 μl/l (station TTR-BL15-146G) - and from the "St. Petersburg" area - 13 684 μl/l (station TTR-BL15-125G). The sediments with high concentrations of gases were sampled from active fluid discharge areas, which also can be well distinguished on the seismic profiles. Gas hydrates were obtained in the areas of "Krasny Yar", "Goloustnoe", and "St. Petersburg" seeps and in the area of the Bolshoy mud volcano. Isotopic composition δ13C(CH4) was studied for 100 samples of hydrocarbon gases collected in areas with high methane concentration in bottom sediments. The average value is -53‰. Overall bottom sediments of the Baikal Lake are very saturated in biogenic shallow methane. However, some evidences of thermogenic methane contribution can be recorded in the areas of focused fluid flows from deeper strata (e.g. mud volcanoes, seepage sites, etc.). Scrupulous examination of gas composition data results in understanding of scope of activity of individual structure and rough estimation of thermogenic gas flow input.

Maritime Domain Awareness: C4I for the 1000 Ship Navy

DTIC Science & Technology

2009-12-04

unit action, provide unit sensed contacts, coordinate unit operations, process unit information, release image , and release contact report, Figure 33...Intelligence Tasking Request Intelligence Summary Release Unit Person Incident Release Unit Vessel Incident Process Intelligence Tasking Release Image ...xi LIST OF FIGURES Figure 1. Functional Problem Sequence Process Flow. ....................................................4 Figure 2. United

Engineering and technology measures to improve large truck safety : state of the practice in Virginia.

DOT National Transportation Integrated Search

2003-01-01

In response to a request by Frank S. Wolf and Jo Ann Davis of the U.S. House of Representatives, Governor Mark Warner formed a Special Task Force on Truck Safety in the fall of 2002. The objective of the task force was to examine ways to reduce the n...

Job Language Performance Requirements for MOS 91C, Clinical Specialist, Reference Soldier’s Manual Dated 30 August 1977.

DTIC Science & Technology

1977-08-30

Administer a rectal suppository 081-91C-1240 Administer an injection (SC or IM) 081-91C-1241 Administer an intradermal injection 081-91C-1242 Administer a...in this language task: Shouting Radio communications Coded messages Spellings Conversation Requests wI-3 SPEAKING *TASK: Formulate and produce

A Case Study of Positive Behavior Supports-Based Interventions in a Seventh-Grade Urban Classroom

ERIC Educational Resources Information Center

Hollingshead, Aleksandra; Kroeger, Stephen D.; Altus, Jillian; Trytten, Joyce Brubaker

2016-01-01

Struggling with frequent off-task behavior, a teacher in a midwestern inner-city high school requested assistance in her social studies classroom. A study was designed to investigate if a combination of positive behavior supports-based interventions such as behavior-specific praise and reduced teacher reprimands might improve on-task behavior. A…

Manpower and Personnel Integration (MANPRINT) and Network Integration Evaluation 13.2: Observations on Cognitive Load in Mission Command

DTIC Science & Technology

2014-03-01

using scales like NASA’s Task Load Index ( TLX ) (Hart and Staveland, 1988). At present, there are no comparable measurement scales for cognitive...Staveland, L. E. Development of NASA- TLX (Task Load Index): Results of empirical and theoretical research. In Human Mental Workload; Hancock, P. A...Requests for Information SA situation awareness TLX Task Load Index TOC tactical operations center WSMR White Sands Missile Range XO executive

U.S. Marine Corps Study of Establishing Time Criteria for Logistics Tasks

DTIC Science & Technology

2004-09-30

STATISTICS FOR REQUESTS PER DAY FOR TWO BATTALIONS II-25 II-6 SUMMARY STATISTICS IN HOURS FOR RESOURCE REQUIREMENTS PER DAY FOR TWO BATTALIONS II-26 II-7...SUMMARY STATISTICS FOR INDIVIDUALS FOR RESOURCE REQUIREMENTS PER DAY FOR TWO BATTALIONS II-27 Study of Establishing Time Criteria for Logistics...developed and run to provide statistical information for analysis. In Task Four, the study team used Task Three findings to determine data requirements

Software Product Lines: Report of the 2010 US Army Software Product Line Workshop

DTIC Science & Technology

2010-06-01

requirements and statement of work ( SOW ) tasks can be in- cluded in the request for proposal (RFP) and the contract. 2.2.1 Basic Product Line Acquisition... SOW tasks in Figure 1. Two additional tasks (at the third tier level) ac- count for sustaining the production capability over the life cycle and...Acquisition Strategy RFP and SOW Initial Product Line Scope Product Line Business Case Capability Description Document Teaming Product Line

Assessment of Surface Ship Maintenance Requirements

DTIC Science & Technology

2015-01-01

specifically Operational Availability (Ao) and Expected Service Life ( ESL ). Second, it requested NDRI to develop a maintenance requirement concept for each...ship class that supports ESL but allows for some risk within the maintenance strategy. It also asked researchers to define the risks to Ao and ESL ...to minimize negative effects to Ao and ESL and maintain the largest, most capable fleet possible. Note that the tasking did not request a complete

Veterans’ Employment and Training: Better Targeting, Coordinating, and Reporting Needed to Enhance Program Effectiveness

DTIC Science & Technology

2012-12-01

Effectiveness Report to Congressional Requesters December 2012 GAO-13-29 United States Government Accountability Office GAO Report Documentation...TASK NUMBER 5f. WORK UNIT NUMBER 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) U.S. Government Accountability Office,441 G Street NW,Washington...by ANSI Std Z39-18 United States Government Accountability Office Highlights of GAO-13-29, a report to congressional requesters

Efficiently Selecting the Best Web Services

NASA Astrophysics Data System (ADS)

Goncalves, Marlene; Vidal, Maria-Esther; Regalado, Alfredo; Yacoubi Ayadi, Nadia

Emerging technologies and linking data initiatives have motivated the publication of a large number of datasets, and provide the basis for publishing Web services and tools to manage the available data. This wealth of resources opens a world of possibilities to satisfy user requests. However, Web services may have similar functionality and assess different performance; therefore, it is required to identify among the Web services that satisfy a user request, the ones with the best quality. In this paper we propose a hybrid approach that combines reasoning tasks with ranking techniques to aim at the selection of the Web services that best implement a user request. Web service functionalities are described in terms of input and output attributes annotated with existing ontologies, non-functionality is represented as Quality of Services (QoS) parameters, and user requests correspond to conjunctive queries whose sub-goals impose restrictions on the functionality and quality of the services to be selected. The ontology annotations are used in different reasoning tasks to infer service implicit properties and to augment the size of the service search space. Furthermore, QoS parameters are considered by a ranking metric to classify the services according to how well they meet a user non-functional condition. We assume that all the QoS parameters of the non-functional condition are equally important, and apply the Top-k Skyline approach to select the k services that best meet this condition. Our proposal relies on a two-fold solution which fires a deductive-based engine that performs different reasoning tasks to discover the services that satisfy the requested functionality, and an efficient implementation of the Top-k Skyline approach to compute the top-k services that meet the majority of the QoS constraints. Our Top-k Skyline solution exploits the properties of the Skyline Frequency metric and identifies the top-k services by just analyzing a subset of the services that meet the non-functional condition. We report on the effects of the proposed reasoning tasks, the quality of the top-k services selected by the ranking metric, and the performance of the proposed ranking techniques. Our results suggest that the number of services can be augmented by up two orders of magnitude. In addition, our ranking techniques are able to identify services that have the best values in at least half of the QoS parameters, while the performance is improved.

A wirelessly programmable actuation and sensing system for structural health monitoring

NASA Astrophysics Data System (ADS)

Long, James; Büyüköztürk, Oral

2016-04-01

Wireless sensor networks promise to deliver low cost, low power and massively distributed systems for structural health monitoring. A key component of these systems, particularly when sampling rates are high, is the capability to process data within the network. Although progress has been made towards this vision, it remains a difficult task to develop and program 'smart' wireless sensing applications. In this paper we present a system which allows data acquisition and computational tasks to be specified in Python, a high level programming language, and executed within the sensor network. Key features of this system include the ability to execute custom application code without firmware updates, to run multiple users' requests concurrently and to conserve power through adjustable sleep settings. Specific examples of sensor node tasks are given to demonstrate the features of this system in the context of structural health monitoring. The system comprises of individual firmware for nodes in the wireless sensor network, and a gateway server and web application through which users can remotely submit their requests.

Wellness

MedlinePlus

... Nurses Exercise for Polio Survivors Anesthesia Concerns Pool/Water Therapy Other Resources Reports & CD from Task Force Medical/Clinical Publications ADVOCACY Issues Organizations Resources RESEARCH About The Research Fund New Request for 2018 ...

Orthotics

MedlinePlus

... Nurses Exercise for Polio Survivors Anesthesia Concerns Pool/Water Therapy Other Resources Reports & CD from Task Force Medical/Clinical Publications ADVOCACY Issues Organizations Resources RESEARCH About The Research Fund New Request for 2018 ...

Coughing

MedlinePlus

... Nurses Exercise for Polio Survivors Anesthesia Concerns Pool/Water Therapy Other Resources Reports & CD from Task Force Medical/Clinical Publications ADVOCACY Issues Organizations Resources RESEARCH About The Research Fund New Request for 2018 ...

Disclosure, accommodations and self-care at work among adolescents with disabilities.

PubMed

Lindsay, Sally; McDougall, Carolyn; Sanford, Robyn

2013-01-01

The purpose of this study is to explore whether adolescents with disabilities disclose their condition and what types of accommodations are requested at work. In-depth, qualitative semi-structured interviews were conducted with 18 adolescents with a physical and/or mobility-related disability. We also reviewed their self- and staff assessments completed throughout an employment training program in which they took part. The findings show that most youth were able to disclose their conditions and recognize some of their limitations in performing tasks at work. Youth requested physical accommodations, more time to complete tasks and cognitive accommodations. Youth also performed several self-care tasks to manage their disability at work including personal care, pain management and fatigue. Within the context of this employment training program, youth were able to disclose their condition to their employer, ask for accommodations and manage their disability in the workplace. Educators and clinicians should: Assist youth in understanding whether, when and how to disclose their disability to their potential employer. Help youth to understand what accommodations are available to them in the workplace and how to access them, to help them to perform their job effectively. Coach youth on how to manage their disability in a work context, especially with regard to personal care, pain management and fatigue. Encourage and facilitate participation in experience-based opportunities to practice disclosure, requesting accommodations and self-management.

Toward Efficient Team Formation for Crowdsourcing in Noncooperative Social Networks.

PubMed

Wang, Wanyuan; Jiang, Jiuchuan; An, Bo; Jiang, Yichuan; Chen, Bing

2017-12-01

Crowdsourcing has become a popular service computing paradigm for requesters to integrate the ubiquitous human-intelligence services for tasks that are difficult for computers but trivial for humans. This paper focuses on crowdsourcing complex tasks by team formation in social networks (SNs) where a requester connects to a large number of workers. A good indicator of efficient team collaboration is the social connection among workers. Most previous social team formation approaches, however, either assume that the requester can maintain information of all workers and can directly communicate with them to build teams, or assume that the workers are cooperative and be willing to join the specific team built by the requester, both of which are impractical in many real situations. To this end, this paper first models each worker as a selfish entity, where the requester prefers to hire inexpensive workers that require less payment and workers prefer to join the profitable teams where they can gain high revenue. Within the noncooperative SNs, a distributed negotiation-based team formation mechanism is designed for the requester to decide which worker to hire and for the worker to decide which team to join and how much should be paid for his skill service provision. The proposed social team formation approach can always build collaborative teams by allowing team members to form a connected graph such that they can work together efficiently. Finally, we conduct a set of experiments on real dataset of workers to evaluate the effectiveness of our approach. The experimental results show that our approach can: 1) preserve considerable social welfare by comparing the benchmark centralized approaches and 2) form the profitable teams within less negotiation time by comparing the traditional distributed approaches, making our approach a more economic option for real-world applications.

Cold Intolerance

MedlinePlus

... Nurses Exercise for Polio Survivors Anesthesia Concerns Pool/Water Therapy Other Resources Reports & CD from Task Force Medical/Clinical Publications ADVOCACY Issues Organizations Resources RESEARCH About The Research Fund New Request for 2018 ...

Alternative Therapies

MedlinePlus

... Nurses Exercise for Polio Survivors Anesthesia Concerns Pool/Water Therapy Other Resources Reports & CD from Task Force Medical/Clinical Publications ADVOCACY Issues Organizations Resources RESEARCH About The Research Fund New Request for 2018 ...

77 FR 61573 - Science Advisory Board Satellite Task Force; Availability of Draft Report and Request for Comments

Federal Register 2010, 2011, 2012, 2013, 2014

2012-10-10

...-2506-01] RIN 0648-XC276 Science Advisory Board Satellite Task Force; Availability of Draft Report and... notice on behalf of the NOAA Science Advisory Board (SAB) to announce the availability of the draft..., 2012. ADDRESSES: The Draft Report of the SATTF will be available on the NOAA Science Advisory Board Web...

76 FR 18798 - Comment Request for Information Collection for The National Agricultural Workers Survey: Revision...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-05

...: (1) The amount of time per day farm workers are engaged working in specific crops and tasks, and (2... the length of the work day for specific crop-task combinations. The Office of Management and Budget (OMB) authorization for the current NAWS questionnaire will expire on October 31, 2013. A copy of the...

Constructing a Scale to Assess L2 Written Speech Act Performance: WDCT and E-Mail Tasks

ERIC Educational Resources Information Center

Chen, Yuan-shan; Liu, Jianda

2016-01-01

This study reports the development of a scale to evaluate the speech act performance by intermediate-level Chinese learners of English. A qualitative analysis of the American raters' comments was conducted on learner scripts in response to a total of 16 apology and request written discourse completion task (WDCT) situations. The results showed…

Dextromethorphan Analogs: Receptor Binding and Pharmacological Profile of Novel Anticonvulsant/Neuroprotectant Drugs

DTIC Science & Technology

1993-05-13

AD-POO8 801 Dextromethorphan Analogs: Receptor Binding and Pharmacological Profile of Novel Anticonvulsant/Neuroprotective Drugs F.C. Tortella, L...Baltimore, MD 21224 CD ABSTRACT A series of 3-substituted 17-methylmorphinan analogs of dextromethorphan (DM) have open developed which are...nTTrTTn) INTRODUCTION The antitussives dextromethorphan (DM), caramiphen and carbetapentane have distinguished themselves as anticonvulsant drugs (1

U.S. EPA, Pesticide Product Label, PRENTOX 35% MALATHION OIL SOLUBLE CONC. - REFINED, 10/03/1983

EPA Pesticide Factsheets

2011-04-14

... 1. ~':}l.lt .tt.%r C1lP llll dat.a leciulrfA(~ tul It.'(ji&t.Illtiull/ It!rt:'glf;:tldt.lOH (It Y0UI l·rOduct und~r i·l ... ..A t;ec .. )(c) (~) "t.er. tl.e I .. (.:t I.('j' lef';\\lllt.! .. :li. ...

A novel ATTR L32V mutation causes familial amyloid polyneuropathy in a Bolivian family.

PubMed

Martínez-Ulloa, Pedro L; Vallejo, Manuela; Corral, Iñigo; García-Barragán, Nuria; Alcazar, Alberto; Martínez-Alonso, Emma; Martínez-Poles, Javier; Pian, Hector; Jiménez-Escrig, Adriano

2017-09-01

We report a new transthyretin (ATTR) gene c.272C>G mutation and variant protein, p.Leu32Val, in a kindred of Bolivian origin with a rapid progressive peripheral neuropathy and cardiomyopathy. Three individuals from a kindred with peripheral nerve and cardiac amyloidosis were examined. Analysis of the TTR gene was performed by Sanger direct sequencing. Neuropathologic examination was obtained on the index patient with mass spectrometry study of the ATTR deposition. Direct DNA sequence analysis of exons 2, 3, and 4 of the TTR gene demonstrated a c.272 C>G mutation in exon 2 (p.L32V). Sural nerve biopsy revealed massive amyloid deposition in the perineurium, endoneurium and vasa nervorum. Mass spectrometric analyses of ATTR immunoprecipitated from nerve biopsy showed the presence of both wild-type and variant proteins. The observed mass results for the wild-type and variant proteins were consistent with the predicted values calculated from the genetic analysis data. The ATTR L32V is associated with a severe course. This has implications for treatment of affected individuals and counseling of family members. © 2017 Peripheral Nerve Society.

Activated microglia mediate synapse loss and short-term memory deficits in a mouse model of transthyretin-related oculoleptomeningeal amyloidosis.

PubMed

Azevedo, E P; Ledo, J H; Barbosa, G; Sobrinho, M; Diniz, L; Fonseca, A C C; Gomes, F; Romão, L; Lima, F R S; Palhano, F L; Ferreira, S T; Foguel, D

2013-09-05

Oculoleptomeningeal amyloidosis (OA) is a fatal and untreatable hereditary disease characterized by the accumulation of transthyretin (TTR) amyloid within the central nervous system. The mechanisms underlying the pathogenesis of OA, and in particular how amyloid triggers neuronal damage, are still unknown. Here, we show that amyloid fibrils formed by a mutant form of TTR, A25T, activate microglia, leading to the secretion of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and nitric oxide. Further, we found that A25T amyloid fibrils induce the activation of Akt, culminating in the translocation of NFκB to the nucleus of microglia. While A25T fibrils were not directly toxic to neurons, the exposure of neuronal cultures to media conditioned by fibril-activated microglia caused synapse loss that culminated in extensive neuronal death via apoptosis. Finally, intracerebroventricular (i.c.v.) injection of A25T fibrils caused microgliosis, increased brain TNF-α and IL-6 levels and cognitive deficits in mice, which could be prevented by minocycline treatment. These results indicate that A25T fibrils act as pro-inflammatory agents in OA, activating microglia and causing neuronal damage.

Warfarin Management and Outcomes in Patients with Nonvalvular Atrial Fibrillation Within an Integrated Health Care System.

PubMed

An, JaeJin; Niu, Fang; Zheng, Chengyi; Rashid, Nazia; Mendes, Robert A; Dills, Diana; Vo, Lien; Singh, Prianka; Bruno, Amanda; Lang, Daniel T; Le, Paul T; Jazdzewski, Kristin P; Aranda, Gustavus

2017-06-01

Warfarin is a common treatment option to manage patients with nonvalvular atrial fibrillation (NVAF) in clinical practice. Understanding current pharmacist-led anticoagulation clinic management patterns and associated outcomes is important for quality improvement; however, currently little evidence associating outcomes with management patterns exists. To (a) describe warfarin management patterns and (b) evaluate associations between warfarin treatment and clinical outcomes for patients with NVAF in an integrated health care system. A retrospective cohort study was conducted among NVAF patients with warfarin therapy between January 1, 2006, and December 31, 2011, using Kaiser Permanente Southern California data, and followed until December 31, 2013. Management patterns related to international normalized ratio (INR) monitoring, anticoagulation clinic pharmacist intervention (consultation), and warfarin dose adjustments were investigated along with yearly attrition rates, time-in-therapeutic ranges (TTRs), and clinical outcomes (stroke or systemic embolism and major bleeding). Descriptive statistics and multivariable Cox proportional hazard models were used to determine associations between TTR and clinical outcomes. A total of 32,074 NVAF patients on warfarin treatment were identified and followed for a median of 3.8 years. About half (49%) of the patients were newly initiating warfarin therapy. INR monitoring and pharmacist interventions were conducted roughly every 3 weeks after 6 months of warfarin treatment. Sixty-three percent of the study population had ≥ 1 warfarin dose adjustments with a mean (SD) of 6.7 (6.3) annual dose adjustments. Warfarin dose adjustments occurred at a median of 1 day (interquartile ranges [IQR] 1-3) after the INR measurement. Yearly attrition rate was from 3.3% to 6.3% during the follow-up, and median (IQR) TTR was 61% (46%-73%). Patients who received frequent INR monitoring (≥ 27 times per year), pharmacist interventions (≥ 24 times per year), or frequently adjusted warfarin dose (≥ 11 times per year) consistently showed poor TTRs (mean TTR for the highest quartiles was 45.3%-48.3%). A higher TTR was associated with a lower risk of clinical outcomes regardless of frequency of INR monitoring, pharmacist interventions, or number of dose adjustments. Patients whose TTRs were < 65%, even with frequent pharmacist interventions, had similar stroke or systemic embolism event rates, as compared with patients with TTRs < 65% and less frequent interventions (1.88 vs. 1.54 stroke or systemic embolism rates per 100 person-years, respectively, P = 0.78). The lowest TTR quartile (< 46%) was associated with a 3 times higher risk of stroke or systemic embolism (hazard ratio [HR] = 3.19, 95% CI = 2.71-3.77) and a 2 times higher risk of major bleeding (HR = 2.10, 95% CI = 1.96-2.24) compared with the highest TTR quartile (≥ 73%). Despite close monitoring with timely warfarin dose adjustments, there were still a substantial number of challenging patients whose TTRs were suboptimal despite a higher number of pharmacist interventions. These patients eventually experienced more stroke or systemic embolism and bleeding events among NVAF patients managed by anticoagulation clinics. New individualized treatment or management strategies for patients who are not able to reach optimal therapeutic ranges are necessary to improve outcomes. This research and manuscript were funded by Bristol-Myers Squibb Company and Pfizer. Authors from Bristol-Myers Squibb Company and Pfizer participated in the design of the study, interpretation of the data, review/revision of the manuscript, and approval of the final version of the manuscript. An received a grant for research support from Bristol-Myers Squibb/Pfizer. Niu, Rashid, and Zheng received a grant from Bristol-Myers Squibb/Pfizer to their institutions for salary reimbursement. Vo, Singh, and Aranda are employed by Bristol-Myers Squibb; Bruno was employed by Bristol-Myers Squibb at the time of this study. Mendes and Dills are employed by Pfizer, and Mendes was a member of the Pfizer Cardiovascular and Metabolic Field Medical Team during the time of this study. Lang, Jazdzewski, and Le have no known conflicts of interest to report. Study concept and design were contributed primarily by An and Rashid, along with the other authors. Niu took the lead in data collection, along with Zheng, and data interpretation was performed by An, along with Mendes and Dills, with assistance from the other authors. The manuscript was written by An and revised by Mendes, Dills, Vo, Singh, Bruno, and Aranda, along with Lang, Le, and Jazdezewski. Part of this study's findings was presented at the CHEST 2015 Annual Meeting in Montreal, Canada, on October 28, 2015.

Request queues for interactive clients in a shared file system of a parallel computing system

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bent, John M.; Faibish, Sorin

Interactive requests are processed from users of log-in nodes. A metadata server node is provided for use in a file system shared by one or more interactive nodes and one or more batch nodes. The interactive nodes comprise interactive clients to execute interactive tasks and the batch nodes execute batch jobs for one or more batch clients. The metadata server node comprises a virtual machine monitor; an interactive client proxy to store metadata requests from the interactive clients in an interactive client queue; a batch client proxy to store metadata requests from the batch clients in a batch client queue;more » and a metadata server to store the metadata requests from the interactive client queue and the batch client queue in a metadata queue based on an allocation of resources by the virtual machine monitor. The metadata requests can be prioritized, for example, based on one or more of a predefined policy and predefined rules.« less

Research of GIS-services applicability for solution of spatial analysis tasks.

NASA Astrophysics Data System (ADS)

Terekhin, D. A.; Botygin, I. A.; Sherstneva, A. I.; Sherstnev, V. S.

2017-01-01

Experiments for working out the areas of applying various gis-services in the tasks of spatial analysis are discussed in this paper. Google Maps, Yandex Maps, Microsoft SQL Server are used as services of spatial analysis. All services have shown a comparable speed of analyzing the spatial data when carrying out elemental spatial requests (building up the buffer zone of a point object) as well as the preferences of Microsoft SQL Server in operating with more complicated spatial requests. When building up elemental spatial requests, internet-services show higher efficiency due to cliental data handling with JavaScript-subprograms. A weak point of public internet-services is an impossibility to handle data on a server side and a barren variety of spatial analysis functions. Microsoft SQL Server offers a large variety of functions needed for spatial analysis on the server side. The authors conclude that when solving practical problems, the capabilities of internet-services used in building up routes and completing other functions with spatial analysis with Microsoft SQL Server should be involved.

Property Accountability Task Force

DTIC Science & Technology

1978-06-30

accountability. Many organizations have initiated innovative changes. I can as’,ure you that the pro, edures being put into effect will not be "auick...08184Z MAR 78 B. TRADOC MSG, DTG 031705Z APR 78, SAB 1. REF A REQUESTED THAT YOU PROVIDE DIRECTION TO ALL SERVICE SCHOOLS ON THE USE OF THE LOGISTICS...ABOVE. 3. REQUEST YOU INFORM DAPATF OF YOUR PLANS CONCERNING THE FOLLLOWING POINTS: A. ENSURING THAT ALL STUDENTS MASTER THE SUPPLY PROCEDURES

Identification of V122I (Val122Ile) transthyretin cardiac amyloidosis (ATTR) using serum retinol-binding protein 4 (RBP4) and a clinical prediction model

PubMed Central

Arvanitis, Marios; Koch, Clarissa M; Chan, Gloria G.; Arancivia, Celia M.T.; LaValley, Michael; Jacobson, Daniel; Berk, John L.; Connors, Lawreen H.; Ruberg, Frederick L.

2017-01-01

Importance Transthyretin amyloid cardiomyopathy (ATTR) is an under-recognized cause of heart failure (HF) in the elderly, owing in part to difficulty in diagnosis. ATTR can result from mutant TTR protein with one of the most common mutations in the United States, V122I, present in 3.43% of African Americans. Objective To determine whether serum retinol-binding protein 4 (RBP4), an endogenous TTR ligand, could be used as a diagnostic test for ATTR V122I amyloidosis. Design Combined prospective and retrospective cohort study Setting Tertiary care referral center Participants Fifty prospectively genotyped African American patients over age 60 years with non-amyloid HF and cardiac wall thickening, and a comparator cohort of biopsy proven ATTR V122I amyloidosis patients (n=25) comprised the development cohort. Twenty-seven prospectively genotyped African American patients and 9 ATTR V122I amyloidosis patients comprised the validation cohort. Main Outcomes and Measures Circulating RBP4, TTR, B-type natriuretic peptide (BNP) and troponin I (TnI) concentrations, electrocardiography (ECG), echocardiography, and clinical characteristics were assessed in all patients. Receiver operating characteristic (ROC) analysis was performed to identify optimal thresholds for ATTR V122I amyloidosis identification. A clinical prediction rule was developed using penalized logistic regression, evaluated using ROC analysis and validated in an independent cohort of cases and controls. Results Age, gender, BNP and TnI were similar between ATTR V122I amyloidosis patients and controls. Serum RBP4 concentration was lower in patients with ATTR V122I amyloidosis compared to non-amyloid controls (31.5 vs. 49.4 ug/ml, p < 0.001) and the difference persisted after controlling for potential confounding parameters. Left ventricular ejection fraction (LVEF) was lower in ATTR V122I amyloidosis (40% vs. 57%, p<0.001), while interventricular septal diameter (IVSd) was higher (16 vs. 14 mm, p<0.001). ROC analysis identified RBP4 as a sensitive identifier of ATTR V122I amyloidosis (AUC 0.78). A clinical prediction algorithm comprised of RBP4, TTR, LVEF, IVSd, mean limb lead ECG voltage and grade 3 diastolic dysfunction yielded excellent discriminatory capacity for ATTR V122I amyloidosis (AUC 0.97), while a 4 parameter model including RBP4 concentration retained excellent discrimination (AUC 0.92). The models maintained excellent discrimination in the validation cohort. Conclusions and Relevance A prediction model employing circulating RBP4 concentration and readily available clinical parameters accurately discriminated ATTR V122I amyloid cardiomyopathy from non-amyloid HF in a case matched cohort. We propose that this clinical algorithm may be useful for identification of ATTR V122I amyloidosis in elderly, African American patients with heart failure. PMID:28196196

Does user-centred design affect the efficiency, usability and safety of CPOE order sets?

PubMed

Chan, Julie; Shojania, Kaveh G; Easty, Anthony C; Etchells, Edward E

2011-05-01

Application of user-centred design principles to Computerized provider order entry (CPOE) systems may improve task efficiency, usability or safety, but there is limited evaluative research of its impact on CPOE systems. We evaluated the task efficiency, usability, and safety of three order set formats: our hospital's planned CPOE order sets (CPOE Test), computer order sets based on user-centred design principles (User Centred Design), and existing pre-printed paper order sets (Paper). 27 staff physicians, residents and medical students. Sunnybrook Health Sciences Centre, an academic hospital in Toronto, Canada. Methods Participants completed four simulated order set tasks with three order set formats (two CPOE Test tasks, one User Centred Design, and one Paper). Order of presentation of order set formats and tasks was randomized. Users received individual training for the CPOE Test format only. Completion time (efficiency), requests for assistance (usability), and errors in the submitted orders (safety). 27 study participants completed 108 order sets. Mean task times were: User Centred Design format 273 s, Paper format 293 s (p=0.73 compared to UCD format), and CPOE Test format 637 s (p<0.0001 compared to UCD format). Users requested assistance in 31% of the CPOE Test format tasks, whereas no assistance was needed for the other formats (p<0.01). There were no significant differences in number of errors between formats. The User Centred Design format was more efficient and usable than the CPOE Test format even though training was provided for the latter. We conclude that application of user-centred design principles can enhance task efficiency and usability, increasing the likelihood of successful implementation.

Does user-centred design affect the efficiency, usability and safety of CPOE order sets?

PubMed Central

Chan, Julie; Shojania, Kaveh G; Easty, Anthony C

2011-01-01

Background Application of user-centred design principles to Computerized provider order entry (CPOE) systems may improve task efficiency, usability or safety, but there is limited evaluative research of its impact on CPOE systems. Objective We evaluated the task efficiency, usability, and safety of three order set formats: our hospital's planned CPOE order sets (CPOE Test), computer order sets based on user-centred design principles (User Centred Design), and existing pre-printed paper order sets (Paper). Participants 27staff physicians, residents and medical students. Setting Sunnybrook Health Sciences Centre, an academic hospital in Toronto, Canada. Methods Participants completed four simulated order set tasks with three order set formats (two CPOE Test tasks, one User Centred Design, and one Paper). Order of presentation of order set formats and tasks was randomized. Users received individual training for the CPOE Test format only. Main Measures Completion time (efficiency), requests for assistance (usability), and errors in the submitted orders (safety). Results 27 study participants completed 108 order sets. Mean task times were: User Centred Design format 273 s, Paper format 293 s (p=0.73 compared to UCD format), and CPOE Test format 637 s (p<0.0001 compared to UCD format). Users requested assistance in 31% of the CPOE Test format tasks, whereas no assistance was needed for the other formats (p<0.01). There were no significant differences in number of errors between formats. Conclusions The User Centred Design format was more efficient and usable than the CPOE Test format even though training was provided for the latter. We conclude that application of user-centred design principles can enhance task efficiency and usability, increasing the likelihood of successful implementation. PMID:21486886

Job Language Performance Requirements for MOS 62B, Construction Equipment Repairer, Reference Soldier’s Manual Dated 13 March 1978.

DTIC Science & Technology

1978-03-13

STANDARDS: 100% understandable and legible written content III. TASK NUMBERS AND TITLES 051-191- 1241 Prepare An M72A2 LAW For Firing; Restore M72A2 LAW To...understanding of ornl comr.|nication TASK: Produce appropriate oral respoa5es spontaii.-,)usly or upon request CONDITIONS: Given any vcrbz! stimulur in

What's Happening in Freshman Composition in the California Two-Year College: A Collection of Writing Tasks. "A Working Book."

ERIC Educational Resources Information Center

Hale, Helena, Comp.

Designed as a looseleaf resource, a supplement to established teaching plans, and an aid to meeting individual needs, this compilation of writing exercises represents the responses of 157 teachers from 87 two-year colleges to the request, "Describe a successful writing task -- what it is, how you teach it, and why." The compilation includes tasks…

The Comparative Power of "Type/Token" and "Hapax Legomena/Type" Ratios: A Corpus-Based Study of Authorial Differentiation

ERIC Educational Resources Information Center

Ali, Sundus Muhsin; Hussein, Khalid Shakir

2014-01-01

This paper presents an attempt to verify the comparative power of two statistical features: Type/Token, and Hapax legomena/Token ratios (henceforth TTR and HTR). A corpus of ten novels is compiled. Then sixteen samples (each is 5,000 tokens in length) are taken randomly out of these novels as representative blocks. The researchers observe the way…

Lumped Nonlinear System Analysis with Volterra Series.

DTIC Science & Technology

1980-04-01

f h2 (t-=,t-r )x(r)x(t2)dl d 2 (4- 1 )O0 0 Consider the input signal comprising two unit sinusoidal signals at fre- quencies wa and wb. The input x... 1 - 2 . Nonlinear System Analysis Methods. .............. 2 1 -3. Objectives of the Investigation ....... ............... 6 1 -4. Organization of...the Report ..... ... ................. 9 CHAPTER 2 - VOLTERRA FUNCTIONAL SERIES ...... ............... 12 2 - 1 . Introduction

The use of the AOA TTR-4P GPS receiver in operation at the BIPM for real-time restitution of GPS time

NASA Technical Reports Server (NTRS)

Thomas, Claudine

1994-01-01

The Global Positioning System is an outstanding tool for the dissemination of time. Using mono-channel C/A-code GPS time receivers, the restitution of GPS time through the satellite constellation presents a peak-to-peak discrepancy of several tens of nanoseconds without SA but may be as high as several hundreds of nanoseconds with SA. As a consequence, civil users are more and more interested in implementing hardware and software methods for efficient restitution of GPS time, especially in the framework of the project of a real-time prediction of UTC (UTCp) which could be available in the form of time differences (UTCp - GPS time). Previous work, for improving the real-time restitution of GPS time with SA, to the level obtained without SA, focused on the implementation of a Kalman filter based on past data and updated at each new observation. An alternative solution relies upon the statistical features of the noise brought about by SA; it has already been shown that the SA noise is efficiently reduced by averaging data from numerous satellites observed simultaneously over a sufficiently long time. This method was successfully applied to data from a GPS time receiver, model AOA TTR-4P, connected to the cesium clock kept at the BIPM. This device, a multi-channel, dual frequency, P-code GPS time receiver, is one of the first TTR-4P units in operation in a civil laboratory. Preliminary comparative studies of this new equipment with conventional GPS time receivers are described in this paper. The results of an experimental restitution of GPS time, obtained in June 1993, are also detailed: 3 to 6 satellites were observed simultaneously with a sample interval of 15 s, an efficient smoothing of SA noise was realized by averaging data on all observed satellites over more than 1 hour. When the GPS system is complete in 1994, 8 satellites will be observable continuously from anywhere in the world and the same level of uncertainty will be obtained using a shorter averaging time.

Validation of serum markers for blood-brain barrier disruption in traumatic brain injury.

PubMed

Blyth, Brian J; Farhavar, Arash; Gee, Christopher; Hawthorn, Brendan; He, Hua; Nayak, Akshata; Stöcklein, Veit; Bazarian, Jeffrey J

2009-09-01

The blood-brain barrier (BBB), which prevents the entry into the central nervous system (CNS) of most water-soluble molecules over 500 Da, is often disrupted after trauma. Post-traumatic BBB disruption may have important implications for prognosis and therapy. Assessment of BBB status is not routine in clinical practice because available techniques are invasive. The gold-standard measure, the cerebrospinal fluide (CSF)-serum albumin quotient (Q(A)), requires the measurement of albumin in CSF and serum collected contemporaneously. Accurate, less invasive techniques are necessary. The objective of this study was to evaluate the relationship between Q(A) and serum concentrations of monomeric transthyretin (TTR) or S100B. Nine subjects with severe traumatic brain injury (TBI; Glasgow Coma Scale [GCS] score < or =8) and 11 subjects with non-traumatic headache who had CSF collected by ventriculostomy or lumbar puncture (LP) were enrolled. Serum and CSF were collected at the time of LP for headache subjects and at 12, 24, and 48 h after ventriculostomy for TBI subjects. The Q(A) was calculated for all time points at which paired CSF and serum samples were available. Serum S100B and TTR levels were also measured. Pearson's correlation coefficient and area under the receiver operating characteristic (ROC) curve were used to determine the relationship between the serum proteins and QA. Seven TBI subjects had abnormal Q(A)'s indicating BBB dysfunction. The remaining TBI and control subjects had normal BBB function. No significant relationship between TTR and QA was found. A statistically significant linear correlation between serum S100B and Q(A) was present (r = 0.432, p = 0.02). ROC analysis demonstrated a significant relationship between Q(A) and serum S100B concentrations at 12 h after TBI (AUC = 0.800; SE 0.147, 95% CI 0.511-1.089). Using an S100B concentration cutoff of 0.027 ng=ml, specificity for abnormal Q(A) was 90% or higher at each time point. We conclude that serum S100B concentrations accurately indicate BBB dysfunction at 12 h after TBI.

Trojan Tour and Rendezvous (TTR): A New Frontiers Mission to Conduct the First Detailed Reconnaissance of the Jupiter Trojan Asteroids

NASA Astrophysics Data System (ADS)

Bell, James F.; Olkin, Cathy; Castillo-Rogez, Julie

2015-11-01

Among the most potentially diagnostic but least explored populations of small bodies are the Jupiter Trojan asteroids, which orbit at ~5 AU in the L4 and L5 Lagrange points of Jupiter. The Trojans provide a unique perspective on solar system history, because their locations and physical, compositional, and mineralogic properties preserve evidence for important gravitational interactions among the giant planets. The locations and orbital properties of more than 6200 Jupiter Trojans are now known, but that is likely only a small fraction of a population of up to ~1e6 Trojans >1 km in size. The Trojans are hypothesized to be either former KBOs scattered into the inner solar system by early giant planet migration and then trapped in L4 and L5, or bodies formed near 5 AU in a more quiescent early solar system.Important Planetary Decadal Survey questions that can be addressed by studying the Trojans include: (a) How did the giant planets and their satellite systems accrete, and is there evidence that they migrated to new orbital positions? (b) What is the relationship between large and small KBOs? Is the small population derived by impact disruption of the large one? (c) What kinds of surface evolution, radiation chemistry, and surface-atmosphere interactions occur on distant icy primitive bodies? And (d) What are the sources of asteroid groups (Trojans and Centaurs) that remain to be explored by spacecraft?Here we describe the Trojan Tour and Rendezvous (TTR) New Frontiers mission concept, which is designed to answer these Decadal questions and to test hypotheses for early giant planet migration and solar system evolution. Via close flybys of many of these objects, and orbital characterization of at least one large Trojan, TTR will enable the initial up-close exploration of this population. Our primary mission goals are to characterize the overall surface geology, geochemistry and mineralogy of these worlds; to characterize their internal structure and dynamical properties; to investigate the nature, sources and history of activity on these bodies; and to explore the diversity of the broader Trojan asteroid population.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wills, Cathy

This report was prepared to meet the information needs of the public and the requirements and guidelines of the U.S. Department of Energy (DOE) for annual site environmental reports. It was prepared by National Security Technologies, LLC (NSTec), for the U.S. Department of Energy, National Nuclear Security Administration Nevada Field Office (NNSA/NFO) (formerly designated as the Nevada Site Office [NNSA/NSO]). The new field office designation occurred in March 2013. Published reports cited in this 2012 report, therefore, may bear the name or authorship of NNSA/NSO. This and previous years’ reports, called Annual Site Environmental Reports (ASERs), Nevada Test Site Environmentalmore » Reports (NTSERs), and, beginning in 2010, Nevada National Security Site Environmental Reports (NNSSERs), are posted on the NNSA/NFO website at http://www.nv.energy.gov/library/publications/aser.aspx. This NNSSER was prepared to satisfy DOE Order DOE O 231.1B, “Environment, Safety and Health Reporting.” Its purpose is to (1) report compliance status with environmental standards and requirements, (2) present results of environmental monitoring of radiological and nonradiological effluents, (3) report estimated radiological doses to the public from releases of radioactive material, (4) summarize environmental incidents of noncompliance and actions taken in response to them, (5) describe the NNSA/NFO Environmental Management System and characterize its performance, and (6) highlight significant environmental programs and efforts. This NNSSER summarizes data and compliance status for calendar year 2012 at the Nevada National Security Site (NNSS) (formerly the Nevada Test Site) and its two support facilities, the North Las Vegas Facility (NLVF) and the Remote Sensing Laboratory–Nellis (RSL-Nellis). It also addresses environmental restoration (ER) projects conducted at the Tonopah Test Range (TTR) and the Nevada Test and Training Range (NTTR). Through a Memorandum of Agreement, NNSA/NFO is responsible for the oversight of these ER projects, and the Sandia Site Office of NNSA (NNSA/SSO) has oversight of all other TTR and NTTR activities. NNSA/SSO produces the TTR annual environmental report available at http://www.sandia.gov/news/publications/environmental/index.html.« less

Late Effects of Polio: An Overview

MedlinePlus

... Nurses Exercise for Polio Survivors Anesthesia Concerns Pool/Water Therapy Other Resources Reports & CD from Task Force Medical/Clinical Publications ADVOCACY Issues Organizations Resources RESEARCH About The Research Fund New Request for 2018 ...

Information about the Late Effects of Polio

MedlinePlus

... Nurses Exercise for Polio Survivors Anesthesia Concerns Pool/Water Therapy Other Resources Reports & CD from Task Force Medical/Clinical Publications ADVOCACY Issues Organizations Resources RESEARCH About The Research Fund New Request for 2018 ...

Automated Formosat Image Processing System for Rapid Response to International Disasters

NASA Astrophysics Data System (ADS)

Cheng, M. C.; Chou, S. C.; Chen, Y. C.; Chen, B.; Liu, C.; Yu, S. J.

2016-06-01

FORMOSAT-2, Taiwan's first remote sensing satellite, was successfully launched in May of 2004 into the Sun-synchronous orbit at 891 kilometers of altitude. With the daily revisit feature, the 2-m panchromatic, 8-m multi-spectral resolution images captured have been used for researches and operations in various societal benefit areas. This paper details the orchestration of various tasks conducted in different institutions in Taiwan in the efforts responding to international disasters. The institutes involved including its space agency-National Space Organization (NSPO), Center for Satellite Remote Sensing Research of National Central University, GIS Center of Feng-Chia University, and the National Center for High-performance Computing. Since each institution has its own mandate, the coordinated tasks ranged from receiving emergency observation requests, scheduling and tasking of satellite operation, downlink to ground stations, images processing including data injection, ortho-rectification, to delivery of image products. With the lessons learned from working with international partners, the FORMOSAT Image Processing System has been extensively automated and streamlined with a goal to shorten the time between request and delivery in an efficient manner. The integrated team has developed an Application Interface to its system platform that provides functions of search in archive catalogue, request of data services, mission planning, inquiry of services status, and image download. This automated system enables timely image acquisition and substantially increases the value of data product. Example outcome of these efforts in recent response to support Sentinel Asia in Nepal Earthquake is demonstrated herein.

A strategic stakeholder approach for addressing further analysis requests in whole genome sequencing research.

PubMed

Thornock, Bradley Steven O

2016-01-01

Whole genome sequencing (WGS) can be a cost-effective and efficient means of diagnosis for some children, but it also raises a number of ethical concerns. One such concern is how researchers derive and communicate results from WGS, including future requests for further analysis of stored sequences. The purpose of this paper is to think about what is at stake, and for whom, in any solution that is developed to deal with such requests. To accomplish this task, this paper will utilize stakeholder theory, a common method used in business ethics. Several scenarios that connect stakeholder concerns and WGS will also posited and analyzed. This paper concludes by developing criteria composed of a series of questions that researchers can answer in order to more effectively address requests for further analysis of stored sequences.

QSAR classification models for the prediction of endocrine disrupting activity of brominated flame retardants.

PubMed

Kovarich, Simona; Papa, Ester; Gramatica, Paola

2011-06-15

The identification of potential endocrine disrupting (ED) chemicals is an important task for the scientific community due to their diffusion in the environment; the production and use of such compounds will be strictly regulated through the authorization process of the REACH regulation. To overcome the problem of insufficient experimental data, the quantitative structure-activity relationship (QSAR) approach is applied to predict the ED activity of new chemicals. In the present study QSAR classification models are developed, according to the OECD principles, to predict the ED potency for a class of emerging ubiquitary pollutants, viz. brominated flame retardants (BFRs). Different endpoints related to ED activity (i.e. aryl hydrocarbon receptor agonism and antagonism, estrogen receptor agonism and antagonism, androgen and progesterone receptor antagonism, T4-TTR competition, E2SULT inhibition) are modeled using the k-NN classification method. The best models are selected by maximizing the sensitivity and external predictive ability. We propose simple QSARs (based on few descriptors) characterized by internal stability, good predictive power and with a verified applicability domain. These models are simple tools that are applicable to screen BFRs in relation to their ED activity, and also to design safer alternatives, in agreement with the requirements of REACH regulation at the authorization step. Copyright © 2011 Elsevier B.V. All rights reserved.

A Proposal for Program Assessment at Kean College of New Jersey. Final Report of the Presidential Task Force on Student Learning and Development.

ERIC Educational Resources Information Center

Kean Coll. of New Jersey, Union.

In response to a request from its president, an institutional task force at Kean College of New Jersey studied approaches to program assessment used at other colleges, identified the measurement approaches being used at Kean College, and made policy recommendations for implementing an assessment program at the college. A major finding was that no…

Identifying Speech Acts in E-Mails: Toward Automated Scoring of the "TOEIC"® E-Mail Task. Research Report. ETS RR-12-16

ERIC Educational Resources Information Center

De Felice, Rachele; Deane, Paul

2012-01-01

This study proposes an approach to automatically score the "TOEIC"® Writing e-mail task. We focus on one component of the scoring rubric, which notes whether the test-takers have used particular speech acts such as requests, orders, or commitments. We developed a computational model for automated speech act identification and tested it…

Icon and user interface design for emergency medical information systems: a case study.

PubMed

Salman, Y Batu; Cheng, Hong-In; Patterson, Patrick E

2012-01-01

A usable medical information system should allow for reliable and accurate interaction between users and the system in emergencies. A participatory design approach was used to develop a medical information system in two Turkish hospitals. The process consisted of task and user analysis, an icon design survey, initial icon design, final icon design and evaluation, and installation of the iconic medical information system with the icons. We observed work sites to note working processes and tasks related to the information system and interviewed medical personnel. Emergency personnel then participated in the design process to develop a usable graphical user interface, by drawing icon sketches for 23 selected tasks. Similar sketches were requested for specific tasks such as family medical history, contact information, translation, addiction, required inspections, requests and applications, and nurse observations. The sketches were analyzed and redesigned into computer icons by professional designers and the research team. A second group of physicians and nurses then tested the understandability of the icons. The user interface layout was examined and evaluated by system users, followed by the system's installation. Medical personnel reported the participatory design process was interesting and believed the resulting designs would be more familiar and friendlier. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Pilot-Configurable Information on a Display Unit

NASA Technical Reports Server (NTRS)

Bell, Charles Frederick (Inventor); Ametsitsi, Julian (Inventor); Che, Tan Nhat (Inventor); Shafaat, Syed Tahir (Inventor)

2017-01-01

A small thin display unit that can be installed in the flight deck for displaying only flight crew-selected tactical information needed for the task at hand. The flight crew can select the tactical information to be displayed by means of any conventional user interface. Whenever the flight crew selects tactical information for processes the request, including periodically retrieving measured current values or computing current values for the requested tactical parameters and returning those current tactical parameter values to the display unit for display.

The National Shipbuilding Research Program, Proceedings of the REAPS Technical Symposium (2nd) held in Palm Beach Shores, Florida, on 24-25 Jun 1975: Full Proceedings

DTIC Science & Technology

1975-06-01

AUTOKON-71 System. Her major tasks include processing Analysis Requests, releasing new system versions, and coordinating program modifications. Some past...for deformed meshes; improvement of crane boom analysis test data and a post-pro- cessing program. I. BACKGROUND 1. What is the AUTOKON System n? a...updates to either enhance or correct the capa- bilities has been generated. Two major sources contribute these updates: the REAPS Analysis Request (AR

78 FR 79392 - Initiation of Antidumping and Countervailing Duty Administrative Reviews and Request for...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-30

... Limited Shijiazhuang Global New Century Tools Co., Ltd. Sichuan Huili Tools Co. Task Tools & Abrasives... Global Logistics (Shanghai) Co., Ltd. APS Qingdao Cangshan Qingshui Vegetable Foods Co., Ltd. Chengwu...

Post-Polio Health International including International Ventilator Users Network

MedlinePlus

... Nurses Exercise for Polio Survivors Anesthesia Concerns Pool/Water Therapy Other Resources Reports & CD from Task Force Medical/Clinical Publications ADVOCACY Issues Organizations Resources RESEARCH About The Research Fund New Request for 2018 ...

78 FR 4158 - Notice of Proposed Information Collection: Comment Request Rent Reform Demonstration (Task Order 1)

Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-18

... technology, e.g., permitting electronic submission of responses. This notice also lists the following.... Data will be gathered through a variety of methods including informational interviews, direct...

Development of a Streamlined Work Flow for Handling Patients' Genetic Testing Insurance Authorizations.

PubMed

Uhlmann, Wendy R; Schwalm, Katie; Raymond, Victoria M

2017-08-01

Obtaining genetic testing insurance authorizations for patients is a complex, time-involved process often requiring genetic counselor (GC) and physician involvement. In an effort to mitigate this complexity and meet the increasing number of genetic testing insurance authorization requests, GCs formed a novel partnership with an industrial engineer (IE) and a patient services associate (PSA) to develop a streamlined work flow. Eight genetics clinics and five specialty clinics at the University of Michigan were surveyed to obtain benchmarking data. Tasks needed for genetic testing insurance authorization were outlined and time-saving work flow changes were introduced including 1) creation of an Excel password-protected shared database between GCs and PSAs, used for initiating insurance authorization requests, tracking and follow-up 2) instituting the PSAs sending GCs a pre-clinic email noting each patients' genetic testing insurance coverage 3) inclusion of test medical necessity documentation in the clinic visit summary note instead of writing a separate insurance letter and 4) PSAs development of a manual with insurance providers and genetic testing laboratories information. These work flow changes made it more efficient to request and track genetic testing insurance authorizations for patients, enhanced GCs and PSAs communication, and reduced tasks done by clinicians.

Ordered Linear Logic Programming

DTIC Science & Technology

1998-12-22

ttR = ttRLCttRR. By ind. hyp. (using part 2) we know T; AxA^; (Q, LQA (A^>B)£1RL; £lRR) —> C y> P. Then nLnA(A ~ B)ÜRLCÜRR —► P. cases 4,5,6,7 : II...national origin, sex or handicap in violation of Title VI of the Civil Rights Act of 1964, Title IX of the Educational Amendments of 1972 and

Dental Hygiene and Orthodontics: Effect of Ultrasonic Instrumentation on Bonding Efficacy of Different Lingual Orthodontic Brackets.

PubMed

Scribante, Andrea; Sfondrini, Maria Francesca; Collesano, Vittorio; Tovt, Gaia; Bernardinelli, Luisa; Gandini, Paola

2017-01-01

Dental hygienists are often faced with patients wearing lingual orthodontic therapy, as ultrasonic instrumentation (UI) is crucial for oral health. As the application of external forces can lead to premature bonding failure, the aim of this study was to evaluate the effect of UI on shear bond strength (SBS) and on adhesive remnant index (ARI) of different lingual orthodontic brackets. 200 bovine incisors were divided into 10 groups. Four different lingual (STB, Ormco; TTR, Rocky Mountain Orthodontics; Idea, Leone; 2D, Forestadent) and vestibular control (Victory, 3M) brackets were bonded. UI was performed in half of specimens, whereas the other half did not receive any treatment. All groups were tested with a universal testing machine. SBS and ARI values were recorded. Statistical analysis was performed (significance: P = 0.05). TTR, Idea, and 2D lingual brackets significantly lowered SBS after UI, whereas for other braces no effect was recorded. Appliances with lower mesh area significantly reduced their adhesion capacity after UI. Moreover groups subjected to UI showed higher ARI scores than controls. UI lowered SBS of lingual appliances of small dimensions so particular care should be posed avoiding prolonged instrumentation around bracket base during plaque removal. Moreover, UI influenced also ARI scores.

Dental Hygiene and Orthodontics: Effect of Ultrasonic Instrumentation on Bonding Efficacy of Different Lingual Orthodontic Brackets

PubMed Central

Collesano, Vittorio; Tovt, Gaia; Bernardinelli, Luisa; Gandini, Paola

2017-01-01

Dental hygienists are often faced with patients wearing lingual orthodontic therapy, as ultrasonic instrumentation (UI) is crucial for oral health. As the application of external forces can lead to premature bonding failure, the aim of this study was to evaluate the effect of UI on shear bond strength (SBS) and on adhesive remnant index (ARI) of different lingual orthodontic brackets. 200 bovine incisors were divided into 10 groups. Four different lingual (STB, Ormco; TTR, Rocky Mountain Orthodontics; Idea, Leone; 2D, Forestadent) and vestibular control (Victory, 3M) brackets were bonded. UI was performed in half of specimens, whereas the other half did not receive any treatment. All groups were tested with a universal testing machine. SBS and ARI values were recorded. Statistical analysis was performed (significance: P = 0.05). TTR, Idea, and 2D lingual brackets significantly lowered SBS after UI, whereas for other braces no effect was recorded. Appliances with lower mesh area significantly reduced their adhesion capacity after UI. Moreover groups subjected to UI showed higher ARI scores than controls. UI lowered SBS of lingual appliances of small dimensions so particular care should be posed avoiding prolonged instrumentation around bracket base during plaque removal. Moreover, UI influenced also ARI scores. PMID:28904955

Tonopah Test Range Air Monitoring: CY2015 Meteorological, Radiological, and Airborne Particulate Observations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nikolich, George; Shadel, Craig; Chapman, Jenny

2016-09-01

In 1963, the U.S. Department of Energy (DOE) (formerly the Atomic Energy Commission [AEC]), implemented Operation Roller Coaster on the Tonopah Test Range (TTR) and an adjacent area of the Nevada Test and Training Range (NTTR) (formerly the Nellis Air Force Range). The operation resulted in radionuclide-contaminated soils at the Clean Slate I, II, and III sites. This report documents observations made during ongoing monitoring of radiological, meteorological, and dust conditions at stations installed adjacent to Clean Slate I and Clean Slate III, and at the TTR Sandia National Laboratories (SNL) Range Operations Control (ROC) center. The primary objective ofmore » the monitoring effort is to determine if winds blowing across the Clean Slate sites are transporting particles of radionuclide-contaminated soil beyond the physical and administrative boundaries of the sites. Radionuclide assessment of airborne particulates in 2015 found the gross alpha and gross beta values of dust collected from the filters at the monitoring stations are consistent with background conditions. The meteorological and particle monitoring indicate that conditions for wind-borne contaminant movement exist at the Clean Slate sites and that, although the transport of radionuclide-contaminated soil by suspension has not been detected, movement by saltation is occurring.« less

The V122I cardiomyopathy variant of transthyretin increases the velocity of rate-limiting tetramer dissociation, resulting in accelerated amyloidosis

PubMed Central

Jiang, Xin; Buxbaum, Joel N.; Kelly, Jeffery W.

2001-01-01

The transthyretin (TTR) amyloid diseases are of keen interest, because there are >80 mutations that cause, and a few mutations that suppress, disease. The V122I variant is the most common amyloidogenic mutation worldwide, producing familial amyloidotic cardiomyopathy primarily in individuals of African descent. The substitution shifts the tetramer-folded monomer equilibrium toward monomer (lowers tetramer stability) and lowers the kinetic barrier associated with rate-limiting tetramer dissociation (pH 7; relative to wild-type TTR) required for amyloid fibril formation. Fibril formation is also accelerated because the folded monomer resulting from the tetramer-folded monomer equilibrium rapidly undergoes partial denaturation and self-assembles into amyloid (in vitro) when subjected to a mild denaturation stress (e.g., pH 4.8). Incorporation of the V122I mutation into a folded monomeric variant of transthyretin reveals that this mutation does not destabilize the tertiary structure or alter the rate of amyloidogenesis relative to the wild-type monomer. The increase in the velocity of rate-limiting tetramer dissociation coupled with the lowered tetramer stability (increasing the mol fraction of folded monomer present at equilibrium) may explain why V122I confers an apparent absolute anatomic risk for cardiac amyloid deposition. PMID:11752443

DOE Office of Scientific and Technical Information (OSTI.GOV)

None, None

Operations of Sandia National Laboratories, Nevada (SNL/NV) at the Tonopah Test Range (TTR) resulted in no planned point radiological releases during 1996. Other releases from SNL/NV included diffuse transuranic sources consisting of the three Clean Slate sites. Air emissions from these sources result from wind resuspension of near-surface transuranic contaminated soil particulates. The total area of contamination has been estimated to exceed 20 million square meters. Soil contamination was documented in an aerial survey program in 1977 (EG&G 1979). Surface contamination levels were generally found to be below 400 pCi/g of combined plutonium-238, plutonium-239, plutonium-240, and americium-241 (i.e., transuranic) activity.more » Hot spot areas contain up to 43,000 pCi/g of transuranic activity. Recent measurements confirm the presence of significant levels of transuranic activity in the surface soil. An annual diffuse source term of 0.39 Ci of transuranic material was calculated for the cumulative release from all three Clean Slate sites. A maximally exposed individual dose of 1.1 mrem/yr at the TTR airport area was estimated based on the 1996 diffuse source release amounts and site-specific meteorological data. A population dose of 0.86 person-rem/yr was calculated for the local residents. Both dose values were attributable to inhalation of transuranic contaminated dust.« less

Vitamin K antagonist use: evidence of the difficulty of achieving and maintaining target INR range and subsequent consequences.

PubMed

Schein, Jeff R; White, C Michael; Nelson, Winnie W; Kluger, Jeffrey; Mearns, Elizabeth S; Coleman, Craig I

2016-01-01

Vitamin K antagonists (VKAs) are effective oral anticoagulants that are titrated to a narrow therapeutic international normalized ratio (INR) range. We reviewed published literature assessing the impact of INR stability - getting into and staying in target INR range - on outcomes including thrombotic events, major bleeding, and treatment costs, as well as key factors that impact INR stability. A time in therapeutic range (TTR) of ≥65 % is commonly accepted as the definition of INR stability. In the real-world setting, this is seldom achieved with standard-of-care management, thus increasing the patients' risks of thrombotic or major bleeding events. There are many factors associated with poor INR control. Being treated in community settings, newly initiated on a VKA, younger in age, or nonadherent to therapy, as well as having polymorphisms of CYP2C9 or VKORC1, or multiple physical or mental co-morbid disease states have been associated with lower TTR. Clinical prediction tools are available, though they can only explain <10 % of the variance behind poor INR control. Clinicians caring for patients who require anticoagulation are encouraged to intensify diligence in INR management when using VKAs and to consider appropriate use of newer anticoagulants as a therapeutic option.

A Systems Approach to Designing Effective Clinical Trials Using Simulations

PubMed Central

Fusaro, Vincent A.; Patil, Prasad; Chi, Chih-Lin; Contant, Charles F.; Tonellato, Peter J.

2013-01-01

Background Pharmacogenetics in warfarin clinical trials have failed to show a significant benefit compared to standard clinical therapy. This study demonstrates a computational framework to systematically evaluate pre-clinical trial design of target population, pharmacogenetic algorithms, and dosing protocols to optimize primary outcomes. Methods and Results We programmatically created an end-to-end framework that systematically evaluates warfarin clinical trial designs. The framework includes options to create a patient population, multiple dosing strategies including genetic-based and non-genetic clinical-based, multiple dose adjustment protocols, pharmacokinetic/pharmacodynamics (PK/PD) modeling and international normalization ratio (INR) prediction, as well as various types of outcome measures. We validated the framework by conducting 1,000 simulations of the CoumaGen clinical trial primary endpoints. The simulation predicted a mean time in therapeutic range (TTR) of 70.6% and 72.2% (P = 0.47) in the standard and pharmacogenetic arms, respectively. Then, we evaluated another dosing protocol under the same original conditions and found a significant difference in TTR between the pharmacogenetic and standard arm (78.8% vs. 73.8%; P = 0.0065), respectively. Conclusions We demonstrate that this simulation framework is useful in the pre-clinical assessment phase to study and evaluate design options and provide evidence to optimize the clinical trial for patient efficacy and reduced risk. PMID:23261867

Recombinant plasmid-based quantitative Real-Time PCR analysis of Salmonella enterica serotypes and its application to milk samples.

PubMed

Gokduman, Kurtulus; Avsaroglu, M Dilek; Cakiris, Aris; Ustek, Duran; Gurakan, G Candan

2016-03-01

The aim of the current study was to develop, a new, rapid, sensitive and quantitative Salmonella detection method using a Real-Time PCR technique based on an inexpensive, easy to produce, convenient and standardized recombinant plasmid positive control. To achieve this, two recombinant plasmids were constructed as reference molecules by cloning the two most commonly used Salmonella-specific target gene regions, invA and ttrRSBC. The more rapid detection enabled by the developed method (21 h) compared to the traditional culture method (90 h) allows the quantitative evaluation of Salmonella (quantification limits of 10(1)CFU/ml and 10(0)CFU/ml for the invA target and the ttrRSBC target, respectively), as illustrated using milk samples. Three advantages illustrated by the current study demonstrate the potential of the newly developed method to be used in routine analyses in the medical, veterinary, food and water/environmental sectors: I--The method provides fast analyses including the simultaneous detection and determination of correct pathogen counts; II--The method is applicable to challenging samples, such as milk; III--The method's positive controls (recombinant plasmids) are reproducible in large quantities without the need to construct new calibration curves. Copyright © 2016 Elsevier B.V. All rights reserved.

Thermoelectric anisotropy in the iron-based superconductor Ba (Fe1-xCox) 2As2

NASA Astrophysics Data System (ADS)

Matusiak, Marcin; Rogacki, Krzysztof; Wolf, Thomas

2018-06-01

We report on the in-plane anisotropy of the Seebeck and Nernst coefficients as well as of the electrical resistivity determined for a series of strain-detwinned single crystals of Ba (Fe1-xC ox) 2A s2 . Two underdoped samples (x =0.024 , 0.045) exhibiting a transition from the tetragonal paramagnetic phase to the orthorhombic spin density wave (SDW) phase (at Ttr=100 and 60 K, respectively) show an onset of Nernst anisotropy at temperatures above 200 K, which is significantly higher than Ttr. In the optimally doped sample (x =0.06 ) the transport properties also appear to be in-plane anisotropic below T ≈120 K, despite the fact that this particular composition does not show any evidence of long-range magnetic order. However, the anisotropy observed in the optimally doped crystal is rather small, and for the Seebeck and Nernst coefficients the difference between values measured along and across the uniaxial strain has an opposite sign to those observed for underdoped crystals with x =0.024 and 0.045. For these two samples, the insensitivity of the Nernst anisotropy to the SDW transition suggests that the origin of nematicity might be something other than magnetic.

The Oklahoma Attorney General's Task Force report on the State of End-of-Life Health Care, 2005.

PubMed

Edmondson, W A Drew

2005-05-01

This article includes the recommendations submitted by the 15 members of the Oklahoma Attorney General's Task Force in their Report on the State of End-of-Life Health Care. The task force was created on April 21, 2004, and their report was accepted by Attorney General W.A. Drew Edmondson at a press conference April 11, 2005. It has been forwarded to members of the Oklahoma Legislature, relevant state agencies and organizations with an invitation to join with members of the task force to continue efforts to improve end-of-life care for Oklahomans. Copies of the report are available upon request to the Office of Attorney General.

78 FR 44931 - Agency Information Collection Activities: Submission for OMB Review; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-25

... services. The tasks of developing new questions and improving upon existing complaint questions along with... of the generic clearance process. This generic clearance will allow the Bureau to test and pilot new...

77 FR 25503 - Agency Information Collection Activities: Proposed Collection; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-30

....3, of the Near-Term Task Force Review of Insights from the Fukushima Dai-ichi Event. 2. Current OMB... the Fukushima Dai-ichi nuclear power plant resulting from the March 11, 2011, earthquake and...

Collision Scenarios for Assessing Crashworthiness of Passenger Rail Equipment

DOT National Transportation Integrated Search

2010-10-12

In June 2009, at the request of the Federal Railroad Administration (FRA), the Railroad Safety Advisory Committee established the Engineering Task Force (ETF). The ETF is comprised of government, railroads, suppliers, and labor organizations and thei...

Why People Play: Artificial Lives Acquiring Play Instinct to Stabilize Productivity

PubMed Central

Tamura, Shinichi; Inabayashi, Shoji; Hayakawa, Waichi; Yokouchi, Takahiro; Mitsumoto, Hiroshi; Taketani, Hisashi

2012-01-01

We propose a model to generate a group of artificial lives capable of coping with various environments which is equivalent to a set of requested task, and likely to show that the plays or hobbies are necessary for the group of individuals to maintain the coping capability with various changes of the environment as a whole. This may be an another side of saying that the wide variety of the abilities in the group is necessary, and if the variety in a species decreased, its species will be extinguished. Thus, we show some simulation results, for example, in the world where more variety of abilities are requested in the plays, performance of the whole world becomes stable and improved in spite of being calculated only from job tasks, and can avoid the risk of extinction of the species. This is the good effect of the play. PMID:23304120

Why people play: artificial lives acquiring play instinct to stabilize productivity.

PubMed

Tamura, Shinichi; Inabayashi, Shoji; Hayakawa, Waichi; Yokouchi, Takahiro; Mitsumoto, Hiroshi; Taketani, Hisashi

2012-01-01

We propose a model to generate a group of artificial lives capable of coping with various environments which is equivalent to a set of requested task, and likely to show that the plays or hobbies are necessary for the group of individuals to maintain the coping capability with various changes of the environment as a whole. This may be an another side of saying that the wide variety of the abilities in the group is necessary, and if the variety in a species decreased, its species will be extinguished. Thus, we show some simulation results, for example, in the world where more variety of abilities are requested in the plays, performance of the whole world becomes stable and improved in spite of being calculated only from job tasks, and can avoid the risk of extinction of the species. This is the good effect of the play.

When customers exhibit verbal aggression, employees pay cognitive costs.

PubMed

Rafaeli, Anat; Erez, Amir; Ravid, Shy; Derfler-Rozin, Rellie; Treister, Dorit Efrat; Scheyer, Ravit

2012-09-01

In 4 experimental studies, we show that customer verbal aggression impaired the cognitive performance of the targets of this aggression. In Study 1, customers' verbal aggression reduced recall of customers' requests. Study 2 extended these findings by showing that customer verbal aggression impaired recognition memory and working memory among employees of a cellular communication provider. In Study 3, the ability to take another's perspective attenuated the negative effects of customer verbal aggression on participants' cognitive performance. Study 4 linked customer verbal aggression to quality of task performance, showing a particularly negative influence of aggressive requests delivered by high-status customers. Together, these studies suggest that the effects of even minor aggression from customers can strongly affect the immediate cognitive performance of customer service employees and reduce their task performance. The implications for research on aggression and for the practice of customer service are discussed.

Driving performance at lateral system limits during partially automated driving.

PubMed

Naujoks, Frederik; Purucker, Christian; Wiedemann, Katharina; Neukum, Alexandra; Wolter, Stefan; Steiger, Reid

2017-11-01

This study investigated driver performance during system limits of partially automated driving. Using a motion-based driving simulator, drivers encountered different situations in which a partially automated vehicle could no longer safely keep the lateral guidance. Drivers were distracted by a non-driving related task on a touch display or driving without an additional secondary task. While driving in partially automated mode drivers could either take their hands off the steering wheel for only a short period of time (10s, so-called 'Hands-on' variant) or for an extended period of time (120s, so-called 'Hands-off' variant). When the system limit was reached (e.g., when entering a work zone with temporary lines), the lateral vehicle control by the automation was suddenly discontinued and a take-over request was issued to the drivers. Regardless of the hands-off interval and the availability of a secondary task, all drivers managed the transition to manual driving safely. No lane exceedances were observed and the situations were rated as 'harmless' by the drivers. The lack of difference between the hands-off intervals can be partly attributed to the fact that most of the drivers kept contact to the steering wheel, even in the hands-off condition. Although all drivers were able to control the system limits, most of them could not explain why exactly the take-over request was issued. The average helpfulness of the take-over request was rated on an intermediate level. Consequently, providing drivers with information about the reason for a system limit can be recommended. Copyright © 2017 Elsevier Ltd. All rights reserved.

Maintenance, repair, and rehabilitation unit costs for PONTIS.

DOT National Transportation Integrated Search

1995-01-01

In the summer of 1993, the Bridge Management Task Force chairman requested that the Virginia Transportation Research Council begin a study of the maintenance, repair, and rehabilitation unit costs needed for the operation of the Pontis system. Becaus...

SLUDGE BATCH 7B QUALIFICATION ACTIVITIES WITH SRS TANK FARM SLUDGE

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pareizs, J.; Click, D.; Lambert, D.

2011-11-16

Waste Solidification Engineering (WSE) has requested that characterization and a radioactive demonstration of the next batch of sludge slurry - Sludge Batch 7b (SB7b) - be completed in the Shielded Cells Facility of the Savannah River National Laboratory (SRNL) via a Technical Task Request (TTR). This characterization and demonstration, or sludge batch qualification process, is required prior to transfer of the sludge from Tank 51 to the Defense Waste Processing Facility (DWPF) feed tank (Tank 40). The current WSE practice is to prepare sludge batches in Tank 51 by transferring sludge from other tanks. Discharges of nuclear materials from Hmore » Canyon are often added to Tank 51 during sludge batch preparation. The sludge is washed and transferred to Tank 40, the current DWPF feed tank. Prior to transfer of Tank 51 to Tank 40, SRNL typically simulates the Tank Farm and DWPF processes with a Tank 51 sample (referred to as the qualification sample). With the tight schedule constraints for SB7b and the potential need for caustic addition to allow for an acceptable glass processing window, the qualification for SB7b was approached differently than past batches. For SB7b, SRNL prepared a Tank 51 and a Tank 40 sample for qualification. SRNL did not receive the qualification sample from Tank 51 nor did it simulate all of the Tank Farm washing and decanting operations. Instead, SRNL prepared a Tank 51 SB7b sample from samples of Tank 7 and Tank 51, along with a wash solution to adjust the supernatant composition to the final SB7b Tank 51 Tank Farm projections. SRNL then prepared a sample to represent SB7b in Tank 40 by combining portions of the SRNL-prepared Tank 51 SB7b sample and a Tank 40 Sludge Batch 7a (SB7a) sample. The blended sample was 71% Tank 40 (SB7a) and 29% Tank 7/Tank 51 on an insoluble solids basis. This sample is referred to as the SB7b Qualification Sample. The blend represented the highest projected Tank 40 heel (as of May 25, 2011), and thus, the highest projected noble metals content for SB7b. Characterization was performed on the Tank 51 SB7b samples and SRNL performed DWPF simulations using the Tank 40 SB7b material. This report documents: (1) The preparation and characterization of the Tank 51 SB7b and Tank 40 SB7b samples. (2) The performance of a DWPF Chemical Process Cell (CPC) simulation using the SB7b Tank 40 sample. The simulation included a Sludge Receipt and Adjustment Tank (SRAT) cycle, where acid was added to the sludge to destroy nitrite and reduce mercury, and a Slurry Mix Evaporator (SME) cycle, where glass frit was added to the sludge in preparation for vitrification. The SME cycle also included replication of five canister decontamination additions and concentrations. Processing parameters were based on work with a nonradioactive simulant. (3) Vitrification of a portion of the SME product and characterization and durability testing (as measured by the Product Consistency Test (PCT)) of the resulting glass. (4) Rheology measurements of the SRAT receipt, SRAT product, and SME product. This program was controlled by a Task Technical and Quality Assurance Plan (TTQAP), and analyses were guided by an Analytical Study Plan. This work is Technical Baseline Research and Development (R&D) for the DWPF. It should be noted that much of the data in this document has been published in interoffice memoranda. The intent of this technical report is bring all of the SB7b related data together in a single permanent record and to discuss the overall aspects of SB7b processing.« less

Putting ROSE to Work: A Proposed Application of a Request-Oriented Scheduling Engine for Space Station Operations

NASA Technical Reports Server (NTRS)

Jaap, John; Muery, Kim

2000-01-01

Scheduling engines are found at the core of software systems that plan and schedule activities and resources. A Request-Oriented Scheduling Engine (ROSE) is one that processes a single request (adding a task to a timeline) and then waits for another request. For the International Space Station, a robust ROSE-based system would support multiple, simultaneous users, each formulating requests (defining scheduling requirements), submitting these requests via the internet to a single scheduling engine operating on a single timeline, and immediately viewing the resulting timeline. ROSE is significantly different from the engine currently used to schedule Space Station operations. The current engine supports essentially one person at a time, with a pre-defined set of requirements from many payloads, working in either a "batch" scheduling mode or an interactive/manual scheduling mode. A planning and scheduling process that takes advantage of the features of ROSE could produce greater customer satisfaction at reduced cost and reduced flow time. This paper describes a possible ROSE-based scheduling process and identifies the additional software component required to support it. Resulting changes to the management and control of the process are also discussed.

Enhancing Brigade Combat Team Adaptability

DTIC Science & Technology

2010-06-11

S3 DUTIES AND RESPONSIBILITIES S3 SGM S3 Operations Fires and EffectsS3 Training S3 Plans CYCLIC TNG GUIDANCE UNIT ASSESSMENT APPROVE DTU TOC/TAC SET...UP TEAM LEADER COURSE BOC MTT Requests/Tracking MTT OVERSIGHT TMPs RECLAMAS LOE OVERSIGHT MONITOR DIV O&I DTU /Task Management TOP 5 CALENDAR...referenced in Chapter 5 to this thesis. SLIDE: 1FOR OFFICIAL USE ONLY OPERATIONAL TASKS/SYSTEMS BOC Shift Change MONITOR DIV O&I DTU SDO BRIEFING

Engineering and Design: Civil Works Cost Engineering

DTIC Science & Technology

1994-03-31

labor cost requirements are broken into tasks of work. Each task is usually performd by a labor crew. Crews may vary in size and mix of skills. The...requested in advance of the expected purchase date. Suppliers are reluctant to guarantee future pricw and ofien will only quote current prices. It may be...unit cost is the overhead cost for the item. g. Sources for Pricing. The Cost Engineer must rely on judgement, historical data, and current labor market

Structural mapping in statistical word problems: A relational reasoning approach to Bayesian inference.

PubMed

Johnson, Eric D; Tubau, Elisabet

2017-06-01

Presenting natural frequencies facilitates Bayesian inferences relative to using percentages. Nevertheless, many people, including highly educated and skilled reasoners, still fail to provide Bayesian responses to these computationally simple problems. We show that the complexity of relational reasoning (e.g., the structural mapping between the presented and requested relations) can help explain the remaining difficulties. With a non-Bayesian inference that required identical arithmetic but afforded a more direct structural mapping, performance was universally high. Furthermore, reducing the relational demands of the task through questions that directed reasoners to use the presented statistics, as compared with questions that prompted the representation of a second, similar sample, also significantly improved reasoning. Distinct error patterns were also observed between these presented- and similar-sample scenarios, which suggested differences in relational-reasoning strategies. On the other hand, while higher numeracy was associated with better Bayesian reasoning, higher-numerate reasoners were not immune to the relational complexity of the task. Together, these findings validate the relational-reasoning view of Bayesian problem solving and highlight the importance of considering not only the presented task structure, but also the complexity of the structural alignment between the presented and requested relations.

Fourth Report of the Task Force on the Shuttle-Mir Rendezvous and Docking Missions

NASA Technical Reports Server (NTRS)

1995-01-01

On December 6, 1994, the NASA Administrator, Mr. Daniel Goldin, requested that Lt. Gen. Thomas P. Stafford, in his role as the Chairman of the NASA Advisory Council Task Force on the Shuttle-Mir Rendezvous and Docking Missions, lead a team composed of several Task Force members and technical advisors' to Russia with the goal of reviewing preparations and readiness for the upcoming international Space Station Phase 1 missions. In his directions to Gen. Stafford, Mr. Goldin requested that the review team focus its initial efforts on safety of flight issues for the following Phase 1A missions: the Soyuz TM-21 mission which will carry U.S. astronaut Dr. Norman Thagard and cosmonauts Lt. Col. Vladimir Dezhurov and Mr. Gennady Strekalov aboard a Soyuz spacecraft to the Mir Station; the Mir 18 Main Expedition during which Thagard and his fellow cosmonauts, Dezhurov and Strokalov, will spend approximately three months aboard the Mir Station; the STS-71 Space Shuttle mission which will perform the first Shuttle-Mir docking, carry cosmonauts Col. Anatoly SoloViev and Mr. Nikolai Budarin to the Mir Station, and return Thagard, Dezhurov, and Strekalov to Earth.

Autotasked Performance in the NAS Workload: A Statistical Analysis

NASA Technical Reports Server (NTRS)

Carter, R. L.; Stockdale, I. E.; Kutler, Paul (Technical Monitor)

1998-01-01

A statistical analysis of the workload performance of a production quality FORTRAN code for five different Cray Y-MP hardware and system software configurations is performed. The analysis was based on an experimental procedure that was designed to minimize correlations between the number of requested CPUs and the time of day the runs were initiated. Observed autotasking over heads were significantly larger for the set of jobs that requested the maximum number of CPUs. Speedups for UNICOS 6 releases show consistent wall clock speedups in the workload of around 2. which is quite good. The observed speed ups were very similar for the set of jobs that requested 8 CPUs and the set that requested 4 CPUs. The original NAS algorithm for determining charges to the user discourages autotasking in the workload. A new charging algorithm to be applied to jobs run in the NQS multitasking queues also discourages NAS users from using auto tasking. The new algorithm favors jobs requesting 8 CPUs over those that request less, although the jobs requesting 8 CPUs experienced significantly higher over head and presumably degraded system throughput. A charging algorithm is presented that has the following desirable characteristics when applied to the data: higher overhead jobs requesting 8 CPUs are penalized when compared to moderate overhead jobs requesting 4 CPUs, thereby providing a charging incentive to NAS users to use autotasking in a manner that provides them with significantly improved turnaround while also maintaining system throughput.

17 CFR 200.17 - Chief Management Analyst.

Code of Federal Regulations, 2013 CFR

2013-04-01

...; CONDUCT AND ETHICS; AND INFORMATION AND REQUESTS Organization and Program Management General Organization... Officer for overseeing the performance of management analysis tasks which pertain, but are not limited, to... utilization; (c) Organizational structures and delegations of authority; (d) Management information systems...

Trojan Tour and Rendezvous (TTR): A New Frontiers Mission to Explore the Origin and Evolution of the Early Solar System

NASA Astrophysics Data System (ADS)

Bell, J. F., III; Olkin, C.; Castillo, J. C.

2015-12-01

The orbital properties, compositions, and physical properties of the diverse populations of small outer solar system bodies provide a forensic map of how our solar system formed and evolved. Perhaps the most potentially diagnostic, but least explored, of those populations are the Jupiter Trojan asteroids, which orbit at ~5 AU in the L4 and L5 Lagrange points of Jupiter. More than 6200 Jupiter Trojans are presently known, but these are predicted to be only a small fraction of the 500,000 to 1 million Trojans >1 km in size. The Trojans are hypothesized to be either former Kuiper Belt Objects (KBOs) that were scattered into the inner solar system by early giant planet migration and then trapped in the 1:1 Jupiter mean motion resonance, or bodies formed near 5 AU in a much more quiescent early solar system, and then trapped at L4 and L5. The 2011 Planetary Science Decadal Survey identified important questions about the origin and evolution of the solar system that can be addressed by studying of the Trojan asteroids, including: (a) How did the giant planets and their satellite systems accrete, and is there evidence that they migrated to new orbital positions? (b) What is the relationship between large and small KBOs? Is the small population derived by impact disruption of the large one? (c) What kinds of surface evolution, radiation chemistry, and surface-atmosphere interactions occur on distant icy primitive bodies? And (d) What are the sources of asteroid groups (Trojans and Centaurs) that remain to be explored by spacecraft? The Trojan Tour and Rendezvous (TTR) is a New Frontiers-class mission designed to answer these questions, and to test hypotheses for early giant planet migration and solar system evolution. Via close flybys of a large number of these objects,, and orbital characterization of at least one large Trojan, TTR will enable the first-time exploration of this population. Our primary mission goals are to characterize the overall surface geology, geochemistry and mineralogy of these worlds; to characterize their internal structure and dynamical properties; to investigate the nature, sources and history of activity on these bodies; and to explore the diversity of the broader Trojan asteroid population.

Expression of thyroid hormone transporters and deiodinases at the brain barriers in the embryonic chicken: Insights into the regulation of thyroid hormone availability during neurodevelopment.

PubMed

Van Herck, Stijn L J; Delbaere, Joke; Bourgeois, Nele M A; McAllan, Bronwyn M; Richardson, Samantha J; Darras, Veerle M

2015-04-01

Thyroid hormones (THs) are key regulators in the development of the vertebrate brain. Therefore, TH access to the developing brain needs to be strictly regulated. The brain barriers separate the central nervous system from the rest of the body and impose specific transport mechanisms on the exchange of molecules between the general circulation and the nervous system. As such they form ideal structures for regulating TH exchange between the blood and the brain. To investigate the mechanism by which the developing brain regulates TH availability, we investigated the ontogenetic expression profiles of TH transporters, deiodinases and the TH distributor protein transthyretin (TTR) at the brain barriers during embryonic and early postnatal development using the chicken as a model. In situ hybridisation revealed expression of the TH transporters monocarboxylate transporter 8 (MCT8) and 10 (MCT10), organic anion transporting polypeptide 1C1 (OATP1C1) and L-type amino acid transporter 1 (LAT1) and the inactivating type 3 deiodinase (D3) in the choroid plexus which forms the blood-cerebrospinal fluid barrier. This was confirmed by quantitative PCR which additionally indicated strongly increasing expression of TTR as well as detectable expression of the activating type 2 deiodinase (D2) and the (in)activating type 1 deiodinase (D1). In the brain capillaries forming the blood-brain barrier in situ hybridisation showed exclusive expression of LAT1 and D2. The combined presence of LAT1 and D2 in brain capillaries suggests that the blood-brain barrier forms the main route for receptor-active T3 uptake into the embryonic chicken brain. Expression of multiple transporters, deiodinases and TTR in the choroid plexus indicates that the blood-cerebrospinal fluid barrier is also important in regulating early TH availability. The impact of these barrier systems can be deduced from the clear difference in T3 and T4 levels as well as the T3/T4 ratio between the developing brain and the general circulation. We conclude that the tight regulation of TH exchange at the brain barriers from early embryonic stages is one of the factors needed to allow the brain to develop within a relative microenvironment. Copyright © 2015 Elsevier Inc. All rights reserved.

Combined sensing platform for advanced diagnostics in exhaled mouse breath

NASA Astrophysics Data System (ADS)

Fortes, Paula R.; Wilk, Andreas; Seichter, Felicia; Cajlakovic, Merima; Koestler, Stefan; Ribitsch, Volker; Wachter, Ulrich; Vogt, Josef; Radermacher, Peter; Carter, Chance; Raimundo, Ivo M.; Mizaikoff, Boris

2013-03-01

Breath analysis is an attractive non-invasive strategy for early disease recognition or diagnosis, and for therapeutic progression monitoring, as quantitative compositional analysis of breath can be related to biomarker panels provided by a specific physiological condition invoked by e.g., pulmonary diseases, lung cancer, breast cancer, and others. As exhaled breath contains comprehensive information on e.g., the metabolic state, and since in particular volatile organic constituents (VOCs) in exhaled breath may be indicative of certain disease states, analytical techniques for advanced breath diagnostics should be capable of sufficient molecular discrimination and quantification of constituents at ppm-ppb - or even lower - concentration levels. While individual analytical techniques such as e.g., mid-infrared spectroscopy may provide access to a range of relevant molecules, some IR-inactive constituents require the combination of IR sensing schemes with orthogonal analytical tools for extended molecular coverage. Combining mid-infrared hollow waveguides (HWGs) with luminescence sensors (LS) appears particularly attractive, as these complementary analytical techniques allow to simultaneously analyze total CO2 (via luminescence), the 12CO2/13CO2 tracer-to-tracee (TTR) ratio (via IR), selected VOCs (via IR) and O2 (via luminescence) in exhaled breath, yet, establishing a single diagnostic platform as both sensors simultaneously interact with the same breath sample volume. In the present study, we take advantage of a particularly compact (shoebox-size) FTIR spectrometer combined with novel substrate-integrated hollow waveguide (iHWG) recently developed by our research team, and miniaturized fiberoptic luminescence sensors for establishing a multi-constituent breath analysis tool that is ideally compatible with mouse intensive care stations (MICU). Given the low tidal volume and flow of exhaled mouse breath, the TTR is usually determined after sample collection via gas chromatography coupled to mass spectrometric detection. Here, we aim at potentially continuously analyzing the TTR via iHWGs and LS flow-through sensors requiring only minute (< 1 mL) sample volumes. Furthermore, this study explores non-linearities observed for the calibration functions of 12CO2 and 13CO2 potentially resulting from effects related to optical collision diameters e.g., in presence of molecular oxygen. It is anticipated that the simultaneous continuous analysis of oxygen via LS will facilitate the correction of these effects after inclusion within appropriate multivariate calibration models, thus providing more reliable and robust calibration schemes for continuously monitoring relevant breath constituents.

Effects of total saponins from Trillium tschonoskii rhizome on grey and white matter injury evaluated by quantitative multiparametric MRI in a rat model of ischemic stroke.

PubMed

Li, Manzhong; Ouyang, Junyao; Zhang, Yi; Cheng, Brian Chi Yan; Zhan, Yu; Yang, Le; Zou, Haiyan; Zhao, Hui

2018-04-06

Trillium tschonoskii rhizome (TTR), a medicinal herb, has been traditionally used to treat traumatic brain injury and headache in China. Although the potential neuroprotective efficacy of TTR has gained increasing interest, the pharmacological mechanism remains unclear. Steroid saponins are the main bioactive components of the herb. To investigate the protective and repair-promoting effects of the total saponins from TTR (TSTT) on grey and white matter damages in a rat model of middle cerebral artery occlusion (MCAO) using magnetic resonance imaging (MRI) assay. Ischemic stroke was induced by MCAO. TSTT and Ginaton (positive control) were administered orally to rats 6h after stroke and daily thereafter. After 15 days of treatment, the survival rate of each group was calculated. We then conducted neurological deficit scores and beam walking test to access the neurological function after ischemic stroke. Subsequently, T2-weighted imaging (T2WI) and T2 relaxometry mapping were performed to measure infarct volume and grey and white matter integrity, respectively. Moreover, diffusion tensor imaging (DTI) was carried out to evaluate the grey and white matter microstructural damage. Additionally, arterial spin labelling (ASL) - cerebral blood flow (CBF) and magnetic resonance angiography (MRA) images provided dynamic information about vascular hemodynamic dysfunction after ischemic stroke. Finally, haematoxylin and eosin (HE) staining was carried out to evaluate the stroke-induced pathological changes in the brain. The survival rate and neurological behavioural outcomes (Bederson scores and beam walking tests) were markedly ameliorated by TSTT (65mg/kg) treatment within 15 days after ischemic stroke. Moreover, T2WI and T2 relaxometry mapping showed that TSTT (65mg/kg) significantly reduced infarct volume and attenuated grey and white matter injury, respectively, which was confirmed by histopathological evaluation of brain tissue. The results obtained from DTI showed that TSTT (65mg/kg) not only significantly alleviated axonal damage and demyelination, but also promoted axonal remodelling and re-myelination. In addition, TSTT treatment also enhanced vascular signal density and increased CBF in rats after MCAO. Our results suggested the potential protective and repair-promoting effects of TSTT on grey and white matter from damage induced by ischemia. This study provides a modern pharmacological basis for the application of TSTT in managing ischemic stroke. Copyright © 2018 Elsevier B.V. All rights reserved.

Impact of co-exposure with butachlor and triadimefon on thyroid endocrine system in larval zebrafish.

PubMed

Cao, Chuyan; Wang, Qiangwei; Jiao, Fang; Zhu, Guonian

2016-09-01

Butachlor (BTL) and triadimefon (TDF), the widely used herbicide and fungicide, are unavoidable enter into the aquatic environment. However, there were limited study regarding to the joint toxicity of these two pesticides on fish at present. To evaluate the potential thyroid-disrupting toxicity and exposed to different concentrations of BTL mixed with TDF. Zebrafish embryo (n=3) were exposed to 0.01 and 0.05 fold of LC50 from the acute joint toxicity test, of which 0.32mg/L (BTL) and 9.41mg/L (TDF) for single or mixture agents (BTL: 0.0064mg/L, 0.032mg/L; TDF: 0.1882mg/L, 0.9410mg/L; co-exposure: 0.0032mg/L BTL+0.0941mg/L TDF, 0.016mg/l BTL+0.4705mg/L TDF) after 10-day post-fertilization. Hatching, malformation, survival rates and thyroid hormones (THs), genes expression involved in HPT-axis of embryos were measured and detected in control and separately/co-exposure treatments. THs contents were evaluated by ELISA kit and the expression levels of genes were determined by RT-PCR. Hatching, malformation and survival rates of embryos exposed to single BTL exhibited no statistically significant difference from the control besides decreased of high concentration in survival rates. Exposure to TDF reduced hatching, survival rate and increased malformation. The combined exposure to BTL and TDF resulted in greater adverse effects on embryonic development. BTL exposure significantly increased free T3 and T4 contents. Elevated free T3 content was also observed in the larvae exposed with single BTL. Co-exposure of the two pesticides caused greater enhanced of T3 and T4 levels. Furthermore, gene data showed BTL up-regulated the mRNA expression of tpo, tshβ, tg, ttr, dio2, TDF up-regulated the mRNA expression of tpo, trα, ttr, dio2 and down-regulated trβ gene. The mixture of the two pesticides caused up-regulation mRNA expression of trα, trβ, tg, ttr, dio2. BTL and TDF resulted in adverse effects on zebrafish embryonic development and caused thyroid endocrine disruption, BTL and TDF have a synergistic effect on development and thyroid endocrine by enhanced level of thyroid hormone. Copyright © 2016 Elsevier GmbH. All rights reserved.

Children Facial Expression Production: Influence of Age, Gender, Emotion Subtype, Elicitation Condition and Culture

PubMed Central

Grossard, Charline; Chaby, Laurence; Hun, Stéphanie; Pellerin, Hugues; Bourgeois, Jérémy; Dapogny, Arnaud; Ding, Huaxiong; Serret, Sylvie; Foulon, Pierre; Chetouani, Mohamed; Chen, Liming; Bailly, Kevin; Grynszpan, Ouriel; Cohen, David

2018-01-01

The production of facial expressions (FEs) is an important skill that allows children to share and adapt emotions with their relatives and peers during social interactions. These skills are impaired in children with Autism Spectrum Disorder. However, the way in which typical children develop and master their production of FEs has still not been clearly assessed. This study aimed to explore factors that could influence the production of FEs in childhood such as age, gender, emotion subtype (sadness, anger, joy, and neutral), elicitation task (on request, imitation), area of recruitment (French Riviera and Parisian) and emotion multimodality. A total of one hundred fifty-seven children aged 6–11 years were enrolled in Nice and Paris, France. We asked them to produce FEs in two different tasks: imitation with an avatar model and production on request without a model. Results from a multivariate analysis revealed that: (1) children performed better with age. (2) Positive emotions were easier to produce than negative emotions. (3) Children produced better FE on request (as opposed to imitation); and (4) Riviera children performed better than Parisian children suggesting regional influences on emotion production. We conclude that facial emotion production is a complex developmental process influenced by several factors that needs to be acknowledged in future research. PMID:29670561

Simplified Distributed Computing

NASA Astrophysics Data System (ADS)

Li, G. G.

2006-05-01

The distributed computing runs from high performance parallel computing, GRID computing, to an environment where idle CPU cycles and storage space of numerous networked systems are harnessed to work together through the Internet. In this work we focus on building an easy and affordable solution for computationally intensive problems in scientific applications based on existing technology and hardware resources. This system consists of a series of controllers. When a job request is detected by a monitor or initialized by an end user, the job manager launches the specific job handler for this job. The job handler pre-processes the job, partitions the job into relative independent tasks, and distributes the tasks into the processing queue. The task handler picks up the related tasks, processes the tasks, and puts the results back into the processing queue. The job handler also monitors and examines the tasks and the results, and assembles the task results into the overall solution for the job request when all tasks are finished for each job. A resource manager configures and monitors all participating notes. A distributed agent is deployed on all participating notes to manage the software download and report the status. The processing queue is the key to the success of this distributed system. We use BEA's Weblogic JMS queue in our implementation. It guarantees the message delivery and has the message priority and re-try features so that the tasks never get lost. The entire system is built on the J2EE technology and it can be deployed on heterogeneous platforms. It can handle algorithms and applications developed in any languages on any platforms. J2EE adaptors are provided to manage and communicate the existing applications to the system so that the applications and algorithms running on Unix, Linux and Windows can all work together. This system is easy and fast to develop based on the industry's well-adopted technology. It is highly scalable and heterogeneous. It is an open system and any number and type of machines can join the system to provide the computational power. This asynchronous message-based system can achieve second of response time. For efficiency, communications between distributed tasks are often done at the start and end of the tasks but intermediate status of the tasks can also be provided.

Is Your Biobank Up to Standards? A Review of the National Canadian Tissue Repository Network Required Operational Practice Standards and the Controlled Documents of a Certified Biobank.

PubMed

Hartman, Victoria; Castillo-Pelayo, Tania; Babinszky, Sindy; Dee, Simon; Leblanc, Jodi; Matzke, Lise; O'Donoghue, Sheila; Carpenter, Jane; Carter, Candace; Rush, Amanda; Byrne, Jennifer; Barnes, Rebecca; Mes-Messons, Anne-Marie; Watson, Peter

2018-02-01

Ongoing quality management is an essential part of biobank operations and the creation of high quality biospecimen resources. Adhering to the standards of a national biobanking network is a way to reduce variability between individual biobank processes, resulting in cross biobank compatibility and more consistent support for health researchers. The Canadian Tissue Repository Network (CTRNet) implemented a set of required operational practices (ROPs) in 2011 and these serve as the standards and basis for the CTRNet biobank certification program. A review of these 13 ROPs covering 314 directives was conducted after 5 years to identify areas for revision and update, leading to changes to 7/314 directives (2.3%). A review of all internal controlled documents (including policies, standard operating procedures and guides, and forms for actions and processes) used by the BC Cancer Agency's Tumor Tissue Repository (BCCA-TTR) to conform to these ROPs was then conducted. Changes were made to 20/106 (19%) of BCCA-TTR documents. We conclude that a substantial fraction of internal controlled documents require updates at regular intervals to accommodate changes in best practices. Reviewing documentation is an essential aspect of keeping up to date with best practices and ensuring the quality of biospecimens and data managed by biobanks.

Assessment of psychometric properties of the Brazilian version of the oral anticoagulation knowledge test.

PubMed

Praxedes, Marcus Fernando da Silva; de Abreu, Mauro Henrique Nogueira Guimarães; Paiva, Saul Martins; Mambrini, Juliana Vaz de Melo; Marcolino, Milena Soriano; Martins, Maria Auxiliadora Parreiras

2016-06-24

The aim of this study was to evaluate the psychometric properties of the Brazilian version of the Oral Anticoagulation Knowledge (OAK) Test. This study, conducted in an anticoagulation clinic, included 201 Brazilian participants aged over 18 years, who had been using warfarin for more than two months. The reliability of the instrument was evaluated by assessing internal consistency (Kuder-Richardson coefficient) and reproducibility (test-retest reliability). The validity was evaluated by hypothesizing that there would be a positive correlation of moderate to strong intensity between the correctness levels of the OAK Test and time within therapeutic range (TTR) values, which is a measure used to evaluate the quality of oral anticoagulation. The instrument exhibited good psychometric properties. The total a Kuder-Richardson coefficient value was 0.818 and intraclass correlation coefficient was 0.967. The validity revealed a strong positive correlation between the values of the level of knowledge, as measured by the OAK Test and the TTR values (rs = 0.780). The instrument proved to be a reliable and valid tool for evaluating the knowledge of Brazilian patients on oral anticoagulation therapy with warfarin. This instrument may be incorporated into the practice of health care for substantiating the structuring of educational activities to ensure the improvement of knowledge about the use of warfarin, thereby increasing the effectiveness and safety of treatment.

Apolipoproteins C-II and C-III as nutritional markers unaffected by inflammation.

PubMed

Isshiki, Miwa; Hirayama, Satoshi; Ueno, Tsuyoshi; Ito, Masayuki; Furuta, Ayaka; Yano, Kouji; Yamatani, Kotoko; Sugihara, Masami; Idei, Mayumi; Miida, Takashi

2018-06-01

Rapid turnover proteins (RTPs), such as transthyretin (TTR), retinol binding protein (RBP), and transferrin (Tf), provide an accurate assessment of nutritional status but are susceptible to inflammation. Lipid-related markers, which have short half-lives in serum, may be better suited for nutritional assessment. We sought to identify sensitive nutritional markers unaffected by inflammation. Fasting serum samples were collected from 30 malnourished inpatients and 25 healthy volunteers. Malnourished inpatients were divided into 2 groups: a low-C-reactive protein (CRP) group (CRP < 20 mg/l, n = 15) and a high-CRP group (CRP ≥ 20 mg/l, n = 15). Lipid-related markers, traditional nutritional markers, RTPs, micronutrients, and ketone bodies were measured and compared among the groups. Apolipoprotein (Apo)C-II and ApoC-III concentrations were lower in malnourished inpatients than in the control group. There was no significant difference in ApoC-II and ApoC-III between the low- and high-CRP groups. Carnitine transporters and ketone bodies did not show a significant difference among the three groups. Albumin, TTR, RBP, and Tf concentrations were lowest in the high-CRP group, intermediate in the low-CRP group, and highest in the control group. These results indicate that ApoC-II and ApoC-III are appropriate nutritional biomarkers unaffected by inflammation. Copyright © 2018 Elsevier B.V. All rights reserved.

The significance of PIWI family expression in human lung embryogenesis and non-small cell lung cancer.

PubMed

Navarro, Alfons; Tejero, Rut; Viñolas, Nuria; Cordeiro, Anna; Marrades, Ramon M; Fuster, Dolors; Caritg, Oriol; Moises, Jorge; Muñoz, Carmen; Molins, Laureano; Ramirez, Josep; Monzo, Mariano

2015-10-13

The expression of Piwi-interacting RNAs, small RNAs that bind to PIWI proteins, was until recently believed to be limited to germinal stem cells. We have studied the expression of PIWI genes during human lung embryogenesis and in paired tumor and normal tissue prospectively collected from 71 resected non-small-cell lung cancer patients. The mRNA expression analysis showed that PIWIL1 was highly expressed in 7-week embryos and downregulated during the subsequent weeks of development. PIWIL1 was expressed in 11 of the tumor samples but in none of the normal tissue samples. These results were validated by immunohistochemistry, showing faint cytoplasmic reactivity in the PIWIL1-positive samples. Interestingly, the patients expressing PIWIL1 had a shorter time to relapse (TTR) (p = 0.006) and overall survival (OS) (p = 0.0076) than those without PIWIL1 expression. PIWIL2 and 4 were downregulated in tumor tissue in comparison to the normal tissue (p < 0.001) and the patients with lower levels of PIWIL4 had shorter TTR (p = 0.048) and OS (p = 0.033). In the multivariate analysis, PIWIL1 expression emerged as an independent prognostic marker. Using 5-Aza-dC treatment and bisulfite sequencing, we observed that PIWIL1 expression could be regulated in part by methylation. Finally, an in silico study identified a stem-cell expression signature associated with PIWIL1 expression.

Weaknesses in Oversight of Naval Sea Systems Command Ship Maintenance Contract in Southwest Asia

DTIC Science & Technology

2010-09-27

task orders for engineering services under the contract to bank approximately $20.3 million in O& M funds. The task orders functioned as a way to bank...profit on repair parts obtained from IFM and has requested cost and pricing data to support that IFM has not charged FMSNA profit on the parts. In a ...Fincantieri.9 See the figure for a Fincantieri Corporate organizational chart that shows the relationship of FMSNA and IFM under the parent company

Maternal responses to child frustration and requests for help in dyads with fragile X syndrome.

PubMed

Wheeler, A C; Hatton, D; Holloway, V T; Sideris, J; Neebe, E C; Roberts, J E; Reznick, J S

2010-06-01

Variability in behaviour displayed by children with fragile X syndrome (FXS) may be partially attributable to environmental factors such as maternal responsivity. The purpose of this study was to explore variables associated with maternal behaviour during a task designed to elicit frustration in their children with FXS. Forty-six mother-child dyads, in which the child had full-mutation FXS, were observed in their homes during a task designed to elicit frustration in the child. Each child was given a wrong set of keys and asked to open a box to retrieve a desired toy. Mothers were provided with the correct set of keys and instructed to intervene when they perceived their child was getting too frustrated. Child-expressed frustration and requests for help and maternal behaviours (comforting, negative control, and encouraging/directing) were observed and coded. Maternal variables (e.g. depression, stress, education levels), child variables (e.g. autistic behaviours, age, medication use) and child behaviours (frustration, requests for help) were explored as predictors of maternal behaviour. Almost all mothers intervened to help their children and most used encouraging/directing behaviours, whereas very few used comforting or negative control. Child age and child behaviours during the frustrating event were significant predictors of encouraging/directing behaviours in the mothers. Children whose mothers reported higher depressive symptomology used fewer requests for help, and mothers of children with more autistic behaviours used more negative control. The results of this study suggest that child age and immediate behaviours are more strongly related to maternal responsivity than maternal traits such as depression and stress.

Cooperation in Human-Agent Systems to Support Resilience: A Microworld Experiment.

PubMed

Chiou, Erin K; Lee, John D

2016-09-01

This study uses a dyadic approach to understand human-agent cooperation and system resilience. Increasingly capable technology fundamentally changes human-machine relationships. Rather than reliance on or compliance with more or less reliable automation, we investigate interaction strategies with more or less cooperative agents. A joint-task microworld scenario was developed to explore the effects of agent cooperation on participant cooperation and system resilience. To assess the effects of agent cooperation on participant cooperation, 36 people coordinated with a more or less cooperative agent by requesting resources and responding to requests for resources in a dynamic task environment. Another 36 people were recruited to assess effects following a perturbation in their own hospital. Experiment 1 shows people reciprocated the cooperative behaviors of the agents; a low-cooperation agent led to less effective interactions and less resource sharing, whereas a high-cooperation agent led to more effective interactions and greater resource sharing. Experiment 2 shows that an initial fast-tempo perturbation undermined proactive cooperation-people tended to not request resources. However, the initial fast tempo had little effect on reactive cooperation-people tended to accept resource requests according to cooperation level. This study complements the supervisory control perspective of human-automation interaction by considering interdependence and cooperation rather than the more common focus on reliability and reliance. The cooperativeness of automated agents can influence the cooperativeness of human agents. Design and evaluation for resilience in teams involving increasingly autonomous agents should consider the cooperative behaviors of these agents. © 2016, Human Factors and Ergonomics Society.

Phthalates and Cumulative Risk Assessment (NAS Final Report)

EPA Science Inventory

On December 18, 2008, the National Academy of Sciences' National Research Council released a final report, requested and sponsored by the EPA, entitled Phthalates and Cumulative Risk Assessment: The Task Ahead.

Risk assessment has become a dominant public policy ...

Dynamic Involvement of Real World Objects in the IoT: A Consensus-Based Cooperation Approach

PubMed Central

Pilloni, Virginia; Atzori, Luigi; Mallus, Matteo

2017-01-01

A significant role in the Internet of Things (IoT) will be taken by mobile and low-cost unstable devices, which autonomously self-organize and introduce highly dynamic and heterogeneous scenarios for the deployment of distributed applications. This entails the devices to cooperate to dynamically find the suitable combination of their involvement so as to improve the system reliability while following the changes in their status. Focusing on the above scenario, we propose a distributed algorithm for resources allocation that is run by devices that can perform the same task required by the applications, allowing for a flexible and dynamic binding of the requested services with the physical IoT devices. It is based on a consensus approach, which maximizes the lifetime of groups of nodes involved and ensures the fulfillment of the requested Quality of Information (QoI) requirements. Experiments have been conducted with real devices, showing an improvement of device lifetime of more than 20%, with respect to a uniform distribution of tasks. PMID:28257030

Dynamic Involvement of Real World Objects in the IoT: A Consensus-Based Cooperation Approach.

PubMed

Pilloni, Virginia; Atzori, Luigi; Mallus, Matteo

2017-03-01

A significant role in the Internet of Things (IoT) will be taken by mobile and low-cost unstable devices, which autonomously self-organize and introduce highly dynamic and heterogeneous scenarios for the deployment of distributed applications. This entails the devices to cooperate to dynamically find the suitable combination of their involvement so as to improve the system reliability while following the changes in their status. Focusing on the above scenario, we propose a distributed algorithm for resources allocation that is run by devices that can perform the same task required by the applications, allowing for a flexible and dynamic binding of the requested services with the physical IoT devices. It is based on a consensus approach, which maximizes the lifetime of groups of nodes involved and ensures the fulfillment of the requested Quality of Information (QoI) requirements. Experiments have been conducted with real devices, showing an improvement of device lifetime of more than 20 % , with respect to a uniform distribution of tasks.

Standards of resuscitation during inter-hospital transportation: the effects of structured team briefing or guideline review - a randomised, controlled simulation study of two micro-interventions.

PubMed

Høyer, Christian B; Christensen, Erika F; Eika, Berit

2011-03-03

Junior physicians are sometimes sent in ambulances with critically ill patients who require urgent transfer to another hospital. Unfamiliar surroundings and personnel, time pressure, and lack of experience may imply a risk of insufficient treatment during transportation as this can cause the physician to loose the expected overview of the situation. While health care professionals are expected to follow complex algorithms when resuscitating, stress can compromise both solo-performance and teamwork. To examine whether inter-hospital resuscitation improved with a structured team briefing between physician and ambulance crew in preparation for transfer vs. review of resuscitation guidelines. The effect parameters were physician team leadership (requesting help, delegating tasks), time to resuscitation key elements (chest compressions, defibrillation, ventilations, medication, or a combination of these termed "the first meaningful action"), and hands-off ratio. 46 physicians graduated within 5 years. A simulation intervention study with a control group and two interventions (structured team briefing or review of guidelines). Scenario: Cardiac arrest during simulated inter-hospital transfer. Forty-six candidates participated: 16 (control), 13 (review), and 17 (team briefing). Reviewing guidelines delayed requesting help to 162 seconds, compared to 21 seconds in control and team briefing groups (p = 0.021). Help was not requested in 15% of cases; never requesting help was associated with an increased hands-off ratio, from 39% if the driver's assistance was requested to 54% if not (p < 0.01). No statistically significant differences were found between groups regarding time to first chest compression, defibrillation, ventilation, drug administration, or the combined "time to first meaningful action". Neither review nor team briefing improved the time to resuscitation key elements. Review led to an eight-fold increase in the delay to requesting help. The association between never requesting help and an increased hands-off ratio underpins the importance of prioritising available resources. Other medical and non-medical domains have benefited from the use of guidelines reviews and structured team briefings. Reviewing guidelines may compromise the ability to focus on aspects such as team leading and delegating tasks and warrants the need for further studies focusing on how to avoid this cognitive impairment.

Standards of resuscitation during inter-hospital transportation: the effects of structured team briefing or guideline review - A randomised, controlled simulation study of two micro-interventions

PubMed Central

2011-01-01

Background Junior physicians are sometimes sent in ambulances with critically ill patients who require urgent transfer to another hospital. Unfamiliar surroundings and personnel, time pressure, and lack of experience may imply a risk of insufficient treatment during transportation as this can cause the physician to loose the expected overview of the situation. While health care professionals are expected to follow complex algorithms when resuscitating, stress can compromise both solo-performance and teamwork. Aim To examine whether inter-hospital resuscitation improved with a structured team briefing between physician and ambulance crew in preparation for transfer vs. review of resuscitation guidelines. The effect parameters were physician team leadership (requesting help, delegating tasks), time to resuscitation key elements (chest compressions, defibrillation, ventilations, medication, or a combination of these termed "the first meaningful action"), and hands-off ratio. Methods Participants: 46 physicians graduated within 5 years. Design: A simulation intervention study with a control group and two interventions (structured team briefing or review of guidelines). Scenario: Cardiac arrest during simulated inter-hospital transfer. Results Forty-six candidates participated: 16 (control), 13 (review), and 17 (team briefing). Reviewing guidelines delayed requesting help to 162 seconds, compared to 21 seconds in control and team briefing groups (p = 0.021). Help was not requested in 15% of cases; never requesting help was associated with an increased hands-off ratio, from 39% if the driver's assistance was requested to 54% if not (p < 0.01). No statistically significant differences were found between groups regarding time to first chest compression, defibrillation, ventilation, drug administration, or the combined "time to first meaningful action". Conclusion Neither review nor team briefing improved the time to resuscitation key elements. Review led to an eight-fold increase in the delay to requesting help. The association between never requesting help and an increased hands-off ratio underpins the importance of prioritising available resources. Other medical and non-medical domains have benefited from the use of guidelines reviews and structured team briefings. Reviewing guidelines may compromise the ability to focus on aspects such as team leading and delegating tasks and warrants the need for further studies focusing on how to avoid this cognitive impairment. PMID:25928019

Unit Costs of Interlibrary Loans and Photocopies at a Regional Medical Library: Preliminary Report *

PubMed Central

Spencer, Carol C.

1970-01-01

Unit costs of providing interlibrary loans and photocopies were determined by a method not previously used for library cost studies: random time sampling with self-observation. The working time of all appropriate personnel was sampled using Random Alarm Mechanisms and a structured checklist of tasks. The total lender's unit cost per request received, including direct labor, materials, fringe benefits, and overhead, was $1.526 for originals mailed postpaid by lender, and $1.534 for photocopies mailed. Corresponding unit costs per request filled were: originals, $1.932, and photocopies, $1.763. PMID:5439910

Artificial intelligence planning applications for space exploration and space robotics

NASA Technical Reports Server (NTRS)

Rokey, Mark; Grenander, Sven

1986-01-01

Mission sequencing involves the plan for actuation of the experiments to be conducted aboard a spacecraft; automation is under study by NASA as a means to reduce time and manpower costs in mission planning and in robotic implementation. The development of a mission sequence is conditioned by the limited duration of advantageous spacecraft encounters with objects of study, more research requests than can be satisfied, and requested changes in objectives. Autonomous robot development is hampered by the absence of task-level programming languages, the existence of anomalies in real-world interactions, and a lack of required capabilities in current sensor technology.

Training anesthesiology residents in providing anesthesia for awake craniotomy: learning curves and estimate of needed case load.

PubMed

Bilotta, Federico; Titi, Luca; Lanni, Fabiana; Stazi, Elisabetta; Rosa, Giovanni

2013-08-01

To measure the learning curves of residents in anesthesiology in providing anesthesia for awake craniotomy, and to estimate the case load needed to achieve a "good-excellent" level of competence. Prospective study. Operating room of a university hospital. 7 volunteer residents in anesthesiology. Residents underwent a dedicated training program of clinical characteristics of anesthesia for awake craniotomy. The program was divided into three tasks: local anesthesia, sedation-analgesia, and intraoperative hemodynamic management. The learning curve for each resident for each task was recorded over 10 procedures. Quantitative assessment of the individual's ability was based on the resident's self-assessment score and the attending anesthesiologist's judgment, and rated by modified 12 mm Likert scale, reported ability score visual analog scale (VAS). This ability VAS score ranged from 1 to 12 (ie, very poor, mild, moderate, sufficient, good, excellent). The number of requests for advice also was recorded (ie, resident requests for practical help and theoretical notions to accomplish the procedures). Each task had a specific learning rate; the number of procedures necessary to achieve "good-excellent" ability with confidence, as determined by the recorded results, were 10 procedures for local anesthesia, 15 to 25 procedures for sedation-analgesia, and 20 to 30 procedures for intraoperative hemodynamic management. Awake craniotomy is an approach used increasingly in neuroanesthesia. A dedicated training program based on learning specific tasks and building confidence with essential features provides "good-excellent" ability. © 2013 Elsevier Inc. All rights reserved.

Feedback is the breakfast of champions: the significance of self-controlled formal feedback for autonomous task engagement.

PubMed

Meng, Liang; Yang, Zijing

2018-01-03

With the aim of examining the positive effect of the formal feedback mechanism itself beyond its informational aspect, we engaged participants in the stopwatch task and recorded their electroencephalogram throughout the experiment. This task requires a button press to stop the watch within a given time interval, the completion of which is simultaneously accompanied by adequate information on task performance. In the self-controlled feedback mode, participants could freely choose whether to request formal feedback after completing the task. In another mode, additional feedback was not provided. The 'non-choice' cue was found to elicit a more negative cue-elicited feedback negativity compared with 'choice', suggesting that the opportunity to solicit formal feedback was perceived as more desirable. In addition, a more enhanced stimulus-preceding negativity was observed prior to the task initiation cue in the self-controlled feedback condition, indicating that participants paid more sustained anticipatory attention during task preparation. Taken together, these electrophysiological results suggested an inherent reward within the formal feedback mechanism itself and the significance of self-controlled formal feedback for autonomous task engagement.

Load Balancing in Cloud Computing Environment Using Improved Weighted Round Robin Algorithm for Nonpreemptive Dependent Tasks.

PubMed

Devi, D Chitra; Uthariaraj, V Rhymend

2016-01-01

Cloud computing uses the concepts of scheduling and load balancing to migrate tasks to underutilized VMs for effectively sharing the resources. The scheduling of the nonpreemptive tasks in the cloud computing environment is an irrecoverable restraint and hence it has to be assigned to the most appropriate VMs at the initial placement itself. Practically, the arrived jobs consist of multiple interdependent tasks and they may execute the independent tasks in multiple VMs or in the same VM's multiple cores. Also, the jobs arrive during the run time of the server in varying random intervals under various load conditions. The participating heterogeneous resources are managed by allocating the tasks to appropriate resources by static or dynamic scheduling to make the cloud computing more efficient and thus it improves the user satisfaction. Objective of this work is to introduce and evaluate the proposed scheduling and load balancing algorithm by considering the capabilities of each virtual machine (VM), the task length of each requested job, and the interdependency of multiple tasks. Performance of the proposed algorithm is studied by comparing with the existing methods.

Load Balancing in Cloud Computing Environment Using Improved Weighted Round Robin Algorithm for Nonpreemptive Dependent Tasks

PubMed Central

Devi, D. Chitra; Uthariaraj, V. Rhymend

2016-01-01

Cloud computing uses the concepts of scheduling and load balancing to migrate tasks to underutilized VMs for effectively sharing the resources. The scheduling of the nonpreemptive tasks in the cloud computing environment is an irrecoverable restraint and hence it has to be assigned to the most appropriate VMs at the initial placement itself. Practically, the arrived jobs consist of multiple interdependent tasks and they may execute the independent tasks in multiple VMs or in the same VM's multiple cores. Also, the jobs arrive during the run time of the server in varying random intervals under various load conditions. The participating heterogeneous resources are managed by allocating the tasks to appropriate resources by static or dynamic scheduling to make the cloud computing more efficient and thus it improves the user satisfaction. Objective of this work is to introduce and evaluate the proposed scheduling and load balancing algorithm by considering the capabilities of each virtual machine (VM), the task length of each requested job, and the interdependency of multiple tasks. Performance of the proposed algorithm is studied by comparing with the existing methods. PMID:26955656

Sandia National Laboratories, Tonopah Test Range Askania Tower (Building 02-00): Photographs and Written Historical and Descriptive Data

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ullrich, Rebecca A.

The Askania Tower (Building 02-00) was built in 1956 as part of the first wave of construction at the newly established Tonopah Test Range (TTR). Located at Station 2, near the primary target area at the range, the tower was one of the first four built to house Askania phototheodolites used in tracking test units dropped from aircraft. This report includes historical information, architectural information, sources of information, project information, maps, blueprints, and photographs.

The validation of procedures to assess prevocational task preferences in retarded adults.

PubMed

Mithaug, D E; Hanawalt, D A

1978-01-01

Three severely retarded young adults between the ages of 19 and 21 years participated in a prevocational training program, and worked regularly on six different tasks during the scheduled six-hour day. The study attempted to assess each subject's preferences for the six tasks: collating, stuffing, sorting, pulley assembly, flour-sifter assembly, and circuit-board stuffing. In Phase I, the procedure consisted of randomly pairing each task with all other tasks in a two-choice situation that required the subjects to select one task from each pair combination to work for a seven-minute period. The selection procedure consisted of presenting two representative task objects on a tray and requesting the subject to pick up one object and place it on the work table. The object selected represented the task worked for that period. The 15 possible pair combinations were presented randomly every two days for a period of 34 days to determine the preferences. During the validation phase (Phase II), each subject's least- and most-preferred tasks were paired separately with moderately-preferred tasks. As expected, these manipulations confirmed the baseline data, as choices for the moderately-preferred tasks decreased when consistently paired with the preferred tasks and increased when consistently paired with the least-preferred tasks.

40 CFR 63.1401 - Compliance schedule.

Code of Federal Regulations, 2010 CFR

2010-07-01

... needed and the date when the owner or operator first learned of the circumstances necessitating a request for compliance extension. (e) All terms in this subpart that define a period of time for completion of required tasks (e.g., weekly, monthly, quarterly, annual), unless specified otherwise, refer to the...

Scheduling techniques in the Request Oriented Scheduling Engine (ROSE)

NASA Technical Reports Server (NTRS)

Zoch, David R.

1991-01-01

Scheduling techniques in the ROSE are presented in the form of the viewgraphs. The following subject areas are covered: agenda; ROSE summary and history; NCC-ROSE task goals; accomplishments; ROSE timeline manager; scheduling concerns; current and ROSE approaches; initial scheduling; BFSSE overview and example; and summary.

76 FR 35007 - Notice of Issuance of Final Determination Concerning the Country of Origin of Certain Office Chairs

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-15

... learning environments. The merchandise at issue is the Herman Miller SAYL task chair and the SAYL side... exact size and shape requested by Herman Miller. The TPU mesh is placed in a custom-made machine, which...

Using Real Colors to Transform Organizational Culture

ERIC Educational Resources Information Center

Roback, Paul

2017-01-01

Extension educators are frequently tasked with strengthening organizations they collaborate with or provide education to. When a county government in Wisconsin experienced significant personnel changes in a span of less than 18 months, department heads contacted Extension to request professional development and team-building education for their…

Technical memo, project 0-6132 : task 6 - test sections in the districts.

DOT National Transportation Integrated Search

2011-02-01

This Tech Memo provides a summary of the Lab Test, Distress Survey, and Construction Reports for the CAM Test Sections constructed on FM 158 (E William J. Bryan Pkwy) in the Bryan District. TTI was requested by both the Contractor (Knife River Corpor...

75 FR 3926 - Submission for OMB Emergency Review: Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2010-01-25

... DEPARTMENT OF LABOR Bureau of Labor Statistics Submission for OMB Emergency Review: Comment.... Agency: Bureau of Labor Statistics. Type of Review: New collection. Title of Collection: Quarterly Census... appropriation tasks the Bureau of Labor Statistics (BLS) Quarterly Census of Employment and Wages (QCEW) program...

The eye movements of dyslexic children during reading and visual search: impact of the visual attention span.

PubMed

Prado, Chloé; Dubois, Matthieu; Valdois, Sylviane

2007-09-01

The eye movements of 14 French dyslexic children having a VA span reduction and 14 normal readers were compared in two tasks of visual search and text reading. The dyslexic participants made a higher number of rightward fixations in reading only. They simultaneously processed the same low number of letters in both tasks whereas normal readers processed far more letters in reading. Importantly, the children's VA span abilities related to the number of letters simultaneously processed in reading. The atypical eye movements of some dyslexic readers in reading thus appear to reflect difficulties to increase their VA span according to the task request.

Human Factors in Aeronautics at NASA

NASA Technical Reports Server (NTRS)

Mogford, Richard

2016-01-01

This is a briefing to a regularly meeting DoD group called the Human Systems Community of Interest: Mission Effectiveness. I was asked to address human factors in aeronautics at NASA. (Exploration (space) human factors has apparently already been covered.) The briefing describes human factors organizations at NASA Ames and Langley. It then summarizes some aeronautics tasks that involve the application of human factors in the development of specific tools and capabilities. The tasks covered include aircrew checklists, dispatch operations, Playbook, Dynamic Weather Routes, Traffic Aware Strategic Aircrew Requests, and Airplane State Awareness and Prediction Technologies. I mention that most of our aeronautics work involves human factors as embedded in development tasks rather than basic research.

Distributed computation of graphics primitives on a transputer network

NASA Technical Reports Server (NTRS)

Ellis, Graham K.

1988-01-01

A method is developed for distributing the computation of graphics primitives on a parallel processing network. Off-the-shelf transputer boards are used to perform the graphics transformations and scan-conversion tasks that would normally be assigned to a single transputer based display processor. Each node in the network performs a single graphics primitive computation. Frequently requested tasks can be duplicated on several nodes. The results indicate that the current distribution of commands on the graphics network shows a performance degradation when compared to the graphics display board alone. A change to more computation per node for every communication (perform more complex tasks on each node) may cause the desired increase in throughput.

The equipment access software for a distributed UNIX-based accelerator control system

NASA Astrophysics Data System (ADS)

Trofimov, Nikolai; Zelepoukine, Serguei; Zharkov, Eugeny; Charrue, Pierre; Gareyte, Claire; Poirier, Hervé

1994-12-01

This paper presents a generic equipment access software package for a distributed control system using computers with UNIX or UNIX-like operating systems. The package consists of three main components, an application Equipment Access Library, Message Handler and Equipment Data Base. An application task, which may run in any computer in the network, sends requests to access equipment through Equipment Library calls. The basic request is in the form Equipment-Action-Data and is routed via a remote procedure call to the computer to which the given equipment is connected. In this computer the request is received by the Message Handler. According to the type of the equipment connection, the Message Handler either passes the request to the specific process software in the same computer or forwards it to a lower level network of equipment controllers using MIL1553B, GPIB, RS232 or BITBUS communication. The answer is then returned to the calling application. Descriptive information required for request routing and processing is stored in the real-time Equipment Data Base. The package has been written to be portable and is currently available on DEC Ultrix, LynxOS, HPUX, XENIX, OS-9 and Apollo domain.

Sensorimotor adaptations to microgravity in humans.

PubMed

Edgerton, V R; McCall, G E; Hodgson, J A; Gotto, J; Goulet, C; Fleischmann, K; Roy, R R

2001-09-01

Motor function is altered by microgravity, but little detail is available as to what these changes are and how changes in the individual components of the sensorimotor system affect the control of movement. Further, there is little information on whether the changes in motor performance reflect immediate or chronic adaptations to changing gravitational environments. To determine the effects of microgravity on the neural control properties of selected motor pools, four male astronauts from the NASA STS-78 mission performed motor tasks requiring the maintenance of either ankle dorsiflexor or plantarflexor torque. Torques of 10 or 50% of a maximal voluntary contraction (MVC) were requested of the subjects during 10 degrees peak-to-peak sinusoidal movements at 0.5 Hz. When 10% MVC of the plantarflexors was requested, the actual torques generated in-flight were similar to pre-flight values. Post-flight torques were higher than pre- and in-flight torques. The actual torques when 50% MVC was requested were higher in- and post-flight than pre-flight. Soleus (Sol) electromyographic (EMG) amplitudes during plantarflexion were higher in-flight than pre- or post-flight for both the 10 and 50% MVC tasks. No differences in medial gastrocnemius (MG) EMG amplitudes were observed for either the 10 or 50% MVC tasks. The EMG amplitudes of the tibialis anterior (TA), an antagonist to plantarflexion, were higher in- and post-flight than pre-flight for the 50% MVC task. During the dorsiflexion tasks, the torques generated in both the 10 and 50% MVC tasks did not differ pre-, in- and post-flight. TA EMG amplitudes were significantly higher in- than pre-flight for both the 10 or 50% MVC tasks, and remained elevated post-flight for the 50% MVC test. Both the Sol and MG EMG amplitudes were significantly higher in-flight than either pre- or post-flight for both the 10 and 50% MVC tests. These data suggest that the most consistent response to space flight was an elevation in the level of contractions of agonists and antagonists when attempting to maintain constant torques at a given level of MVC. Also, the chronic levels of EMG activity in selected ankle flexor and extensor muscles during space flight and during routine activities on Earth were recorded. Compared with pre- and post-flight values, there was a marked increase in the total EMG activity of the TA and the Sol and no change in the MG EMG activity in-flight. These data indicate that space flight, as occurs on shuttle missions, is a model of elevated activation of both flexor and extensor muscles, probably reflecting the effects of programmed work schedules in flight rather than a direct effect of microgravity.

Sensorimotor adaptations to microgravity in humans

NASA Technical Reports Server (NTRS)

Edgerton, V. R.; McCall, G. E.; Hodgson, J. A.; Gotto, J.; Goulet, C.; Fleischmann, K.; Roy, R. R.

2001-01-01

Motor function is altered by microgravity, but little detail is available as to what these changes are and how changes in the individual components of the sensorimotor system affect the control of movement. Further, there is little information on whether the changes in motor performance reflect immediate or chronic adaptations to changing gravitational environments. To determine the effects of microgravity on the neural control properties of selected motor pools, four male astronauts from the NASA STS-78 mission performed motor tasks requiring the maintenance of either ankle dorsiflexor or plantarflexor torque. Torques of 10 or 50% of a maximal voluntary contraction (MVC) were requested of the subjects during 10 degrees peak-to-peak sinusoidal movements at 0.5 Hz. When 10% MVC of the plantarflexors was requested, the actual torques generated in-flight were similar to pre-flight values. Post-flight torques were higher than pre- and in-flight torques. The actual torques when 50% MVC was requested were higher in- and post-flight than pre-flight. Soleus (Sol) electromyographic (EMG) amplitudes during plantarflexion were higher in-flight than pre- or post-flight for both the 10 and 50% MVC tasks. No differences in medial gastrocnemius (MG) EMG amplitudes were observed for either the 10 or 50% MVC tasks. The EMG amplitudes of the tibialis anterior (TA), an antagonist to plantarflexion, were higher in- and post-flight than pre-flight for the 50% MVC task. During the dorsiflexion tasks, the torques generated in both the 10 and 50% MVC tasks did not differ pre-, in- and post-flight. TA EMG amplitudes were significantly higher in- than pre-flight for both the 10 or 50% MVC tasks, and remained elevated post-flight for the 50% MVC test. Both the Sol and MG EMG amplitudes were significantly higher in-flight than either pre- or post-flight for both the 10 and 50% MVC tests. These data suggest that the most consistent response to space flight was an elevation in the level of contractions of agonists and antagonists when attempting to maintain constant torques at a given level of MVC. Also, the chronic levels of EMG activity in selected ankle flexor and extensor muscles during space flight and during routine activities on Earth were recorded. Compared with pre- and post-flight values, there was a marked increase in the total EMG activity of the TA and the Sol and no change in the MG EMG activity in-flight. These data indicate that space flight, as occurs on shuttle missions, is a model of elevated activation of both flexor and extensor muscles, probably reflecting the effects of programmed work schedules in flight rather than a direct effect of microgravity.

Children with Autism Understand Indirect Speech Acts: Evidence from a Semi-Structured Act-Out Task

PubMed Central

Kissine, Mikhail; Cano-Chervel, Julie; Carlier, Sophie; De Brabanter, Philippe; Ducenne, Lesley; Pairon, Marie-Charlotte; Deconinck, Nicolas; Delvenne, Véronique; Leybaert, Jacqueline

2015-01-01

Children with Autism Spectrum Disorder are often said to present a global pragmatic impairment. However, there is some observational evidence that context-based comprehension of indirect requests may be preserved in autism. In order to provide experimental confirmation to this hypothesis, indirect speech act comprehension was tested in a group of 15 children with autism between 7 and 12 years and a group of 20 typically developing children between 2:7 and 3:6 years. The aim of the study was to determine whether children with autism can display genuinely contextual understanding of indirect requests. The experiment consisted of a three-pronged semi-structured task involving Mr Potato Head. In the first phase a declarative sentence was uttered by one adult as an instruction to put a garment on a Mr Potato Head toy; in the second the same sentence was uttered as a comment on a picture by another speaker; in the third phase the same sentence was uttered as a comment on a picture by the first speaker. Children with autism complied with the indirect request in the first phase and demonstrated the capacity to inhibit the directive interpretation in phases 2 and 3. TD children had some difficulty in understanding the indirect instruction in phase 1. These results call for a more nuanced view of pragmatic dysfunction in autism. PMID:26551648

Effects of subliminal affective priming on helping behavior using the foot-in-the-door technique.

PubMed

Skandrani-Marzouki, Inès; Marzouki, Yousri; Joule, Robert-Vincent

2012-12-01

Two experiments examined the effect of subliminal affective priming on compliance using the foot-in-the-door (FITD) paradigm. Prior to the target request, participants were exposed to subliminal emotional expressions. FITD (presence vs. absence of initial request) was crossed with Priming (positive, negative, neutral, and absence of prime-blank screen) in a between-subjects design. 180 students volunteered as participants (M=22 years). 20 participants (10 females) were assigned to each of eight experimental conditions plus the control condition that neither involved the initial request nor the priming experiment. Participants were asked to judge whether target sentences were relevant or not for road safety instruction. In Experiment 1, emotional valence of prime stimuli affected both endorsement rate and time devoted to the target request but not participants' attitude. Affective priming effects did not interact significantly with the FITD effect. In experiment 2, in 180 more students, the attitude measure was replaced by an implicit recognition task. Results showed that regardless of priming condition, in the absence of FITD, participants recognized target sentences better than in the presence of FITD. Conversely, in the presence of the FITD, participants recognized more accurately previously seen sentences that were primed by positive emotions relative to other priming conditions. The latter result suggests that the presence of the FITD involves a significant amount of cognitive resources so that only stimuli emotionally relevant to the task's goal (i.e., positive) tend to be processed. Together, these results could explain how, contrary to helping behavior, compliant behavior that has no direct association with the prime stimuli was not easily influenced by the affective subliminal priming.

Fire toxicology from the National Academy of Sciences (NAS) point of view

NASA Technical Reports Server (NTRS)

Winter, D. L.

1978-01-01

At the request of NASA the Subcommittee on Fire Toxicology undertook the tasks of evaluating the state-of-knowledge in fire toxicology and recommending guidelines for establishing standard approaches for testing the toxicity of polymeric materials in fires. The recommended guidelines on methodology for evaluation of toxicity of pyrolysis and combustion products are presented. Flow charts reflecting the organizations responsible for the evaluation tasks are presented to show organizational changes which took place between 1977 and 1978. Also listed are the names, phone numbers and companies in attendance at the meeting.

Commercial Eyes in Space: Implications for U.S. Military Operations in 2030

DTIC Science & Technology

2008-03-01

r C om m er ci al Im ag er y C om pa ny Su bj ec t Figure 2: Notional Satellite Remote Sensing Flow and...Government will most likely continue to rely on commercial sensors to supplement national intelligence 14 A dv er sa ry U se r C om m er ci al Im ag er y...C om pa ny Su bj ec t Potential Counter ISR Strategies for 2030 Image Request Tasking Recv’d Satellite Tasked Image Processed & Stored

77 FR 20834 - Merchant Mariner Medical Advisory Committee

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-06

... services for individuals with disabilities or to request special assistance at the meeting, contact LT..., issue of the Federal Register (73 FR 3316). If you would like a copy of your material distributed to... Guidelines for Merchant Mariner Credentials. (b) Task Statement 2, top medical conditions leading to denial...

78 FR 11213 - Merchant Mariner Medical Advisory Committee

Federal Register 2010, 2011, 2012, 2013, 2014

2013-02-15

... facilities or services for individuals with disabilities or to request special assistance at the meeting... of the Federal Register (73 FR 3316). If you would like a copy of your material distributed to each... medical conditions leading to denial of mariner credentials. (c) Task Statement 4, Revising the CG-719K...

Interactive Information Organization: Techniques and Evaluation

DTIC Science & Technology

2001-05-01

information search and access. Locating interesting information on the World Wide Web is the main task of on-line search engines . Such engines accept a...likelihood of being relevant to the user’s request. The majority of today’s Web search engines follow this scenario. The ordering of documents in the

77 FR 21087 - Renewal of Department of Defense Federal Advisory Committees

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-09

..., engineering, and manufacturing, and will ensure the identification of new technologies and new applications of... for Acquisition, Technology and Logistics, the Chairman of the Joint Chiefs of Staff, and as requested..., technology, manufacturing, acquisition process, and other matters of special interest to the DoD. Tasks...

77 FR 8216 - Request for Stakeholder Comments on “National Travel and Tourism Strategy”

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-14

... ``National Travel and Tourism Strategy'' AGENCY: International Trade Administration, Department of Commerce... ``National Travel and Tourism Strategy'' (``Strategy''), to be produced by the Task Force on Travel and... sent to: Tourism[email protected] . Written comments may be sent to: Jennifer Pilat, 1401...

Evidence Based Education Request Desk. EBE #131

ERIC Educational Resources Information Center

Regional Educational Laboratory Southeast, 2007

2007-01-01

To complement the information gathered on middle school and high school literacy initiatives as reported in "Middle and High School Literacy across the Curriculum" (Task 1.2 Fast Response Project), the Regional Educational Laboratory Southeast (REL-SE) staff conducted a scan of the six southeast states to gather the following information…

75 FR 45091 - Notice of Request for Nominations to the Agricultural Air Quality Task Force

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-02

... minorities, women, and persons with disabilities. USDA prohibits discrimination in its programs and activities on the basis of race, color, national origin, gender, religion, age, sexual orientation, or disability. Additionally, discrimination on the basis of political beliefs and marital or family status is...

77 FR 33221 - Agency Information Collection Activities: Proposed Collection; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-05

... medical health insurance (hereon referred to as issuers) and other affected parties, it will be displayed... tasked with providing information on their major medical insurance products and plans. They will... collection; Title: Health Care Reform Insurance Web Portal Requirements 45 CFR part 159; Use: In compliance...

Planetary Nomenclature: An Overview and Update for 2017

NASA Astrophysics Data System (ADS)

Gaither, Tenielle; Hayward, Rose; IAU Working GroupPlanetary System Nomenclature

2017-10-01

The task of naming planetary surface features, rings, and natural satellites is managed by the International Astronomical Union’s (IAU) Working Group for Planetary System Nomenclature (WGPSN). There are currently 15,361 IAU-approved surface feature names on 41 planetary bodies, including moons and asteroids. The members of the WGPSN and its task groups have worked since the early 1970s to provide a clear, unambiguous system of planetary nomenclature that represents cultures and countries from all regions of Earth. WGPSN members include Rita Schulz (Chair) and 9 other members representing countries around the globe. The participation of knowledgeable scientists and experts in this process is vital to its success of the IAU WGPSN . Planetary nomenclature is a tool used to uniquely identify features on the surfaces of planets or satellites so they can be located, described, and discussed in publications, including peer-review journals, maps and conference presentations. Approved names are listed in the Transactions of the IAU and on the Gazetteer of Planetary Nomenclature website. Any names currently in use that are not listed the Gazetteer are not official. Planetary names must adhere to rules and conventions established by the IAU WGPSN (see http://planetarynames.wr.usgs.gov/Page/Rules for the complete list). The gazetteer includes an online Name Request Form (http://planetarynames.wr.usgs.gov/FeatureNameRequest) that can be used by members of the professional science community. Name requests are first reviewed by one of six task groups (Mercury, Venus, Moon, Mars, Outer Solar System, and Small Bodies). After a task group has reviewed a proposal, it is submitted to the WGPSN. Allow four to six weeks for the review and approval process. Upon WGPSN approval, names are considered formally approved and it is then appropriate to use them in publications. Approved names are immediately entered into the database and shown on the website. Questions about the nomenclature database and the naming process can be sent to Rosalyn Hayward, USGS Astrogeology Science Center, 2255 N. Gemini Dr., Flagstaff, AZ 86001, or by email to rhayward@usgs.gov.

Concentration of carotenoids, retinol and alpha-tocopherol in plasma of six microchiroptera species.

PubMed

Müller, Kerstin; Voigt, Christian C; Raila, Jens; Hurtienne, Andrea; Vater, Marianne; Brunnberg, Leo; Schweigert, Florian J

2007-07-01

To adequately feed species in captivity it is necessary to know their nutritional habits and their natural availability of specific nutrients. Such essential nutrients are vitamin A, vitamin E and selected carotenoids as vitamin-A-precursors. Because their blood plasma concentration are valid biomarkers of nutritional status of dietary intake, we determined the concentrations of carotenoids, retinol and alpha-tocopherol by HPLC as well as the transport proteins for retinol, the retinol-binding protein (RBP) and transthyretin (TTR) immunologically in the plasma of six species of microchiroptera from free-ranging animals and compared it in one species (Carollia perspicillata) to a group held in captivity. Plasma concentrations of the investigated components were generally much lower compared to most other mammals. Within the bats, differences were observed for all components. As in other species retinol, RBP and TTR were present but no retinyl esters could be detected. Plasma of the insectivorous bat species Molossus molossus contained carotenoids. Within the group of carotenoids, beta-carotene was dominant and only traces of lutein were present. Phyllostomus hastatus revealed the highest alpha-tocopherol concentration. No differences in the plasma content of the investigated compounds were found between a group of Carollia perspicillata kept in captivity for 20 years and free-ranging individuals from a population in Central America. No sex related differences were obvious. In conclusion, nutritional biomarkers in bats were highly variable due to dietary and possible species-specific differences.

Phylogeny of the bears (Ursidae) based on nuclear and mitochondrial genes.

PubMed

Yu, Li; Li, Qing-wei; Ryder, O A; Zhang, Ya-ping

2004-08-01

The taxomic classification and phylogenetic relationships within the bear family remain argumentative subjects in recent years. Prior investigation has been concentrated on the application of different mitochondrial (mt) sequence data, herein we employ two nuclear single-copy gene segments, the partial exon 1 from gene encoding interphotoreceptor retinoid binding protein (IRBP) and the complete intron 1 from transthyretin (TTR) gene, in conjunction with previously published mt data, to clarify these enigmatic problems. The combined analyses of nuclear IRBP and TTR datasets not only corroborated prior hypotheses, positioning the spectacled bear most basally and grouping the brown and polar bear together but also provided new insights into the bear phylogeny, suggesting the sister-taxa association of sloth bear and sun bear with strong support. Analyses based on combination of nuclear and mt genes differed from nuclear analysis in recognizing the sloth bears as the earliest diverging species among the subfamily ursine representatives while the exact placement of the sun bear did not resolved. Asiatic and American black bears clustered as sister group in all analyses with moderate levels of bootstrap support and high posterior probabilities. Comparisons between the nuclear and mtDNA findings suggested that our combined nuclear dataset have the resolving power comparable to mtDNA dataset for the phylogenetic interpretation of the bear family. As can be seen from present study, the unanimous phylogeny for this recently derived family was still not produced and additional independent genetic markers were in need.

CpG island methylator phenotype identifies high risk patients among microsatellite stable BRAF mutated colorectal cancers

PubMed Central

Vedeld, Hege Marie; Merok, Marianne; Jeanmougin, Marine; Danielsen, Stine A.; Honne, Hilde; Presthus, Gro Kummeneje; Svindland, Aud; Sjo, Ole H.; Hektoen, Merete; Eknæs, Mette; Nesbakken, Arild; Lothe, Ragnhild A.

2017-01-01

The prognostic value of CpG island methylator phenotype (CIMP) in colorectal cancer remains unsettled. We aimed to assess the prognostic value of this phenotype analyzing a total of 1126 tumor samples obtained from two Norwegian consecutive colorectal cancer series. CIMP status was determined by analyzing the 5‐markers CAGNA1G, IGF2, NEUROG1, RUNX3 and SOCS1 by quantitative methylation specific PCR (qMSP). The effect of CIMP on time to recurrence (TTR) and overall survival (OS) were determined by uni‐ and multivariate analyses. Subgroup analyses were conducted according to MSI and BRAF mutation status, disease stage, and also age at time of diagnosis (<60, 60‐74, ≥75 years). Patients with CIMP positive tumors demonstrated significantly shorter TTR and worse OS compared to those with CIMP negative tumors (multivariate hazard ratio [95% CI] 1.86 [1.31‐2.63] and 1.89 [1.34‐2.65], respectively). In stratified analyses, CIMP tumors showed significantly worse outcome among patients with microsatellite stable (MSS, P < 0.001), and MSS BRAF mutated tumors (P < 0.001), a finding that persisted in patients with stage II, III or IV disease, and that remained significant in multivariate analysis (P < 0.01). Consistent results were found for all three age groups. To conclude, CIMP is significantly associated with inferior outcome for colorectal cancer patients, and can stratify the poor prognostic patients with MSS BRAF mutated tumors. PMID:28542846

Laparoscopic Complete Mesocolic Excision versus Open Complete Mesocolic Excision for Transverse Colon Cancer: Long-Term Survival Results of a Prospective Single Centre Non-Randomized Study.

PubMed

Storli, Kristian Eeg; Eide, Geir Egil

2016-01-01

Laparoscopic complete mesocolic excision (CME) used in the treatment of transverse colon cancer has been questioned on the basis of the technical challenges. The aim of this study was to evaluate the medium- and long-term clinical and survival outcomes after laparoscopic and open CME for transverse colon cancer and to compare the 2 approaches. This study was a retrospective non-randomized study of patients with prospectively registered data on open and laparoscopic CME for transverse colon cancer tumour-node-metastasis stages I-III operated on between 2007 and 2014. This was a single-centre study in a community teaching hospital. A total of 56 patients with transverse colon cancer were included, excluding those with tumours in the colonic flexures. The outcome aims were 4-year time to recurrence (TTR) and cancer-specific survival (CSS). Morbidity was also measured. The 4-year TTR was 93.9% in the laparoscopic group and 91.3% in the open group (p = 0.71). The 4-year CSS was 97.0% in the laparoscopic group and 91.3% in the open group (p = 0.42). This was a prospective single-institution study with a small sample size. Results of the study suggest that the laparoscopic CME approach might be the preferred approach for transverse colon cancer, especially regarding its benefits in terms of short-term morbidity, length of stay and oncological outcome. © 2016 S. Karger AG, Basel.

The significance of PIWI family expression in human lung embryogenesis and non-small cell lung cancer

PubMed Central

Navarro, Alfons; Tejero, Rut; Viñolas, Nuria; Cordeiro, Anna; Marrades, Ramon M.; Fuster, Dolors; Caritg, Oriol; Moises, Jorge; Muñoz, Carmen; Molins, Laureano; Ramirez, Josep; Monzo, Mariano

2015-01-01

The expression of Piwi-interacting RNAs, small RNAs that bind to PIWI proteins, was until recently believed to be limited to germinal stem cells. We have studied the expression of PIWI genes during human lung embryogenesis and in paired tumor and normal tissue prospectively collected from 71 resected non-small-cell lung cancer patients. The mRNA expression analysis showed that PIWIL1 was highly expressed in 7-week embryos and downregulated during the subsequent weeks of development. PIWIL1 was expressed in 11 of the tumor samples but in none of the normal tissue samples. These results were validated by immunohistochemistry, showing faint cytoplasmic reactivity in the PIWIL1-positive samples. Interestingly, the patients expressing PIWIL1 had a shorter time to relapse (TTR) (p = 0.006) and overall survival (OS) (p = 0.0076) than those without PIWIL1 expression. PIWIL2 and 4 were downregulated in tumor tissue in comparison to the normal tissue (p < 0.001) and the patients with lower levels of PIWIL4 had shorter TTR (p = 0.048) and OS (p = 0.033). In the multivariate analysis, PIWIL1 expression emerged as an independent prognostic marker. Using 5-Aza-dC treatment and bisulfite sequencing, we observed that PIWIL1 expression could be regulated in part by methylation. Finally, an in silico study identified a stem-cell expression signature associated with PIWIL1 expression. PMID:25742785

Stroke prevention in atrial fibrillation and 'real world' adherence to guidelines in the Balkan Region: The BALKAN-AF Survey.

PubMed

Potpara, Tatjana S; Dan, Gheorghe-Andrei; Trendafilova, Elina; Goda, Artan; Kusljugic, Zumreta; Manola, Sime; Music, Ljilja; Musetescu, Rodica; Badila, Elisabeta; Mitic, Gorana; Paparisto, Vilma; Dimitrova, Elena S; Polovina, Marija M; Petranov, Stanislav L; Djergo, Hortensia; Loncar, Daniela; Bijedic, Amira; Brusich, Sandro; Lip, Gregory Y H

2016-02-12

Data on the management of atrial fibrillation (AF) in the Balkan Region are limited. The Serbian AF Association (SAFA) prospectively investigated contemporary 'real-world' AF management in clinical practice in Albania, Bosnia&Herzegovina, Bulgaria, Croatia, Montenegro, Romania and Serbia through a 14-week (December 2014-February 2015) prospective, multicentre survey of consecutive AF patients. We report the results pertinent to stroke prevention strategies. Of 2712 enrolled patients, 2663 (98.2%) with complete data were included in this analysis (mean age 69.1 ± 10.9 years, female 44.6%). Overall, 1960 patients (73.6%) received oral anticoagulants (OAC) and 762 (28.6%) received antiplatelet drugs. Of patients given OAC, 17.2% received non-vitamin K antagonist oral anticoagulants (NOACs). CHA2DS2-VASc score was not significantly associated with OAC use. Of the 'truly low-risk' patients (CHA2DS2-VASc = 0 [males], or 1 [females]) 56.5% received OAC. Time in Therapeutic Range (TTR) was available in only 18.7% of patients (mean TTR: 49.5% ± 22.3%). Age ≥ 80 years, prior myocardial infarction and paroxysmal AF were independent predictors of OAC non-use. Our survey shows a relatively high overall use of OAC in AF patients, but with low quality of vitamin K antagonist therapy and insufficient adherence to AF guidelines. Additional efforts are needed to improve AF-related thromboprophylaxis in clinical practice in the Balkan Region.

Wind Tunnel Interference Effects on Tilt Rotor Testing Using Computational Fluid Dynamics

NASA Technical Reports Server (NTRS)

Koning, Witold J. F.

2016-01-01

Experimental techniques to measure rotorcraft aerodynamic performance are widely used. However, most of them are either unable to capture interference effects from bodies, or require an extremely large computational budget. The objective of the present research is to develop an XV-15 Tiltrotor Research Aircraft rotor model for investigation of wind tunnel wall interference using a novel Computational Fluid Dynamics (CFD) solver for rotorcraft, RotCFD. In RotCFD, a mid-fidelity Unsteady Reynolds Averaged Navier-Stokes (URANS) solver is used with an incompressible flow model and a realizable k-e turbulence model. The rotor is, however, not modeled using a computationally expensive, unsteady viscous body-fitted grid, but is instead modeled using a blade-element model (BEM) with a momentum source approach. Various flight modes of the XV-15 isolated rotor, including hover, tilt, and airplane mode, have been simulated and correlated to existing experimental and theoretical data. The rotor model is subsequently used for wind tunnel wall interference simulations in the National Full-Scale Aerodynamics Complex (NFAC) at Ames Research Center in California. The results from the validation of the isolated rotor performance showed good correlation with experimental and theoretical data. The results were on par with known theoretical analyses. In RotCFD the setup, grid generation, and running of cases is faster than many CFD codes, which makes it a useful engineering tool. Performance predictions need not be as accurate as high-fidelity CFD codes, as long as wall effects can be properly simulated. For both test sections of the NFAC wall, interference was examined by simulating the XV-15 rotor in the test section of the wind tunnel and with an identical grid but extended boundaries in free field. Both cases were also examined with an isolated rotor or with the rotor mounted on the modeled geometry of the Tiltrotor Test Rig (TTR). A "quasi linear trim" was used to trim the thrust for the rotor to compare the power as a unique variable. Power differences between free field and wind tunnel cases were found from -7 to 0 percent in the 80- by 120-Foot Wind Tunnel and -1.6 to 4.8 percent in the 40- by 80-Foot Wind Tunnel, depending on the TTR orientation, tunnel velocity, and blade setting. The TTR will be used in 2016 to test the Bell 609 rotor in a similar fashion to the research in this report.

Corrective Action Investigation Plan for Corrective Action Unit 410: Waste Disposal Trenches, Tonopah Test Range, Nevada, Revision 0 (includes ROTCs 1, 2, and 3)

DOE Office of Scientific and Technical Information (OSTI.GOV)

NNSA /NV

This Corrective Action Investigation Plan contains the U.S. Department of Energy, National Nuclear Security Administration Nevada Operations Office's approach to collect the data necessary to evaluate corrective action alternatives appropriate for the closure of Corrective Action Unit (CAU) 410 under the Federal Facility Agreement and Consent Order. Corrective Action Unit 410 is located on the Tonopah Test Range (TTR), which is included in the Nevada Test and Training Range (formerly the Nellis Air Force Range) approximately 140 miles northwest of Las Vegas, Nevada. This CAU is comprised of five Corrective Action Sites (CASs): TA-19-002-TAB2, Debris Mound; TA-21-003-TANL, Disposal Trench; TA-21-002-TAAL,more » Disposal Trench; 09-21-001-TA09, Disposal Trenches; 03-19-001, Waste Disposal Site. This CAU is being investigated because contaminants may be present in concentrations that could potentially pose a threat to human health and/or the environment, and waste may have been disposed of with out appropriate controls. Four out of five of these CASs are the result of weapons testing and disposal activities at the TTR, and they are grouped together for site closure based on the similarity of the sites (waste disposal sites and trenches). The fifth CAS, CAS 03-19-001, is a hydrocarbon spill related to activities in the area. This site is grouped with this CAU because of the location (TTR). Based on historical documentation and process know-ledge, vertical and lateral migration routes are possible for all CASs. Migration of contaminants may have occurred through transport by infiltration of precipitation through surface soil which serves as a driving force for downward migration of contaminants. Land-use scenarios limit future use of these CASs to industrial activities. The suspected contaminants of potential concern which have been identified are volatile organic compounds; semivolatile organic compounds; high explosives; radiological constituents including depleted uranium, beryllium, total petroleum hydrocarbons; and total Resource Conservation and Recovery Act metals. Field activities will consist of geophysical and radiological surveys, and collecting soil samples at biased locations by appropriate methods. A two-step data quality objective strategy will be followed: (1) define the nature of contamination at each CAS location by identifying any contamination above preliminary action levels (PALs); and, (2) determine the extent of contamination identified above PALs. The results of this field investigation will support a defensible evaluation of corrective action alternatives in the corrective action decision document.« less

Real-time PCR method combined with immunomagnetic separation for detecting healthy and heat-injured Salmonella Typhimurium on raw duck wings.

PubMed

Zheng, Qianwang; Mikš-Krajnik, Marta; Yang, Yishan; Xu, Wang; Yuk, Hyun-Gyun

2014-09-01

Conventional culture detection methods are time consuming and labor-intensive. For this reason, an alternative rapid method combining real-time PCR and immunomagnetic separation (IMS) was investigated in this study to detect both healthy and heat-injured Salmonella Typhimurium on raw duck wings. Firstly, the IMS method was optimized by determining the capture efficiency of Dynabeads(®) on Salmonella cells on raw duck wings with different bead incubation (10, 30 and 60 min) and magnetic separation (3, 10 and 30 min) times. Secondly, three Taqman primer sets, Sal, invA and ttr, were evaluated to optimize the real-time PCR protocol by comparing five parameters: inclusivity, exclusivity, PCR efficiency, detection probability and limit of detection (LOD). Thirdly, the optimized real-time PCR, in combination with IMS (PCR-IMS) assay, was compared with a standard ISO and a real-time PCR (PCR) method by analyzing artificially inoculated raw duck wings with healthy and heat-injured Salmonella cells at 10(1) and 10(0) CFU/25 g. Finally, the optimized PCR-IMS assay was validated for Salmonella detection in naturally contaminated raw duck wing samples. Under optimal IMS conditions (30 min bead incubation and 3 min magnetic separation times), approximately 85 and 64% of S. Typhimurium cells were captured by Dynabeads® from pure culture and inoculated raw duck wings, respectively. Although Sal and ttr primers exhibited 100% inclusivity and exclusivity for 16 Salmonella spp. and 36 non-Salmonella strains, the Sal primer showed lower LOD (10(3) CFU/ml) and higher PCR efficiency (94.1%) than the invA and ttr primers. Moreover, for Sal and invA primers, 100% detection probability on raw duck wings suspension was observed at 10(3) and 10(4) CFU/ml with and without IMS, respectively. Thus, the Sal primer was chosen for further experiments. The optimized PCR-IMS method was significantly (P=0.0011) better at detecting healthy Salmonella cells after 7-h enrichment than traditional PCR method. However there was no significant difference between the two methods with longer enrichment time (14 h). The diagnostic accuracy of PCR-IMS was shown to be 98.3% through the validation study. These results indicate that the optimized PCR-IMS method in this study could provide a sensitive, specific and rapid detection method for Salmonella on raw duck wings, enabling 10-h detection. However, a longer enrichment time could be needed for resuscitation and reliable detection of heat-injured cells. Copyright © 2014 Elsevier B.V. All rights reserved.

Wind Tunnel Interference Effects on Tilt Rotor Testing Using Computational Fluid Dynamics

NASA Technical Reports Server (NTRS)

Koning, Witold J. F.

2015-01-01

Experimental techniques to measure rotorcraft aerodynamic performance are widely used. However, most of them are either unable to capture interference effects from bodies, or require an extremely large computational budget. The objective of the present research is to develop an XV-15 Tilt Rotor Research Aircraft rotor model for investigation of wind tunnel wall interference using a novel Computational Fluid Dynamics (CFD) solver for rotorcraft, RotCFD. In RotCFD, a mid-fidelity URANS solver is used with an incompressible flow model and a realizable k-e turbulence model. The rotor is, however, not modeled using a computationally expensive, unsteady viscous body-fitted grid, but is instead modeled using a blade element model with a momentum source approach. Various flight modes of the XV-15 isolated rotor, including hover, tilt and airplane mode, have been simulated and correlated to existing experimental and theoretical data. The rotor model is subsequently used for wind tunnel wall interference simulations in the National Full-Scale Aerodynamics Complex (NFAC) at NASA Ames Research Center in California. The results from the validation of the isolated rotor performance showed good correlation with experimental and theoretical data. The results were on par with known theoretical analyses. In RotCFD the setup, grid generation and running of cases is faster than many CFD codes, which makes it a useful engineering tool. Performance predictions need not be as accurate as high-fidelity CFD codes, as long as wall effects can be properly simulated. For both test sections of the NFAC wall interference was examined by simulating the XV-15 rotor in the test section of the wind tunnel and with an identical grid but extended boundaries in free field. Both cases were also examined with an isolated rotor or with the rotor mounted on the modeled geometry of the Tiltrotor Test Rig (TTR). A 'quasi linear trim' was used to trim the thrust for the rotor to compare the power as a unique variable. Power differences between free field and wind tunnel cases were found from -7 % to 0 % in the 80- by 120-Foot Wind Tunnel test section and -1.6 % to 4.8 % in the 40- by 80-Foot Wind Tunnel, depending on the TTR orientation, tunnel velocity and blade setting. The TTR will be used in 2016 to test the Bell 609 rotor in a similar fashion to the research in this report.

Exponential Decay Nonlinear Regression Analysis of Patient Survival Curves: Preliminary Assessment in Non-Small Cell Lung Cancer

PubMed Central

Stewart, David J.; Behrens, Carmen; Roth, Jack; Wistuba, Ignacio I.

2010-01-01

Background For processes that follow first order kinetics, exponential decay nonlinear regression analysis (EDNRA) may delineate curve characteristics and suggest processes affecting curve shape. We conducted a preliminary feasibility assessment of EDNRA of patient survival curves. Methods EDNRA was performed on Kaplan-Meier overall survival (OS) and time-to-relapse (TTR) curves for 323 patients with resected NSCLC and on OS and progression-free survival (PFS) curves from selected publications. Results and Conclusions In our resected patients, TTR curves were triphasic with a “cured” fraction of 60.7% (half-life [t1/2] >100,000 months), a rapidly-relapsing group (7.4%, t1/2=5.9 months) and a slowly-relapsing group (31.9%, t1/2=23.6 months). OS was uniphasic (t1/2=74.3 months), suggesting an impact of co-morbidities; hence, tumor molecular characteristics would more likely predict TTR than OS. Of 172 published curves analyzed, 72 (42%) were uniphasic, 92 (53%) were biphasic, 8 (5%) were triphasic. With first-line chemotherapy in advanced NSCLC, 87.5% of curves from 2-3 drug regimens were uniphasic vs only 20% of those with best supportive care or 1 drug (p<0.001). 54% of curves from 2-3 drug regimens had convex rapid-decay phases vs 0% with fewer agents (p<0.001). Curve convexities suggest that discontinuing chemotherapy after 3-6 cycles “synchronizes” patient progression and death. With postoperative adjuvant chemotherapy, the PFS rapid-decay phase accounted for a smaller proportion of the population than in controls (p=0.02) with no significant difference in rapid-decay t1/2, suggesting adjuvant chemotherapy may move a subpopulation of patients with sensitive tumors from the relapsing group to the cured group, with minimal impact on time to relapse for a larger group of patients with resistant tumors. In untreated patients, the proportion of patients in the rapid-decay phase increased (p=0.04) while rapid-decay t1/2 decreased (p=0.0004) with increasing stage, suggesting that higher stage may be associated with tumor cells that both grow more rapidly and have a higher probability of surviving metastatic processes than in early stage tumors. This preliminary assessment of EDNRA suggests that it may be worth exploring this approach further using more sophisticated, statistically rigorous nonlinear modelling approaches. Using such approaches to supplement standard survival analyses could suggest or support specific testable hypotheses. PMID:20627364

Corrective Action Plan for Corrective Action Unit 428: Area 3 Septic Waste Systems 1 and 5 Tonopah Test Range, Nevada

DOE Office of Scientific and Technical Information (OSTI.GOV)

D. S. Tobiason

Area 3 Septic Waste Systems 1 and 5 are located in Area 3 of the Tonopah Test Range (TTR) (Figure 1). The site is listed in the Federal Facility Agreement and Consent Order (FFACO, 1996) as Corrective Action Unit (CAU) 428 and includes Corrective Action Sites 03-05-002-SW01 (Septic Waste System 1 [SWS 1]), and 03-05-002-SW05 (Septic Waste System 5 [SWS 5]). The site history for the CAU is provided in the Corrective Action Investigation Plan (U.S. Department of Energy, Nevada Operations Office [DOE/NV], 1999). SWS 1 consists of two leachfields and associated septic tanks. SWS 1 received effluent from bothmore » sanitary and industrial sources from various buildings in Area 3 of the TTR (Figure 2). SWS 5 is comprised of one leachfield and outfall with an associated septic tank. SWS 5 received effluent from sources in Building 03-50 in Area 3 of the TTR (Figure 2). Both systems were active until 1990 when a consolidated sewer system was installed. The purpose of this Corrective Action Plan (CAP) is to provide the strategy and methodology to close the Area 3 SWS 1 and 5. The CAU will be closed following state and federal regulations and the FFACO (1996). Site characterization was done during May and June 1999. Samples of the tank contents, leachfield soil, and soil under the tanks and pipes were collected. The results of the characterization were reported in the Corrective Action Decision Document (CADD) (DOE/NV, 2000). Additional sampling was done in May 2000, the results of which are presented in this plan. Soil sample results indicated that two constituents of concern were detected above Preliminary Action Levels (PALs). Total arsenic was detected at a concentration of 68.7 milligrams per kilogram (mg/kg). The arsenic was found under the center distribution line at the proximal end of the SWS 5 Leachfield (Figure 3). Total benzo(a)pyrene was detected at a concentration of 480 micrograms per kilogram ({micro}g/kg). The benzo(a)pyrene was found in the soil under the discharge line at SWS 1 Septic Tank 33-1A (Figure 3). These concentrations are above the PALs of 3.0 mg/kg and 360 {micro}g/kg, respectively (DOE/NV, 1999) but are below the hazardous regulatory levels for these constituents. The soil will be excavated and disposed in the Nevada Test Site (NTS) Area 23 Sanitary Landfill.« less

In-Space Crew-Collaborative Task Scheduling

NASA Technical Reports Server (NTRS)

Jaap, John; Meyer, Patrick; Davis, Elizabeth; Richardson, Lea

2007-01-01

For all past and current human space missions, the final scheduling of tasks to be done in space has been devoid of crew control, flexibility, and insight. Ground controllers, with minimal input from the crew, schedule the tasks and uplink the timeline to the crew or uplink the command sequences to the hardware. Prior to the International Space Station (ISS), the crew could make requests about tomorrow s timeline, they could omit a task, or they could request that something in the timeline be delayed. This lack of control over one's own schedule has had negative consequences. There is anecdotal consensus among astronauts that control over their own schedules will mitigate the stresses of long duration missions. On ISS, a modicum of crew control is provided by the job jar. Ground controllers prepare a task list (a.k.a. "job jar") of non-conflicting tasks from which jobs can be chosen by the in space crew. Because there is little free time and few interesting non-conflicting activities, the task-list approach provides little relief from the tedium of being micro-managed by the timeline. Scheduling for space missions is a complex and laborious undertaking which usually requires a large cadre of trained specialists and suites of complex software tools. It is a giant leap from today s ground prepared timeline (with a job jar) to full crew control of the timeline. However, technological advances, currently in-work or proposed, make it reasonable to consider scheduling a collaborative effort by the ground-based teams and the in-space crew. Collaboration would allow the crew to make minor adjustments, add tasks according to their preferences, understand the reasons for the placement of tasks on the timeline, and provide them a sense of control. In foreseeable but extraordinary situations, such as a quick response to anomalies and extended or unexpected loss of signal, the crew should have the autonomous ability to make appropriate modifications to the timeline, extend the timeline, or even start over with a new timeline. The Vision for Space Exploration (VSE), currently being pursued by the National Aeronautics and Space Administration (NASA), will send humans to Mars in a few decades. Stresses on the human mind will be exacerbated by the longer durations and greater distances, and it will be imperative to implement stress-reducing innovations such as giving the crew control of their daily activities.

How to staff for RACs.

PubMed

Brocato, Lori; Hirschl, Nancy; Padfield, Stanley

2010-01-01

To meet the challenges presented by recovery audit contractors (RACs), hospitals should perform six tasks that require appropriate investments in staff: conduct a financial risk assessment of the impact of RAC reviews on the organization; establish a RAC team and assign a coordinator; receive and fill RAC requests; track RAC activity; manage RAC appeals; analyze RAC audit outcomes.

Mining for Evidence in Enterprise Corpora

ERIC Educational Resources Information Center

Almquist, Brian Alan

2011-01-01

The primary research aim of this dissertation is to identify the strategies that best meet the information retrieval needs as expressed in the "e-discovery" scenario. This task calls for a high-recall system that, in response to a request for all available relevant documents to a legal complaint, effectively prioritizes documents from an…

77 FR 75173 - Comprehensive Assessment of the Process for the Review of Device Submissions; Request for Comments

Federal Register 2010, 2011, 2012, 2013, 2014

2012-12-19

... performing the technical analysis, management assessment, and program evaluation tasks required to address... premarket reviews that meet regulatory review standards. 2. Analysis of elements of the review process... process. This includes analysis of root causes for inefficiencies that may affect review performance and...

29 CFR 785.11 - General.

Code of Federal Regulations, 2011 CFR

2011-07-01

... Permittedâ to Work § 785.11 General. Work not requested but suffered or permitted is work time. For example, an employee may voluntarily continue to work at the end of the shift. He may be a pieceworker, he may desire to finish an assigned task or he may wish to correct errors, paste work tickets, prepare time...

Cognitive Flexibility in Drawings of Bilingual Children

ERIC Educational Resources Information Center

Adi-Japha, Esther; Berberich-Artzi, Jennie; Libnawi, Afaf

2010-01-01

A. Karmiloff-Smith's (1990) task of drawing a nonexistent object is considered to be a measure of cognitive flexibility. The notion of earlier emergence of cognitive flexibility in bilingual children motivated the current researchers to request 4- and 5-year-old English-Hebrew and Arabic-Hebrew bilingual children and their monolingual peers to…

School-Based Mutual Support Groups for Parents: An Intervention Guidebook.

ERIC Educational Resources Information Center

Simoni, Jane M.

This handbook focuses on steps and tasks related to establishing mutual support groups for parents in a school setting. A sequential approach is described that involves: working within the school to get started; recruiting members; training parents how to run their own meetings; and offering off-site consultation as requested. The first section…

Deaf Teenagers with Cochlear Implants in Conversation with Hearing Peers

ERIC Educational Resources Information Center

Ibertsson, Tina; Hansson, Kristina; Maki-Torkko, Elina; Willstedt-Svensson, Ursula; Sahlen, Birgitta

2009-01-01

Background: This study investigates the use of requests for clarification in conversations between teenagers with a cochlear implant (CI) and hearing peers. So far very few studies have focused on conversational abilities in children with CI. Aims: The aim was to explore co-construction of dialogue in a referential communication task and the…

A Quantitative Quality Control Model for Parallel and Distributed Crowdsourcing Tasks

ERIC Educational Resources Information Center

Zhu, Shaojian

2014-01-01

Crowdsourcing is an emerging research area that has experienced rapid growth in the past few years. Although crowdsourcing has demonstrated its potential in numerous domains, several key challenges continue to hinder its application. One of the major challenges is quality control. How can crowdsourcing requesters effectively control the quality…

Secretary | Center for Cancer Research

Cancer.gov

We are looking for a pleasant, organized, dependable person to serve as a full-time secretary in the Basic Science Program (BSP) at the Frederick National Laboratory for Cancer Research (FNCLR).  The BSP provides procurement and logistical support to the laboratories of the Center for Cancer Research.  Tasks include high volume procurement (blanket orders, purchase requests,

Notification of SAB Workgroup Public Meeting for the Toxicological Review of Inorganic Arsenic

EPA Pesticide Factsheets

Organic Arsenical Products Task Force (OAPTF), a group of registrants of pesticide products that contain monosodium methanearsonate (MSMA), to request that the Science Advisory Board (SAB) reschedule the public meeting of a workgroup to conduct a review of the draft document entitled Toxicological Review of Inorganic Arsenic

Job Language Performance Requirements for MOS 91B, Medical Specialist, Reference Soldier’s Manual Dated 30 August 1977.

DTIC Science & Technology

1977-08-30

Administer tube feeding (gavage) to a patient. 081-91B-1238 Administer a rectal suppository . 081-91B-1240 Administer an intramuscular injection. 081-91B...communications Coded messages Spellings Conversation Requests VI-3 * * * SPEAKING TASK: Formulate and produce appropriate oral responses spontaneously

75 FR 46904 - Request for Proposals: Fiscal Year 2010 Funding Opportunity for Research on the Economic Impact...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-04

... supporting documentation for completed tasks include, but are not limited to, questionnaire or interview... 2009 research. 6. The performance of subcontracting services, oversight, and financial controls for the... United States Government and the eligible recipient during the performance of the research in the...

RE: Notification of SAB Workgroup Public Meeting for the Toxicological Review of Inorganic Arsenic

EPA Pesticide Factsheets

Request from the Organic Arsenical Products Task Force for the Science Advisory Board to reschedule the public meeting of a workgroup to conduct a review of the draft document Toxicological Review of Inorganic Arsenic: In Support of the Summary Information on the Integrated Risk Information System (IRIS).

48 CFR 3452.239-70 - Internet protocol version 6 (IPv6).

Code of Federal Regulations, 2013 CFR

2013-10-01

... (IPv6). 3452.239-70 Section 3452.239-70 Federal Acquisition Regulations System DEPARTMENT OF EDUCATION... Clauses 3452.239-70 Internet protocol version 6 (IPv6). As prescribed in 3439.701, insert the following...) version 6 (IPv6) as set forth in Internet Engineering Task Force (IETF) Request for Comments (RFC) 2460...

Development of a shuttle recovery Commercial Materials Processing in Space (CMPS) program

NASA Technical Reports Server (NTRS)

1989-01-01

The work performed has covered the following tasks: update commercial users requirements; assess availability of carriers and facilities; shuttle availability assessment; development of optimum accommodations plan; and payload documentation requirements assessment. The results from the first four tasks are presented. To update commercial user requirements, contacts were made with the JEA and CCDS partners to obtain copies of their most recent official flight requests. From these requests the commercial partners' short and long range plans for flight dates, flight frequency, experiment hardware and carriers was determined. A 34 by 44 inch chart was completed to give a snapshot view of the progress of commercialization in space. Further, an assessment was made of the availability of carriers and facilities. Both existing carriers and those under development were identified for use by the commercial partners. A data base was compiled to show the capabilities of the carriers. A shuttle availability assessment was performed using the primary and secondary shuttle manifests released by NASA. Analysis of the manifest produced a flight-by-flight list of flight opportunities available to commercial users. Using inputs from the first three tasks, an Optimum Accommodations Plan was developed. The Accommodation Plan shows the commercial users manifested by flight, the experiment flown, the carrier used and complete list of commercial users that could not be manifested in each calendar year.

Nonpreemptive run-time scheduling issues on a multitasked, multiprogrammed multiprocessor with dependencies, bidimensional tasks, folding and dynamic graphs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miller, Allan Ray

1987-05-01

Increases in high speed hardware have mandated studies in software techniques to exploit the parallel capabilities. This thesis examines the effects a run-time scheduler has on a multiprocessor. The model consists of directed, acyclic graphs, generated from serial FORTRAN benchmark programs by the parallel compiler Parafrase. A multitasked, multiprogrammed environment is created. Dependencies are generated by the compiler. Tasks are bidimensional, i.e., they may specify both time and processor requests. Processor requests may be folded into execution time by the scheduler. The graphs may arrive at arbitrary time intervals. The general case is NP-hard, thus, a variety of heuristics aremore » examined by a simulator. Multiprogramming demonstrates a greater need for a run-time scheduler than does monoprogramming for a variety of reasons, e.g., greater stress on the processors, a larger number of independent control paths, more variety in the task parameters, etc. The dynamic critical path series of algorithms perform well. Dynamic critical volume did not add much. Unfortunately, dynamic critical path maximizes turnaround time as well as throughput. Two schedulers are presented which balance throughput and turnaround time. The first requires classification of jobs by type; the second requires selection of a ratio value which is dependent upon system parameters. 45 refs., 19 figs., 20 tabs.« less

Town of Sandwich, MA | 2012 Annual Report |  NPDES Phase II Small MS4 General Permit

EPA Pesticide Factsheets

2012-07-12

... rJñ lrtt¿ 2. r¡tlllr oufi ¡l ÞlnxEf nl auFil¡ tîf. t. ül rltit t ¡r ? rto 0{ l¡lö¡Lt ¡r¡l! ß tþ sm^r ttr¡ìt0 t¡üa t t^Yû.tLl atlv tlol.t ,¡aÞ ¡rBñO l{Ol toff¡ ¡¡O ¡tr tüû!. ...

Integrated Development of Serum Molecular Markers for Early Diagnosis of Breast Cancer

DTIC Science & Technology

2006-09-01

Fas, FasL, Cyfra 21-1, TPA/TPS, IGFBP1, S100, angiostatin, SSC, ULBP1,2,3, βHCG, MICA , HE4, SMRP, mesothelin, SAA, and TTR. The procedure we used for... MICA , S-100, DR5, mesothelin, and myeloperoxidase (MPO), ULBP-1,2, S100, angiostatin. Our results have demonstrated that the expression of CA 125, EGF...4066. (8) Adam, B. L.; Qu , Y.; Davis, J. W.; Ward, M. D.; Clements, M. A.; Cazares, L. H.; Semmes, O. J.; Schellhammer, P. F.; Yasui, Y.; Feng, Z

The effective use of virtualization for selection of data centers in a cloud computing environment

NASA Astrophysics Data System (ADS)

Kumar, B. Santhosh; Parthiban, Latha

2018-04-01

Data centers are the places which consist of network of remote servers to store, access and process the data. Cloud computing is a technology where users worldwide will submit the tasks and the service providers will direct the requests to the data centers which are responsible for execution of tasks. The servers in the data centers need to employ the virtualization concept so that multiple tasks can be executed simultaneously. In this paper we proposed an algorithm for data center selection based on energy of virtual machines created in server. The virtualization energy in each of the server is calculated and total energy of the data center is obtained by the summation of individual server energy. The tasks submitted are routed to the data center with least energy consumption which will result in minimizing the operational expenses of a service provider.

An Overview of the NIRA Status

NASA Technical Reports Server (NTRS)

Hughes, William

2003-01-01

The NASA Glenn Research Center (GRC) has been tasked by NASA JSC's ISS Payloads Office to perform the NIRA (Non-Isolated Rack Assessment) microgravity prediction analysis task for the International Space Station. Previously, the NIRA analysis task had been performed by Boeing/Houston. Boeing's last NIRA analysis was released in 1999 and was denoted as "NIRA 99." GRC is currently close to completing our first full-NIRA analysis (encompassing the frequency range from 0 to 50 Hz) to be released as "NIRA 2003." This presentation will focus on describing the NIRA analysis, the transition of this analysis task from Boeing to GRC, and the current status and schedule for release of the NIRA 2003 results. Additionally, the results obtained from a mini-NIRA analysis requested by ESA and completed by GRC in the Spring of 2003 will be shown. This mini-analysis focused solely on predicting the microgravity environment at the COF-EPF (Columbus Orbiting Facility - External Payload Facility).

Asleep at the automated wheel-Sleepiness and fatigue during highly automated driving.

PubMed

Vogelpohl, Tobias; Kühn, Matthias; Hummel, Thomas; Vollrath, Mark

2018-03-20

Due to the lack of active involvement in the driving situation and due to monotonous driving environments drivers with automation may be prone to become fatigued faster than manual drivers (e.g. Schömig et al., 2015). However, little is known about the progression of fatigue during automated driving and its effects on the ability to take back manual control after a take-over request. In this driving simulator study with Nö=ö60 drivers we used a three factorial 2ö×ö2ö×ö12 mixed design to analyze the progression (12ö×ö5ömin; within subjects) of driver fatigue in drivers with automation compared to manual drivers (between subjects). Driver fatigue was induced as either mainly sleep related or mainly task related fatigue (between subjects). Additionally, we investigated the drivers' reactions to a take-over request in a critical driving scenario to gain insights into the ability of fatigued drivers to regain manual control and situation awareness after automated driving. Drivers in the automated driving condition exhibited facial indicators of fatigue after 15 to 35ömin of driving. Manual drivers only showed similar indicators of fatigue if they suffered from a lack of sleep and then only after a longer period of driving (approx. 40ömin). Several drivers in the automated condition closed their eyes for extended periods of time. In the driving with automation condition mean automation deactivation times after a take-over request were slower for a certain percentage (about 30%) of the drivers with a lack of sleep (Mö=ö3.2; SDö=ö2.1ös) compared to the reaction times after a long drive (Mö=ö2.4; SDö=ö0.9ös). Drivers with automation also took longer than manual drivers to first glance at the speed display after a take-over request and were more likely to stay behind a braking lead vehicle instead of overtaking it. Drivers are unable to stay alert during extended periods of automated driving without non-driving related tasks. Fatigued drivers could pose a serious hazard in complex take-over situations where situation awareness is required to prepare for threats. Driver fatigue monitoring or controllable distraction through non-driving tasks could be necessary to ensure alertness and availability during highly automated driving. Copyright © 2018 Elsevier Ltd. All rights reserved.

Comparing spatially static and dynamic vibrotactile take-over requests in the driver seat.

PubMed

Petermeijer, S M; Cieler, S; de Winter, J C F

2017-02-01

Vibrotactile stimuli can be effective as warning signals, but their effectiveness as directional take-over requests in automated driving is yet unknown. This study aimed to investigate the correct response rate, reaction times, and eye and head orientation for static versus dynamic directional take-over requests presented via vibrating motors in the driver seat. In a driving simulator, eighteen participants performed three sessions: 1) a session involving no driving (Baseline), 2) driving a highly automated car without additional task (HAD), and 3) driving a highly automated car while performing a mentally demanding task (N-Back). Per session, participants received four directional static (in the left or right part of the seat) and four dynamic (moving from one side towards the opposite left or right of the seat) take-over requests via two 6×4 motor matrices embedded in the seat back and bottom. In the Baseline condition, participants reported whether the cue was left or right, and in the HAD and N-Back conditions participants had to change lanes to the left or to the right according to the directional cue. The correct response rate was operationalized as the accuracy of the self-reported direction (Baseline session) and the accuracy of the lane change direction (HAD & N-Back sessions). The results showed that the correct response rate ranged between 94% for static patterns in the Baseline session and 74% for dynamic patterns in the N-Back session, although these effects were not statistically significant. Steering wheel touch and steering input reaction times were approximately 200ms faster for static patterns than for dynamic ones. Eye tracking results revealed a correspondence between head/eye-gaze direction and lane change direction, and showed that head and eye-gaze movements where initiated faster for static vibrations than for dynamic ones. In conclusion, vibrotactile stimuli presented via the driver seat are effective as warnings, but their effectiveness as directional take-over requests may be limited. The present study may encourage further investigation into how to get drivers safely back into the loop. Copyright © 2016 Elsevier Ltd. All rights reserved.