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

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

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

Closure Letter Report for Corrective Action Unit 496: Buried Rocket Site - Antelope Lake

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

NSTec Environmental Restoration

A Streamlined Approach for Environmental Restoration (SAFER) Plan for investigation and closure of CAU 496, Corrective Action Site (CAS) TA-55-008-TAAL (Buried Rocket), at the Tonopah Test Range (TTR), was approved by the Nevada Department of Environmental Protection (NDEP) on July 21,2004. Approval to transfer CAS TA-55-008-TAAL from CAU 496 to CAU 4000 (No Further Action Sites) was approved by NDEP on December 21, 2005, based on the assumption that the rocket did not present any environmental concern. The approval letter included the following condition: ''NDEP understands, from the NNSA/NSO letter dated November 30,2005, that a search will be conducted formore » the rocket during the planned characterization of other sites at the Tonopah Test Range and, if found, the rocket will be removed as a housekeeping measure''. NDEP and U.S. Department of Energy, National Nuclear Security Administration Nevada Site Office personnel located the rocket on Mid Lake during a site visit to TTR, and a request to transfer CAS TA-55-008-TAAL from CAU 4000 back to CAU 496 was approved by NDEP on September 11,2006. CAS TA-55-008-TAAL was added to the ''Federal Facility Agreement and Consent Order'' of 1996, based on an interview with a retired TTR worker in 1993. The original interview documented that a rocket was launched from Area 9 to Antelope Lake and was never recovered due to the high frequency of rocket tests being conducted during this timeframe. The interviewee recalled the rocket being an M-55 or N-55 (the M-50 ''Honest John'' rocket was used extensively at TTR from the 1960s to early 1980s). A review of previously conducted interviews with former TTR personnel indicated that the interviewees confused information from several sites. The location of the CAU 496 rocket on Mid Lake is directly south of the TTR rocket launch facility in Area 9 and is consistent with information gathered on the lost rocket during recent interviews. Most pertinently, an interview in 2005 with a former TTR range manager recalled a lost rocket that possibly contained a depleted uranium ballast in an inert warhead. The interviewee confirmed that the last tracking coordinate for the rocket indicated it was lost in an area south of Area 9 near the l T R range coordinates X = 6,614.57 feet (ft) and Y = -20,508.79 ft. These coordinates correspond to a location approximately 2,295 ft northeast of the Mid Target, on Mid Lake. CAS TA-55-008-TAAL was removed from CAU 496 before the SAFER investigation could be completed, and before the new information could be evaluated and the conceptual site model assumptions confirmed.« less

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.

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.

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

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.

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

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.

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

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.

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%.

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.

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.

[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.

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

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

Selective binding to transthyretin and tetramer stabilization in serum from patients with familial amyloidotic polyneuropathy by an iodinated diflunisal derivative

PubMed Central

2004-01-01

In familial amyloidotic polyneuropathy, TTR (transthyretin) variants are deposited as amyloid fibrils. It is thought that this process involves TTR tetramer dissociation, which leads to partially unfolded monomers that aggregate and polymerize into amyloid fibrils. This process can be counteracted by stabilization of the tetramer. Several small compounds, such as diclofenac, diflunisal and flufenamic acid, have been reported to bind to TTR in vitro, in the T4 (thyroxine) binding channel that runs through the TTR tetramer, and consequently are considered to stabilize TTR. However, if these agents bind plasma proteins other than TTR, decreased drug availability will occur, compromising their use as therapeutic agents for TTR amyloidosis. In the present work, we compared the action of these compounds and of new derivatives designed to increase both selectivity of binding to TTR and inhibitory potency in relation to TTR amyloid fibril formation. We found two diflunisal derivatives that, in contrast with diclofenac, flufenamic acid and diflunisal, displaced T4 from TTR in plasma preferentially over binding to albumin and thyroxine binding globulin. The same diflunisal derivatives also had a stabilizing effect on TTR tetramers in plasma, as studied by isoelectric focusing of whole plasma under semi-denaturing conditions. In addition, by transmission electron microscopy, we demonstrated that, in contrast with other proposed TTR stabilizers (namely diclofenac, flufenamic acid and diflunisal), one of the diflunisal derivatives tested efficiently inhibited TTR aggregation. Taken together, our ex vivo and in vitro studies present evidence for the selectivity and efficiency of novel diflunisal derivates as TTR stabilizers and as inhibitors of fibril formation. PMID:15080795

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

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.

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.

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.

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.

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.

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.

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

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

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

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.

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

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.

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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

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.

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.

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.

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.

Physiological IgM Class Catalytic Antibodies Selective for Transthyretin Amyloid*

PubMed Central

Planque, Stephanie A.; Nishiyama, Yasuhiro; Hara, Mariko; Sonoda, Sari; Murphy, Sarah K.; Watanabe, Kenji; Mitsuda, Yukie; Brown, Eric L.; Massey, Richard J.; Primmer, Stanley R.; O'Nuallain, Brian; Paul, Sudhir

2014-01-01

Peptide bond-hydrolyzing catalytic antibodies (catabodies) could degrade toxic proteins, but acquired immunity principles have not provided evidence for beneficial catabodies. Transthyretin (TTR) forms misfolded β-sheet aggregates responsible for age-associated amyloidosis. We describe nucleophilic catabodies from healthy humans without amyloidosis that degraded misfolded TTR (misTTR) without reactivity to the physiological tetrameric TTR (phyTTR). IgM class B cell receptors specifically recognized the electrophilic analog of misTTR but not phyTTR. IgM but not IgG class antibodies hydrolyzed the particulate and soluble misTTR species. No misTTR-IgM binding was detected. The IgMs accounted for essentially all of the misTTR hydrolytic activity of unfractionated human serum. The IgMs did not degrade non-amyloidogenic, non-superantigenic proteins. Individual monoclonal IgMs (mIgMs) expressed variable misTTR hydrolytic rates and differing oligoreactivity directed to amyloid β peptide and microbial superantigen proteins. A subset of the mIgMs was monoreactive for misTTR. Excess misTTR was dissolved by a hydrolytic mIgM. The studies reveal a novel antibody property, the innate ability of IgMs to selectively degrade and dissolve toxic misTTR species as a first line immune function. PMID:24648510

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.

Results from the interim salt disposition program macrobatch 10 tank 21H qualification samples

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

Peters, T. B.; Bannochie, C. J.

2017-02-23

Savannah River National Laboratory (SRNL) analyzed samples from Tank 21H in support of qualification of Macrobatch (Salt Batch) 10 for the Interim Salt Disposition Program (ISDP). This document reports characterization data on the samples of Tank 21H and fulfills the requirements of Deliverable 3 of the Technical Task Request (TTR). Further work will report the results of the Extraction-Scrub-Strip (ESS) testing (Task 5 of the TTR) using the Tank 21H material. Task 4 of the TTR (MST Strike) will not be completed for Salt Batch 10.

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.

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.

Global Positioning System Time Transfer Receiver (GPS/TTR) prototype design and initial test evaluation

NASA Technical Reports Server (NTRS)

Oaks, J.; Frank, A.; Falvey, S.; Lister, M.; Buisson, J.; Wardrip, C.; Warren, H.

1982-01-01

Time transfer equipment and techniques used with the Navigation Technology Satellites were modified and extended for use with the Global Positioning System (GPS) satellites. A prototype receiver was built and field tested. The receiver uses the GPS L1 link at 1575 MHz with C/A code only to resolve a measured range to the satellite. A theoretical range is computed from the satellite ephemeris transmitted in the data message and the user's coordinates. Results of user offset from GPS time are obtained by differencing the measured and theoretical ranges and applying calibration corrections. Results of the first field test evaluation of the receiver are presented.

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

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.

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.

Repositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicity

PubMed Central

Sant'Anna, Ricardo; Gallego, Pablo; Robinson, Lei Z.; Pereira-Henriques, Alda; Ferreira, Nelson; Pinheiro, Francisca; Esperante, Sebastian; Pallares, Irantzu; Huertas, Oscar; Rosário Almeida, Maria; Reixach, Natàlia; Insa, Raul; Velazquez-Campoy, Adrian; Reverter, David; Reig, Núria; Ventura, Salvador

2016-01-01

Transthyretin (TTR) is a plasma homotetrameric protein implicated in fatal systemic amyloidoses. TTR tetramer dissociation precedes pathological TTR aggregation. Native state stabilizers are promising drugs to treat TTR amyloidoses. Here we repurpose tolcapone, an FDA-approved molecule for Parkinson's disease, as a potent TTR aggregation inhibitor. Tolcapone binds specifically to TTR in human plasma, stabilizes the native tetramer in vivo in mice and humans and inhibits TTR cytotoxicity. Crystal structures of tolcapone bound to wild-type TTR and to the V122I cardiomyopathy-associated variant show that it docks better into the TTR T4 pocket than tafamidis, so far the only drug on the market to treat TTR amyloidoses. These data indicate that tolcapone, already in clinical trials for familial amyloid polyneuropathy, is a strong candidate for therapeutic intervention in these diseases, including those affecting the central nervous system, for which no small-molecule therapy exists. PMID:26902880

Quantification of the Thermodynamically Linked Quaternary and Tertiary Structural Stabilities of Transthyretin and its Disease-Associated Variants–the Relationship between Stability and Amyloidosis†

PubMed Central

Hurshman Babbes, Amy R.; Powers, Evan T.; Kelly, Jeffery W.

2009-01-01

Urea denaturation studies were carried out as a function of transthyretin (TTR) concentration to quantify the thermodynamically linked quaternary and tertiary structural stability and to better understand the relationship between mutant folding energetics and amyloid disease phenotype. Urea denaturation of TTR involves at least two equilibria—dissociation of tetramers into folded monomers, and monomer unfolding. To deal with the thermodynamic linkage of these equilibria, we analyzed concentration-dependent denaturation data by global fitting to an equation that simultaneously accounts for the two-step denaturation process. Using this method, the quaternary and tertiary structural stabilities of well-behaved TTR sequences, wild type (WT) TTR and the disease-associated variant V122I, were scrutinized. The V122I variant is linked to late onset familial amyloid cardiomyopathy, the most common familial TTR amyloid disease. V122I TTR exhibits a destabilized quaternary structure and a stable tertiary structure relative to WT TTR. Three other variants of TTR were also examined, L55P, V30M, and A25T TTR. The L55P mutation is associated with the most aggressive familial TTR amyloid disease. L55P TTR has a complicated denaturation pathway that includes dimers and trimers, and so globally fitting its concentration-dependent urea denaturation data yielded error-laden estimates of stability parameters. Nevertheless, it is clear that L55P TTR is substantially less stable than WT TTR, primarily because its tertiary structure is unstable, although its quaternary structure is destabilized as well. V30M is the most common mutation associated with neuropathic forms of TTR amyloid disease. V30M TTR is certainly destabilized relative to WT TTR, but like L55P TTR it has a complex denaturation pathway that cannot be fit to the aforementioned two-step denaturation model. Literature data suggest that V30M TTR has stable quaternary structure but unstable tertiary structure. The A25T mutant, associated with central nervous system amyloidosis, is highly aggregation-prone and exhibits drastically reduced quaternary and tertiary structural stability. The observed differences in stability amongst the disease-associated TTR variants highlight the complexity and the heterogeneity of TTR amyloid disease, an observation having important implications for the treatment of these diseases. PMID:18537267

[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.

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.

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.

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.

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.

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

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.

Non-coding variants contribute to the clinical heterogeneity of TTR amyloidosis.

PubMed

Iorio, Andrea; De Lillo, Antonella; De Angelis, Flavio; Di Girolamo, Marco; Luigetti, Marco; Sabatelli, Mario; Pradotto, Luca; Mauro, Alessandro; Mazzeo, Anna; Stancanelli, Claudia; Perfetto, Federico; Frusconi, Sabrina; My, Filomena; Manfellotto, Dario; Fuciarelli, Maria; Polimanti, Renato

2017-09-01

Coding mutations in TTR gene cause a rare hereditary form of systemic amyloidosis, which has a complex genotype-phenotype correlation. We investigated the role of non-coding variants in regulating TTR gene expression and consequently amyloidosis symptoms. We evaluated the genotype-phenotype correlation considering the clinical information of 129 Italian patients with TTR amyloidosis. Then, we conducted a re-sequencing of TTR gene to investigate how non-coding variants affect TTR expression and, consequently, phenotypic presentation in carriers of amyloidogenic mutations. Polygenic scores for genetically determined TTR expression were constructed using data from our re-sequencing analysis and the GTEx (Genotype-Tissue Expression) project. We confirmed a strong phenotypic heterogeneity across coding mutations causing TTR amyloidosis. Considering the effects of non-coding variants on TTR expression, we identified three patient clusters with specific expression patterns associated with certain phenotypic presentations, including late onset, autonomic neurological involvement, and gastrointestinal symptoms. This study provides novel data regarding the role of non-coding variation and the gene expression profiles in patients affected by TTR amyloidosis, also putting forth an approach that could be used to investigate the mechanisms at the basis of the genotype-phenotype correlation of the disease.

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.

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

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.

Quantification of Transthyretin Kinetic Stability in Human Plasma Using Subunit Exchange

PubMed Central

2015-01-01

The transthyretin (TTR) amyloidoses are a group of degenerative diseases caused by TTR aggregation, requiring rate-limiting tetramer dissociation. Kinetic stabilization of TTR, by preferential binding of a drug to the native tetramer over the dissociative transition state, dramatically slows the progression of familial amyloid polyneuropathy. An established method for quantifying the kinetic stability of recombinant TTR tetramers in buffer is subunit exchange, in which tagged TTR homotetramers are added to untagged homotetramers at equal concentrations to measure the rate at which the subunits exchange. Herein, we report a subunit exchange method for quantifying the kinetic stability of endogenous TTR in human plasma. The subunit exchange reaction is initiated by the addition of a substoichiometric quantity of FLAG-tagged TTR homotetramers to endogenous TTR in plasma. Aliquots of the subunit exchange reaction, taken as a function of time, are then added to an excess of a fluorogenic small molecule, which immediately arrests further subunit exchange. After binding, the small molecule reacts with the TTR tetramers, rendering them fluorescent and detectable in human plasma after subsequent ion exchange chromatography. The ability to report on the extent of TTR kinetic stabilization resulting from treatment with oral tafamidis is important, especially for selection of the appropriate dose for patients carrying rare mutations. This method could also serve as a surrogate biomarker for the prediction of the clinical outcome. Subunit exchange was used to quantify the stabilization of WT TTR from senile systemic amyloidosis patients currently being treated with tafamidis (20 mg orally, once daily). TTR kinetic stability correlated with the tafamidis plasma concentration. PMID:24661308

Inhibition of TTR Aggregation-Induced Cell Death – A New Role for Serum Amyloid P Component

PubMed Central

Dacklin, Ingrid; Lundgren, Erik

2013-01-01

Background Serum amyloid P component (SAP) is a glycoprotein that is universally found associated with different types of amyloid deposits. It has been suggested that it stabilizes amyloid fibrils and therefore protects them from proteolytic degradation. Methodology/Principal Findings In this paper, we show that SAP binds not only to mature amyloid fibrils but also to early aggregates of amyloidogenic mutants of the plasma protein transthyretin (TTR). It does not inhibit fibril formation of TTR mutants, which spontaneously form amyloid in vitro at physiological pH. We found that SAP prevents cell death induced by mutant TTR, while several other molecules that are also known to decorate amyloid fibrils do not have such effect. Using a Drosophila model for TTR-associated amyloidosis, we found a new role for SAP as a protective factor in inhibition of TTR-induced toxicity. Overexpression of mutated TTR leads to a neurological phenotype with changes in wing posture. SAP-transgenic flies were crossed with mutated TTR-expressing flies and the results clearly confirmed a protective effect of SAP on TTR-induced phenotype, with an almost complete reduction in abnormal wing posture. Furthermore, we found in vivo that binding of SAP to mutated TTR counteracts the otherwise detrimental effects of aggregation of amyloidogenic TTR on retinal structure. Conclusions/Significance Together, these two approaches firmly establish the protective effect of SAP on TTR-induced cell death and degenerative phenotypes, and suggest a novel role for SAP through which the toxicity of early amyloidogenic aggregates is attenuated. PMID:23390551

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.

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.

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

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.

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.

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.

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.

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.

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

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.

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

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.

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.

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

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

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.

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.

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

Corrrective action decision document for the Cactus Spring Waste Trenches (Corrective Action Unit No. 426). Revision No. 1

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

NONE

The Corrective Action Decision Document (CADD) for the Cactus Spring Waste Trenches (Corrective Action Unit [CAU] No. 426) has been prepared for the US Department of Energy`s (DOE) Nevada Environmental Restoration Project. This CADD has been developed to meet the requirements of the Federal Facility Agreement and Consent Order (FFACO) of 1996, stated in Appendix VI, {open_quotes}Corrective Action Strategy{close_quotes} (FFACO, 1996). The Cactus Spring Waste Trenches Corrective Action Site (CAS) No. RG-08-001-RG-CS is included in CAU No. 426 (also referred to as the {open_quotes}trenches{close_quotes}); it has been identified as one of three potential locations for buried, radioactively contaminated materials frommore » the Double Tracks Test. The trenches are located on the east flank of the Cactus Range in the eastern portion of the Cactus Spring Ranch at the Tonopah Test Range (TTR) in Nye County, Nevada, on the northern portion of Nellis Air Force Range. The TTR is approximately 225 kilometers (km) (140 miles [mi]) northwest of Las Vegas, Nevada, by air and approximately 56 km (35 mi) southeast of Tonopah, Nevada, by road. The trenches were dug for the purpose of receiving waste generated during Operation Roller Coaster, primarily the Double Tracks Test. This test, conducted in 1963, involved the use of live animals to assess the biological hazards associated with non-nuclear detonation of plutonium-bearing devices (i.e., inhalation uptake of plutonium aerosol). The CAS consists of four trenches that received solid waste and had an overall impacted area of approximately 36 meters (m) (120 feet [ft]) long x 24 m (80 ft) wide x 3 to 4.5 m (10 to 15 ft) deep. The average depressions at the trenches are approximately 0.3 m (1 ft) below land surface.« less

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 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

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.

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.

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

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.

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.

Plant Mounds as Concentration and Stabilization Agents for Actinide Soil Contaminants in Nevada

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

D.S. Shafer; J. Gommes

Plant mounds or blow-sand mounds are accumulations of soil particles and plant debris around the base of shrubs and are common features in deserts in the southwestern United States. An important factor in their formation is that shrubs create surface roughness that causes wind-suspended particles to be deposited and resist further suspension. Shrub mounds occur in some plant communities on the Nevada Test Site, the Nevada Test and Training Range (NTTR), and Tonopah Test Range (TTR), including areas of surface soil contamination from past nuclear testing. In the 1970s as part of early studies to understand properties of actinides inmore » the environment, the Nevada Applied Ecology Group (NAEG) examined the accumulation of isotopes of Pu, 241Am, and U in plant mounds at safety experiment and storage-transportation test sites of nuclear devices. Although aerial concentrations of these contaminants were highest in the intershrub or desert pavement areas, the concentration in mounds were higher than in equal volumes of intershrub or desert pavement soil. The NAEG studies found the ratio of contaminant concentration of actinides in soil to be greater (1.6 to 2.0) in shrub mounds than in the surrounding areas of desert pavement. At Project 57 on the NTTR, 17 percent of the area was covered in mounds while at Clean Slate III on the TTR, 32 percent of the area was covered in mounds. If equivalent volumes of contaminated soil were compared between mounds and desert pavement areas at these sites, then the former might contain as much as 34 and 62 percent of the contaminant inventory, respectively. Not accounting for radionuclides associated with shrub mounds would cause the inventory of contaminants and potential exposure to be underestimated. In addition, preservation of shrub mounds could be important part of long-term stewardship if these sites are closed by fencing and posting with administrative controls.« less

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

Supervised Patient Self-Testing of Warfarin Therapy Using an Online System

PubMed Central

2013-01-01

Background Point-of-care international normalized ratio (INR) monitoring devices simplify warfarin management by allowing selected patients to monitor their own therapy in their homes. Patient self-testing (PST) has been shown to improve the clinical outcomes of warfarin therapy compared to usual care. Objective To compare management of warfarin therapy using PST combined with online supervision by physicians via a custom system with usual warfarin management, which involved laboratory testing and physician dosing. Methods Interested patients were recruited via community pharmacies to participate in a warfarin PST training program. Participants were required to have a long-term indication for warfarin, have been taking warfarin for at least 6 months, and have Internet access in their home. The training involved two sessions covering theoretical aspects of warfarin therapy, use of the CoaguChek XS, and the study website. Following training, patients monitored their INR once weekly for up to 3 months. Patients and physicians utilized a secure website to communicate INR values, dosage recommendations, and clinical incidents. Physicians provided a 6-12 month history of INR results for comparison with study results. The percentage of time spent within the therapeutic INR range (TTR) was the primary outcome, with participants acting as their own historical controls. The percentage of INR tests in range and participant satisfaction were secondary outcomes. Results Sixteen patients completed training requirements. The mean age of participants was 69.8 (SD 10.1) years. TTR improved significantly from 66.4% to 78.4% during PST (P=.01), and the number of tests within the target range also improved significantly (from 66.0% at prior to the study to 75.9% during PST; P=.04). Patients and physicians expressed a high degree of satisfaction with the monitoring strategy and online system. Conclusions PST supported by an online system for supervision was associated with improved INR control compared to usual care in a small group of elderly patients. Further research is warranted to investigate the clinical outcomes and cost-effectiveness of online systems to support patients monitoring medications and chronic conditions in the home. PMID:23853350

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

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

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

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

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.

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.

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.

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.

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

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.

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

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.

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.

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.

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

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.

[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.

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.

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.

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.

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

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.

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.

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...

Corrective Action Decision Document 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)

U.S. Department of Energy, Nevada Operations Office

2000-02-08

This Corrective Action Decision Document identifies and rationalizes the US Department of Energy, Nevada Operations Office's selection of a recommended corrective action alternative (CAA) appropriate to facilitate the closure of Corrective Action Unit (CAU) 428, Septic Waste Systems 1 and 5, under the Federal Facility Agreement and Consent Order. Located in Area 3 at the Tonopah Test Range (TTR) in Nevada, CAU 428 is comprised of two Corrective Action Sites (CASs): (1) CAS 03-05-002-SW01, Septic Waste System 1 and (2) CAS 03-05-002- SW05, Septic Waste System 5. A corrective action investigation performed in 1999 detected analyte concentrations that exceeded preliminarymore » action levels; specifically, contaminants of concern (COCs) included benzo(a) pyrene in a septic tank integrity sample associated with Septic Tank 33-1A of Septic Waste System 1, and arsenic in a soil sample associated with Septic Waste System 5. During this investigation, three Corrective Action Objectives (CAOs) were identified to prevent or mitigate exposure to contents of the septic tanks and distribution box, to subsurface soil containing COCs, and the spread of COCs beyond the CAU. Based on these CAOs, a review of existing data, future use, and current operations in Area 3 of the TTR, three CAAs were developed for consideration: Alternative 1 - No Further Action; Alternative 2 - Closure in Place with Administrative Controls; and Alternative 3 - Clean Closure by Excavation and Disposal. These alternatives were evaluated based on four general corrective action standards and five remedy selection decision factors. Based on the results of the evaluation, the preferred CAA was Alternative 3. This alternative meets all applicable state and federal regulations for closure of the site and will eliminate potential future exposure pathways to the contaminated soils at the Area 3 Septic Waste Systems 1 and 5.« less

Corrective Action Decision Document/Closure Report for Corrective Action 405: Area 3 Septic Systems, Tonopah Test Range, Nevada Rev. No.: 0, April 2002

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

IT Coroporation, Las Vegas, NV

2002-04-17

This Corrective Action Decision Document/Closure Report (CADD/CR) has been prepared for Corrective Action Unit (CAU) 405, Area 3 Septic Systems, in accordance with the Federal Facility Agreement and Consent Order. Located on the Tonopah Test Range (TTR) approximately 235 miles north of Las Vegas, Nevada, CAU 405 consists of three Corrective Action Sites (CASs): 03-05-002-SW03, Septic Waste System (aka: Septic Waste System [SWS] 3); 03-05-002-SW04, Septic Waste System (aka: SWS 4); 03-05-002-SW07, Septic Waste System (aka: SWS 7). The CADD and CR have been combined into one report because no further action is recommended for this CAU, and this reportmore » provides specific information necessary to support this recommendation. The CAU consists of three leachfields and associated collection systems that were installed in or near Area 3 for wastewater disposal. These systems were used until a consolidated sewer system was installed in 1990. Historically, operations within various buildin gs in and near Area 3 of the TTR generated sanitary and industrial wastewaters. There is a potential that contaminants of concern (COCs) were present in the wastewaters and were disposed of in septic tanks and leachfields. The justification for closure of this CAU without further action is based on process knowledge and the results of the investigative activities. Closure activities were performed at these CASs between January 14 and February 2, 2002, and included the removal and proper disposal of media containing regulated constituents and proper closure of septic tanks. No further action is appropriate because all necessary activities have been completed. No use restrictions are required to be imposed for these sites since the investigation showed no evidence of COCs identified in the soil for CAU 405.« less

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.

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.

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.

TANK 18-F AND 19-F TANK FILL GROUT SCALE UP TEST SUMMARY

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

Stefanko, D.; Langton, C.

2012-01-03

High-level waste (HLW) tanks 18-F and 19-F have been isolated from FTF facilities. To complete operational closure the tanks will be filled with grout for the purpose of: (1) physically stabilizing the tanks, (2) limiting/eliminating vertical pathways to residual waste, (3) entombing waste removal equipment, (4) discouraging future intrusion, and (5) providing an alkaline, chemical reducing environment within the closure boundary to control speciation and solubility of select radionuclides. This report documents the results of a four cubic yard bulk fill scale up test on the grout formulation recommended for filling Tanks 18-F and 19-F. Details of the scale upmore » test are provided in a Test Plan. The work was authorized under a Technical Task Request (TTR), HLE-TTR-2011-008, and was performed according to Task Technical and Quality Assurance Plan (TTQAP), SRNL-RP-2011-00587. The bulk fill scale up test described in this report was intended to demonstrate proportioning, mixing, and transportation, of material produced in a full scale ready mix concrete batch plant. In addition, the material produced for the scale up test was characterized with respect to fresh properties, thermal properties, and compressive strength as a function of curing time.« less

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.

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.

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.

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.

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.

Corrective action investigation plan: Cactus Spring Waste Trenches. Revision 2

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

NONE

This Correction Action Investigation Plan (CAIP) contains environmental sample collection objectives and logic for the CAU No. 426, which includes the Cactus Spring Waste Trenches, CAS No. RG-08-001-RG-CS. The Cactus Spring Waste Trenches are located at the Tonopah Test Range (TTR) which is part of the Nellis Air Force Range, approximately 255 kilometers (km) (140 miles [mi]) northwest of Las Vegas, Nevada, by air. The purpose of this investigation is to generate sufficient data to establish the types of waste buried in the trenches, identify the presence and nature of contamination, determine the vertical extent of contaminant migration below themore » Cactus Spring Waste Trenches, and determine the appropriate course of action for the site. The potential courses of action for the site are clean closure, closure in place (with or without remediation), or no further action.« less

Evaluation of warfarin management with international normalized ratio self-testing and online remote monitoring and management plus low-dose vitamin k with genomic considerations: a pilot study.

PubMed

Bussey, Henry I; Bussey, Marie; Bussey-Smith, Kristin L; Frei, Christopher R

2013-11-01

As better international normalized ratio (INR) control and self-testing reduce events in warfarin-treated patients, and vitamin K supplementation may improve INR control, our primary objective was to evaluate the effect of a system combining frequent INR self-testing with online remote monitoring and management (STORM₂) and low-dose vitamin K supplementation on INR control; our secondary objectives were to assess the impact of STORM₂ on clinician time and to evaluate the influence of pharmacogenomics on INR stability and warfarin dose after vitamin K supplementation. Prospective pre- and postintervention study. Freestanding clinical research center. Fifty-five patients treated with long-term warfarin therapy who were referred from four anticoagulation clinics and seven medical practices. All patients performed weekly INR self-testing and received vitamin K 100 µg/day and online anticoagulation management for 1 year. INR control and time required for anticoagulation management were assessed, and an analysis of warfarin dosing and INR stability by genetic polymorphism subgroup (vitamin K epoxide reductase complex 1 [VKORC1] and cytochrome P450 2C9 isoenzyme) was performed; vitamin K product content was also analyzed. The percentage of time that the INR is within the time in therapeutic range (TTR) improved from 56% before the intervention to 81% after the intervention (p<0.0001), and time spent at extreme INR values of lower than 1.5 or higher than 5 was reduced from 3.1% to 0.4% (p=0.01). Clinician time was less than 10 minutes per four patient visits per month. Genetic polymorphisms did not correlate with INR stability or the increase in warfarin dose after vitamin K supplementation. The content of the vitamin K product, however, was only 34-76% of the labeled amount. Patients with the GG VKORC1 genotype required a higher warfarin dose than predicted by the genomic-based dosing chart in the warfarin package insert. The 25% point improvement in TTR with STORM₂ is a greater improvement than reported previously with other efforts to improve TTR. STORM₂ required a minimum amount of clinician time. Pharmacogenomics were not predictive of improved INR control or the magnitude of the warfarin dose after vitamin K supplementation, although the content of the product was unreliable. Patients with the GG VKORC1 genotype required a higher warfarin dose than predicted by the product information. The potential clinical impact of improved INR control with this method warrants comparisons with conventionally managed warfarin and with the new oral anticoagulants. © 2013 Pharmacotherapy Publications, Inc.

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

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.

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

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

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.

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.

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

[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.

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

Williams, M. S.; Miller, D. H.; Fowley, M. D.

The Savannah River National Laboratory (SRNL) was tasked to support validation of the Defense Waste Processing Facility (DWPF) melter offgas flammability model for the nitric-glycolic (NG) flowsheet. The work supports Deliverable 4 of the DWPF & Saltstone Facility Engineering Technical Task Request (TTR)1 and is supplemental to the Cold Cap Evaluation Furnace (CEF) testing conducted in 2014.2 The Slurry-fed Melt Rate Furnace (SMRF) was selected for the supplemental testing as it requires significantly less resources than the CEF and could provide a tool for more rapid analysis of melter feeds in the future. The SMRF platform has been used previouslymore » to evaluate melt rate behavior of DWPF glasses, but was modified to accommodate analysis of the offgas stream. Additionally, the Melt Rate Furnace (MRF) and Quartz Melt Rate Furnace (QMRF) were utilized for evaluations. MRF data was used exclusively for melt behavior observations and REDuction/OXidation (REDOX) prediction comparisons and will be briefly discussed in conjunction with its support of the SMRF testing. The QMRF was operated similarly to the SMRF for the same TTR task, but will be discussed in a separate future report. The overall objectives of the SMRF testing were to; 1) Evaluate the efficacy of the SMRF as a platform for steady state melter testing with continuous feeding and offgas analysis; and 2) Generate supplemental melter offgas flammability data to support the melter offgas flammability modelling effort for DWPF implementation of the NG flowsheet.« 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.

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.

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

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.

Corrective Action Decision Document/Corrective Action Plan for Corrective Action Unit 413: Clean Slate II Plutonium Dispersion (TTR) Tonopah Test Range, Nevada. Revision 0

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

Matthews, Patrick

This Corrective Action Decision Document/Corrective Action Plan provides the rationale and supporting information for the selection and implementation of corrective actions at Corrective Action Unit (CAU) 413, Clean Slate II Plutonium Dispersion (TTR). CAU 413 is located on the Tonopah Test Range and includes one corrective action site, TA-23-02CS. CAU 413 consists of the release of radionuclides to the surface and shallow subsurface from the Clean Slate II (CSII) storage–transportation test conducted on May 31, 1963. The CSII test was a non-nuclear detonation of a nuclear device located inside a concrete bunker covered with 2 feet of soil. To facilitatemore » site investigation and the evaluation of data quality objectives decisions, the releases at CAU 413 were divided into seven study groups: 1 Undisturbed Areas 2 Disturbed Areas 3 Sedimentation Areas 4 Former Staging Area 5 Buried Debris 6 Potential Source Material 7 Soil Mounds Corrective action investigation (CAI) activities, as set forth in the CAU 413 Corrective Action Investigation Plan, were performed from June 2015 through May 2016. Radionuclides detected in samples collected during the CAI were used to estimate total effective dose using the Construction Worker exposure scenario. Corrective action was required for areas where total effective dose exceeded, or was assumed to exceed, the radiological final action level (FAL) of 25 millirem per year. The results of the CAI and the assumptions made in the data quality objectives resulted in the following conclusions: The FAL is exceeded in surface soil in SG1, Undisturbed Areas; The FAL is assumed to be exceeded in SG5, Buried Debris, where contaminated debris and soil were buried after the CSII test; The FAL is not exceeded at SG2, SG3, SG4, SG6, or SG7. Because the FAL is exceeded at CAU 413, corrective action is required and corrective action alternatives (CAAs) must be evaluated. For CAU 413, three CAAs were evaluated: no further action, clean closure, and closure in place. The CAAs were evaluated on technical merit focusing on performance, reliability, feasibility, safety, and cost. Based on the evaluation of analytical data from the CAI, review of future and current operations at CAU 413, and the detailed and comparative analysis of CAAs, clean closure was selected as the preferred CAA for CAU 413 by the U.S. Air Force, Nevada Division of Environmental Protection, and U.S. Department of Energy at the CAA meeting held on August 24, 2016.« less

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

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.

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.

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.

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

1990 Environmental monitoring report, Tonopah Test Range, Tonopah, Nevada

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

Hwang, A.; Phelan, J.; Wolff, T.

1991-05-01

There is no routine radioactive emission from Sandia National Laboratories, Tonopah Test Range (SNL, TTR). However, based on the types of test activities such as air drops, gun firings, ground- launched rockets, air-launched rockets, and other explosive tests, possibilities exist that small amounts of depleted uranium (DU) (as part of weapon components) may be released to the air or to the ground because of unusual circumstances (failures) during testing. Four major monitoring programs were used in 1990 to assess radiological impact on the public. The EPA Air Surveillance Network (ASN) found that the only gamma ({gamma}) emitting radionuclide on themore » prefilters was beryllium-7 ({sup 7}Be), a naturally-occurring spallation product formed by the interaction of cosmic radiation with atmospheric oxygen and nitrogen. The weighted average results were consistent with the area background concentrations. The EPA Thermoluminescent Dosimetry (TLD) Network and Pressurized Ion Chamber (PIC) reported normal results. In the EPA Long-Term Hydrological Monitoring Program (LTHMP), analytical results for tritium ({sup 3}H) in well water were reported and were well below DOE-derived concentration guides (DCGs). In the Reynolds Electrical and Engineering Company (REECo) Drinking Water Sampling Program, analytical results for {sup 3}H, gross alpha ({alpha}), beta ({beta}), and {gamma} scan, strontium-90 ({sup 90}Sr) and plutonium-239 ({sup 239}Pu) were within the EPA's primary drinking water standards. 29 refs., 5 figs., 15 tabs.« less

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

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.

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.

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.

Acute exposure to synthetic pyrethroids causes bioconcentration and disruption of the hypothalamus-pituitary-thyroid axis in zebrafish embryos.

PubMed

Tu, Wenqing; Xu, Chao; Lu, Bin; Lin, Chunmian; Wu, Yongming; Liu, Weiping

2016-01-15

Synthetic pyrethroids (SPs) have the potential to disrupt the thyroid endocrine system in mammals; however, little is known of the effects of SPs and underlying mechanisms in fish. In the current study, embryonic zebrafish were exposed to various concentrations (1, 3 and 10 μg/L) of bifenthrin (BF) or λ-cyhalothrin (λ-CH) until 72 h post fertilization, and body condition, bioaccumulation, thyroid hormone levels and transcription of related genes along the hypothalamus-pituitary-thyroid (HPT) axis examined. Body weight was significantly decreased in the λ-CH exposure groups, but not the BF exposure groups. BF and λ-CH markedly accumulated in the larvae, with concentrations ranging from 90.7 to 596.8 ng/g. In both exposure groups, alterations were observed in thyroxine (T4) and triiodothyronine (T3) levels. In addition, the majority of the HPT axis-related genes examined, including CRH, TSHβ, TTR, UGT1ab, Pax8, Dio2 and TRα, were significantly upregulated in the presence of BF. Compared to BF, λ-CH induced different transcriptional regulation patterns of the tested genes, in particular, significant stimulation of TTR, Pax8, Dio2 and TRα levels along with concomitant downregulation of Dio1. Molecular docking analyses revealed that at the atomic level, BF binds to thyroid hormone receptor (TRα) protein more potently than λ-CH, consequently affecting HPT axis signal transduction. In vitro and in silico experiments disclosed that during the early stages of zebrafish development, BF and λ-CH have the potential to disrupt thyroid endocrine system. Copyright © 2015 Elsevier B.V. All rights reserved.

Cold-induced vasodilation comparison between Bangladeshi and Japanese natives.

PubMed

Khatun, Aklima; Ashikaga, Sakura; Nagano, Hisaho; Hasib, Md Abdul; Taimura, Akihiro

2016-05-03

The human thermoregulation system responds to changes in environmental temperature, so humans can self-adapt to a wide range of climates. People from tropical and temperate areas have different cold tolerance. This study compared the tolerance of Bangladeshi (tropical) and Japanese (temperate) people to local cold exposure on cold-induced vasodilation (CIVD). Eight Bangladeshi males (now residing in Japan) and 14 Japanese males (residing in Japan) participated in this study. All are sedentary, regular university students. The Bangladeshi subject's duration of stay in Japan was 2.50 ± 2.52 years. The subject's left hand middle finger was immersed in 5 °C water for 20 min to assess their CIVD response (the experiment was conducted in an artificial climate chamber controlled at 25 °C with 50% RH). Compared with the Bangladeshi (BD) group, the Japanese (JP) group displayed some differences. There were significant differences between the BD and JP groups in temperature before immersion (TBI), which were 33.04 ± 1.98 and 34.62 ± 0.94 °C, and time of temperature rise (TTR), which were 5.35 ± 0.82 and 3.72 ± 0.68 min, respectively. There was also a significant difference in the time of sensation rise (TSR) of 8.69 ± 6.49 and 3.26 ± 0.97 min between the BD and JP groups, respectively (P < 0.05). Moreover, the JP group showed a quick TTR after finishing immersion. The Japanese group (temperate) has a higher tolerance to local cold exposure than the Bangladeshi group (tropical) evaluated by the CIVD test.

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.

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.

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

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

Corrective Action Investigation Plan for Corrective Action Unit 414: Clean Slate III Plutonium Dispersion (TTR) Tonopah Test Range, Nevada, Revision 1

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

Matthews, Patrick

Corrective Action Unit (CAU) 414 is located on the Tonopah Test Range, which is approximately 130 miles northwest of Las Vegas, Nevada, and approximately 40 miles southeast of Tonopah, Nevada. The CAU 414 site consists of the release of radionuclides to the surface and shallow subsurface from the conduct of the Clean Slate III (CSIII) storage–transportation test conducted on June 9, 1963. CAU 414 includes one corrective action site (CAS), TA-23-03CS (Pu Contaminated Soil). The known releases at CAU 414 are the result of the atmospheric dispersal of contamination from the 1963 CSIII test. The CSIII test was a nonnuclearmore » detonation of a nuclear device located inside a reinforced concrete bunker covered with 8 feet of soil. This test dispersed radionuclides, primarily uranium and plutonium, on the ground surface. The presence and nature of contamination at CAU 414 will be evaluated based on information collected from a corrective action investigation (CAI). The investigation is based on the data quality objectives (DQOs) developed on June 7, 2016, by representatives of the Nevada Division of Environmental Protection; the U.S. Air Force; and the U.S. Department of Energy (DOE), National Nuclear Security Administration Nevada Field Office. The DQO process was used to identify and define the type, amount, and quality of data needed to develop and evaluate appropriate corrective action alternatives for CAU 414.« less

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

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.

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.

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

Corrective Action Investigation Plan for Corrective Action Unit 405: Area 3 Septic Systems, Tonopah Test Range, Nevada(April 2001, Rev. 0) with Record of Technical Change No. 1

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

DOE /NV

2001-04-26

This Corrective Action Investigation Plan contains the U.S. Department of Energy, Nevada Operations Office's (DOE/NV's) approach to collect the data necessary to evaluate corrective action alternatives appropriate for the closure of Corrective Action Unit (CAU) 405, Area 3 Septic Systems, Tonopah Test Range (TTR), under the Federal Facility Agreement and Consent Order. Corrective Action Unit 405 consists of Corrective Action Sites 03-05-002-SW03, 03-05-002-SW04, and 03-05-002-SW07 (also collectively known as: Septic Waste Systems [SWSs] 3, 4, and 7). Located in Area 3 in the northwest section of the TTR, approximately 140 miles northwest of Las Vegas, this location was historically (betweenmore » 1960 and 1990) used as a research facility with the mission to perform defense-related projects, and whose operations generated sanitary and industrial wastewaters potentially contaminated with COPCs and disposed of in septic tanks and leachfields. Though Septic Waste Systems 3, 4, and 7 were origin ally constructed to receive sanitary sewage, they may have inadvertently received effluent containing potentially hazardous and radiological constituents containing acetone, benzene, ethylbenzene, 4-methyl-2-pentanone, toluene, xylenes, volatile organic compound constituents, phenols, arsenic, barium, lead, mercury, hydrocarbons of oil and grease, and uranium-234, -235, and -238. The Area 3 septic systems were documented in a DOE/NV 1996 report as being included in the septic tank abandonment program conducted by Sandia National Laboratories in 1993; however, this program was not completed and the possibility exists that some of the Area 3 septic tanks may not have been abandoned. Even though all of the SWSs addressed in this CAIP are inactive, geophysical surveys conducted in 1993 were generally inconclusive and did not provide useful data for the purposes of this investigation. The scope of this current investigation, therefore, will be to determine the existence of the identified CO PCs and excavation will be the primary investigation method employed for these leachfield systems, but this effort may be limited by existing facilities and utilities. The results of this field investigation will support a defensible evaluation of corrective action alternatives in the subsequent corrective action decision document.« less

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.

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.

Handbook for Strategic Air Command (SAC) Management Engineering Officers (MEOs)

DTIC Science & Technology

1985-04-01

JACK D. MARTIN, USAF FACULTY ADVISOR« MAJOR ROBERT M. WEIS, ACSC/ EDX SPONSOR« COLONEL DENNIS D. GRAVES, HQ SAC/XPM Submitted to the...8217^^^!^^^’T^^T^^TTT^"?,^w, Fr ’,^’TTrT^TTrTT,Tr,T^’ in AFR 25-5, then close the book and perform the task satisfac- tcsrily? The key to...Command and Staff College, Air University (ATC), Maxwell AFB, Alabama, 1981. 130 o.V ^^^^^^ WWW ^^^^T^^^^^^^I^^^^^^^^^^^^^W»^»>T»>il)’»M’j MJM ■iii.ii

Statistical analysis of $sup 239-240$Pu and $sup 241$Am contamination of soil and vegetation on NAEG study sites

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

Gilbert, R.O.; Eberhardt, L.L.; Fowler, E.B.

Reported here are results of the statistical design and analysis work conducted during Calendar Year 1974 for the Nevada Applied Ecology Group (NAEG) at plutonium study sites on the Nevada Test Site (NTS) and the Tonopah Test Range (TTR). Estimates of $sup 239-240$Pu inventory in surface soil (0 to 5-cm depth) are given for each of the NAEG intensive study sites, together with activity maps based on FIDLER surveys showing the field areas to which these estimates apply. There is evidence of a preliminary nature to suggest that the plutonium present in surface soil may be covered by a thinmore » (less than 2.5 cm) layer of soil whose alpha activity is considerably less than that directly below. Computer-drawn $sup 239-240$Pu concentration contours and three-dimensional surfaces in soil and vegetation are given for Area 13 and GMX as a first attempt at estimating the geographical distribution of $sup 239-240$Pu at these sites. (CH)« less

[Update on the control of patients on treatment with vitaminK antagonist oral anticoagulants in Primary Care].

PubMed

Fernández López, P; López Ramiro, M I; Merino de Haro, I; Cedeño Manzano, G; Díaz Siles, F J; Hermoso Sabio, A

In Spain, more than 80% of patients with atrial fibrillation (AF) receive oral anticoagulant therapy (OAT), and 72% of these patients are followed up in the Primary Care (PC) setting. Recent studies have shown that there is insufficient control of patients on OAT. The objective of the present study was to obtain more detailed information on the state of control of patients on treatment with vitaminK antagonist (VKA) oral anticoagulants (OAC), on the diseases for which the therapy was indicated and on concomitant diseases. This was a retrospective, cross-sectional, observational study with the participation of patients from a single health area included in an OAT programme throughout 2014. In patients on treatment with OAC, International Normalised Ratio (INR) control was considered insufficient when the percentage time in therapeutic range (TTR) was below 65% during an evaluation period of at least 6months. A total of 368 patients were included in the study, where the most frequent indication for oral anticoagulation was non-valvular AF. A total of 5,128 INR controls were performed, of which 2,359 (46%) were outside the therapeutic range, and 2,769 (54%) were within range. The risk of thromboembolism was very high in 91% of patients on treatment with VKA OAC. The indication for anticoagulation is correct in our population, assuming a low-intermediate risk of haemorrhage in the majority of patients. Measurement of the TTR using the Rosendaal method shows that the control of patients on treatment with VKA OAC is insufficient. Copyright © 2016 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España, S.L.U. All rights reserved.

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.

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

Concentration of Actinides in Plant Mounds at Safety Test Nuclear Sites in Nevada

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

David S. Shafer; Jenna Gommes

Plant mounds or blow-sand mounds are accumulations of soil particles and plant debris around large shrubs and are common features in deserts in the southwestern United States. Believed to be an important factor in their formation, the shrubs create surface roughness that causes wind-suspended particles to be deposited and resist further suspension. Shrub mounds occur in some plant communities on the Nevada Test Site, the Nevada Test and Training Range (NTTR), and Tonopah Test Range (TTR), including areas of surface soil contamination from past nuclear testing. In the 1970s as part of early studies to understand properties of actinides inmore » the environment, the Nevada Applied Ecology Group (NAEG) examined the accumulation of isotopes of Pu, {sup 241}Am, and U in plant mounds at safety test sites. The NAEG studies found concentrations of these contaminants to be greater in shrub mounds than in the surrounding areas of desert pavement. For example, at Project 57 on the NTTR, it was estimated that 15 percent of the radionuclide inventory of the site was associated with shrub mounds, which accounted for 17 percent of the surface area of the site, a ratio of inventory to area of 0.85. At Clean Slate III at the TTR, 29 percent of the inventory was associated with approximately 32 percent of the site covered by shrub mounds, a ratio of 0.91. While the total inventory of radionuclides in intershrub areas was greater, the ratio of radionuclide inventory to area was 0.40 and 0.38, respectively, at the two sites. The comparison between the shrub mounds and adjacent desert pavement areas was made for only the top 5 cm since radionuclides at safety test sites are concentrated in the top 5 cm of intershrub areas. Not accounting for radionuclides associated with the shrub mounds would cause the inventory of contaminants and potential exposure to be underestimated. As part of its Environmental Restoration Soils Subproject, the U.S. Department of Energy (DOE), National Nuclear Security Administration Nevada Site Office has proposed that the majority of its contaminated soil 'Corrective Action Units', including the safety test sites, be closed by fencing and posting with administrative controls. The concentration of actinides in the shrub mounds has important implications for postclosure management of the safety test sites. Because resuspension factors at safety test sites can be three to four orders-of-magnitude higher than soil sites associated with atmospheric tests where criticality occurred, the shrub mounds are an important factor in stabilization of actinide contaminants. Loss of shrubs associated with mounds from fire or plant die-back from drought could cause radionuclides at these sites to become more prone to suspension and water erosion until the sites are stabilized. Alternatively, although shrub mounds are usually composed of predominantly fine sand size particles, smaller silt and clay size particles in them are often high in CaCO{sub 3} content. The CaCO{sub 3} may act as a cementing agent to limit erosion of the shrub mounds even if the vegetation cover is temporarily lost.« less

Post-Closure Strategy for Use-Restricted Sites on the Nevada National Security Site, Nevada Test and Training Range, and Tonopah Test Range, Nevada

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

Silvas, A. J.

The purpose of this Post-Closure Strategy is to provide a consistent methodology for continual evaluation of post-closure requirements for use-restricted areas on the Nevada National Security Site (NNSS), Nevada Test and Training Range (NTTR), and Tonopah Test Range (TTR) to consolidate, modify, or streamline the program. In addition, this document stipulates the creation of a single consolidated Post-Closure Plan that will detail the current post-closure requirements for all active use restrictions (URs) and outlines its implementation and subsequent revision. This strategy will ensure effective management and control of the post-closure sites. There are currently over 200 URs located on themore » NNSS, NTTR, and TTR. Post-closure requirements were initially established in the Closure Report for each site. In some cases, changes to the post-closure requirements have been implemented through addenda, errata sheets, records of technical change, or letters. Post-closure requirements have been collected from these multiple sources and consolidated into several formats, such as summaries and databases. This structure increases the possibility of inconsistencies and uncertainty. As more URs are established and the post-closure program is expanded, the need for a comprehensive approach for managing the program will increase. Not only should the current requirements be obtainable from a single source that supersedes all previous requirements, but the strategy for modifying the requirements should be standardized. This will enable more effective management of the program into the future. This strategy document and the subsequent comprehensive plan are to be implemented under the assumption that the NNSS and outlying sites will be under the purview of the U.S. Department of Energy, National Nuclear Security Administration for the foreseeable future. This strategy was also developed assuming that regulatory control of the sites remains static. The comprehensive plan is not intended to be a permanent long-term stewardship plan. However, it is intended to clarify requirements and identify components to effectively manage the sites until regulatory requirements are met or management of the site changes. The Environmental Management Program is required to manage these sites until the NNSS Environmental Restoration program is completed, currently planned for 2030. Prior to completion of the Environmental Restoration program, additional planning will be conducted to ensure that long-term stewardship of the sites is maintained. A comprehensive post-closure plan can be transitioned effectively into any future site-wide long-term stewardship program that may be developed. Therefore, the post-closure plan will include current aspects of the post-closure program that are also important aspects of long-term stewardship, including the following: • Management of physical and engineering controls such as fences, signs, and soil covers • Management of institutional and administrative controls such as use restrictions and real estate systems • Management of monitoring and maintenance programs • Management of information related to the sites such as geographic information system data and related documentation The strategy will also allow for periodic review and modification of any aspect of the program to ensure continued effectiveness.« less

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

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.

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.

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.

Corrective Action Investigation Plan for Corrective Action Unit 413: Clean Slate II Plutonium Dispersion (TTR) Tonopah Test Range, Nevada, Revision 1

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

Matthews, Patrick; Burmeister, Mark; Gallo, Patricia

Corrective Action Unit (CAU) 413 is located on the Tonopah Test Range, which is approximately 130 miles northwest of Las Vegas, Nevada, and approximately 40 miles southeast of Tonopah, Nevada. The CAU 413 site consists of the release of radionuclides to the surface and shallow subsurface from the conduct of the Clean Slate II (CSII) storage–transportation test conducted on May 31, 1963. CAU 413 includes one corrective action site (CAS), TA-23-02CS (Pu Contaminated Soil). The known releases at CAU 413 are the result of the atmospheric deposition of contamination from the 1963 CSII test. The CSII test was a non-nuclearmore » detonation of a nuclear device located inside a reinforced concrete bunker covered with 2 feet of soil. This test dispersed radionuclides, primarily plutonium, on the ground surface. The presence and nature of contamination at CAU 413 will be evaluated based on information collected from a corrective action investigation (CAI). The investigation is based on the data quality objectives (DQOs) developed on June 17, 2015, by representatives of the Nevada Division of Environmental Protection; the U.S. Air Force; and the U.S. Department of Energy (DOE), National Nuclear Security Administration Nevada Field Office. The DQO process was used to identify and define the type, amount, and quality of data needed to develop and evaluate appropriate corrective actions for CAU 413. The CAI will include radiological surveys, geophysical surveys, collection and analyses of soil samples, and assessment of investigation results. The collection of soil samples will be accomplished using both probabilistic and judgmental sampling approaches. To facilitate site investigation and the evaluation of DQO decisions, the releases at CAU 413 have been divided into seven study groups.« less

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.

ISOLOK VALVE ACCEPTANCE TESTING FOR DWPF SME SAMPLING PROCESS

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

Edwards, T.; Hera, K.; Coleman, C.

2011-12-05

Evaluation of the Defense Waste Processing Facility (DWPF) Chemical Process Cell (CPC) cycle time identified several opportunities to improve the CPC processing time. Of the opportunities, a focus area related to optimizing the equipment and efficiency of the sample turnaround time for DWPF Analytical Laboratory was identified. The Mechanical Systems & Custom Equipment Development (MS&CED) Section of the Savannah River National Laboratory (SRNL) evaluated the possibility of using an Isolok{reg_sign} sampling valve as an alternative to the Hydragard{reg_sign} valve for taking process samples. Previous viability testing was conducted with favorable results using the Isolok sampler and reported in SRNL-STI-2010-00749 (1).more » This task has the potential to improve operability, reduce maintenance time and decrease CPC cycle time. This report summarizes the results from acceptance testing which was requested in Task Technical Request (TTR) HLW-DWPF-TTR-2010-0036 (2) and which was conducted as outlined in Task Technical and Quality Assurance Plan (TTQAP) SRNL-RP-2011-00145 (3). The Isolok to be tested is the same model which was tested, qualified, and installed in the Sludge Receipt Adjustment Tank (SRAT) sample system. RW-0333P QA requirements apply to this task. This task was to qualify the Isolok sampler for use in the DWPF Slurry Mix Evaporator (SME) sampling process. The Hydragard, which is the current baseline sampling method, was used for comparison to the Isolok sampling data. The Isolok sampler is an air powered grab sampler used to 'pull' a sample volume from a process line. The operation of the sampler is shown in Figure 1. The image on the left shows the Isolok's spool extended into the process line and the image on the right shows the sampler retracted and then dispensing the liquid into the sampling container. To determine tank homogeneity, a Coliwasa sampler was used to grab samples at a high and low location within the mixing tank. Data from the two locations were compared to determine if the contents of the tank were well mixed. The Coliwasa sampler is a tube with a stopper at the bottom and is designed to obtain grab samples from specific locations within the drum contents. A position paper (4) was issued to address the prototypic flow loop issues and simulant selections. A statistically designed plan (5) was issued to address the total number of samples each sampler needed to pull, to provide the random order in which samples were pulled and to group samples for elemental analysis. The TTR required that the Isolok sampler perform as well as the Hydragard sampler during these tests to ensure the acceptability of the Isolok sampler for use in the DWPF sampling cells. Procedure No.L9.4-5015 was used to document the sample parameters and process steps. Completed procedures are located in R&D Engineering job folder 23269.« less

Thermal tolerance in the Andean toad Rhinella spinulosa (Anura: Bufonidae) at three sites located along a latitudinal gradient in Chile.

PubMed

Riquelme, Nicza Alveal; Díaz-Páez, Helen; Ortiz, Juan Carlos

2016-08-01

Rhinella spinulosa is one of the anuran species with the greatest presence in Chile. This species mainly inhabits mountain habitats and is distributed latitudinally along the western slope of the Andes Range. These habitats undergo great temperature fluctuations, exerting pressure on the amphibian. To identify the physiological strategies and thermal behavior of this species, we analyzed the temperature variables CTmin, CTmax, TTR, τheat, and τcool in individuals of three sites from a latitudinal gradient (22°S to 37°S). The amphibians were acclimated to 10°C and 20°C and fed ad libitum. The results indicate that the species has a high thermal tolerance range, with a mean of 38.14±1.34°C, a critical thermal maxima of 34.6-41.4°C, and a critical thermal minima of 2.6-0.8°C, classifying the species as eurythermic. Furthermore, there were significant differences in CTmáx and TTR only in the northern site. The differences in thermal time constants between sites are due to the effects of size and body mass. For example, those from the central site had larger size and greater thermal inertia; therefore, they warmed and cooled in a slower manner. The wide thermal limits determined in R. spinulosa confirm that it is a thermo-generalist species, a characteristic that allows the species to survive in adverse microclimatic conditions. The level of plasticity in critical temperatures seems ecologically relevant and supports the acclimatization of thermal limits as an important factor for ectothermic animals to adapt to climate change. Copyright © 2016 Elsevier Ltd. All rights reserved.

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.

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

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

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.

EVALUATION OF ARG-1 SAMPLES PREPARED BY CESIUM CARBONATE DISSOLUTION DURING THE ISOLOK SME ACCEPTABILITY TESTING

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

Edwards, T.; Hera, K.; Coleman, C.

2011-12-05

Evaluation of Defense Waste Processing Facility (DWPF) Chemical Process Cell (CPC) cycle time identified several opportunities to improve the CPC processing time. The Mechanical Systems & Custom Equipment Development (MS&CED) Section of the Savannah River National Laboratory (SRNL) recently completed the evaluation of one of these opportunities - the possibility of using an Isolok sampling valve as an alternative to the Hydragard valve for taking DWPF process samples at the Slurry Mix Evaporator (SME). The use of an Isolok for SME sampling has the potential to improve operability, reduce maintenance time, and decrease CPC cycle time. The SME acceptability testingmore » for the Isolok was requested in Task Technical Request (TTR) HLW-DWPF-TTR-2010-0036 and was conducted as outlined in Task Technical and Quality Assurance Plan (TTQAP) SRNLRP-2011-00145. RW-0333P QA requirements applied to the task, and the results from the investigation were documented in SRNL-STI-2011-00693. Measurement of the chemical composition of study samples was a critical component of the SME acceptability testing of the Isolok. A sampling and analytical plan supported the investigation with the analytical plan directing that the study samples be prepared by a cesium carbonate (Cs{sub 2}CO{sub 3}) fusion dissolution method and analyzed by Inductively Coupled Plasma - Optical Emission Spectroscopy (ICP-OES). The use of the cesium carbonate preparation method for the Isolok testing provided an opportunity for an additional assessment of this dissolution method, which is being investigated as a potential replacement for the two methods (i.e., sodium peroxide fusion and mixed acid dissolution) that have been used at the DWPF for the analysis of SME samples. Earlier testing of the Cs{sub 2}CO{sub 3} method yielded promising results which led to a TTR from Savannah River Remediation, LLC (SRR) to SRNL for additional support and an associated TTQAP to direct the SRNL efforts. A technical report resulting from this work was issued that recommended that the mixed acid method be replaced by the Cs{sub 2}CO{sub 3} method for the measurement of magnesium (Mg), sodium (Na), and zirconium (Zr) with additional testing of the method by DWPF Laboratory being needed before further implementation of the Cs{sub 2}CO{sub 3} method at that laboratory. While the SME acceptability testing of the Isolok does not address any of the open issues remaining after the publication of the recommendation for the replacement of the mixed acid method by the Cs{sub 2}CO{sub 3} method (since those issues are to be addressed by the DWPF Laboratory), the Cs{sub 2}CO{sub 3} testing associated with the Isolok testing does provide additional insight into the performance of the method as conducted by SRNL. The performance is to be investigated by looking to the composition measurement data generated by the samples of a standard glass, the Analytical Reference Glass - 1 (ARG-1), that were prepared by the Cs{sub 2}CO{sub 3} method and included in the SME acceptability testing of the Isolok. The measurements of these samples were presented as part of the study results, but no statistical analysis of these measurements was conducted as part of those results. It is the purpose of this report to provide that analysis, which was supported using JMP Version 7.0.2.« less

INR goal attainment and oral anticoagulation knowledge of patients enrolled in an anticoagulation clinic in a Veterans Affairs medical center.

PubMed

Baker, Jennifer W; Pierce, Kristi L; Ryals, Casey A

2011-03-01

In January 2009, the Joint Commission implemented a National Patient Safety Goal (NPSG) for ambulatory care, NPSG 3E, intended to reduce harm associated with the use of anticoagulation therapy. The 2011 NPSG 3E encompasses 8 elements of performance, including requirements that each organization (a) provide education regarding anticoagulation therapy to staff, patients, and families and (b) evaluate its safety practices and take appropriate action to improve its practices. The Alvin C. York (ACY) outpatient anticoagulation clinic provides education to new patients and their families at the initial clinic visit, with follow-up reinforcement of education as needed throughout their care. To (a) assess the knowledge level of patients receiving warfarin therapy in an anticoagulation clinic using the validated Anticoagulation Knowledge Assessment (AKA) questionnaire and (b) examine the relationship between patient anticoagulation knowledge and anticoagulation control as measured by the international normalized ratio (INR). All ACY Veterans Affairs (VA) anticoagulation clinic patients seen during their routine visit within an 8-week recruitment period from February 2010 to April 2010 were asked to complete the AKA questionnaire. Upon voluntary consent, the questionnaire was completed by the patient either during the clinic visit or returned later by mail. Demographic and clinical data were manually extracted from the computerized patient record system and included age, gender, indication for and duration of anticoagulation therapy, goal INR range, and the 10 INR values preceding the date of consent. A passing score was defined as at least 21 correct responses on the 29-item AKA questionnaire (72.4% correct). Statistical analyses included comparisons of demographic and clinical characteristics for patients with passing versus failing scores, assessed with Pearson chi-square and Fisher's exact test, and bivariate analyses of INR control with anticoagulation knowledge, assessed with Spearman's rho correlation. INR control was defined by 3 outcome measures: number of INRs within therapeutic range, time in therapeutic range (TTR) calculated using the Rosendaal method, and standard deviation (SD) of INR values. Anticoagulation knowledge was assessed with 2 measures: total AKA score and count of correct answers to a subset of 15 AKA items deemed by the investigators to be relevant to INR control. Of 447 patients enrolled in the anticoagulation clinic, 260 consented to participate in the survey, of whom 185 patients completed the AKA instrument (n=171 [92.4%] by mail) and were successfully matched to patient record system data. 178 (96.2%) respondents were male with a mean (SD) age of 68 (10.1) years. The majority of patients were undergoing anticoagulation treatment for atrial fibrillation (n=113, 61.1%) or deep venous/pulmonary thromboembolism (n=48, 25.9%). The majority of patients had been treated with warfarin for at least 1 year (n=162, 87.6%). Most patients had goal INR ranges of 2.0 to 3.0 (n=166, 89.7%). Of the 185 patients who completed the questionnaire, 137 (74.1%) achieved a passing score. The mean (SD) AKA questionnaire score was 78.1% (12.1%). There were 8 questions that were answered correctly by less than 70% of patients and identified as potential deficiencies in patient education. For the 167 patients who had been on warfarin therapy for at least 6 months and had 10 previous INR values, there was no significant Spearman's rho correlation between total number of correct questionnaire responses and INR control, defined as the count of the 10 previous INR values within goal range (rho =-0.022, P=0.776), TTR (rho=0.015, P=0.848), and SD (rho=0.047, P=0.550). There was also no significant relationship between number of correct INR-relevant responses and INR control by any of the 3 outcome measures (count in range rho=0.033, P=0.676; TTR rho=0.067, P=0.388; and SD rho=-0.029, P=0.708). Although 74.1% of patients on long-term warfarin therapy achieved a passing score of at least 21 correct answers on the 29-question AKA instrument, there was no significant relationship between patient warfarin knowledge and INR control. Areas for improvement in patient education have been identified and procedures for educational modification are currently in development. Copyright © 2011, Academy of Managed Care Pharmacy. All rights reserved.

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.

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).

MODELING CST ION EXCHANGE FOR CESIUM REMOVAL FROM SCIX BATCHES 1 - 4

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

Smith, F.

2011-04-25

The objective of this work is, through modeling, to predict the performance of Crystalline Silicotitinate (CST) for the removal of cesium from Small Column Ion Exchange (SCIX) Batches 1-4 (as proposed in Revision 16 of the Liquid Waste System Plan). The scope of this task is specified in Technical Task Request (TTR) 'SCIX Feed Modeling', HLE-TTR-2011-003, which specified using the Zheng, Anthony, Miller (ZAM) code to predict CST isotherms for six given SCIX feed compositions and the VErsatile Reaction and SEparation simulator for Liquid Chromatography (VERSE-LC) code to predict ion-exchange column behavior. The six SCIX feed compositions provided in themore » TTR represent SCIX Batches 1-4 and Batches 1 and 2 without caustic addition. The study also investigated the sensitivity in column performance to: (1) Flow rates of 5, 10, and 20 gpm with 10 gpm as the nominal flow; and (2) Temperatures of 25, 35, and 45 C with 35 C as the nominal temperature. The isotherms and column predictions presented in this report reflect the expected performance of engineered CST IE-911. This form of CST was used in experiments conducted at the Savannah River National Laboratory (SRNL) that formed the basis for estimating model parameters (Hamm et al., 2002). As has been done previously, the engineered resin capacity is estimated to be 68% of the capacity of particulate CST without binder.« less

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.

Advanced Rotorcraft Transmission (ART) program-Boeing helicopters status report

NASA Technical Reports Server (NTRS)

Lenski, Joseph W., Jr.; Valco, Mark J.

1991-01-01

The Advanced Rotorcraft Transmission (ART) program is structured to incorporate key emerging material and component technologies into an advanced rotorcraft transmission with the intention of making significant improvements in the state of the art (SOA). Specific objectives of ART are: (1) Reduce transmission weight by 25 pct.; (2) Reduce transmission noise by 10 dB; and (3) Improve transmission life and reliability, while extending Mean Time Between Removal to 5000 hr. Boeing selected a transmission sized for the Tactical Tilt Rotor (TTR) aircraft which meets the Future Air Attack Vehicle (FAVV) requirements. Component development testing will be conducted to evaluate the high risk concepts prior to finalizing the advanced transmission configuration. The results of tradeoff studies and development test which were completed are summarized.

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.

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

Diagnostic Value of Combining Tumor and Inflammatory Markers in Lung Cancer

PubMed Central

Yoon, Ho Il; Kwon, Oh-Ran; Kang, Kyung Nam; Shin, Yong Sung; Shin, Ho Sang; Yeon, Eun Hee; Kwon, Keon Young; Hwang, Ilseon; Jeon, Yoon Kyung; Kim, Yongdai; Kim, Chul Woo

2016-01-01

Background Despite major advances in lung cancer treatment, early detection remains the most promising way of improving outcomes. To detect lung cancer in earlier stages, many serum biomarkers have been tested. Unfortunately, no single biomarker can reliably detect lung cancer. We combined a set of 2 tumor markers and 4 inflammatory or metabolic markers and tried to validate the diagnostic performance in lung cancer. Methods We collected serum samples from 355 lung cancer patients and 590 control subjects and divided them into training and validation datasets. After measuring serum levels of 6 biomarkers (human epididymis secretory protein 4 [HE4], carcinoembryonic antigen [CEA], regulated on activation, normal T cell expressed and secreted [RANTES], apolipoprotein A2 [ApoA2], transthyretin [TTR], and secretory vascular cell adhesion molecule-1 [sVCAM-1]), we tested various sets of biomarkers for their diagnostic performance in lung cancer. Results In a training dataset, the area under the curve (AUC) values were 0.821 for HE4, 0.753 for CEA, 0.858 for RANTES, 0.867 for ApoA2, 0.830 for TTR, and 0.552 for sVCAM-1. A model using all 6 biomarkers and age yielded an AUC value of 0.986 and sensitivity of 93.2% (cutoff at specificity 94%). Applying this model to the validation dataset showed similar results. The AUC value of the model was 0.988, with sensitivity of 93.33% and specificity of 92.00% at the same cutoff point used in the validation dataset. Analyses by stages and histologic subtypes all yielded similar results. Conclusions Combining multiple tumor and systemic inflammatory markers proved to be a valid strategy in the diagnosis of lung cancer. PMID:27722145

Diagnostic Value of Combining Tumor and Inflammatory Markers in Lung Cancer.

PubMed

Yoon, Ho Il; Kwon, Oh-Ran; Kang, Kyung Nam; Shin, Yong Sung; Shin, Ho Sang; Yeon, Eun Hee; Kwon, Keon Young; Hwang, Ilseon; Jeon, Yoon Kyung; Kim, Yongdai; Kim, Chul Woo

2016-09-01

Despite major advances in lung cancer treatment, early detection remains the most promising way of improving outcomes. To detect lung cancer in earlier stages, many serum biomarkers have been tested. Unfortunately, no single biomarker can reliably detect lung cancer. We combined a set of 2 tumor markers and 4 inflammatory or metabolic markers and tried to validate the diagnostic performance in lung cancer. We collected serum samples from 355 lung cancer patients and 590 control subjects and divided them into training and validation datasets. After measuring serum levels of 6 biomarkers (human epididymis secretory protein 4 [HE4], carcinoembryonic antigen [CEA], regulated on activation, normal T cell expressed and secreted [RANTES], apolipoprotein A2 [ApoA2], transthyretin [TTR], and secretory vascular cell adhesion molecule-1 [sVCAM-1]), we tested various sets of biomarkers for their diagnostic performance in lung cancer. In a training dataset, the area under the curve (AUC) values were 0.821 for HE4, 0.753 for CEA, 0.858 for RANTES, 0.867 for ApoA2, 0.830 for TTR, and 0.552 for sVCAM-1. A model using all 6 biomarkers and age yielded an AUC value of 0.986 and sensitivity of 93.2% (cutoff at specificity 94%). Applying this model to the validation dataset showed similar results. The AUC value of the model was 0.988, with sensitivity of 93.33% and specificity of 92.00% at the same cutoff point used in the validation dataset. Analyses by stages and histologic subtypes all yielded similar results. Combining multiple tumor and systemic inflammatory markers proved to be a valid strategy in the diagnosis of lung cancer.

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

Outcomes of anticoagulation therapy in patients with mental health conditions.

PubMed

Paradise, Helen T; Berlowitz, Dan R; Ozonoff, Al; Miller, Donald R; Hylek, Elaine M; Ash, Arlene S; Jasuja, Guneet K; Zhao, Shibei; Reisman, Joel I; Rose, Adam J

2014-06-01

Patients with mental health conditions (MHCs) experience poor anticoagulation control when using warfarin, but we have limited knowledge of the association between specific mental illness and warfarin treatment outcomes. To examine the relationship between the severity of MHCs and outcomes of anticoagulation therapy. Retrospective cohort analysis. We studied 103,897 patients on warfarin for 6 or more months cared for by the Veterans Health Administration during fiscal years 2007-2008. We identified 28,216 patients with MHCs using ICD-9 codes: anxiety disorders, bipolar disorder, depression, post-traumatic stress disorder, schizophrenia, and other psychotic disorders. Outcomes included anticoagulation control, as measured by percent time in the therapeutic range (TTR), as well as major hemorrhage. Predictors included different categories of MHC, Global Assessment of Functioning (GAF) scores, and psychiatric hospitalizations. Patients with bipolar disorder, depression, and other psychotic disorders experienced TTR decreases of 2.63 %, 2.26 %, and 2.92 %, respectively (p < 0.001), after controlling for covariates. Patients with psychotic disorders other than schizophrenia experienced increased hemorrhage after controlling for covariates [hazard ratio (HR) 1.24, p = 0.03]. Having any MHC was associated with a slightly increased hazard for hemorrhage (HR 1.19, p < 0.001) after controlling for covariates. Patients with specific MHCs (bipolar disorder, depression, and other psychotic disorders) experienced slightly worse anticoagulation control. Patients with any MHC had a slightly increased hazard for major hemorrhage, but the magnitude of this difference is unlikely to be clinically significant. Overall, our results suggest that appropriately selected patients with MHCs can safely receive therapy with warfarin.

Educational Level, Anticoagulation Quality, and Clinical Outcomes in Elderly Patients with Acute Venous Thromboembolism: A Prospective Cohort Study.

PubMed

Hofmann, Eveline; Faller, Nicolas; Limacher, Andreas; Méan, Marie; Tritschler, Tobias; Rodondi, Nicolas; Aujesky, Drahomir

2016-01-01

Whether the level of education is associated with anticoagulation quality and clinical outcomes in patients with acute venous thromboembolism (VTE) is uncertain. We thus aimed to investigate the association between educational level and anticoagulation quality and clinical outcomes in elderly patients with acute VTE. We studied 817 patients aged ≥65 years with acute VTE from a Swiss prospective multicenter cohort study (09/2009-12/2013). We defined three educational levels: 1) less than high school, 2) high school, and 3) post-secondary degree. The primary outcome was the anticoagulation quality, expressed as the percentage of time spent in the therapeutic INR range (TTR). Secondary outcomes were the time to a first recurrent VTE and major bleeding. We adjusted for potential confounders and periods of anticoagulation. Overall, 56% of patients had less than high school, 25% a high school degree, and 18% a post-secondary degree. The mean percentage of TTR was similar across educational levels (less than high school, 61%; high school, 64%; and post-secondary, 63%; P = 0.36). Within three years of follow-up, patients with less than high school, high school, and a post-secondary degree had a cumulative incidence of recurrent VTE of 14.2%, 12.9%, and 16.4%, and a cumulative incidence of major bleeding of 13.3%, 15.1%, and 15.4%, respectively. After adjustment, educational level was neither associated with anticoagulation quality nor with recurrent VTE or major bleeding. In elderly patients with VTE, we did not find an association between educational level and anticoagulation quality or clinical outcomes.

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 ...

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.

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.

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.

The first pharmacist-managed anticoagulation clinic under a collaborative practice agreement in Qatar: clinical and patient-oriented outcomes.

PubMed

Elewa, H F; AbdelSamad, O; Elmubark, A E; Al-Taweel, H M; Mohamed, A; Kheir, N; Mohamed Ibrahim, M I; Awaisu, A

2016-08-01

Optimal outpatient anticoagulation management requires a systematic and coordinated approach. Extensive evidence regarding the benefits of pharmacist-managed anticoagulation services has been reported in the literature. The quality and outcomes associated with pharmacist-managed anticoagulation clinics under collaborative practice agreements in the Middle East have rarely been reported. The first pharmacist-managed ambulatory anticoagulation clinic in Qatar was launched at Al-Wakrah Hospital in March 2013. The objectives of this study were to: (i) describe the practice model of the clinic, (ii) evaluate the quality of the clinic [i.e. the time in therapeutic range (TTR)] and the clinical outcomes (i.e. the efficacy and safety), and (iii) determine the patients' satisfaction and overall quality of life (QoL). Clinical outcome data were collected through a retrospective chart review of all patients managed from March 2013 to October 2014 at the pharmacist-managed anticoagulation clinic. Furthermore, the patient-oriented outcomes data were prospectively collected using the 24-item Duke Anticoagulation Satisfaction Scale (DASS). Each item was assessed using a 7-point Likert-type scale on which lower scores indicated better QoL and greater satisfaction. The clinical outcome data analyses included 119 patients who were enrolled at the clinic during the 19-month study period. The mean number of international normalized ratio (INR) tests/month was 65 ± 9, the average testing frequency was 2·7 ± 1·6 weeks, and the average %TTR was 76·8 ± 22·9%. There was one major bleeding event (0·67%/year), 12 minor bleeding events (8%/year) and two thromboembolic events (1·35%/year) recorded during the study period. Of the 119 patients, 50 participated in the satisfaction and QoL survey. The median (IQR) total QoL score of these subjects was 63 (48) (minimum-maximum achievable score: 24-168). Seventy-six per cent of the patients indicated 'a lot to very much' in terms of their overall satisfaction with the anticoagulation treatment. The participants who were naïve to anticoagulation treatment reported a significantly greater satisfaction and better QoL than the experienced patients [58 (44) vs. 82 (59); P = 0·009]. These findings provide early evidence that the patients who were managed at a pharmacy-based anticoagulation clinic in an evolving healthcare system experienced optimal anticoagulation management. © 2016 John Wiley & Sons Ltd.

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.

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.

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

Statistical design and analysis of environmental studies for plutonium and other transuranics at NAEG ''safety-shot'' sites

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

Gilbert, R.O.; Eberhardt, L.L.; Fowler, E.B.

This paper is centered around the use of stratified random sampling for estimating the total amount (inventory) of $sup 239-240$Pu and uranium in surface soil at ten ''safety-shot'' sites on the Nevada Test Site (NTS) and Tonopah Test Range (TTR) that are currently being studied by the Nevada Applied Ecology Group (NAEG). The use of stratified random sampling has resulted in estimates of inventory at these desert study sites that have smaller standard errors than would have been the case had simple random sampling (no stratification) been used. Estimates of inventory are given for $sup 235$U, $sup 238$U, and $supmore » 239-240$Pu in soil at A Site of Area 11 on the NTS. Other results presented include average concentrations of one or more of these isotopes in soil and vegetation and in soil profile samples at depths to 25 cm. The regression relationship between soil and vegetation concentrations of $sup 235$U and $sup 238$U at adjacent sampling locations is also examined using three different models. The applicability of stratified random sampling to the estimation of concentration contours of $sup 239-240$Pu in surface soil using computer algorithms is also investigated. Estimates of such contours are obtained using several different methods. The planning of field sampling plans for estimating inventory and distribution is discussed. (auth)« less

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...

The changing characteristics of atrial fibrillation patients treated with warfarin.

PubMed

Putnam, Andrew; Gu, Xiaokui; Haymart, Brian; Kline-Rogers, Eva; Almany, Steve; Kozlowski, Jay; Krol, Gregory D; Kaatz, Scott; Froehlich, James B; Barnes, Geoffrey D

2015-11-01

It has been suggested that direct oral anticoagulants are being preferentially used in low risk atrial fibrillation (AF) patients. Understanding the changing risk profile of new AF patients treated with warfarin is important for interpreting the quality of warfarin delivery through an anticoagulation clinic. Six anticoagulation clinics participating in the Michigan Anticoagulation Quality Improvement Initiative enrolled 1293 AF patients between 2010 and 2014 as an inception cohort. Abstracted data included demographics, comorbidities, medication use and all INR values. Risk scores including CHADS2, CHA2DS2-VASc, HAS-BLED, SAMe-TT2R2, and Charlson comorbidity index (CCI) were calculated for each patient at the time of warfarin initiation. The quality of anticoagulation was assessed using the Rosendaal time in the therapeutic range (TTR) during the first 6 months of treatment. Between 2010 and 2014, patients initiating warfarin therapy for AF had an increasing mean CHADS2 (2.0 ± 1.1 to 2.2 ± 1.4, p = 0.02) and CCI (4.7 ± 1.8 to 5.1 ± 2.0, p = 0.03), and a trend towards increasing mean CHA2DS2-VASc, HAS-BLED, and SAMe-TT2R2 scores. The actual TTR remained unchanged over the study period (62.6 ± 18.2 to 62.7 ± 17.0, p = 0.98), and the number of INR checks did not change (18.9 ± 5.2 to 18.5 ± 5.1, p = 0.06). Between 2010 and 2014, AF patients newly starting warfarin had mild increases in risk for stroke and death with sustained quality of warfarin therapy.

The nutritional relationship linking sulfur to nitrogen in living organisms.

PubMed

Ingenbleek, Yves

2006-06-01

Nitrogen (N) and sulfur (S) coexist in the biosphere as free elements or in the form of simple inorganic NO3- and SO4(2-) oxyanions, which must be reduced before undergoing anabolic processes leading to the production of methionine (Met) and other S-containing molecules. Both N and S pathways are tightly regulated in plant tissues so as to maintain S:N ratios ranging from 1:20 to 1:35. As a result, plant products do not adequately fulfill human tissue requirements, whose mean S:N ratios amount to 1:14.5. The evolutionary patterns of total body N (TBN) and of total body S (TBS) offer from birth to death sex- and age-related specificities well identified by the serial measurement of plasma transthyretin (TTR). Met is regarded as the most limiting of all indispensable amino acids (IAAs) because of its participation in a myriad of molecular, structural, and metabolic activities of survival importance. Met homeostasis is regulated by subtle competitive interactions between transsulfuration and remethylation pathways of homocysteine (Hcy) and by the actual level of TBN reserves working as a direct sensor of cystathionine-beta-synthase activity. Under steady-state conditions, the dietary intake of SO4(2-) is essentially equal to total sulfaturia. The recommended dietary allowances for both S-containing AAs allotted to replace the minimal obligatory losses resulting from endogenous catabolism is largely covered by Western customary diets. By contrast, strict vegans and low-income populations living in plant-eating countries incur the risk of chronic N and Met dietary deficiencies causing undesirable hyperhomocysteinemia best explained by the downsizing of their TBN resources and documented by declining TTR plasma values.

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.

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.

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.

Comparison of four modeling tools for the prediction of potential distribution for non-indigenous weeds in the United States

USGS Publications Warehouse

Magarey, Roger; Newton, Leslie; Hong, Seung C.; Takeuchi, Yu; Christie, Dave; Jarnevich, Catherine S.; Kohl, Lisa; Damus, Martin; Higgins, Steven I.; Miller, Leah; Castro, Karen; West, Amanda; Hastings, John; Cook, Gericke; Kartesz, John; Koop, Anthony

2018-01-01

This study compares four models for predicting the potential distribution of non-indigenous weed species in the conterminous U.S. The comparison focused on evaluating modeling tools and protocols as currently used for weed risk assessment or for predicting the potential distribution of invasive weeds. We used six weed species (three highly invasive and three less invasive non-indigenous species) that have been established in the U.S. for more than 75 years. The experiment involved providing non-U. S. location data to users familiar with one of the four evaluated techniques, who then developed predictive models that were applied to the United States without knowing the identity of the species or its U.S. distribution. We compared a simple GIS climate matching technique known as Proto3, a simple climate matching tool CLIMEX Match Climates, the correlative model MaxEnt, and a process model known as the Thornley Transport Resistance (TTR) model. Two experienced users ran each modeling tool except TTR, which had one user. Models were trained with global species distribution data excluding any U.S. data, and then were evaluated using the current known U.S. distribution. The influence of weed species identity and modeling tool on prevalence and sensitivity effects was compared using a generalized linear mixed model. Each modeling tool itself had a low statistical significance, while weed species alone accounted for 69.1 and 48.5% of the variance for prevalence and sensitivity, respectively. These results suggest that simple modeling tools might perform as well as complex ones in the case of predicting potential distribution for a weed not yet present in the United States. Considerations of model accuracy should also be balanced with those of reproducibility and ease of use. More important than the choice of modeling tool is the construction of robust protocols and testing both new and experienced users under blind test conditions that approximate operational conditions.

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.

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

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

Peters, T. B.; Bannochie, C. J.

Savannah River National Laboratory (SRNL) analyzed samples from Tank 21H in support of verification of Macrobatch (Salt Batch) 11 for the Interim Salt Disposition Program (ISDP) for processing. This document reports characterization data on the samples of Tank 21H and fulfills the requirements of Deliverable 3 of the Technical Task Request (TTR).

Economic evaluation of a randomized controlled trial of pharmacist-supervized patient self-testing of warfarin therapy.

PubMed

Gallagher, J; Mc Carthy, S; Woods, N; Ryan, F; O' Shea, S; Byrne, S

2015-02-01

The increase in numbers of patients requiring oral anti-coagulation testing in outpatient clinics has focused attention on alternative flexible systems of anti-coagulation management. One option is pharmacist led patient self-testing (PST) of international normalised ratio (INR) levels. PST has demonstrated improvements in anti-coagulation control, but its cost-effectiveness is inconclusive. This study reports the first cost-effectiveness evaluation of a randomized controlled trial of an automated direct-to-patient expert system, enabling remote and effective management of patients on oral anti-coagulation therapy. We conducted an economic evaluation alongside a randomised controlled trial investigating a pharmacist led PST method. The primary outcome was to determine the cost effectiveness of PST in comparison with usual care (management in a hospital based anti-coagulation clinic). Long term anti-coagulation patients were recruited to a 6 month cross over study between PST and routine care in an anti-coagulation clinic. Economic evaluation was from the healthcare payer perspective. On a per patient basis over a 6 month period, PST resulted in an incremental cost of €59.08 in comparison with routine care. Patients achieved a significantly higher time in therapeutic range (TTR) during the PST arm in comparison with routine care, (72 ± 19.7% vs. 59 ± 13.5%). Overall cost of managing a patient through pharmacist supervised PST for a 6 month period is €226.45. Additional analysis of strategies from a societal perspective indicated that PST was the dominant strategy. Pharmacist led patient self-testing is a viable method of management. It provides significant increases in anti-coagulation control for a minimal increase in cost. © 2014 John Wiley & Sons Ltd.

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.

Exposure to butachlor causes thyroid endocrine disruption and promotion of metamorphosis in Xenopus laevis.

PubMed

Li, Shuying; Li, Meng; Wang, Qiangwei; Gui, Wenjun; Zhu, Guonian

2016-06-01

Butachlor is extensively applied in rice paddy ecosystem in china, and has been widespread contaminant in the aquatic environment. Here, Xenopus laevis was used for the evaluation of teratogenesis developmental toxicity, and disruption of thyroid system when exposure to different concentrations of butachlor by window phase exposure. Acute toxicity investigation shown that 96 h-LC50 value of butachlor was 1.424 mg L(-1) and 0.962 mg L(-1) for tadpoles (starting from stages 46/47) and embryos (starting from stages 8/9), respectively. Exposure to butachlor caused malformation, including abnormal eye, pericardial edema, enlarged proctodaeum and bent tail. Window phase exposure test indicated that butachlor significantly promote the contents of whole-body thyroid hormones (THs, T3 and T4) at higher levels, indicating thyroid endocrine disruption. At 7 days, exposure to butachlor up-regulated the mRNA expression of genes involved in THs synthesis and metabolism (tshα, tg, tpo and dio1) and THs receptors (trα and trβ). At 14 days, up-regulation of the mRNA expression of genes related to THs synthesis and metabolism (tshα, tshβ, tg, tpo, dio1, dio2 and ttr) and THs receptors (trβ) were also observed after the exposure to butachlor. At 21 days, butachlor up-regulated the mRNA expression of tshα, tg, tpo genes and down-regulated the mRNA expression of tshβ, tg, dio1, ttr and trα genes. These results showed that butachlor could change the mRNA expression of genes involved in the HPT axis and increase whole-body thyroid hormones levels of X. laevis tadpoles in a dose- and time-dependent manner, causing thyroid endocrine disruption and developmental toxicity. Copyright © 2016 Elsevier Ltd. All rights reserved.

The autophagy-related marker LC3 can predict prognosis in human hepatocellular carcinoma.

PubMed

Lee, Yoo Jin; Hah, Yu Jin; Ha, Yu Jin; Kang, Yu Na; Kang, Koo Jeong; Hwang, Jae Seok; Chung, Woo Jin; Cho, Kwang Bum; Park, Kyung Sik; Kim, Eun Soo; Seo, Hye-Young; Kim, Mi-Kyung; Park, Keun-Gyu; Jang, Byoung Kuk

2013-01-01

Defects of autophagy and endoplasmic reticulum (ER) stress are related to many diseases and tumors. However, only a few studies have examined hepatocellular carcinoma (HCC) as related to these processes. Therefore, in this study, we investigated the expression and extent of autophagy and ER stress-related markers in HCC and their influence on clinical characteristics and prognosis for each protein. The expression of autophagy-related markers (LC3 and Beclin-1) and ER stress-related markers (GRP78 and CHOP) was analyzed by immunohistochemistry on tissues from completely resected specimens of 190 HCC patients. Their influence on clinicopathologic features and prognosis were evaluated using the chi-square test and Kaplan-Meier analysis. Correlations of each protein were determined by Spearman's correlation analysis. LC3 expression was not correlated with TNM, BCLC stage, or Edmonson-Steiner grading, whereas it was correlated with longer overall survival (OS) (p = 0.039) and tended to be related with longer time to recurrence (TTR) (p=0.068) although it did not show statistical significance. Multivariate analysis indicated that LC3 expression was a significantly independent prognostic factor of OS (HR, 0.42; 95% CI, 0.22-0.80; p-value=0.009) and TTR (HR, 0.54; 95% CI, 0.33-0.90; p=0.017). Expression of LC3 in advanced stages of TNM (III) (p=0.045) and Edmonson-Steiner Grades (III and IV) (p=0.043) was correlated with longer survival, but not in the early stages. A positive correlation was not observed between the expression of autophagy-related markers and ER stress-related markers. Our results suggest that the expression and extent of LC3 might be a strong prognostic factor of HCC, especially in patients with surgical resection.

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.

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.

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.

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

Reduced anticoagulation variability in patients on warfarin monitored with Fiix-prothrombin time associates with reduced thromboembolism: The Fiix-trial.

PubMed

Oskarsdóttir, Alma Rut; Gudmundsdottir, Brynja R; Indridason, Olafur S; Lund, Sigrun H; Arnar, David O; Bjornsson, Einar S; Magnusson, Magnus K; Jensdottir, Hulda M; Vidarsson, Brynjar; Francis, Charles W; Onundarson, Pall T

2017-05-01

Fiix-prothrombin time (Fiix-PT) differs from traditional PT in being affected by reduced factor (F) II or FX only. In the randomized controlled Fiix-trial, patients on warfarin monitored with Fiix-PT (Fiix-warfarin patients) had fewer thromboembolisms (TE), similar major bleeding (MB) and more stable anticoagulation than patients monitored with PT (PT-warfarin patients). In the current Fiix-trial report we analyzed how reduced anticoagulation variability during Fiix-PT monitoring was reflected in patients with TE or bleeding. Data from 1143 randomized patients was used. We analyzed the groups for anticoagulation intensity (time within target range; TTR), international normalized ratio (INR) variability (variance growth rate B 1 ; VGR) and dose adjustment frequency. We assessed how these parameters associated with clinically relevant vascular events (CRVE), ie TE or MB or clinically relevant non-MB. TTR was highest in Fiix-warfarin patients without CRVE (median 82%;IQR 72-91) and lowest in PT-warfarin patients with TE (62%;56-81). VGR was lowest in Fiix-warfarin patients without CRVE (median VGR B 1 0.17; 95% CI 0.08-0.38) and with TE (0.20;0.07-0.26) and highest in PT-warfarin patients with TE (0.50;0.27-0.90) or MB (0.59;0.07-1.36). The mean annual dose adjustment frequency was lowest in Fiix-warfarin patients with TE (mean 5.4;95% CI 3.9-7.3) and without CRVE (mean 6.0; 5.8-6.2) and highest in PT-warfarin patients with TE (14.2;12.2-16.3). Frequent dose changes predicted MB in both study arms. Compared to patients monitored with PT, high anticoagulation stability in Fiix-warfarin patients coincided with their low TE rate. Those with bleeding had high variability irrespective of monitoring method. Thus, although further improvements are needed to reduce bleeding, stabilization of anticoagulation by Fiix-PT monitoring associates with reduced TE.

Comparison of Warfarin use in terms of efficacy and safety in two different polyclinics

PubMed Central

Kılıç, Salih; Kemal, Hatice Soner; Yüce, Elif İlkay; Şimşek, Evrim; Yağmur, Burcu; Akgül, Nuray Memişoğlu; Çınar, Cahide Soydaş; Zoghi, Mehdi; Gürgün, Cemil

2017-01-01

Objective: This study compared the efficacy and safety of warfarin in specialized international normalized ratio (INR) outpatient clinic (INR-C) and in general cardiology outpatient clinic (General-C). Methods: Herein, 381 consecutive patients with a regular follow-up at INR-C (n=233) or General-C (n=148) for at least 1 year were retrospectively included. While INR-C patients were followed by a single experienced trained nurse, General-C patients were followed by a different cardiologist who worked in a rotational principle every month. During controls, demographic characteristics, INR levels, bleeding events, ischemic stroke, and transient ischemic attacks in the last 1 year were recorded. Primary endpoint was defined as the evaluation of the combined major bleeding and ischemic event, and secondary endpoint was defined as the evaluation of them separately. Results: The mean age of the patients was 62±12.86 and 43.8% were male. Mean time in therapeutic range (TTR) level was statistically higher in INR-C than that in General-C (68.8%±15.88 and 51.6%±23.04, respectively; p<0.001). Primary outcomes were significantly higher in General-C than that in INR-C [13.5% (20) and 6.4% (15); respectively, p=0.020]. Overall, major bleeding was observed in 25 patients (6.5%) and (2.6%) ischemic event was observed in 10 patients. In General-C patients, both major bleeding (8.8% vs. 5.2%; p=0.163) and the ischemic event (4.7% vs. 1.3%; p=0.051) were more, and no statistically significant differences were detected between the two clinics. Conclusion: The findings of our study demonstrate that patients followed in INR-C had higher TTR levels and lower bleeding and ischemic events rates that those followed in General-C. PMID:29145216

Ezetimibe enhances and stabilizes anticoagulant effect of warfarin.

PubMed

Hashikata, Takehiro; Yamaoka-Tojo, Minako; Kakizaki, Ryota; Nemoto, Teruyoshi; Fujiyoshi, Kazuhiro; Namba, Sayaka; Kitasato, Lisa; Hashimoto, Takuya; Ishii, Shunsuke; Kameda, Ryo; Shimohama, Takao; Tojo, Taiki; Ako, Junya

2017-01-01

Ezetimibe reduces plasma levels of low-density lipoprotein cholesterol by inhibiting Niemann-Pick C1-like protein 1 (NPC1L1). A recent study demonstrated that NPC1L1 plays an important role in absorption of fat-soluble vitamins including vitamin K. We evaluated whether the add-on treatment of ezetimibe affects anticoagulation in patients taking warfarin. Between October 2007 and March 2015, the administration of ezetimibe was started to a total of 101 outpatients who were already on oral anticoagulation with warfarin. We retrospectively analyzed blood lipid levels, prothrombin time international normalized ratio (PT-INR) and time in therapeutic INR range (TTR). Seventy-one patients (70 %) showed increase in PT-INR after ezetimibe treatment (1.96 ± 0.45 to 2.20 ± 0.61, p < 0.001). It was necessary to reduce the warfarin dose in 9 of 101 patients for clinical indication. There was a significant positive correlation between change in PT-INR and statin usage at baseline (p = 0.03). The mean value of changes in PT-INR of patients with taking statin was significantly larger than that of patients without taking statin (0.34 ± 0.54 vs. 0.06 ± 0.36, p = 0.03). There was an increase in the TTR (52 ± 26 to 61 ± 23 %, p < 0.0001) and a decrease in the frequency to change the dose of warfarin after the ezetimibe treatment [45 times of 735 examination days (6 %) to 20 times of 695 examination days (3 %), p = 0.02]. Our data suggest possible drug interaction between warfarin and ezetimibe. Ezetimibe may increase and stabilize the anticoagulant effect of warfarin, especially in patients taking statins.

Evaluation of quartz melt rate furnace with the nitric-glycolic flowsheet

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

Williams, M. S.; Miller, D. H.

The Savannah River National Laboratory (SRNL) was tasked to support validation of the Defense Waste Processing Facility (DWPF) melter offgas flammability model for the Nitric-Glycolic (NG) flowsheet. The work is supplemental to the Cold Cap Evaluation Furnace (CEF) testing conducted in 20141 and the Slurry-fed Melt Rate Furnace (SMRF) testing conducted in 20162 that supported Deliverable 4 of the DWPF & Saltstone Facility Engineering Technical Task Request (TTR).3 The Quartz Melt Rate Furnace (QMRF) was evaluated as a bench-scale scoping tool to potentially be used in lieu of or simply prior to the use of the larger-scale SMRF or CEF.more » The QMRF platform has been used previously to evaluate melt rate behavior and offgas compositions of DWPF glasses prepared from the Nitric-Formic (NF) flowsheet but not for the NG flowsheet and not with continuous feeding.4 The overall objective of the 2016-2017 testing was to evaluate the efficacy of the QMRF as a lab-scale platform for steady state, continuously fed melter testing with the NG flowsheet as an alternative to more expensive and complex testing with the SMRF or CEF platforms.« less

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.

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

Enhancing the 'real world' prediction of cardiovascular events and major bleeding with the CHA2DS2-VASc and HAS-BLED scores using multiple biomarkers.

PubMed

Roldán, Vanessa; Rivera-Caravaca, José Miguel; Shantsila, Alena; García-Fernández, Amaya; Esteve-Pastor, María Asunción; Vilchez, Juan Antonio; Romera, Marta; Valdés, Mariano; Vicente, Vicente; Marín, Francisco; Lip, Gregory Y H

2018-02-01

Atrial fibrillation (AF)-European guidelines suggest the use of biomarkers to stratify patients for stroke and bleeding risks. We investigated if a multibiomarker strategy improved the predictive performance of CHA 2 DS 2 -VASc and HAS-BLED in anticoagulated AF patients. We included consecutive patients stabilized for six months on vitamin K antagonists (INRs 2.0-3.0). High sensitivity troponin T, NT-proBNP, interleukin-6, von Willebrand factor concentrations and glomerular filtration rate (eGFR; using MDRD-4 formula) were quantified at baseline. Time in therapeutic range (TTR) was recorded at six months after inclusion. Patients were follow-up during a median of 2375 (IQR 1564-2887) days and all adverse events were recorded. In 1361 patients, adding four blood biomarkers, TTR and MDRD-eGFR, the predictive value of CHA 2 DS 2 -VASc increased significantly by c-index (0.63 vs. 0.65; p = .030) and IDI (0.85%; p < .001), but not by NRI (-2.82%; p < .001). The predictive value of HAS-BLED increased up to 1.34% by IDI (p < .001). Nevertheless, the overall predictive value remains modest (c-indexes approximately 0.65) and decision curve analyses found lower net benefit compared with the originals scores. Addition of biomarkers enhanced the predictive value of CHA 2 DS 2 -VASc and HAS-BLED, although the overall improvement was modest and the added predictive advantage over original scores was marginal. Key Messages Recent atrial fibrillation (AF)-European guidelines for the first time suggest the use of biomarkers to stratify patients for stroke and bleeding risks, but their usefulness in real world for risk stratification is still questionable. In this cohort study involving 1361 AF patients optimally anticoagulated with vitamin K antagonists, adding high sensitivity troponin T, N-terminal pro-B-type natriuretic peptide, interleukin 6, von Willebrand factor, glomerular filtration rate (by the MDRD-4 formula) and time in therapeutic range, increased the predictive value of CHA 2 DS 2 -VASc for cardiovascular events, but not the predictive value of HAS-BLED for major bleeding. Reclassification analyses did not show improvement adding multiple biomarkers. Despite the improvement observed, the added predictive advantage is marginal and the clinical usefulness and net benefit over current clinical scores is lower.

Magnetic phase separation and unusual scenario of its temperature evolution in porous carbon-based nanomaterials doped with Au and Co

NASA Astrophysics Data System (ADS)

Ryzhov, V. A.; Lashkul, A. V.; Matveev, V. V.; Molkanov, P. L.; Kurbakov, A. I.; Kiselev, I. A.; Lisunov, K. G.; Galimov, D.; Lähderanta, E.

2018-01-01

Two porous glassy carbon-based samples doped with Au and Co were investigated. The magnetization study as well as measurements of the nonlinear longitudinal response to a weak ac field (NLR) and electron magnetic resonance give evidences for a presence of magnetic nanoparticles (MNPs) embedded in paramagnetic/ferromagnetic matrix respectively, both samples being in magnetically phase-separated state at temperatures above 300 K. Matrix, forming by paramagnetic centers located in matrix outside the MNPs, reveals exchange interactions providing its ferromagnetic (FM) ordering below TC ≈ 210 K in Au-doped sample and well above 350 K in Co-doped one. For the former, NLR data suggest a percolation character of the matrix long-range FM order, which is mainly caused by a porous amorphous sample structure. Temperature dependence of the magnetization in the Au-doped sample evidences presence of antiferromagnetic (AF) interactions of MNPs with surrounding matrix centers. At magnetic ordering below TC these interactions promote origination of "domains" involving matrix fragment and surrounding MNPs with near opposite orientation of their moments that decreases the magnetostatic energy. On further cooling, the domains exhibit AF ordering below Tcr ∼ 140 K < TC, resulting in formation of a peculiar "ferrimagnet". The porous amorphous structure leads to absence of translational and other symmetry features through the samples that allows canted ordering of magnetic moments in domains and in whole sample providing "canted ferrimagnetism". At low temperatures Ttr ∼ 3 K, "order-oder" transition, evidencing the non-Heisenberg character of this magnetic material, occurs from ordering like "canted ferrimagnet" to FM alignment, which is stimulated by external magnetic field. The data for Co-doped sample imply the similar evolution of magnetic state but at higher temperatures above 350 K. This state exhibits more homogeneous arrangement of the FM nanoparticles and the FM matrix. Order-order transition occurs in it at higher Ttr ∼ 10-15 K as well and followed by formation of long-range FM ordering found earlier by neutron diffraction. Doping of carbon-based nanomaterials by magnetic metals provides advantages for their possible practical applications as Co-doped sample with higher TC (>350 K) and larger remanent magnetization evidences.

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.

White Matter Injuries in Mild Traumatic Brain Injury and Posttraumatic Migraines: Diffusion Entropy Analysis.

PubMed

Delic, Joseph; Alhilali, Lea M; Hughes, Marion A; Gumus, Serter; Fakhran, Saeed

2016-06-01

Purpose To determine the performance of Shannon entropy (SE) as a diagnostic tool in patients with mild traumatic brain injury (mTBI) with posttraumatic migraines (PTMs) and those without PTMs on the basis of analysis of fractional anisotropy (FA) maps. Materials and Methods The institutional review board approved this retrospective study, with waiver of informed consent. FA maps were obtained and neurocognitive testing was performed in 74 patients with mTBI (57 with PTM, 17 without PTM). FA maps were obtained in 22 healthy control subjects and in 20 control patients with migraine headaches. Mean FA and SE were extracted from total brain FA histograms and were compared between patients with mTBI and control subjects and between patients with and those without PTM. Mean FA and SE were correlated with clinical variables and were used to determine the areas under the receiver operating characteristic curve (AUCs) and likelihood ratios for mTBI and development of PTM. Results Patients with mTBI had significantly lower SE (P < .001) and trended toward lower mean FA (P = .07) compared with control subjects. SE inversely correlated with time to recovery (TTR) (r = -0.272, P = .02). Patients with mTBI with PTM had significantly lower SE (P < .001) but not mean FA (P = .15) than did other patients with mTBI. SE provided better discrimination between patients with mTBI and control subjects than mean FA (AUC = 0.92; P = .01), as well as better discrimination between patients with mTBI with PTM and those without PTM (AUC = 0.85; P < .001). SE of less than 0.751 resulted in a 16.1 increased likelihood of having experienced mTBI and a 3.2 increased likelihood of developing PTM. Conclusion SE more accurately reveals mTBI than mean FA, more accurately reveals those patients with mTBI who develop PTM, and inversely correlates with TTR. (©) RSNA, 2016.

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.

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.

Management of asymptomatic gene carriers of transthyretin familial amyloid polyneuropathy

PubMed Central

Barroso, Fabio; González‐Duarte, Alejandra; Conceição, Isabel; Obici, Laura; Keohane, Denis; Amass, Leslie

2016-01-01

ABSTRACT 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 PMID:27273296

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

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

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.

Quality of anticoagulation management with warfarin among outpatients in a tertiary hospital in Addis Ababa, Ethiopia: a retrospective cross-sectional study.

PubMed

Fenta, Teferi Gedif; Assefa, Tamrat; Alemayehu, Bekele

2017-06-06

Warfarin is the most widely used anticoagulant in the world. The difficulty of managing warfarin contributes to great potential for patient harm, both from excessive anticoagulation and insufficient anticoagulation. This study assessed the International Normalized Ratio (INR) control outcome measures and warfarin dose adjustment practices at cardiology and hematology outpatient clinics at a teaching hospital in Addis Ababa, Ethiopia. The study was based on a cross - sectional study design involving 360 retrospective patients' chart review among outpatients who received warfarin for its various indications. The mean frequency of INR monitoring per patient was 62.9 days (17.2-143.7 days). Patients spent 52.2%, 29.0% and 18.8% of the time in sub-therapeutic, therapeutic and supra-therapeutic ranges, respectively. The daily warfarin dose was increased 50.9% and 36.9% and decreased in 52.8% and 60.9% of the time for occurrences of sub-therapeutic and supra-therapeutic INRs to achieve target ranges of 2.0-3.0 and 2.5-3.5, respectively. The quality of anticoagulation management with warfarin among outpatients in Tikur Anbessa Specialized Hospital was sub-optimal. This was reflected by low Time in Therapeutic Range (TTR), longer than recommended INR monitoring frequency, and minimal actions taken to adjust warfarin dose after occurrences of non-therapeutic INRs.

CORRECTIVE ACTION DECISION DOCUMENT FOR AREA 9 UXO LANDFILL, TONOPAH TEST RNGE, CAU 453, REVISION 0, MARCH 1998

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

none

1998-03-01

This Corrective Action Decision Document (CADD) has been prepared for the Area 9 Unexploded Ordnance (UXO) Landfill (Corrective Action Unit [CAU] 453) in accordance with the Federal Facility Agreement and Consent Order (FFACO) of 1996. Corrective Action Unit 453 is located at the Tonopah Test Range (TTR), Nevada, and is comprised of three individual landfill cells located northwest of Area 9. The cells are listed as one Corrective Action Site (CAS) 09-55-001-0952. The landfill cells have been designated as: � Cell A9-1 � Cell A9-2 � Cell A9-3 The purpose of this CADD is to identify and provide a rationalemore » for the selection of a recommended corrective action alternative for CAU 453. The scope of this CADD consists of the following tasks: � Develop corrective action objectives. � Identify corrective action alternative screening criteria. � Develop corrective action alternatives. � Perform detailed and comparative evaluations of the corrective action alternatives in relation to the corrective action objectives and screening criteria. � Recommend and justify a preferred corrective action alternative for the CAU. In June and July 1997, a corrective action investigation was performed that consisted of activities set forth in the Corrective Action Investigation Plan (CAIP) (DOE/NV, 1997). Subsurface investigation of the soils surrounding the cells revealed no contaminants of concern (COCs) above preliminary action levels. The cell contents were not investigated due to the potential for live UXO. Details concerning the analytical and investigation results can be found in Appendix A of this CADD. Based on the potential exposure pathways, the following corrective action objectives have been identified for CAU 453: � Prevent or mitigate human exposure to subsurface soils containing COCs, solid waste, and/or UXO. � Prevent adverse impacts to groundwater quality. Based on the review of existing data, future land use, and current operations at the TTR, the following alternatives have been developed for consideration at the Area 9 UXO Landfill CAU: � Alternative 1 - No Further Action � Alternative 2 - Closure in Place by Administrative Controls � Alternative 3 - Closure in Place by Capping � Alternative 4 - Clean Closure by Removal The corrective action alternatives were evaluated based on four general corrective action standards and five remedy selection decision factors. Based on the results of this evaluation, Alternative 2, Closure in Place by Administrative Controls, was selected as the preferred corrective action alternative. The preferred corrective action alternative was evaluated on its technical merits, focusing on performance, reliability, feasibility, and safety. The alternative was judged to meet all requirements for the technical components evaluated and to represent the most cost-effective corrective action. The alternative meets all applicable state and federal regulations for closure of the site and will reduce potential future exposure pathways to the contents of the landfill. During corrective action implementation, this alternative will present minimal potential threat to site workers. However, appropriate health and safety procedures will be developed and implemented.« less

Genetic testing improves identification of transthyretin amyloid (ATTR) subtype in cardiac amyloidosis.

PubMed

Brown, Emily E; Lee, Yi Zhen Joan; Halushka, Marc K; Steenbergen, Charles; Johnson, Nicole M; Almansa, Johana; Tedford, Ryan J; Cingolani, Oscar; Russell, Stuart D; Sharma, Kavita; Judge, Daniel P

2017-06-01

Amyloidosis is a group of conditions characterized by the accumulation of amyloid deposits in various tissues. Among these disorders, ATTR amyloidosis occurs either with or without a TTR pathogenic variant. Treatment for amyloidosis depends on the subtype, which is often identified through a tissue biopsy followed by liquid chromatography tandem mass spectrometry (LC-MS/MS). Genetic testing may be done to confirm these results for patients with ATTR amyloidosis; however, the necessity of genetic testing after LC-MS/MS has not been evaluated. A retrospective review identified 153 patients diagnosed with biopsy-proven ATTR amyloidosis, and 56 of these patients underwent both genetic testing and LC-MS/MS. LC-MS/MS and proteomics correctly reported the mutant peptide and heterozygosity in 47/56 (84%) cases. It failed to identify two individuals who were homozygous for the ATTRV122I mutation and failed to detect the following mutations in six other individuals: ATTRA19D, ATTRF44L, ATTRT60A, ATTRI68L and ATTRV122I. Therefore, LC-MS/MS is not sufficient to rule out a pathogenic mutation in cases of ATTR amyloid, and genetic testing should be performed in most cases of ATTR amyloidosis. Correct recognition of hereditary ATTR amyloidosis is important for estimating prognosis, proper familial counselling and guiding use of therapies, such as liver transplantation.

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.

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.

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.

Relative potency for altered humoral immunity induced by polybrominated and polychlorinated dioxins/furans in female B6C3F1/N mice.

PubMed

Frawley, Rachel; DeVito, Michael; Walker, Nigel J; Birnbaum, Linda; White, Kimber; Smith, Matthew; Maynor, Timothy; Recio, Leslie; Germolec, Dori

2014-06-01

The use of brominated flame retardants and incineration of bromine-containing materials has lead to an increase in polybrominated dibenzo-p-dioxins and dibenzofurans (PBDD/Fs) in the environment. Measurable amounts of PBDD/Fs have been detected in soil, seafood, and human breast milk and serum. Studies indicate that the relative potencies of some PBDD/Fs based on enzyme induction are equivalent to those of some polychlorinated dibenzo-p-dioxins and dibenzofurans. To assess the humoral immunity relative potencies of PBDD/Fs and compare them to their chlorinated analogs, female B6C3F1/N mice received a single oral exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,7,8-tetrabromodibenzofuran (TBDF), 2,3,7,8-tetrachlorodibenzofuran (TCDF), 1,2,3,7,8-pentabromodibenzofuran (1PeBDF), 1,2,3,7,8-pentachlorodibenzofuran (1PeCDF), 2,3,4,7,8-pentabromodibenzofuran (4PeBDF), 2,3,4,7,8-pentachlorodibenzofuran (4PeCDF), 2,3-dibromo-7,8-dichlorodibenzo-p-dioxin (DBDCDD), or 2,3,7-tribromodibenzo-p-dioxin (TriBDD). Inhibition of the immunoglobulin M (IgM) antibody forming cell response was measured 4 days following immunization with sheep red blood cells. The data were fit to a Hill model to estimate the ED50 for inhibition. Expression of xenobiotic metabolizing enzyme (XME) and thyroxine transport protein (Ttr) genes in liver was measured by PCR to assess aryl hydrocarbon-mediated responses. TCDD, TBDF, TCDF, 1PeBDF, 4PeBDF, 4PeCDF, and DBDCDD suppressed the IgM antibody response and Ttr gene expression, and upregulated phase I XME genes. 1PeCDF suppressed the IgM antibody response but only upregulated phase I XME genes; TriBDD had no effect on antibody response. The rank order of potency (ED50) for these chemicals was TCDD>TBDF>4PeBDF>TCDF/4PeCDF/1PeBDF>1PeCDF. Whereas TCDD was the most potent compound tested, the brominated analogs were more potent than their chlorinated analogs, suggesting that these compounds should be considered in toxic equivalency factor evaluation and risk assessment.

Lumbosacral stenosis in Labrador retriever military working dogs - an exomic exploratory study.

PubMed

Mukherjee, Meenakshi; Jones, Jeryl C; Yao, Jianbo

2017-01-01

Canine lumbosacral stenosis is defined as narrowing of the caudal lumbar and/or sacral vertebral canal. A risk factor for neurologic problems in many large sized breeds, lumbosacral stenosis can also cause early retirement in Labrador retriever military working dogs. Though vital for conservative management of the condition, early detection is complicated by the ambiguous nature of clinical signs of lumbosacral stenosis in stoic and high-drive Labrador retriever military working dogs. Though clinical diagnoses of lumbosacral stenosis using CT imaging are standard, they are usually not performed unless dogs present with clinical symptoms. Understanding the underlying genomic mechanisms would be beneficial in developing early detection methods for lumbosacral stenosis, which could prevent premature retirement in working dogs. The exomes of 8 young Labrador retriever military working dogs (4 affected and 4 unaffected by lumbosacral stenosis, phenotypically selected by CT image analyses from 40 dogs with no reported clinical signs of the condition) were sequenced to identify and annotate exonic variants between dogs negative and positive for lumbosacral stenosis. Two-hundred and fifty-two variants were detected to be homozygous for the wild allele and either homozygous or heterozygous for the variant allele. Seventeen non-disruptive variants were detected that could affect protein effectiveness in 7 annotated (SCN1B, RGS9BP, ASXL3, TTR, LRRC16B, PTPRO, ZBBX) and 3 predicted genes (EEF1A1, DNAJA1, ZFX). No exonic variants were detected in any of the canine orthologues for human lumbar spinal stenosis candidate genes. TTR (transthyretin) gene could be a possible candidate for lumbosacral stenosis in Labrador retrievers based on previous human studies that have reported an association between human lumbar spinal stenosis and transthyretin protein amyloidosis. Other genes identified with exonic variants in this study but with no known published association with lumbosacral stenosis and/or lumbar spinal stenosis could also be candidate genes for future canine lumbosacral stenosis studies but their roles remain currently unknown. Human lumbar spinal stenosis candidate genes also cannot be ruled out as lumbosacral stenosis candidate genes. More definitive genetic investigations of this condition are needed before any genetic test for lumbosacral stenosis in Labrador retriever can be developed.

Determination of viable Salmonellae from potable and source water through PMA assisted qPCR.

PubMed

Singh, Gulshan; Vajpayee, Poornima; Bhatti, Saurabh; Ronnie, Nirmala; Shah, Nimish; McClure, Peter; Shanker, Rishi

2013-07-01

Resource constrained countries identified as endemic zones for pathogenicity of Salmonella bear an economic burden due to recurring expenditure on medical treatment. qPCR used for Salmonella detection could not discriminate between viable and nonviable cells. Propidium monoazide (PMA) that selectively penetrates nonviable cells to cross-link their DNA, was coupled with ttr gene specific qPCR for quantifying viable salmonellae in source/potable waters collected from a north Indian city. Source water (raw water for urban potable water supply) and urban potable water exhibited viable salmonellae in the range of 2.1×10(4)-2.6×10(6) and 2-7160CFU/100mL, respectively. Potable water at water works exhibited DNA from dead cells but no viable cells were detected. PMA assisted qPCR could specifically detect low numbers of live salmonellae in Source and potable waters. This strategy can be used in surveillance of urban potable water distribution networks to map contamination points for better microbial risk management. Copyright © 2013 Elsevier Inc. All rights reserved.

A transthyretin-related protein is functionally expressed in Herbaspirillum seropedicae.

PubMed

Matiollo, Camila; Vernal, Javier; Ecco, Gabriela; Bertoldo, Jean Borges; Razzera, Guilherme; de Souza, Emanuel M; Pedrosa, Fábio O; Terenzi, Hernán

2009-10-02

Transthyretin-related proteins (TRPs) constitute a family of proteins structurally related to transthyretin (TTR) and are found in a large range of bacterial, fungal, plant, invertebrate, and vertebrate species. However, it was recently recognized that both prokaryotic and eukaryotic members of this family are not functionally related to transthyretins. TRPs are in fact involved in the purine catabolic pathway and function as hydroxyisourate hydrolases. An open reading frame encoding a protein similar to the Escherichia coli TRP was identified in Herbaspirillum seropedicae genome (Hs_TRP). It was cloned, overexpressed in E. coli, and purified to homogeneity. Mass spectrometry data confirmed the identity of this protein, and circular dichroism spectrum indicated a predominance of beta-sheet structure, as expected for a TRP. We have demonstrated that Hs_TRP is a 5-hydroxyisourate hydrolase and by site-directed mutagenesis the importance of three conserved catalytic residues for Hs_TRP activity was further confirmed. The production of large quantities of this recombinant protein opens up the possibility of obtaining its 3D-structure and will help further investigations into purine catabolism.

Nevada National Security Site Environmental Report 2016

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

Wills

This Nevada National Security Site Environmental Report (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 National Nuclear Security Administration Nevada Field Office (NNSA/NFO) Environmental Management System and characterize its performance, and (6) highlight significant environmental programs and efforts. This NNSSERmore » summarizes data and compliance status for calendar year 2016 at the Nevada National Security Site (NNSS) and its two Nevada-based 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). NNSA/NFO directs the management and operation of the NNSS and six sites across the nation. In addition to the NNSA itself, the six sites include two in Nevada (NLVF and RSL-Nellis) and four in other states (RSL-Andrews in Maryland, Livermore Operations in California, Los Alamos Operations in New Mexico, and Special Technologies Laboratory in California). Los Alamos, Lawrence Livermore, and Sandia National Laboratories are the principal organizations that sponsor and implement the nuclear weapons programs at the NNSS. National Security Technologies, LLC (NSTec), is the current Management and Operating contractor accountable for the successful execution of work and ensuring that work is performed in compliance with environmental regulations. The six sites all provide support to enhance the NNSS as a location for its multiple missions. The three major NNSS missions include National Security/Defense, Environmental Management, and Nondefense. The major programs that support these missions are Stockpile Stewardship and Management, Nonproliferation and Counterterrorism, Nuclear Emergency Response, Strategic Partnership Projects, Environmental Restoration, Waste Management, Conservation and Renewable Energy, Other Research and Development, and Infrastructure. The major facilities that support the programs include the U1a Facility, Big Explosives Experimental Facility (BEEF), Device Assembly Facility, Dense Plasma Focus Facility, Joint Actinide Shock Physics Experimental Research Facility, Radiological/Nuclear Countermeasures Test and Evaluation Complex, Nonproliferation Test and Evaluation Complex (NPTEC), Radiological/Nuclear Weapons of Mass Destruction Incident Exercise Site, the Area 5 Radioactive Waste Management Complex (RWMC), and the Area 3 Radioactive Waste Management Site (RWMS).« less

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

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.

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

Town of Sandwich, MA | 2012 Annual Report |  NPDES Phase II Small MS4 General Permit

EPA Pesticide Factsheets

2012-07-12

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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

3,3',5-Triiodo-L-thyronine-like activity in effluents from domestic sewage treatment plants detected by in vitro and in vivo bioassays

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

Murata, Tomonori; Yamauchi, Kiyoshi

2008-02-01

Thyroid system-disrupting activity in effluents from municipal domestic sewage treatment plants was detected using three in vitro assays and one in vivo assay. Contaminants in the effluents were extracted by solid-phase extraction (SPE) and eluted stepwise with different organic solvents. The majority of the thyroid system-disrupting activity was detected in the dichloromethane/methanol (1/1) fraction after SPE in all three in vitro assays: competitive assays of 3,3',5-[{sup 125}I]triiodo-L-thyronine ([{sup 125}I]T{sub 3}) binding to the plasma protein transthyretin (TTR assay) and thyroid hormone receptor (TR assay) and T{sub 3}-dependent luciferase assay (Luc assay). Subsequent reverse-phase high-performance liquid chromatography (RP-HPLC) of the dichloromethane/methanolmore » (1/1) fraction separated contaminants potent in the TR and Luc assays from those potent in the TTR assay. The contaminants potent in the TR and Luc assays were also potent in an in vivo short-term gene expression assay in Xenopus laevis (Tadpole assay). The present study demonstrated that the effluents from domestic sewage treatment plants contain contaminants with T{sub 3}-like activity of {approx} 10{sup -10} M T{sub 3}-equivalent concentration (T{sub 3}EQ) and that the TR and Luc assays are powerful in vitro bioassays for detecting thyroid system-disrupting activity in effluents. The availability and applicability of these bioassays for screening contaminants with thyroid system-disrupting activity in the water environment are discussed.« less

CpG island methylator phenotype identifies high risk patients among microsatellite stable BRAF mutated colorectal cancers.

PubMed

Vedeld, Hege Marie; Merok, Marianne; Jeanmougin, Marine; Danielsen, Stine A; Honne, Hilde; Presthus, Gro Kummeneje; Svindland, Aud; Sjo, Ole H; Hektoen, Merete; Eknaes, Mette; Nesbakken, Arild; Lothe, Ragnhild A; Lind, Guro E

2017-09-01

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. © 2017 The Authors International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

Anterior visceral endoderm SMAD4 signaling specifies anterior embryonic patterning and head induction in mice.

PubMed

Li, Cuiling; Li, Yi-Ping; Fu, Xin-Yuan; Deng, Chu-Xia

2010-09-27

SMAD4 serves as a common mediator for signaling of TGF-β superfamily. Previous studies illustrated that SMAD4-null mice die at embryonic day 6.5 (E6.5) due to failure of mesoderm induction and extraembryonic defects; however, functions of SMAD4 in each germ layer remain elusive. To investigate this, we disrupted SMAD4 in the visceral endoderm and epiblast, respectively, using a Cre-loxP mediated approach. We showed that mutant embryos lack of SMAD4 in the visceral endoderm (Smad4(Co/Co);TTR-Cre) died at E7.5-E9.5 without head-fold and anterior embryonic structures. We demonstrated that TGF-β regulates expression of several genes, such as Hex1, Cer1, and Lim1, in the anterior visceral endoderm (AVE), and the failure of anterior embryonic development in Smad4(Co/Co);TTR-Cre embryos is accompanied by diminished expression of these genes. Consistent with this finding, SMAD4-deficient embryoid bodies showed impaired responsiveness to TGF-β-induced gene expression and morphological changes. On the other hand, embryos carrying Cre-loxP mediated disruption of SMAD4 in the epiblasts exhibited relatively normal mesoderm and head-fold induction although they all displayed profound patterning defects in the later stages of gastrulation. Cumulatively, our data indicate that SMAD4 signaling in the epiblasts is dispensable for mesoderm induction although it remains critical for head patterning, which is significantly different from SMAD4 signaling in the AVE, where it specifies anterior embryonic patterning and head induction.

Anterior Visceral Endoderm SMAD4 Signaling Specifies Anterior Embryonic Patterning and Head Induction in Mice

PubMed Central

Li, Cuiling; Li, Yi-Ping; Fu, Xin-Yuan; Deng, Chu-Xia

2010-01-01

SMAD4 serves as a common mediator for signaling of TGF-β superfamily. Previous studies illustrated that SMAD4-null mice die at embryonic day 6.5 (E6.5) due to failure of mesoderm induction and extraembryonic defects; however, functions of SMAD4 in each germ layer remain elusive. To investigate this, we disrupted SMAD4 in the visceral endoderm and epiblast, respectively, using a Cre-loxP mediated approach. We showed that mutant embryos lack of SMAD4 in the visceral endoderm (Smad4Co/Co;TTR-Cre) died at E7.5-E9.5 without head-fold and anterior embryonic structures. We demonstrated that TGF-β regulates expression of several genes, such as Hex1, Cer1, and Lim1, in the anterior visceral endoderm (AVE), and the failure of anterior embryonic development in Smad4Co/Co;TTR-Cre embryos is accompanied by diminished expression of these genes. Consistent with this finding, SMAD4-deficient embryoid bodies showed impaired responsiveness to TGF-β-induced gene expression and morphological changes. On the other hand, embryos carrying Cre-loxP mediated disruption of SMAD4 in the epiblasts exhibited relatively normal mesoderm and head-fold induction although they all displayed profound patterning defects in the later stages of gastrulation. Cumulatively, our data indicate that SMAD4 signaling in the epiblasts is dispensable for mesoderm induction although it remains critical for head patterning, which is significantly different from SMAD4 signaling in the AVE, where it specifies anterior embryonic patterning and head induction. PMID:20941375

Profound CD4+/CCR5+ T cell expansion is induced by CD8+ lymphocyte depletion but does not account for accelerated SIV pathogenesis

PubMed Central

Okoye, Afam; Park, Haesun; Rohankhedkar, Mukta; Coyne-Johnson, Lia; Lum, Richard; Walker, Joshua M.; Planer, Shannon L.; Legasse, Alfred W.; Sylwester, Andrew W.; Piatak, Michael; Lifson, Jeffrey D.; Sodora, Donald L.; Villinger, Francois; Axthelm, Michael K.; Schmitz, Joern E.

2009-01-01

Depletion of CD8+ lymphocytes during acute simian immunodeficiency virus (SIV) infection of rhesus macaques (RMs) results in irreversible prolongation of peak-level viral replication and rapid disease progression, consistent with a major role for CD8+ lymphocytes in determining postacute-phase viral replication set points. However, we report that CD8+ lymphocyte depletion is also associated with a dramatic induction of proliferation among CD4+ effector memory T (TEM) cells and, to a lesser extent, transitional memory T (TTrM) cells, raising the question of whether an increased availability of optimal (activated/proliferating), CD4+/CCR5+ SIV “target” cells contributes to this accelerated pathogenesis. In keeping with this, depletion of CD8+ lymphocytes in SIV− RMs led to a sustained increase in the number of potential CD4+ SIV targets, whereas such depletion in acute SIV infection led to increased target cell consumption. However, we found that the excess CD4+ TEM cell proliferation of CD8+ lymphocyte–depleted, acutely SIV-infected RMs was completely inhibited by interleukin (IL)-15 neutralization, and that this inhibition did not abrogate the rapidly progressive infection in these RMs. Moreover, although administration of IL-15 during acute infection induced robust CD4+ TEM and TTrM cell proliferation, it did not recapitulate the viral dynamics of CD8+ lymphocyte depletion. These data suggest that CD8+ lymphocyte function has a larger impact on the outcome of acute SIV infection than the number and/or activation status of target cells available for infection and viral production. PMID:19546246

THE INVOLVEMENT OF HUMAN MONOGENIC CARDIOMYOPATHY GENES IN EXPERIMENTAL POLYGENIC CARDIAC HYPERTROPHY.

PubMed

Prestes, Priscilla R; Marques, Francine Z; Lopez-Campos, Guillermo; Lewandowski, Paul; Delbridge, Lea M D; Charchar, Fadi J; Harrap, Stephen B

2018-05-18

Hypertrophic cardiomyopathy thickens heart muscles reducing functionality and increasing risk of cardiac disease and morbidity. Genetic factors are involved, but their contribution is poorly understood. We used the hypertrophic heart rat (HHR), a unique normotensive polygenic model of cardiac hypertrophy and heart failure to investigate the role of genes associated with monogenic human cardiomyopathy. We selected 42 genes involved in monogenic human cardiomyopathies to study: 1) DNA variants, by sequencing the whole-genome of 13-week old HHR and age-matched normal heart rat (NHR), its genetic control strain; 2) mRNA expression, by targeted RNA-sequencing in left ventricles of HHR and NHR at five ages (2-days old, 4-, 13-, 33- and 50-weeks old) compared to human idiopathic dilated data; and 3) microRNA expression, with rat microRNA microarrays in left ventricles of 2-days old HHR and age-matched NHR. We also investigated experimentally validated microRNA-mRNA interactions. Whole-genome sequencing revealed unique variants mostly located in non-coding regions of HHR and NHR. We found 29 genes differentially expressed in at least one age. Genes encoding desmoglein 2 (Dsg2) and transthyretin (Ttr) were significantly differentially expressed at all ages in the HHR, but only Ttr was also differentially expressed in human idiopathic cardiomyopathy. Lastly, only two microRNAs differentially expressed in the HHR were present in our comparison of validated microRNA-mRNA interactions. These two microRNAs interact with five of the genes studied. Our study shows that genes involved in monogenic forms of human cardiomyopathies may also influence polygenic forms of the disease.

Retinoid receptors, transporters, and metabolizers as therapeutic targets in late onset Alzheimer disease.

PubMed

Goodman, Ann B

2006-12-01

Vitamin A (retinoid) is required in the adult brain to enable cognition, learning, and memory. While brain levels of retinoid diminish over the course of normal ageing, retinoid deficit is greater in late onset Alzheimer disease (LOAD) brains than in normal-aged controls. This paper reviews recent evidence supporting these statements and further suggests that genes necessary for the synthesis, transport and function of retinoid to and within the ageing brain are appropriate targets for treatment of LOAD. These genes tend to be clustered with genes that have been proposed as candidates in LOAD, are found at chromosomal regions linked to LOAD, and suggest the possibility of an overall coordinated regulation. This phenomenon is termed Chromeron and is analogous to the operon mechanism observed in prokaryotes. Suggested treatment targets are the retinoic-acid inactivating enzymes (CYP26)s, the retinol binding and transport proteins, retinol-binding protein (RBP)4 and transthyretin (TTR), and the retinoid receptors. TTR as a LOAD target is the subject of active investigation. The retinoid receptors and the retinoid-inactivating enzymes have previously been proposed as targets. This is the first report to suggest that RBP4 is an amenable treatment target in LOAD. RBP4 is elevated in type-2 diabetes and obesity, conditions associated with increased risk for LOAD. Fenretinide, a novel synthetic retinoic acid (RA) analog lowers RBP4 in glucose intolerant obese mice. The feasibility of using fenretinide either as an adjunct to present LOAD therapies, or on its own as an early prevention strategy should be determined. (c) 2006 Wiley-Liss, Inc.

Targeted delivery of antisense oligonucleotides to hepatocytes using triantennary N-acetyl galactosamine improves potency 10-fold in mice.

PubMed

Prakash, Thazha P; Graham, Mark J; Yu, Jinghua; Carty, Rick; Low, Audrey; Chappell, Alfred; Schmidt, Karsten; Zhao, Chenguang; Aghajan, Mariam; Murray, Heather F; Riney, Stan; Booten, Sheri L; Murray, Susan F; Gaus, Hans; Crosby, Jeff; Lima, Walt F; Guo, Shuling; Monia, Brett P; Swayze, Eric E; Seth, Punit P

2014-07-01

Triantennary N-acetyl galactosamine (GalNAc, GN3: ), a high-affinity ligand for the hepatocyte-specific asialoglycoprotein receptor (ASGPR), enhances the potency of second-generation gapmer antisense oligonucleotides (ASOs) 6-10-fold in mouse liver. When combined with next-generation ASO designs comprised of short S-cEt (S-2'-O-Et-2',4'-bridged nucleic acid) gapmer ASOs, ∼ 60-fold enhancement in potency relative to the parent MOE (2'-O-methoxyethyl RNA) ASO was observed. GN3: -conjugated ASOs showed high affinity for mouse ASGPR, which results in enhanced ASO delivery to hepatocytes versus non-parenchymal cells. After internalization into cells, the GN3: -ASO conjugate is metabolized to liberate the parent ASO in the liver. No metabolism of the GN3: -ASO conjugate was detected in plasma suggesting that GN3: acts as a hepatocyte targeting prodrug that is detached from the ASO by metabolism after internalization into the liver. GalNAc conjugation also enhanced potency and duration of the effect of two ASOs targeting human apolipoprotein C-III and human transthyretin (TTR) in transgenic mice. The unconjugated ASOs are currently in late stage clinical trials for the treatment of familial chylomicronemia and TTR-mediated polyneuropathy. The ability to translate these observations in humans offers the potential to improve therapeutic index, reduce cost of therapy and support a monthly dosing schedule for therapeutic suppression of gene expression in the liver using ASOs. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

Relative Potency for Altered Humoral Immunity Induced by Polybrominated and Polychlorinated Dioxins/Furans in Female B6C3F1/N Mice

PubMed Central

Frawley, Rachel; DeVito, Michael; Walker, Nigel J.; Birnbaum, Linda; White, Kimber; Smith, Matthew; Maynor, Timothy; Recio, Leslie; Germolec, Dori

2014-01-01

The use of brominated flame retardants and incineration of bromine-containing materials has lead to an increase in polybrominated dibenzo-p-dioxins and dibenzofurans (PBDD/Fs) in the environment. Measurable amounts of PBDD/Fs have been detected in soil, seafood, and human breast milk and serum. Studies indicate that the relative potencies of some PBDD/Fs based on enzyme induction are equivalent to those of some polychlorinated dibenzo-p-dioxins and dibenzofurans. To assess the humoral immunity relative potencies of PBDD/Fs and compare them to their chlorinated analogs, female B6C3F1/N mice received a single oral exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,7,8-tetrabromodibenzofuran (TBDF), 2,3,7,8-tetrachlorodibenzofuran (TCDF), 1,2,3,7,8-pentabromodibenzofuran (1PeBDF), 1,2,3,7,8-pentachlorodibenzofuran (1PeCDF), 2,3,4,7,8-pentabromodibenzofuran (4PeBDF), 2,3,4,7,8-pentachlorodibenzofuran (4PeCDF), 2,3-dibromo-7,8-dichlorodibenzo-p-dioxin (DBDCDD), or 2,3,7-tribromodibenzo-p-dioxin (TriBDD). Inhibition of the immunoglobulin M (IgM) antibody forming cell response was measured 4 days following immunization with sheep red blood cells. The data were fit to a Hill model to estimate the ED50 for inhibition. Expression of xenobiotic metabolizing enzyme (XME) and thyroxine transport protein (Ttr) genes in liver was measured by PCR to assess aryl hydrocarbon-mediated responses. TCDD, TBDF, TCDF, 1PeBDF, 4PeBDF, 4PeCDF, and DBDCDD suppressed the IgM antibody response and Ttr gene expression, and upregulated phase I XME genes. 1PeCDF suppressed the IgM antibody response but only upregulated phase I XME genes; TriBDD had no effect on antibody response. The rank order of potency (ED50) for these chemicals was TCDD>TBDF>4PeBDF>TCDF/4PeCDF/1PeBDF>1PeCDF. Whereas TCDD was the most potent compound tested, the brominated analogs were more potent than their chlorinated analogs, suggesting that these compounds should be considered in toxic equivalency factor evaluation and risk assessment. PMID:24713691

Pharmacokinetics of taurolidine following repeated intravenous infusions measured by HPLC-ESI-MS/MS of the derivatives taurultame and taurinamide in glioblastoma patients.

PubMed

Stendel, Ruediger; Scheurer, Louis; Schlatterer, Kathrin; Stalder, Urs; Pfirrmann, Rolf W; Fiss, Ingo; Möhler, Hanns; Bigler, Laurent

2007-01-01

Taurolidine is known to have antimicrobial activity. Furthermore, at lower concentrations, it has been found to exert a selective antineoplastic effect in vitro and in vivo. The aim of this study was to investigate the pharmacokinetics of taurolidine in vivo following repeated intravenous infusion in a schedule used for the treatment of glioblastoma. As a prerequisite, the pharmacokinetics of taurolidine in human blood plasma and whole blood in vitro was investigated. The pharmacokinetics of taurolidine and its derivatives taurultame and taurinamide were investigated in human blood plasma and in whole blood in vitro using blood from a healthy male volunteer. During repeated intravenous infusion therapy with taurolidine, plasma samples were taken every hour for a period of 13 hours per day in seven patients (three male, four female; mean age 48.4 +/- 12.8 years, range 27-66 years) with a glioblastoma. Following dansyl derivatisation, the concentrations of taurultame and taurinamide were determined using a new method based on high-performance liquid chromatography (HPLC) online coupled to electrospray ionisation tandem mass spectrometry (ESI-MS/MS) in the multiple reaction monitoring mode. Under the experimental conditions used, taurolidine could not be determined directly and was back-calculated from the taurultame and taurinamide values. The new HPLC-ESI-MS/MS method demonstrated high accuracy and reproducibility. In vitro plasma concentrations of taurultame and taurinamide remained constant over the incubation period. In whole blood in vitro, a time-dependent formation of taurinamide was observed. At the start of the incubation, the taurultame-taurinamide ratio (TTR) was 0.95 at an initial taurolidine concentration of 50 microg/mL, and 1.69 at 100 microg/mL. The concentration of taurultame decreased at the same rate as the taurinamide concentration increased, showing logarithmic kinetics. The calculated taurolidine concentration remained largely constant over the 6-hour incubation period. During repeated infusions in patients, calculated plasma concentrations of taurolidine showed a strong increase after the start of each infusion and continued to increase until the end of infusion, followed by a rapid decline. The TTR was found to fluctuate between 0.1 and 0.3, depending on the relation to the previous or next infusion period. The volume of distribution was markedly higher for taurolidine, taurultame and taurinamide than the plasma volume. Taurolidine displayed a stable pattern of derivatives in plasma in vitro, whereas in whole blood, a time- and concentration-dependent conversion was apparent. In patients, the calculated average taurolidine plasma concentration, achieved with the repeated infusion regimen, was in the antineoplastic-effective concentration range. The tissue concentrations of taurolidine and taurultame are expected to be higher than the plasma concentrations, taking into account the calculated volumes of distribution. Repeated infusion of taurolidine is the therapeutically adequate mode of administration for the indication of glioblastoma.

Stop and Go - Waves of Tarsier Dispersal Mirror the Genesis of Sulawesi Island.

PubMed

Driller, Christine; Merker, Stefan; Perwitasari-Farajallah, Dyah; Sinaga, Walberto; Anggraeni, Novita; Zischler, Hans

2015-01-01

The Indonesian island of Sulawesi harbors a highly endemic and diverse fauna sparking fascination since long before Wallace's contemplation of biogeographical patterns in the region. Allopatric diversification driven by geological or climatic processes has been identified as the main mechanism shaping present faunal distribution on the island. There is both consensus and conflict among range patterns of terrestrial species pointing to the different effects of vicariant events on once co-distributed taxa. Tarsiers, small nocturnal primates with possible evidence of an Eocene fossil record on the Asian mainland, are at present exclusively found in insular Southeast Asia. Sulawesi is hotspot of tarsier diversity, whereby island colonization and subsequent radiation of this old endemic primate lineage remained largely enigmatic. To resolve the phylogeographic history of Sulawesi tarsiers we analyzed an island-wide sample for a set of five approved autosomal phylogenetic markers (ABCA1, ADORA3, AXIN1, RAG1, and TTR) and the paternally inherited SRY gene. We constructed ML and Bayesian phylogenetic trees and estimated divergence times between tarsier populations. We found that their arrival at the Proto-Sulawesi archipelago coincided with initial Miocene tectonic uplift and hypothesize that tarsiers dispersed over the region in distinct waves. Intra-island diversification was spurred by land emergence and a rapid succession of glacial cycles during the Plio-Pleistocene. Some tarsier range boundaries concur with spatial limits in other taxa backing the notion of centers of faunal endemism on Sulawesi. This congruence, however, has partially been superimposed by taxon-specific dispersal patterns.

Macrofaunal assemblages from mud volcanoes in the Gulf of Cadiz: abundance, biodiversity and diversity partitioning across spatial scales

NASA Astrophysics Data System (ADS)

Cunha, M. R.; Rodrigues, C. F.; Génio, L.; Hilário, A.; Ravara, A.; Pfannkuche, O.

2012-12-01

The Gulf of Cadiz is an extensive seepage area in the South Iberian Margin (NE Atlantic) encompassing over 40 mud volcanoes (MVs) at depths ranging from 200 to 4000 m. The area has a long geologic history and a central biogeographic location with a complex circulation assuring oceanographic connectivity with the Mediterranean Sea, Equatorial and Northern Atlantic regions. The geodynamics of the region promotes a notorious diversity in the seep regime despite the relatively low fluxes of hydrocarbon-rich gases. We analyse quantitative samples taken during the cruises TTR14, TTR15 and MSM01-03 in seven mud volcanoes grouped into Shallow MVs (Mercator: 350 m, Kidd: 500 m, Meknès: 700 m) and Deep MVs (Captain Arutyunov: 1300 m, Carlos Ribeiro: 2200 m, Bonjardim: 3000 m, Porto: 3900 m) and two additional reference sites (ca. 550 m). Macrofauna (retained by a 500 μm sieve) was identified to species level whenever possible. The samples yielded modest abundances (70-1567 ind. per 0.25 m2) but a number of species among the highest ever reported for cold seeps. Among the 366 recorded species, 22 were symbiont-hosting bivalves (Thyasiridae, Vesicomyidae, Solemyidae) and tubeworms (Siboglinidae). The multivariate analyses indicated significant differences between Shallow and Deep MVs: The environmental conditions at the Shallow MVs makes them highly permeable to the penetration of background fauna leading to high diversity of the attendant assemblages (H': 2.92-3.94; ES(100): 28.3-45.0; J': 0.685-0.881). The Deep MVs showed, in general, contrasting features but were more heterogeneous (H': 1.41-3.06; ES(100): 10.5-30.5; J': 0.340-0.852) and often dominated by one or more siboglinid species. The rarefaction curves confirmed the differences in biodiversity of Deep and Shallow MVs as well as the approximation of the latter to the reference sites. The Bray-Curtis dissimilarity demonstrated the high β-diversity of the assemblages, especially in pairwise comparisons involving samples from the deeper MVs. Diversity partitioning assessed for species richness, Hurlbert's expected number of species and Shannon-Wiener index confirmed the high β-diversity across different spatial scales (within MVs, between MVs, between Deep and Shallow MVs). We suggest that historical and contemporary factors with differential synergies at different depths contribute to the high α-, β- and γ-diversity of the mud volcano faunal assemblages in the Gulf of Cadiz.

Macrofaunal assemblages from mud volcanoes in the Gulf of Cadiz: abundance, biodiversity and diversity partitioning across spatial scales

NASA Astrophysics Data System (ADS)

Cunha, M. R.; Rodrigues, C. F.; Génio, L.; Hilário, A.; Ravara, A.; Pfannkuche, O.

2013-04-01

The Gulf of Cadiz is an extensive seepage area in the south Iberian margin (NE Atlantic) encompassing over 40 mud volcanoes (MVs) at depths ranging from 200 to 4000 m. The area has a long geologic history and a central biogeographic location with a complex circulation ensuring oceanographic connectivity with the Mediterranean Sea, equatorial and North Atlantic regions. The geodynamics of the region promotes a notorious diversity in the seep regime despite the relatively low fluxes of hydrocarbon-rich gases. We analyse quantitative samples taken during the cruises TTR14, TTR15 and MSM01-03 in seven mud volcanoes grouped into Shallow MVs (Mercator: 350 m, Kidd: 500 m, Meknès: 700 m) and Deep MVs (Captain Arutyunov: 1300 m, Carlos Ribeiro: 2200 m, Bonjardim: 3000 m, Porto: 3900 m) and two additional Reference sites (ca. 550 m). Macrofauna (retained by a 500 μm sieve) was identified to species level whenever possible. The samples yielded modest abundances (70-1567 individuals per 0.25 m2), but the local and regional number of species is among the highest ever reported for cold seeps. Among the 366 recorded species, 22 were symbiont-hosting bivalves (Thyasiridae, Vesicomyidae, Solemyidae) and tubeworms (Siboglinidae). The multivariate analyses supported the significant differences between Shallow and Deep MVs: The environmental conditions at the Shallow MVs make them highly permeable to the penetration of background fauna leading to high diversity of the attendant assemblages (H': 2.92-3.94; ES(100): 28.3-45.0; J': 0.685-0.881). The Deep MV assemblages showed, in general, contrasting features but were more heterogeneous (H': 1.41-3.06; ES(100): 10.5-30.5; J': 0.340-0.852) and often dominated by one or more siboglinid species. The rarefaction curves confirmed the differences in biodiversity of Deep and Shallow MVs as well as the convergence of the latter to the Reference sites. The Bray-Curtis dissimilarity demonstrated the high β-diversity of the assemblages, especially in pairwise comparisons involving samples from the Deep MVs. Diversity partitioning assessed for species richness, Hurlbert's expected number of species and Shannon-Wiener index confirmed the high β-diversity across different spatial scales (within MVs, between MVs, between Deep and Shallow MVs). We suggest that historical and contemporary factors with differential synergies at different depths contribute to the high α-, β- and γ-diversity of the mud volcano faunal assemblages in the Gulf of Cadiz.

Validation of the 16-Gene Recurrence Score in patients with locoregional, high-risk renal cell carcinoma from a phase 3 trial of adjuvant sunitinib.

PubMed

Rini, Brian I; Escudier, Bernard; Martini, Jean-Francois; Magheli, Ahmed; Svedman, Christer; Lopatin, Margarita; Knezevic, Dejan; Goddard, Audrey D; Febbo, Phillip G; Li, Rachel; Lin, Xun; Valota, Olga; Staehler, Michael; Motzer, Robert J; Ravaud, Alain

2018-05-17

Adjuvant sunitinib prolonged disease-free survival (DFS) (hazard ratio [HR] 0.76) in patients with locoregional high-risk renal cell carcinoma (RCC) in the S-TRAC trial (ClinicalTrials.gov NCT00375674). The 16-gene Recurrence Score (RS) assay was previously developed and validated to estimate risk for disease recurrence in patients with RCC post-nephrectomy. This analysis further validated the prognostic value of RS assay in patients from S-TRAC and explored association of RS results with prediction of sunitinib benefit. The analysis was prospectively designed with prespecified genes, algorithm, endpoints, and analytical methods. Primary RCC was available from 212 patients with informed consent; primary analysis focused on patients with T3 RCC. Gene expression was quantitated by RT-PCR. Time to recurrence (TTR), DFS, and renal cancer-specific survival (RCSS) were analyzed using Cox proportional hazards regression. Results: Baseline characteristics were similar between patients with and without RS results, and between the sunitinib and placebo arms among patients with RS results. RS results predicted TTR, DFS, and RCSS in both arms, with the strongest results observed in the placebo arm. When high versus low RS groups were compared, HR for recurrence was 9.18 (95% CI, 2.15-39.24; P < 0.001) in the placebo arm; interaction of RS results with treatment was not significant. Conclusions: The strong prognostic performance of the 16-gene RS assay was confirmed in S-TRAC, and the RS assay is now supported by level IB evidence. RS results may help identify patients at high risk for recurrence who may derive higher absolute benefit from adjuvant therapy. Copyright ©2018, American Association for Cancer Research.

Paraspinous Lidocaine Injection for Chronic Nonspecific Low Back Pain: A Randomized Controlled Clinical Trial.

PubMed

Imamura, Marta; Imamura, Satiko Tomikawa; Targino, Rosa Alves; Morales-Quezada, León; Onoda Tomikawa, Luis C; Onoda Tomikawa, Luis G; Alfieri, Fabio M; Filippo, Thais R; da Rocha, Ivan D; Neto, Raul Bolliger; Fregni, Felipe; Battistella, Linamara Rizzo

2016-05-01

In this large, sham-controlled, randomized trial, we examined the efficacy of the combination of standard treatment and paraspinous lidocaine injection compared with standard therapy alone in subjects with chronic low back pain. There is little research-based evidence for the routine clinical use of paraspinous lidocaine injection for low back pain. A total of 378 subjects with nonspecific chronic low back pain were randomized to 3 groups: paraspinous lidocaine injection, analgesics, and exercises (group 1, LID-INJ); sham paraspinous lidocaine injection, analgesics, and exercises (group 2, SH-INJ); and analgesics and exercises (group 3, STD-TTR). A blinded rater assessed the study outcomes at 3 time points: baseline, after treatment, and after 3 months of follow-up. There were increased frequency of pain responses and better low back functional scores in the LID-INJ group compared with the SH-INJ and STD-TTR groups. These effects remained at the 3-month follow-up but differed between all 3 groups. There were significant changes in pain threshold immediately after treatment, supporting the effects of this intervention in reducing central sensitization. Paraspinous lidocaine injection therapy is not associated with a higher risk of adverse effects compared with conventional treatment and sham injection. Its effects on hyperalgesia might correlate with changes in central sensitization. NCT02387567. There are few data to support paraspinous lidocaine injection use in patients with nonspecific chronic low back pain. Our results show that this therapy when combined with standard therapy significantly increases the number of responders versus standard treatment alone. Its effects on hyperalgesia might correlate with a change in central sensitization. Copyright © 2016. Published by Elsevier Inc.

Unraveling the different toxic effect of flufenoxuron on the thyroid endocrine system of the Mongolia racerunner (Eremias Argus) at different stages.

PubMed

Chang, Jing; Li, Wei; Guo, Baoyuan; Xu, Peng; Wang, Yinghuan; Li, Jianzhong; Wang, Huili

2017-04-01

Flufenoxuron is a widely used pesticide to inhibit the synthesis of chitin during insect development and its effect on the growth of lizards has been little addressed. The hypothalamus-pituitary-thyroid (HPT) axis plays an important role on the development of lizards. In this study, the lizards at different development stages (proliferation and resting stages) were exposed to flufenoxuron for 21 days. The plasma thyroid hormone levels, thyroid gland histopathology and expression profiles of thyroid hormone receptors (trα, trβ), deiodinases (dio1, dio2), and transthyretin (ttr) genes were measured to evaluated the toxic effect of flufenoxuron on the HPT axis at different stages. The flufenoxuron exposure showed more seriously effect on the triiodothyronine (T3) level at resting phase than that at proliferation stage. The follicle epithelium cell height in the thyroid was only significantly increased when the exposed male lizards were at proliferation stage. The alteration of HPT axis-related genes expression was gender and tissue dependent after flufenoxuron treatment. The lizards exposed to flufenoxuron showed that the trα, trβ, dio1, dio2, and ttr genes in the female liver were more sensitive at the proliferation stage than that at the resting stage. In the male brain, the expressions of trα, trβ, dio1, and dio2 gene were significant decreased at proliferation stage while significant increased at resting stage after flufenoxuron exposure. Therefore, the thyroid endocrine system of lizards could be affected by the flufenoxuron exposure and the different development stage should also be considered when study the toxic effect of contaminants on the lizards. Copyright © 2017 Elsevier Ltd. All rights reserved.

Abundance of Plasma Antioxidant Proteins Confers Tolerance to Acute Hypobaric Hypoxia Exposure

PubMed Central

Padhy, Gayatri; Sethy, Niroj Kumar; Ganju, Lilly

2013-01-01

Abstract Padhy, Gayatri, Niroj Kumar Sethy, Lilly Ganju, and Kalpana Bhargava. Abundance of plasma antioxidant proteins confers tolerance to acute hypobaric hypoxia exposure. High Alt Med Biol 14:289–297, 2013—Systematic identification of molecular signatures for hypobaric hypoxia can aid in better understanding of human adaptation to high altitude. In an attempt to identify proteins promoting hypoxia tolerance during acute exposure to high altitude, we screened and identified hypoxia tolerant and susceptible rats based on hyperventilation time to a simulated altitude of 32,000 ft (9754 m). The hypoxia tolerance was further validated by estimating 8-isoprotane levels and protein carbonyls, which revealed that hypoxia tolerant rats possessed significant lower plasma levels as compared to susceptible rats. We used a comparative plasma proteome profiling approach using 2-dimensional gel electrophoresis (2-DGE) combined with MALDI TOF/TOF for both groups, along with an hypoxic control group. This resulted in the identification of 19 differentially expressed proteins. Seven proteins (TTR, GPx-3, PON1, Rab-3D, CLC11, CRP, and Hp) were upregulated in hypoxia tolerant rats, while apolipoprotein A-I (APOA1) was upregulated in hypoxia susceptible rats. We further confirmed the consistent higher expression levels of three antioxidant proteins (PON1, TTR, and GPx-3) in hypoxia-tolerant animals using ELISA and immunoblotting. Collectively, these proteomics-based results highlight the role of antioxidant enzymes in conferring hypoxia tolerance during acute hypobaric hypoxia. The expression of these antioxidant enzymes could be used as putative biomarkers for screening altitude adaptation as well as aiding in better management of altered oxygen pathophysiologies. PMID:24067188

Comparison of Outcomes After Fluorouracil-Based Adjuvant Therapy for Stages II and III Colon Cancer Between 1978 to 1995 and 1996 to 2007: Evidence of Stage Migration From the ACCENT Database

PubMed Central

Shi, Qian; Andre, Thierry; Grothey, Axel; Yothers, Greg; Hamilton, Stanley R.; Bot, Brian M.; Haller, Daniel G.; Van Cutsem, Eric; Twelves, Chris; Benedetti, Jacqueline K.; O'Connell, Michael J.; Sargent, Daniel J.

2013-01-01

Purpose With improved patient care, better diagnosis, and more treatment options after tumor recurrence, outcomes after fluorouracil (FU) -based treatment are expected to have improved over time in early-stage colon cancer. Data from 18,449 patients enrolled onto 21 phase III trials conducted from 1978 to 2002 were evaluated for potential differences in time to recurrence (TTR), time from recurrence to death (TRD), and overall survival (OS) with regard to FU-based adjuvant regimens. Methods Trials were predefined as old versus newer era using initial accrual before or after 1995. Outcomes were compared between patients enrolled onto old- or newer-era trials, stratified by stage. Results Within the first 3 years, recurrence rates were lower in newer- versus old-era trials for patients with stage II disease, with no differences among those with stage III disease. Both TRD and OS were significantly longer in newer-era trials overall and within each stage. The lymph node (LN) ratio (ie, number of positive nodes divided by total nodes harvested) in those with stage III disease declined over time. TTR improved slightly, with larger number of LNs examined in both stages. Conclusion Improved TRD in newer trials supports the premise that more aggressive intervention (oxaliplatin- and irinotecan-based chemotherapy and/or surgery for recurrent disease) improves OS for patients previously treated in the adjuvant setting. Lower recurrence rates with identical treatments in those with stage II disease enrolled onto newer-era trials reflect stage migration over time, calling into question historical data related to the benefit of FU-based adjuvant therapy in such patients. PMID:23980089

Effect of hyperinsulinaemia-hyperaminoacidaemia on leg muscle protein synthesis and breakdown: reassessment of the two-pool arterio-venous balance model.

PubMed

Smith, Gordon I; Patterson, Bruce W; Klein, Seth J; Mittendorfer, Bettina

2015-09-15

Accurate measurement of muscle protein turnover is critical for understanding the physiological processes underlying muscle atrophy and hypertrophy. Several mathematical approaches, used in conjunction with a tracer amino acid infusion, have been described to derive protein synthesis and breakdown rates from a two-pool (artery-vein) model. Despite apparently common underlying principles, these approaches differ significantly (some seem to not take into account arterio-venous shunting of amino acids, which comprises ∼80-90% of amino acids appearing in the vein) and most do not specify how tracer enrichment (i.e. mole percent excess (MPE) or tracer-to-tracee ratio (TTR)) and amino acid concentration (i.e. unlabelled only or total labelled plus unlabelled) should be expressed, which could have a significant impact on the outcome when using stable isotope labelled tracers. We developed equations that avoid these uncertainties and used them to calculate leg phenylalanine (Phe) kinetics in subjects who received a [(2) H5 ]Phe tracer infusion during postabsorptive conditions and during a hyperinsulinaemic-euglycaemic clamp with concomitant protein ingestion. These results were compared with those obtained by analysing the same data with previously reported equations. Only some of them computed the results correctly when used with MPE as the enrichment measure and total (tracer+tracee) Phe concentrations; errors up to several-fold in magnitude were noted when the same approaches were used in conjunction with TTR and/or unlabelled concentration only, or when using the other approaches (irrespective of how concentration and enrichment are expressed). Our newly developed equations should facilitate accurate calculation of protein synthesis and breakdown rates. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

Whole-genome sequence-based analysis of thyroid function.

PubMed

Taylor, Peter N; Porcu, Eleonora; Chew, Shelby; Campbell, Purdey J; Traglia, Michela; Brown, Suzanne J; Mullin, Benjamin H; Shihab, Hashem A; Min, Josine; Walter, Klaudia; Memari, Yasin; Huang, Jie; Barnes, Michael R; Beilby, John P; Charoen, Pimphen; Danecek, Petr; Dudbridge, Frank; Forgetta, Vincenzo; Greenwood, Celia; Grundberg, Elin; Johnson, Andrew D; Hui, Jennie; Lim, Ee M; McCarthy, Shane; Muddyman, Dawn; Panicker, Vijay; Perry, John R B; Bell, Jordana T; Yuan, Wei; Relton, Caroline; Gaunt, Tom; Schlessinger, David; Abecasis, Goncalo; Cucca, Francesco; Surdulescu, Gabriela L; Woltersdorf, Wolfram; Zeggini, Eleftheria; Zheng, Hou-Feng; Toniolo, Daniela; Dayan, Colin M; Naitza, Silvia; Walsh, John P; Spector, Tim; Davey Smith, George; Durbin, Richard; Richards, J Brent; Sanna, Serena; Soranzo, Nicole; Timpson, Nicholas J; Wilson, Scott G

2015-03-06

Normal thyroid function is essential for health, but its genetic architecture remains poorly understood. Here, for the heritable thyroid traits thyrotropin (TSH) and free thyroxine (FT4), we analyse whole-genome sequence data from the UK10K project (N=2,287). Using additional whole-genome sequence and deeply imputed data sets, we report meta-analysis results for common variants (MAF≥1%) associated with TSH and FT4 (N=16,335). For TSH, we identify a novel variant in SYN2 (MAF=23.5%, P=6.15 × 10(-9)) and a new independent variant in PDE8B (MAF=10.4%, P=5.94 × 10(-14)). For FT4, we report a low-frequency variant near B4GALT6/SLC25A52 (MAF=3.2%, P=1.27 × 10(-9)) tagging a rare TTR variant (MAF=0.4%, P=2.14 × 10(-11)). All common variants explain ≥20% of the variance in TSH and FT4. Analysis of rare variants (MAF<1%) using sequence kernel association testing reveals a novel association with FT4 in NRG1. Our results demonstrate that increased coverage in whole-genome sequence association studies identifies novel variants associated with thyroid function.

Understanding the Disease Course and Therapeutic Benefit of Tafamidis Across Real-World Studies of Hereditary Transthyretin Amyloidosis with Polyneuropathy: A Proof of Concept for Integrative Data Analytic Approaches.

PubMed

Serrano, Daniel; Atzinger, Christopher B; Botteman, Marc F

2018-06-01

Hereditary transthyretin (TTR) amyloidosis with polyneuropathy (hATTR-PN) is a rare, autosomal dominant amyloidosis characterized primarily by progressive ascending sensorimotor neuropathy often associated with  autonomic involvement. hATTR-PN is caused by a mutation in the TTR gene leading to protein misfolding and amyloid accumulation in peripheral nerves and vital organs. The latest global prevalence estimates point to 10,000 cases worldwide, with an upper end of about 40,000. Tafamidis has been approved in over 40 countries for delaying neurologic disease progression in early-stage hATTR-PN. Multiple observational studies have examined clinical outcomes in hATTR-PN patients treated with tafamidis in the routine clinical setting. Integrative data analysis (IDA) is a technique for optimally constructing synthetic treatment and control cohorts from multiple independent studies, which allows meta-analysis of patient-level data. Herein, we provide a proof of concept for the application of IDA to real-world and natural history hATTR-PN data. IDA permits increased understanding of outcomes in tafamidis-treated and untreated persons with hATTR-PN by optimally pooling all available information. Summary statistics corresponding to the Neuropathy Impairment Score-Lower Limb (NIS-LL) from five published studies were pooled, converted to change from baseline means and variances, and analyzed using IDA. IDA-based synthetic cohorts were generated by averaging across studies stratified on treatment versus control cohort. Trends in change from baseline in each study and the corresponding synthetic cohorts were plotted. Patient-level data were simulated from the synthetic cohort trends in a Monte Carlo simulation to highlight the ability to contrast synthetic cohort trends using the mixed model for repeated measures (MMRM). The average sample size among the five studies was 71 (37-128) patients. The average NIS-LL trends indicated that tafamidis-treated patients experienced slower progression in neuropathy compared to untreated patients. Synthetic cohort trends reflected the trends observed in the contributing studies, while simultaneously shrinking the width of corresponding confidence bands. Monte Carlo simulation results demonstrated precise recovery of the synthetic cohort and time-dependent simulated NIS-LL means by the MMRM. This proof of concept demonstrates the utility of IDA-based synthetic cohorts for increased precision in characterizing and testing hypotheses about treatment outcomes and prognosis in hATTR-PN. Pfizer. Plain language summary available for this article.

Stop and Go – Waves of Tarsier Dispersal Mirror the Genesis of Sulawesi Island

PubMed Central

Driller, Christine; Merker, Stefan; Perwitasari-Farajallah, Dyah; Sinaga, Walberto; Anggraeni, Novita; Zischler, Hans

2015-01-01

The Indonesian island of Sulawesi harbors a highly endemic and diverse fauna sparking fascination since long before Wallace’s contemplation of biogeographical patterns in the region. Allopatric diversification driven by geological or climatic processes has been identified as the main mechanism shaping present faunal distribution on the island. There is both consensus and conflict among range patterns of terrestrial species pointing to the different effects of vicariant events on once co-distributed taxa. Tarsiers, small nocturnal primates with possible evidence of an Eocene fossil record on the Asian mainland, are at present exclusively found in insular Southeast Asia. Sulawesi is hotspot of tarsier diversity, whereby island colonization and subsequent radiation of this old endemic primate lineage remained largely enigmatic. To resolve the phylogeographic history of Sulawesi tarsiers we analyzed an island-wide sample for a set of five approved autosomal phylogenetic markers (ABCA1, ADORA3, AXIN1, RAG1, and TTR) and the paternally inherited SRY gene. We constructed ML and Bayesian phylogenetic trees and estimated divergence times between tarsier populations. We found that their arrival at the Proto-Sulawesi archipelago coincided with initial Miocene tectonic uplift and hypothesize that tarsiers dispersed over the region in distinct waves. Intra-island diversification was spurred by land emergence and a rapid succession of glacial cycles during the Plio-Pleistocene. Some tarsier range boundaries concur with spatial limits in other taxa backing the notion of centers of faunal endemism on Sulawesi. This congruence, however, has partially been superimposed by taxon-specific dispersal patterns. PMID:26559527

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

Genotype–phenotype correlation and course of transthyretin familial amyloid polyneuropathies in France

PubMed Central

Mariani, Louise‐Laure; Lozeron, Pierre; Théaudin, Marie; Mincheva, Zoia; Signate, Aissatou; Ducot, Beatrice; Algalarrondo, Vincent; Denier, Christian; Adam, Clovis; Nicolas, Guillaume; Samuel, Didier; Slama, Michel S.; Lacroix, Catherine; Misrahi, Micheline; Adams, David

2015-01-01

Objective To compare the natural history of familial transthyretin amyloid polyneuropathies (FAP) due to the Val30Met, Ser77Tyr, and Ile107Val mutations in France with the classical Portuguese Val30Met FAP. Methods We compared 84 French patients with a control group of 110 Portuguese patients carrying the Val30Met mutation also living in France, all referred to and followed at the French National FAP Reference Center from 1988 to 2010. Clinical examination, functional and walking disability scores, nerve conduction studies, and muscle biopsies are reported. We also conducted a comprehensive literature review to further determine the range of phenotypic expression. Results By comparison with Portuguese Val30Met FAP, French Ile107Val, Ser77Tyr, and LateVal30Met FAP showed more rapid and severe disease progression; onset of gait disorders was 3 times more rapid (p < 0.0001) and the rate of modified Norris test decline was up to 40 times faster in Ile107Val patients (p < 0.0001). Median survival was much shorter in Ile107Val and in Val30Met mutation with late onset (>50 years; LateMet30) FAP (p = 0.0005). Other distinctive features relative to the Portuguese patients included atypical clinical presentations, demyelination on nerve conduction studies (p = 0.0005), and difficult identification of amyloid deposits in nerve and muscle biopsies. Interpretation Ile107Val and LateMet30 mutations are associated with the most debilitating and severe FAP ever described, with rapid onset of tetraparesis and shorter median survival. It could be explained by frequent large‐fiber involvement and associated demyelination and more severe axonal loss. These findings have major implications for genetic counseling and patient management as new therapeutic options are being assessed in clinical trials (TTR gene silencing). Ann Neurol 2015;78:901–916 PMID:26369527

Word Frequency Analysis. MOS: 68H. Skill Levels 1 & 2.

DTIC Science & Technology

1981-05-01

OENCA R I PcTEtiS BL I KCpEALE I 17:L 7 t~Tr! I 4’ LLY T3 NJE .750P C% R P 10 -Vu C&! v r{ rVF (’ .Z 3 JE C I P- VE IA4JDVI 5=L I ~ SCJ:n:E CA’E e藶...72 2!P -MCI’ 69R LIST; -,sl,/c5ND.NG FRZ𔃻JC’NCY Milk " IZES P ’ N 216 i*I 14 Tr L26 Cl 1^ ’. 7SK 144 L t 1 aLO3CK 1: 9 ElIT 73 WUw8El’ " NL F l 3 1

Documentation of Concurrent programs.

DTIC Science & Technology

1983-07-01

preparing the documentation formats, and Tom McDonald for preparing the supplemental materials and statistical analyses. 16 [ 1 -16- I j REFERENCES I Boehm...IAWb CE:~ r SET _66 (0_W3. o 40 s.~ .MCSG o-Csr-~~ to4 "LQ4 SloeuS RGJEUT P-= I -~E , t.. AcO.4JLG m*CA TI_ G.rL:m!CDP lo. ’ VS -64’ 04 l OE3 (.tt qe tso...34*h (eeeeeotop to enter h, to IAmlOCSot land ,uoMXM to R&’T- kfC ’Cod At 1*1 ,lgo: 0) 4 O ~ en ttR .I SA’ tgOhegl that ’t to 40n. .hi &ren a ~ O toll s

Multisystemic Disease Modeling of Liver-Derived Protein Folding Disorders Using Induced Pluripotent Stem Cells (iPSCs).

PubMed

Leung, Amy; Murphy, George J

2016-01-01

Familial transthyretin amyloidosis (ATTR) is an autosomal dominant protein-folding disorder caused by over 100 distinct mutations in the transthyretin (TTR) gene. In ATTR, protein secreted from the liver aggregates and forms fibrils in target organs, chiefly the heart and peripheral nervous system, highlighting the need for a model capable of recapitulating the multisystem complexity of this clinically variable disease. Here, we describe detailed methodologies for the directed differentiation of protein folding disease-specific iPSCs into hepatocytes that produce mutant protein, and neural-lineage cells often targeted in disease. Methodologies are also described for the construction of multisystem models and drug screening using iPSCs.

Does the Level of Graphical Detail of a Virtual Handball Thrower Influence a Goalkeeper’s Motor Response?

PubMed Central

Vignais, Nicolas; Bideau, Benoit; Craig, Cathy; Brault, Sébastien; Multon, Franck; Delamarche, Paul; Kulpa, Richard

2009-01-01

The authors investigated how different levels of detail (LODs) of a virtual throwing action can influence a handball goalkeeper’s motor response. Goalkeepers attempted to stop a virtual ball emanating from five different graphical LODs of the same virtual throwing action. The five levels of detail were: a textured reference level (L0), a non-textured level (L1), a wire-frame level (L2), a point-light-display (PLD) representation (L3) and a PLD level with reduced ball size (L4). For each motor response made by the goalkeeper we measured and analyzed the time to respond (TTR), the percentage of successful motor responses, the distance between the ball and the closest limb (when the stopping motion was incorrect) and the kinematics of the motion. Results showed that TTR, percentage of successful motor responses and distance with the closest limb were not significantly different for any of the five different graphical LODs. However the kinematics of the motion revealed that the trajectory of the stopping limb was significantly different when comparing the L1 and L3 levels, and when comparing the L1 and L4 levels. These differences in the control of the goalkeeper’s actions suggests that the different level of information available in the PLD representations (L3 and L4) are causing the goalkeeper to adopt different motor strategies to control the approach of their limb to stop the ball. Key points Virtual reality technology can be used to analyze sport performance because it enables standardization and reproduction of sport situations. Defining a minimal graphical level of detail of a virtual action could decrease the real time calculation of a virtual reality system. A Point Light Display graphical representation of a virtual throwing motion seems to influence the regulation of action of real handball goalkeepers. PMID:24149589

Elevated nuclear expression of the SMRT corepressor in breast cancer is associated with earlier tumor recurrence

PubMed Central

Migliaccio, Ilenia; Chaubal, Vaishali; Wu, Meng-Fen; Pace, Margaret C.; Hartmaier, Ryan; Jiang, Shiming; Edwards, Dean P.; Gutiérrez, M. Carolina; Hilsenbeck, Susan G.; Oesterreich, Steffi

2012-01-01

Silencing mediator of retinoic acid and thyroid hormone receptor (SMRT), also known as nuclear corepressor 2 (NCOR2) is a transcriptional corepressor for multiple members of the nuclear receptor superfamily of transcription factors, including estrogen receptor-α (ERα). In the classical model of corepressor action, SMRT binds to antiestrogen-bound ERα at target promoters and represses ERα transcriptional activity and gene expression. Herein SMRT mRNA and protein expression was examined in a panel of 30 breast cancer cell lines. Expression of both parameters was found to vary considerably amongst lines and the correlation between protein and mRNA expression was very poor (R2 = 0.0775). Therefore, SMRT protein levels were examined by immunohistochemical staining of a tissue microarray of 866 patients with stage I–II breast cancer. Nuclear and cytoplasmic SMRT were scored separately according to the Allred score. The majority of tumors (67 %) were negative for cytoplasmic SMRT, which when detected was found at very low levels. In contrast, nuclear SMRT was broadly detected. There was no significant difference in time to recurrence (TTR) according to SMRT expression levels in the ERα-positive tamoxifen-treated patients (P = 0.297) but the difference was significant in the untreated patients (P = 0.01). In multivariate analysis, ERα-positive tamoxifen-untreated patients with high nuclear SMRT expression (SMRT 5-8, i.e., 2nd to 4th quartile) had a shorter TTR (HR = 1.94, 95 % CI, 1.24–3.04; P = 0.004) while there was no association with SMRT expression for ERα-positive tamoxifen-treated patients. There was no association between SMRT expression and overall survival for patients, regardless of whether they received tamoxifen. Thus while SMRT protein expression was not predictive of outcome after antiestrogen therapy, it may have value in predicting tumor recurrence in patients not receiving adjuvant tamoxifen therapy. PMID:23015261

Loss of Nuclear Localized and Tyrosine Phosphorylated Stat5 in Breast Cancer Predicts Poor Clinical Outcome and Increased Risk of Antiestrogen Therapy Failure

PubMed Central

Peck, Amy R.; Witkiewicz, Agnieszka K.; Liu, Chengbao; Stringer, Ginger A.; Klimowicz, Alexander C.; Pequignot, Edward; Freydin, Boris; Tran, Thai H.; Yang, Ning; Rosenberg, Anne L.; Hooke, Jeffrey A.; Kovatich, Albert J.; Nevalainen, Marja T.; Shriver, Craig D.; Hyslop, Terry; Sauter, Guido; Rimm, David L.; Magliocco, Anthony M.; Rui, Hallgeir

2011-01-01

Purpose To investigate nuclear localized and tyrosine phosphorylated Stat5 (Nuc-pYStat5) as a marker of prognosis in node-negative breast cancer and as a predictor of response to antiestrogen therapy. Patients and Methods Levels of Nuc-pYStat5 were analyzed in five archival cohorts of breast cancer by traditional diaminobenzidine-chromogen immunostaining and pathologist scoring of whole tissue sections or by immunofluorescence and automated quantitative analysis (AQUA) of tissue microarrays. Results Nuc-pYStat5 was an independent prognostic marker as measured by cancer-specific survival (CSS) in patients with node-negative breast cancer who did not receive systemic adjuvant therapy, when adjusted for common pathology parameters in multivariate analyses both by standard chromogen detection with pathologist scoring of whole tissue sections (cohort I; n = 233) and quantitative immunofluorescence of a tissue microarray (cohort II; n = 291). Two distinct monoclonal antibodies gave concordant results. A progression array (cohort III; n = 180) revealed frequent loss of Nuc-pYStat5 in invasive carcinoma compared to normal breast epithelia or ductal carcinoma in situ, and general loss of Nuc-pYStat5 in lymph node metastases. In cohort IV (n = 221), loss of Nuc-pYStat5 was associated with increased risk of antiestrogen therapy failure as measured by univariate CSS and time to recurrence (TTR). More sensitive AQUA quantification of Nuc-pYStat5 in antiestrogen-treated patients (cohort V; n = 97) identified by multivariate analysis patients with low Nuc-pYStat5 at elevated risk for therapy failure (CSS hazard ratio [HR], 21.55; 95% CI, 5.61 to 82.77; P < .001; TTR HR, 7.30; 95% CI, 2.34 to 22.78; P = .001). Conclusion Nuc-pYStat5 is an independent prognostic marker in node-negative breast cancer. If confirmed in prospective studies, Nuc-pYStat5 may become a useful predictive marker of response to adjuvant hormone therapy. PMID:21576635

Alcohol consumption and colon cancer prognosis among participants in north central cancer treatment group phase III trial N0147.

PubMed

Phipps, Amanda I; Shi, Qian; Limburg, Paul J; Nelson, Garth D; Sargent, Daniel J; Sinicrope, Frank A; Chan, Emily; Gill, Sharlene; Goldberg, Richard M; Kahlenberg, Morton; Nair, Suresh; Shields, Anthony F; Newcomb, Polly A; Alberts, Steven R

2016-09-01

Alcohol consumption is associated with a modest increased risk of colon cancer, but its relationship with colon cancer survival has not been elucidated. Using data from a phase III randomized adjuvant trial, we assessed the association of alcohol consumption with colon cancer outcomes. Patients completed a risk factor questionnaire before randomization to FOLFOX or FOLFOX + cetuximab (N = 1984). Information was collected on lifestyle factors, including smoking, physical activity and consumption of different types of alcohol. Cox models assessed the association between alcohol consumption and outcomes of disease-free survival (DFS), time-to-recurrence (TTR) and overall survival (OS), adjusting for age, sex, study arm, body mass, smoking, physical activity and performance status. No statistically significant difference in outcomes between ever and never drinkers were noted [hazard ratio (HR)DFS  = 0.86, HRTTR  = 0.87, HROS  = 0.86, p-values = 0.11-0.17]. However, when considering alcohol type, ever consumers of red wine (n = 628) had significantly better outcomes than never consumers (HRDFS  = 0.80, HRTTR  = 0.81, HROS  = 0.78, p-values = 0.01-0.02). Favorable outcomes were confirmed in patients who consumed 1-30 glasses/month of red wine (n = 601, HR = 0.80-0.83, p-values = 0.03-0.049); there was a suggestion of more favorable outcomes in patients who consumed >30 glasses/month of red wine (n = 27, HR = 0.33-0.38, p-values = 0.05-0.06). Beer and liquor consumption were not associated with outcomes. Although alcohol consumption was not associated with colon cancer outcomes overall, mild to moderate red wine consumption was suggestively associated with longer OS, DFS and TTR in stage III colon cancer patients. © 2016 UICC.

The Guadalquivir Diapiric Ridge: Deep Tectonics and Related Gas Structures

NASA Astrophysics Data System (ADS)

Fernández-Puga, M. C.; Somoza, L.; Pinheiro, L. M.; Magalhães, V.; Vázquez, J. T.; Díaz-del-Río, V.; Ivanov, M.

Cooperation between the Spanish TASYO project during the cruises Tasyo/2000, Anastasya/99, Anastasya/00 and Anastasya/01 and the UNESCO-IOC Trainning Trough Research Programme during the TTR9, TTR10 and TTR-11 cruises have per- mitted to identify numerous structures related to hydrocarbon seepages in the Gulf of Cadiz, located between the Africa and Eurasia plate. The interpretation of multibeam bathymetry and a large database of reflection seismic profiles shows two important morphotectonics structures: the Cadiz Diapiric Ridge (CDR) and the Guadalquivir Di- apiric Ridge (GDR). The CDR is a diapiric elongate structure located between 400 and 700m water depth, with a N-S direction. The GDR is an elongated ridge, situated west- ward of this structure and located along the shelf and slope between 300-1100m depth. This highly deformed ridge, formed by several diapirs oriented in NE-SW direction, has been mapped using industrial multifold seismic, core logs, gravity cores, dredge samples and photographs, obtained during the ANASTASYA 01/09 cruise. This data has shown that it is composed of early-middle Miocene blue marls (Maldonado et al, 1999), mud breccias and calcarenites. In fact, this diapiric structure is associated with a complex tectono-sedimentary history related to along slope gravity gliding and tec- tonic compression westward the fronts of the deformed wedges of the SOlistostromic & cedil;allochtonous unitsT (Somoza et al., 1999). According to the observed and sampled structures along the GDR, this ridge can be divided in three areas: (a) The NE area is characterized by the existence of a series of wide single sub-circular mud volcanoes (Anastasya, Tarsis and Pipoca), surrounded by a ring shaped seafloor depression. Mud breccia has been collected from these mud volcanoes (ANAS00-TG5,TG6,TG7,TG8 and ANAS01-TG2); (b) a central sector with long rounded-like crater structures, of unknown origin, from which calcarenites were collected (ANAS01-DA13); and (c) a SW sector, between 8zW and 7z40`W, that is caracterized by a series of mud mounds boundarying the Cadiz channel: Iberico, Cornide and Hormigas. In this area, abundant carbonate chimneys, slab and calcarenites were collected (ANAS00-DA10, ANAS01-DA1,DA2,DA15). All these seabed structures suggest high-pressure expul- sion of methane-enriched muds along thrusting faults. This research has been supported by the "TASYO" project (Tecto-sedimentary transfer 1 from shelf to Horseshoe and Seine abyssal plains in the Gulf of Cadiz) of the Spanish- funded Marine Science and Technology programme (CYTMAR 98-0209) in the frame of the Spanish-Portuguese agreement for scientific co-operation. References: Maldonado, A.,Somoza, L., Pallarés, L., 1999. The Betic orogen and the Iberian- African boundary in the Gulf of Cadiz : geological evolution (Central North Atlantic). Mar. Geol., 155, 9-43. Somoza, L., Maestro, A., Lowrie, A., 1999. Allochtonous Blocks as Hydrocarbon Traps in the Gulf of Cadiz. Offshore Technology Conference OTC 10889, 571-577. 2

Patterns of Adult-Child Linguistic Interaction in Integrated Day Care Groups.

PubMed

Girolametto, Luigi; Hoaken, Lisa; Weitzman, Elaine; Lieshout, Riet van

2000-04-01

This study investigated the language input of eight childcare providers to children with developmental disabilities, including language delay, who were integrated into community day care centers. Structural and discourse features of the adults' language input was compared across two groups (integrated, typical) and two naturalistic day care contexts (book reading, play dough activity). The eight children with developmental disabilities and language delay were between 33-50 months of age; 32 normally developing peers ranged in age from 32-53 months of age. Adult-child interactions were transcribed and coded to yield estimates of structural indices (number of utterances, rate, mean length of utterances, ratio of different words to total words used (TTR) and discourse features (directive, interactive, language-modelling) of their language input. The language input addressed to the children with developmental disabilities was directive and not finely tuned to their expressive language levels. In turn, these children interacted infrequently with the adult or with the other children. Contextual comparisons indicated that the play dough activity promoted adult-child interaction that was less directive and more interaction-promoting than book reading, and that children interacted more frequently in the play-dough activity. Implications for speech-language pathologists include the need for collaborative consultation in integrated settings, modification of adult-child play contexts to promote interaction, and training childcare providers to use language input that promotes communication development.

Diagnostic performance enhancement of pancreatic cancer using proteomic multimarker panel

PubMed Central

Namkung, Junghyun; Yi, Sung Gon; Kim, Hyunsoo; Yu, Jiyoung; Kim, Yongkang; Kwon, Min-Seok; Kwon, Wooil; Oh, Do-Youn; Kim, Sun-Whe; Jeong, Seung-Yong; Han, Wonshik; Lee, Kyu Eun; Heo, Jin Seok; Park, Joon Oh; Park, Joo Kyung; Kim, Song Cheol; Kang, Chang Moo; Lee, Woo Jin; Lee, Seungyeoun; Han, Sangjo; Park, Taesung; Jang, Jin-Young; Kim, Youngsoo

2017-01-01

Due to its high mortality rate and asymptomatic nature, early detection rates of pancreatic ductal adenocarcinoma (PDAC) remain poor. We measured 1000 biomarker candidates in 134 clinical plasma samples by multiple reaction monitoring-mass spectrometry (MRM-MS). Differentially abundant proteins were assembled into a multimarker panel from a training set (n=684) and validated in independent set (n=318) from five centers. The level of panel proteins was also confirmed by immunoassays. The panel including leucine-rich alpha-2 glycoprotein (LRG1), transthyretin (TTR), and CA19-9 had a sensitivity of 82.5% and a specificity of 92.1%. The triple-marker panel exceeded the diagnostic performance of CA19-9 by more than 10% (AUCCA19-9 = 0.826, AUCpanel= 0.931, P < 0.01) in all PDAC samples and by more than 30% (AUCCA19-9 = 0.520, AUCpanel = 0.830, P < 0.001) in patients with normal range of CA19-9 (<37U/mL). Further, it differentiated PDAC from benign pancreatic disease (AUCCA19-9 = 0.812, AUCpanel = 0.892, P < 0.01) and other cancers (AUCCA19-9 = 0.796, AUCpanel = 0.899, P < 0.001). Overall, the multimarker panel that we have developed and validated in large-scale samples by MRM-MS and immunoassay has clinical applicability in the early detection of PDAC. PMID:29190982

Software User’s Manual for Stability and Transition Analysis with the Codes LSH and PSH

DTIC Science & Technology

1993-09-01

thermka(n) = K amul(n) = IA ainu2(n) = P2 dlqk(n,i) d2qk(n,ls) = aQiaQI’ dlqmul(n,i) aQi’ a2p• d2qmul (n,ls) a 8aQ -’ dlqmu2(n,i) - 19, (•Qi d2qmu2(n...same location, ampmax (it, iz) 45 7. growth rate profiles (n = O,jx) of ig-th variable at the location where the mass - flow disturbance of the reference...mode (ttr, izr) is maximum, grate (n, it, iz, ig). Here ig = 1, .., 4 representing growth rates for i, ’, •, and mass flow ,ii, re- spectively. 6.1.8

Results of initial analyses of the salt (macro) batch 10 tank 21H qualification samples

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

Peters, T. B.

2017-01-01

Savannah River National Laboratory (SRNL) analyzed samples from Tank 21H in support of qualification of Interim Salt Disposition Project (ISDP) Salt (Macro) Batch 10 for processing through the Actinide Removal Process (ARP) and the Modular Caustic-Side Solvent Extraction Unit (MCU). This document reports the initial results of the analyses of samples of Tank 21H. Analysis of the Tank 21H Salt (Macro) Batch 10 composite sample indicates that the material does not display any unusual characteristics or observations, such as floating solids, the presence of large amount of solids, or unusual colors. Further sample results will be reported in a futuremore » document. This memo satisfies part of Deliverable 3 of the Technical Task Request (TTR).« less

Results of initial analyses of the salt (macro) batch 11 Tank 21H qualification samples

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

Peters, T. B.

Savannah River National Laboratory (SRNL) analyzed samples from Tank 21H in support of qualification of Interim Salt Disposition Project (ISDP) Salt (Macro) Batch 11 for processing through the Actinide Removal Process (ARP) and the Modular Caustic-Side Solvent Extraction Unit (MCU). This document reports the initial results of the analyses of samples of Tank 21H. Analysis of the Tank 21H Salt (Macro) Batch 11 composite sample indicates that the material does not display any unusual characteristics or observations, such as floating solids, the presence of large amounts of solids, or unusual colors. Further sample results will be reported in a futuremore » document. This memo satisfies part of Deliverable 3 of the Technical Task Request (TTR).« less

Supercritical Wing Preliminary Design Study

DTIC Science & Technology

1975-12-01

SHIN «" NOME« <i./t. TAK t«/C» Ttff MA. TAft 4P) JON*« SO M »<• n y »■« • ii n VT«t 4il rtt-Tin J.l.. .S • T» 4...UPM At 1 54 ;t’ -"fi Vitll TI|K EMS IQH A4 ZEE TAff i>^ /tr TAfE <!•/£► TAK KOMUl CUJT« ■no pl TfJK A« *>1» FT J’ T<»£ 511...N« AMT* Oa/tr I» MB »AIM NO. NO. MATEWAL n «ttr ASSY Ott».!. -1 fio.if 5»»« J («It» TAK , I 1 ftf»6 Sf»* »" Cit/t»T««l

The use of vitamin K supplementation to achieve INR stability: a systematic review and meta-analysis.

PubMed

Kramps, Melissa; Flanagan, Abigail; Smaldone, Arlene

2013-10-01

Systematically review and quantitatively synthesize evidence on use of oral vitamin K supplementation in reducing international normalized ratio (INR) variability. PubMed, The Cochrane Library, PsycINFO, Cumulative Index of Nursing and Allied Health Literature (CINAHL), Turning Research Into Practice (TRIP), Web of Science were searched for studies meeting predetermined inclusion/exclusion criteria. Five studies meeting criteria (three randomized trials, one quasi-experimental pre-post study, one retrospective case series) were appraised for quality and data synthesized by two reviewers. Pooled effect size of time in INR therapeutic range (TTR) was estimated using random effects meta-analysis. Pooled effect size representing data from four studies (678 subjects) was 0.31, 95% confidence interval 0.03-0.59 (Cochran Q = 7.1; p = .07; I(2) = 57.8) and favored vitamin K supplementation. Given wide variability among individual studies, there is not enough evidence to advise for or against the routine use of vitamin K supplementation to achieve INR stability. However, evidence does suggest that it may be of some benefit for some patients with INR instability. There is insufficient evidence to support routine supplementation with vitamin K in patients on chronic anticoagulation therapy but select patients, particularly those with persistent INR instability despite known adherence to regimen and no dietary or drug-drug interactions, may benefit from the intervention. Future research is warranted. ©2013 The Author(s) ©2013 American Association of Nurse Practitioners.

Measurement of a solid-state triple point at the metal-insulator transition in VO2.

PubMed

Park, Jae Hyung; Coy, Jim M; Kasirga, T Serkan; Huang, Chunming; Fei, Zaiyao; Hunter, Scott; Cobden, David H

2013-08-22

First-order phase transitions in solids are notoriously challenging to study. The combination of change in unit cell shape, long range of elastic distortion and flow of latent heat leads to large energy barriers resulting in domain structure, hysteresis and cracking. The situation is worse near a triple point, where more than two phases are involved. The well-known metal-insulator transition in vanadium dioxide, a popular candidate for ultrafast optical and electrical switching applications, is a case in point. Even though VO2 is one of the simplest strongly correlated materials, experimental difficulties posed by the first-order nature of the metal-insulator transition as well as the involvement of at least two competing insulating phases have led to persistent controversy about its nature. Here we show that studying single-crystal VO2 nanobeams in a purpose-built nanomechanical strain apparatus allows investigation of this prototypical phase transition with unprecedented control and precision. Our results include the striking finding that the triple point of the metallic phase and two insulating phases is at the transition temperature, Ttr = Tc, which we determine to be 65.0 ± 0.1 °C. The findings have profound implications for the mechanism of the metal-insulator transition in VO2, but they also demonstrate the importance of this approach for mastering phase transitions in many other strongly correlated materials, such as manganites and iron-based superconductors.

TPOAb and Thyroid Function Are Not Associated with Breast Cancer Outcome: Evidence from a Large-Scale Study Using Data from the Taxotere as Adjuvant Chemotherapy Trial (TACT, CRUK01/001)

PubMed Central

Muller, Ilaria; Kilburn, Lucy S.; Taylor, Peter N.; Barrett-Lee, Peter J.; Bliss, Judith M.; Ellis, Paul; Ludgate, Marian E.; Dayan, Colin M.

2017-01-01

Background Small-scale studies correlated the presence of thyroid autoimmunity with both improved or worsened breast cancer outcome. Objectives We aimed to clarify this association in a large cohort using the phase III, randomized, controlled Taxotere as Adjuvant Chemotherapy Trial (TACT, CRUK01/001). Methods TACT women >18 years old with node-positive or high-risk node-negative early breast cancer (pT1–3a, pN0–1, M0), with stored plasma (n = 1,974), taken 15.5 (median; IQR 7.0–24.0) months after breast surgery were studied. Patients had also received chemotherapy (100%), radiotherapy (1,745/1,974; 88.4%), hormonal therapy (1,378/ 1,974; 69.8%), or trastuzumab (48/1,974; 2.4%). History of thyroid diseases and/or related treatments was not available. The prognostic significance of autoantibodies to thyroid peroxidase (TPOAb; positive ≥6 kIU/L), free-thyroxine and thyrotropin (combined: euthyroid, hypothyroid, hyperthyroid) was evaluated for disease-free survival (DFS), overall-survival (OS), and time-to-recurrence (TTR), with Cox regression models in univariate and multivariable analyses. The extended median follow-up was 97.5 months. Results No difference in DFS was found by TPOAb status (unadjusted hazard ratio [HR]: 0.97, 95%CI: 0.78–1.19; p = 0.75) and/or thyroid function (unadjusted HR [hypothyroid vs. euthyroid]: 1.15, 95% CI: 0.79–1.68; p = 0.46; unadjusted HR [hyperthyroid vs. euthyroid]: 1.14, 95% CI: 0.82–1.61; p = 0.44). Similar results were obtained for OS, TTR, multivariable analyses, when TPOAb titre by tertiles was considered, and in a subgroup of 123 patients with plasma collected before adjuvant treatments. Conclusions No evidence for a prognostic role of TPOAb and/or thyroid function in moderate-to-high-risk early breast cancer was found in the largest and longest observational study to date. PMID:28868260

A Novel Predictive Equation for Potential Diagnosis of Cholangiocarcinoma

PubMed Central

Kraiklang, Ratthaphol; Pairojkul, Chawalit; Khuntikeo, Narong; Imtawil, Kanokwan; Wongkham, Sopit; Wongkham, Chaisiri

2014-01-01

Cholangiocarcinoma (CCA) is the second most common-primary liver cancer. The difficulties in diagnosis limit successful treatment of CCA. At present, histological investigation is the standard diagnosis for CCA. However, there are some poor-defined tumor tissues which cannot be definitively diagnosed by general histopathology. As molecular signatures can define molecular phenotypes related to diagnosis, prognosis, or treatment outcome, and CCA is the second most common cancer found after hepatocellularcarcinoma (HCC), the aim of this study was to develop a predictive model which differentiates CCA from HCC and normal liver tissues. An in-house PCR array containing 176 putative CCA marker genes was tested with the training set tissues of 20 CCA and 10 HCC cases. The molecular signature of CCA revealed the prominent expression of genes involved in cell adhesion and cell movement, whereas HCC showed elevated expression of genes related to cell proliferation/differentiation and metabolisms. A total of 69 genes differentially expressed in CCA and HCC were optimized statistically to formulate a diagnostic equation which distinguished CCA cases from HCC cases. Finally, a four-gene diagnostic equation (CLDN4, HOXB7, TMSB4 and TTR) was formulated and then successfully validated using real-time PCR in an independent testing set of 68 CCA samples and 77 non-CCA controls. Discrimination analysis showed that a combination of these genes could be used as a diagnostic marker for CCA with better diagnostic parameters with high sensitivity and specificity than using a single gene marker or the usual serum markers (CA19-9 and CEA). This new combination marker may help physicians to identify CCA in liver tissues when the histopathology is uncertain. PMID:24586698

DWPF simulant CPC studies for SB8

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

Koopman, D. C.; Zamecnik, J. R.

2013-06-25

The Savannah River National Laboratory (SRNL) accepted a technical task request (TTR) from Waste Solidification Engineering to perform simulant tests to support the qualification of Sludge Batch 8 (SB8) and to develop the flowsheet for SB8 in the Defense Waste Processing Facility (DWPF). These efforts pertained to the DWPF Chemical Process Cell (CPC). Separate studies were conducted for frit development and glass properties (including REDOX). The SRNL CPC effort had two primary phases divided by the decision to drop Tank 12 from the SB8 constituents. This report focuses on the second phase with SB8 compositions that do not contain themore » Tank 12 piece. A separate report will document the initial phase of SB8 testing that included Tank 12. The second phase of SB8 studies consisted of two sets of CPC studies. The first study involved CPC testing of an SB8 simulant for Tank 51 to support the CPC demonstration of the washed Tank 51 qualification sample in the SRNL Shielded Cells facility. SB8-Tank 51 was a high iron-low aluminum waste with fairly high mercury and moderate noble metal concentrations. Tank 51 was ultimately washed to about 1.5 M sodium which is the highest wash endpoint since SB3-Tank 51. This study included three simulations of the DWPF Sludge Receipt and Adjustment Tank (SRAT) cycle and Slurry Mix Evaporator (SME) cycle with the sludge-only flowsheet at nominal DWPF processing conditions and three different acid stoichiometries. These runs produced a set of recommendations that were used to guide the successful SRNL qualification SRAT/SME demonstration with actual Tank 51 washed waste. The second study involved five SRAT/SME runs with SB8-Tank 40 simulant. Four of the runs were designed to define the acid requirements for sludge-only processing in DWPF with respect to nitrite destruction and hydrogen generation. The fifth run was an intermediate acid stoichiometry demonstration of the coupled flowsheet for SB8. These runs produced a set of processing recommendations for DWPF along with some data related to Safety Class documentation at DWPF. Some significant observations regarding SB8 follow: Reduced washing in Tank 51 led to an increase in the wt.% soluble solids of the DWPF feed. If wt.% total solids for the SRAT and SME product weren’t adjusted upward to maintain insoluble solids levels similar to past sludge batches, then the rheological properties of the slurry went below the low end of the DWPF design bases for the SRAT and SME. Much higher levels of dissolved manganese were found in the SRAT and SME products than in recent sludge batches. Closed crucible melts were more reduced than expected. The working hypothesis is that the soluble Mn is less oxidizing than assumed in the REDOX calculations. A change in the coefficient for Mn in the REDOX equation was recommended in a separate report. The DWPF (Hsu) stoichiometric acid equation was examined in detail to better evaluate how to control acid in DWPF. The existing DWPF equation can likely be improved without changing the required sample analyses through a paper study using existing data. The recommended acid stoichiometry for initial SB8 SRAT batches is 115-120% stoichiometry until some processing experience is gained. The conservative range (based on feed properties) of stoichiometric factors derived in this study was from 110-147%, but SRNL recommends using only the lower half of this range, 110-126% even after initial batches provide processing experience. The stoichiometric range for sludge-only processing appears to be suitable for coupled operation based on results from the run in the middle of the range. Catalytic hydrogen was detectable (>0.005 vol%) in all SRAT and SME cycles. Hydrogen reached 30-35% of the SRAT and SME limits at the mid-point of the stoichiometry window (bounding noble metals and acid demand).« 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

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

Exploration of adherence and patient experiences with DOACs one year after switching from vitamin-K antagonists- insights from the switching study.

PubMed

Bartoli-Abdou, John K; Patel, Jignesh P; Crawshaw, Jacob; Vadher, Bipin; Brown, Alison; Roberts, Lara N; Patel, Raj K; Arya, Roopen; Auyeung, Vivian

2018-02-01

Current UK and European guidelines recommend anticoagulated patients prescribed warfarin with time in therapeutic range (TTR) <65% be considered for DOAC therapy. There has been considerable concern that adherence with DOACs may be poor compared with warfarin. Little is known about the patient experience of switching from warfarin to DOAC and how patients manage their DOAC long term. Our aim was to conduct focus groups exploring patient's previous experiences with warfarin, their current experience with DOACs, their adherence to DOACs and the long-term service provision they envisage. Patients enrolled on the Switching Study who had been switched from warfarin to a DOAC >1year previously were invited to participate in focus groups. Two focus groups for atrial fibrillation (AF) and two for secondary prevention of venous thromboembolism (VTE) patients were held at anticoagulation clinics in South London, UK. Data was analysed using framework analysis to extract dominant themes. Five VTE patients and 15 AF patients attended the focus groups. Dominant themes that emerged were: indication specific anticoagulation prioritisation, warfarin as a necessary inconvenience, DOACs as the anticoagulant of choice, concerns regarding DOAC monitoring, high adherence to DOACs and desire for long-term access to specialist anticoagulation services. VTE patients prioritised anticoagulation over other therapies whereas AF patients did not. All participants reported high levels of adherence to DOACs. Patients derived confidence from long-term management in specialist anticoagulation clinics stating a preference to be managed in such a service. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

In vivo quantification of amyloid burden in TTR-related cardiac amyloidosis

PubMed Central

Kollikowski, Alexander Marco; Kahles, Florian; Kintsler, Svetlana; Hamada, Sandra; Reith, Sebastian; Knüchel, Ruth; Röcken, Christoph; Mottaghy, Felix Manuel; Marx, Nikolaus; Burgmaier, Mathias

2017-01-01

Summary Cardiac transthyretin-related (ATTR) amyloidosis is a severe cardiomyopathy for which therapeutic approaches are currently under development. Because non-invasive imaging techniques such as cardiac magnetic resonance imaging and echocardiography are non-specific, the diagnosis of ATTR amyloidosis is still based on myocardial biopsy. Thus, diagnosis of ATTR amyloidosis is difficult in patients refusing myocardial biopsy. Furthermore, myocardial biopsy does not allow 3D-mapping and quantification of myocardial ATTR amyloid. In this report we describe a 99mTc-DPD-based molecular imaging technique for non-invasive single-step diagnosis, three-dimensional mapping and semiquantification of cardiac ATTR amyloidosis in a patient with suspected amyloid heart disease who initially rejected myocardial biopsy. This report underlines the clinical value of SPECT-based nuclear medicine imaging to enable non-invasive diagnosis of cardiac ATTR amyloidosis, particularly in patients rejecting biopsy. PMID:29259858

An autopsy case of leptomeningeal amyloidosis associated with transthyretin Gly47Arg mutation.

PubMed

Uehara, Takuya; Kakuda, Keita; Sumi-Akamaru, Hisae; Yamauchi, Amane; Mochizuki, Hideki; Naka, Takashi

2016-11-29

We report the case of a 47-year-old woman with a 4-year history of progressive numbness in the distal portions of both her lower limbs, diarrhea alternating with periods of constipation, and orthostatic syncope. She demonstrated sensory dominant neuropathy and dysautonomia including orthostatic hypotension, paralytic ileus, and urinary retention. A systemic mutation analysis revealed a G47R mutation in transthyretin (TTR). Her general condition was so poor that we could not perform active treatment. Her consciousness had been impaired for a few months. She died at the age of 47 due to multiple organ failure. An autopsy revealed amyloid deposits in the subarachnoid space of the brainstem and the spinal cord as well as in the peripheral nerve and other organs. To date, this is the first case in which a G47R mutation is associated with leptomeningeal amyloidosis.

Isolation of mouse pancreatic alpha, beta, duct and acinar populations with cell surface markers.

PubMed

Dorrell, Craig; Grompe, Maria T; Pan, Fong Cheng; Zhong, Yongping; Canaday, Pamela S; Shultz, Leonard D; Greiner, Dale L; Wright, Chris V; Streeter, Philip R; Grompe, Markus

2011-06-06

Tools permitting the isolation of live pancreatic cell subsets for culture and/or molecular analysis are limited. To address this, we developed a collection of monoclonal antibodies with selective surface labeling of endocrine and exocrine pancreatic cell types. Cell type labeling specificity and cell surface reactivity were validated on mouse pancreatic sections and by gene expression analysis of cells isolated using FACS. Five antibodies which marked populations of particular interest were used to isolate and study viable populations of purified pancreatic ducts, acinar cells, and subsets of acinar cells from whole pancreatic tissue or of alpha or beta cells from isolated mouse islets. Gene expression analysis showed the presence of known endocrine markers in alpha and beta cell populations and revealed that TTR and DPPIV are primarily expressed in alpha cells whereas DGKB and GPM6A have a beta cell specific expression profile. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Reptilian transferrins: evolution of disulphide bridges and conservation of iron-binding center.

PubMed

Ciuraszkiewicz, Justyna; Biczycki, Marian; Maluta, Aleksandra; Martin, Samuel; Watorek, Wiesław; Olczak, Mariusz

2007-07-01

Transferrins, found in invertebrates and vertebrates, form a physiologically important family of proteins playing a major role in iron acquisition and transport, defense against microbial pathogens, growth and differentiation. These proteins are bilobal in structure and each lobe is composed of two domains divided by a cleft harboring an iron atom. Vertebrate transferrins comprise of serotransferrins, lactoferrins and ovotransferrins. In mammals serotransferrins transport iron in physiological fluids and deliver it to cells, while lactoferrins scavenge iron, limiting its availability to invading microbes. In oviparous vertebrates there is only one transferrin gene, expressed either in the liver to be delivered to physiological fluids as serotransferrin, or in the oviduct with a final localization in egg white as ovotransferrin. Being products of one gene sero- and ovotransferrin are identical at the amino-acid sequence level but with different, cell specific glycosylation patterns. Our knowledge of the mechanisms of transferrin iron binding and release is based on sequence and structural data obtained for human serotransferrin and hen and duck ovotransferrins. No sequence information about other ovotransferrins was available until our recent publication of turkey, ostrich, and red-eared turtle (TtrF) ovotransferrin mRNA sequences [Ciuraszkiewicz, J., Olczak, M., Watorek, W., 2006. Isolation, cloning and sequencing of transferrins from red-eared turtle, African ostrich and turkey. Comp. Biochem. Physiol. 143 B, 301-310]. In the present paper, ten new reptilian mRNA transferrin sequences obtained from the Nile crocodile (NtrF), bearded dragon (BtrF), Cuban brown anole (AtrF), veiled and Mediterranean chameleons (VtrF and KtrF), sand lizard (StrF), leopard gecko (LtrF), Burmese python (PtrF), African house snake (HtrF), and grass snake (GtrF) are presented and analyzed. Nile crocodile and red-eared turtle transferrins have a disulphide bridge pattern identical to known bird homologues. A partially different disulphide bridge pattern was found in the Squamata (snakes and lizards). The possibility of a unique interdomain disulphide bridge was predicted for LtrF. Differences were found in iron-binding centers from those of previously known transferrins. Substitutions were found in the iron-chelating residues of StrF and TtrF and in the synergistic anion-binding residues of NtrF. In snakes, the transferrin (PtrF, HtrF and GtrF) N-lobe "dilysine trigger" occurring in all other known transferrins was not found, which indicates a different mechanism of iron release.

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.

Reconstructing paleoceanographic conditions in the westernmost Mediterranean during the last 4.000 yr: tracking rapid climate variability

NASA Astrophysics Data System (ADS)

Nieto-Moreno, V.; Martínez-Ruiz, F.; Jiménez-Espejo, F. J.; Gallego-Torres, D.; Rodrigo-Gámiz, M.; Sakamoto, T.; Böttcher, M.; García-Orellana, J.; Ortega-Huertas, M.

2009-04-01

The westernmost Mediterranean (Alboran Sea basin) is a key location for paleoceanographic and paleoclimatic reconstructions since high sedimentation rates provide ultra high-resolution records at centennial and millennial scales. Here, we present a paleoenvironmental reconstruction for the last 4000 yr, which is based on a multi-proxy approach that includes major and trace element-content fluctuations and mineral composition of marine sediments. The investigated materials correspond to several gravity and box cores recovered in the Alboran Sea basin during different oceanographic cruises (TTR-14 and TTR-17), which have been sampled at very high resolution. Comparative analysis of these cores allows establishing climate oscillations at centennial to millennial scales. Although relatively more attention have been devoted to major climate changes during the last glacial cycle, such as the Last Glacial Maximun, deglaciation and abrupt cooling events (Heinrich and Younger Dryas), the late Holocene has also been punctuated by significant rapid climate variability including polar cooling, aridity and changes in the intensity of the atmospheric circulation. These climate oscillations coincide with significant fluctuations in chemical and mineral composition of marine sediments. Thus, bulk and clay mineralogy, REE composition and Rb/Al, Zr/Al, La/Lu ratios provide information on the sedimentary regime (eolian-fluvial input and source areas), Ba-based proxies on fluctuations in marine productivity and redox sensitive elements on oxygen conditions at time of deposition. A decrease in fluvial-derived elements/minerals (e.g., Rb, detrital mica) takes places during the so-called Late Bronze Age-Iron Age, Dark Age, and Little Ice Age Period. Meanwhile an increase is evidenced during the Medieval Warm Period and the Roman Humid Period. This last trend runs parallel to a decline of element/minerals of typical eolian source (Zr, kaolinite) with the exception of the Roman Humid Period where Zr/Al ratio increases. These climate oscillations (wet and dry periods) are also accompanied by changes in marine productivity rates, as suggested by the Ba/Al ratio. Additionally, anthropic contribution during the Industrial Period is also evidenced by a significant increase in Pb content in most recent sediments. Acknowledges: Projects Marcal CGL2006-13327-C04-04, Sagas CTM2005-08071-C03-01, Ministerio MARM 200800050084447, RNM 0179, CSD2006-00041.

Hyaluronan injection in murine osteoarthritis prevents TGFbeta 1-induced synovial neovascularization and fibrosis and maintains articular cartilage integrity by a CD44-dependent mechanism

PubMed Central

2012-01-01

Introduction The mechanism by which intra-articular injection of hyaluronan (HA) ameliorates joint pathology is unknown. Animal studies have shown that HA can reduce synovial activation, periarticular fibrosis and cartilage erosion; however, its specific effects on the different cell types involved remain unclear. We have used the TTR (TGFbeta1 injection and Treadmill Running) model of murine osteoarthritis (OA), which exhibits many OA-like changes, including synovial activation, to examine in vivo tissue-specific effects of intra-articular HA. Methods The kinetics of clearance of fluorotagged HA from joints was examined with whole-body imaging. Naïve and treated knee joints were examined macroscopically for cartilage erosion, meniscal damage and fibrosis. Quantitative histopathology was done with Safranin O for cartilage and with Hematoxylin & Eosin for synovium. Gene expression in joint tissues for Acan, Col1a1, Col2a1, Col3a1, Col5a1, Col10a1, Adamts5 and Mmp13 was done by quantitative PCR. The abundance and distribution of aggrecan, collagen types I, II, III, V and X, ADAMTS5 and MMP13 were examined by immunohistochemistry. Results Injected HA showed a half-life of less than 2 h in the murine knee joint. At the tissue level, HA protected against neovascularization and fibrosis of the meniscus/synovium and maintained articular cartilage integrity in wild-type but not in Cd44 knockout mice. HA injection enhanced the expression of chondrogenic genes and proteins and blocked that of fibrogenic/degradative genes and proteins in cartilage/subchondral bone, whereas it blocked activation of both groups in meniscus/synovium. In all locations it reduced the expression/protein for Mmp13 and blocked Adamts5 expression but not its protein abundance in the synovial lining. Conclusions The injection of HA, 24 h after TGFbeta1 injection, inhibited the cascade of OA-like joint changes seen after treadmill use in the TTR model of OA. In terms of mechanism, tissue protection by HA injection was abrogated by Cd44 ablation, suggesting that interaction of the injected HA with CD44 is central to its protective effects on joint tissue remodeling and degeneration in OA progression. PMID:22721434

Transient and Prolonged Response of Chicken Cecum Mucosa to Colonization with Different Gut Microbiota

PubMed Central

Volf, Jiri; Polansky, Ondrej; Varmuzova, Karolina; Gerzova, Lenka; Sekelova, Zuzana; Faldynova, Marcela; Babak, Vladimir; Medvecky, Matej; Smith, Adrian L.; Kaspers, Bernd; Velge, Philippe; Rychlik, Ivan

2016-01-01

In this study we determined protein and gene expression in the caeca of newly hatched chickens inoculated with cecal contents sourced from hens of different ages. Over 250 proteins exhibited modified expression levels in response to microbiota inoculation. The most significant inductions were observed for ISG12-2, OASL, ES1, LYG2, DMBT1-L, CDD, ANGPTL6, B2M, CUZD1, IgM and Ig lambda chain. Of these, ISG12-2, ES1 and both immunoglobulins were expressed at lower levels in germ-free chickens compared to conventional chickens. In contrast, CELA2A, BRT-2, ALDH1A1, ADH1C, AKR1B1L, HEXB, ALDH2, ALDOB, CALB1 and TTR were expressed at lower levels following inoculation of microbiota. When chicks were given microbiota preparations from different age donors, the recipients mounted differential responses to the inoculation which also differed from the response profile in naturally colonised birds. For example, B2M, CUZD1 and CELA2A responded differently to the inoculation with microbiota of 4- or 40-week-old hens. The increased or decreased gene expression could be recorded 6 weeks after the inoculation of newly hatched chickens. To characterise the proteins that may directly interact with the microbiota we characterised chicken proteins that co-purified with the microbiota and identified a range of host proteins including CDD, ANGPTL6, DMBT1-L, MEP1A and Ig lambda. We propose that induction of ISG12-2 results in reduced apoptosis of host cells exposed to the colonizing commensal microbiota and that CDD, ANGPTL6, DMBT1-L, MEP1A and Ig lambda reduce contact of luminal microbiota with the gut epithelium thereby reducing the inflammatory response. PMID:27685470

Airway extravasation induced by increasing airway temperature in ovalbumin-sensitized rats

PubMed Central

Hsu, Chun-Chun; Tapia, Reyno J.; Lee, Lu-Yuan

2015-01-01

This study was carried out to determine whether hyperventilation of humidified warm air (HWA) induced airway extravasation in ovalbumin (Ova)-sensitized rats. Our results showed: 1) After isocapnic hyperventilation with HWA for 2 min, tracheal temperature (Ttr) was increased to 40.3°C, and the Evans blue contents in major airways and lung tissue were elevated to 651% and 707%, respectively, of that after hyperventilation with humidified room air in Ova-sensitized rats; this striking effect of HWA was absent in control rats. 2) The HWA-induced increase in Evans blue content in sensitized rats was completely prevented by a pretreatment with either L-732138, a selective antagonist of neurokinin type 1 (NK-1) receptor, or formoterol, a selective agonist of β2 adrenoceptor. This study demonstrated that an increase in airway temperature induced protein extravasation in the major airways and lung tissue of sensitized rats, and an activation of the NK-1 receptor by tachykinins released from bronchopulmonary C-fiber nerve endings was primarily responsible. PMID:25864799

Time Temperature-Precipitation Behavior in An Al-Cu-Li Alloy 2195

NASA Technical Reports Server (NTRS)

Chen, P. S.; Bhat, B. N.

1999-01-01

Al-Cu-Li alloy 2195, with its combination of good cryogenic properties, low density, and high modulus, has been selected by NASA to be the main structural alloy of the Super Light Weight Tank (SLWT) for the Space Shuttle. Alloy 2195 is strengthened by an aging treatment that precipitates a particular precipitate, labeled as T1(Al2CuLi). Other phases, such as GP zone, (theta)', (theta)", theta, (delta)', S' are also present in this alloy when artificially aged. Cryogenic strength and fracture toughness are critical to the -SLWT application, since the SLWT will house liquid oxygen and hydrogen. Motivation for the Time-Temperature-Precipitation (TTP) study at lower temperature (lower than 350 F) comes in part from a recent study by Chen, The study found that the cryogenic fracture toughness of alloy 2195 is greatly influenced by the phases present in the matrix and subgrain boundaries. Therefore, the understanding of TTP behavior can help develop a guideline to select appropriate heat treatment conditions for the desirable applications. The study of TTP behavior at higher temperature (400 to 1000 F) was prompted by the fact that the SLWT requires a welded construction. Heat conduction from the weld pool affects the microstructure in the heat-affected zone (HAZ), which leads to changes in the mechanical properties. Furthermore, the SLWT may need repair welding for more than one time and any additional thermal cycles will increase precipitate instability and promote phase transformation. As a result considerable changes in HAZ microstructure and mechanical properties are expected during the construction of the SLWT. Therefore, the TTP diagrams can serve to understand the thermal history of the alloy by analyzing the welded microstructure. In the case welding, the effects of thermal cycles on the microstructure and mechanical properties can be predicted with the aid of the TTP diagrams. The 2195 alloy (nominally Al + 4 pct Cu + 1 pct Li + 0.3 pct Ag + 0.3 pct Mg + 0.1 pct Zr) used in this study was received in the form of 1.7 inch thick rolled plates. In brief goal of this study is to develop TTR diagram for the solutiontreated and stretched alloy 2195 from which the precipitation sequence at any service or aging conditions can be preducted.A subgrain boundary TTR diagram is also presented since precipitations at subgrain boundary can control and/or modify a wide veriety of material properties, such as cryogenic fracture toughness.

Generation of Functional Human Hepatic Endoderm from Human iPS cells

PubMed Central

Sullivan, Gareth J.; Hay, David C.; Park, In-Hyun; Fletcher, Judy; Hannoun, Zara; Payne, Catherine M.; Dalgetty, Donna; Black, James R.; Ross, James A.; Samuel, Kay; Wang, Gang; Daley, George Q.; Lee, Je-Hyuk; Church, George M.; Forbes, Stuart J.; Iredale, John P.; Wilmut, Ian

2009-01-01

With the advent of induced pluripotent stem cell (iPSC) technology, it is now feasible to generate iPSCs with a defined genotype or disease state. When coupled with direct differentiation of defined lineage, such as hepatic endoderm (HE). iPSC would revolutionise the way we study human liver biology and generate efficient “off the shelf” models of human liver disease. Here we show the `proof of concept' that iPSC lines representing both male and female sexes and two ethnic origins can be differentiated to HE at efficiencies of between 70–90%, using a method mimicking a physiological condition. iPSC-derived HE exhibited hepatic morphology, and expressed the hepatic markers, Albumin and E-Cadherin as assessed by immuno-histochemistry. They also expressed alpha fetal protein (AFP), HNF4a, and a metabolic marker, Cyp7A1, demonstrating a definitive endodermal lineage differentiation. Furthermore, iPSC-derived hepatocytes produced and secreted the plasma proteins, fibrinogen, fibronectin, transthyretin (TTR) and AFP, an essential feature for functional HE. Additionally iPSC-derived HE supported both CYP1A2 and 3A4 metabolism, which is essential for drug and toxicology testing. Conclusion This work is first to demonstrate the efficient generation of hepatic endodermal lineage from human iPSC that exhibits key attributes of hepatocytes, and the potential application of iPSC-derived HE in studying human liver biology. In particular, iPSC from individuals representing highly polymorphic variants in metabolic genes and different ethnic groups will provide pharmaceutical development and toxicology studies a unique opportunity to revolutionise predictive drug toxicology assays and allow the creation of in vitro hepatic disease models. PMID:19877180

Prognostic significance of kynurenine 3-monooxygenase and effects on proliferation, migration, and invasion of human hepatocellular carcinoma.

PubMed

Jin, Haojie; Zhang, Yurong; You, Haiyan; Tao, Xuemei; Wang, Cun; Jin, Guangzhi; Wang, Ning; Ruan, Haoyu; Gu, Dishui; Huo, Xisong; Cong, Wenming; Qin, Wenxin

2015-06-23

Kynurenine 3-monooxygenase (KMO) is a pivotal enzyme in the kynurenine pathway of tryptophan degradation and plays a critical role in Huntington's and Alzheimer's diseases. This study aimed to examine the expression of KMO in human hepatocellular carcinoma (HCC) and investigate the relationship between its expression and prognosis of HCC patients. We first analyzed KMO expression in 120 paired HCC samples (HCC tissues vs matched adjacent non-cancerous liver tissues), and 205 clinical HCC specimens using immunohistochemistry (IHC). Kaplan-Meier survival and Cox regression analyses were executed to evaluate the prognosis of HCC. The results of IHC analysis showed that KMO expression was significantly higher in HCC tissues than that in normal liver tissues (all p < 0.05). Survival and recurrence analyses showed that KMO was an independent prognostic factor for overall survival (OS) and time to recurrence (TTR) (both p<0.01). And in vitro studies revealed that KMO positively regulated proliferation, migration, and invasion of HCC cells. These results suggest that KMO exhibits tumor-promoting effects towards HCC and it may serve as a novel prognostic marker in HCC.

Transthyretin Cardiac Amyloidosis.

PubMed

Mankad, Anit K; Shah, Keyur B

2017-08-24

Transthyretin (TTR)-related cardiac amyloidosis is a progressive infiltrative cardiomyopathy that mimics hypertensive, hypertrophic heart disease and may go undiagnosed. Transthyretin-derived amyloidosis accounts for 18% of all cases of cardiac amyloidosis. Thus, the study's purpose is to provide a comprehensive review of transthyretin cardiac amyloidosis. Wild-type transthyretin (ATTRwt) protein causes cardiac amyloidosis sporadically, with 25 to 36% of the population older than 80 years of age are at risk to develop a slowly progressive, infiltrative amyloid cardiomyopathy secondary to ATTRwt. In contrast, hereditary amyloidosis (ATTRm) is an autosomal dominant inherited disease associated with more than 100 point mutations in the transthyretin gene and has a tendency to affect the heart and nervous system. Up to 4% of African-Americans carry the Val122Ile mutation in the transthyretin gene, the most prevalent cause of hereditary cardiac amyloidosis in the USA. Identifying transthyretin cardiac amyloidosis requires increased awareness of the prevalence, signs and symptoms, and diagnostic tools available for discrimination of this progressive form of cardiomyopathy associated with left ventricular hypertrophy. While there are no FDA-approved medical treatments, investigation is underway on agents to reduce circulating mutated transthyretin.

Thermochemical and kinetic aspects of the sulfurization of Cu-Sb and Cu-Bi thin films

NASA Astrophysics Data System (ADS)

Colombara, Diego; Peter, Laurence M.; Rogers, Keith D.; Hutchings, Kyle

2012-02-01

CuSbS2 and Cu3BiS3 are being investigated as part of a search for new absorber materials for photovoltaic devices. Thin films of these chalcogenides were produced by conversion of stacked and co-electroplated metal precursor layers in the presence of elemental sulfur vapour. Ex-situ XRD and SEM/EDS analyses of the processed samples were employed to study the reaction sequence with the aim of achieving compact layer morphologies. A new “Time-Temperature-Reaction” (TTR) diagram and modified Pilling-Bedworth coefficients have been introduced for the description and interpretation of the reaction kinetics. For equal processing times, the minimum temperature required for CuSbS2 to appear is substantially lower than for Cu3BiS3, suggesting that interdiffusion across the interfaces between the binary sulfides is a key step in the formation of the ternary compounds. The effects of the heating rate and sulfur partial pressure on the phase evolution as well as the potential losses of Sb and Bi during the processes have been investigated experimentally and the results related to the equilibrium pressure diagrams obtained via thermochemical computation.

The Influence of a TiN Film on the Electronic Contribution to the Thermal Conductivity of a TiC Film in a TiN-TiC Layer System

NASA Astrophysics Data System (ADS)

Jagannadham, K.

2018-01-01

TiC and TiN films were deposited by reactive magnetron sputtering on Si substrates. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) characterization of the microstructure and interface structure have been carried out and the stoichiometric composition of TiC is determined. Thermal conductivity and interface thermal conductance between different layers in the films are evaluated by the transient thermo reflectance (TTR) and three-omega (3- ω) methods. The results showed that the thermal conductivity of the TiC films increased with temperature. The thermal conductivity of TiC in the absence of TiN is dominated by phonon contribution. The electronic contribution to the thermal conductivity of TiC in the presence of TiN is found to be more significant. The interface thermal conductance of the TiC/TiN interface is much larger than that of interfaces at Au/TiC, TiC/Si, or TiN/Si. The interface thermal conductance between TiC and TiN is reduced by the layer formed as a result of interdiffusion.

Prognostic significance of kynurenine 3-monooxygenase and effects on proliferation, migration, and invasion of human hepatocellular carcinoma

PubMed Central

Jin, Haojie; Zhang, Yurong; You, Haiyan; Tao, Xuemei; Wang, Cun; Jin, Guangzhi; Wang, Ning; Ruan, Haoyu; Gu, Dishui; Huo, Xisong; Cong, Wenming; Qin, Wenxin

2015-01-01

Kynurenine 3-monooxygenase (KMO) is a pivotal enzyme in the kynurenine pathway of tryptophan degradation and plays a critical role in Huntington’s and Alzheimer’s diseases. This study aimed to examine the expression of KMO in human hepatocellular carcinoma (HCC) and investigate the relationship between its expression and prognosis of HCC patients. We first analyzed KMO expression in 120 paired HCC samples (HCC tissues vs matched adjacent non-cancerous liver tissues), and 205 clinical HCC specimens using immunohistochemistry (IHC). Kaplan-Meier survival and Cox regression analyses were executed to evaluate the prognosis of HCC. The results of IHC analysis showed that KMO expression was significantly higher in HCC tissues than that in normal liver tissues (all p < 0.05). Survival and recurrence analyses showed that KMO was an independent prognostic factor for overall survival (OS) and time to recurrence (TTR) (both p<0.01). And in vitro studies revealed that KMO positively regulated proliferation, migration, and invasion of HCC cells. These results suggest that KMO exhibits tumor-promoting effects towards HCC and it may serve as a novel prognostic marker in HCC. PMID:26099564

Thyroid endocrine system disruption by pentachlorophenol: an in vitro and in vivo assay.

PubMed

Guo, Yongyong; Zhou, Bingsheng

2013-10-15

The present study aimed to evaluate the disruption caused to the thyroid endocrine system by pentachlorophenol (PCP) using in vitro and in vivo assays. In the in vitro assay, rat pituitary GH3 cells were exposed to 0, 0.1, 0.3, and 1.0 μM PCP. PCP exposure significantly downregulated basal and triiodothyronine (T3)-induced Dio 1 transcription, indicating the antagonistic activity of PCP in vitro. In the in vivo assay, zebrafish embryos were exposed to 0, 1, 3, and 10 μg/L of PCP until 14 days post-fertilization. PCP exposure resulted in decreased thyroxine (T4) levels, but elevated contents of whole-body T3. PCP exposure significantly upregulated the mRNA expression of genes along hypothalamic-pituitary-thyroid (HPT) axis, including those encoding thyroid-stimulating hormone, sodium/iodide symporter, thyroglobulin, Dio 1 and Dio 2, alpha and beta thyroid hormone receptor, and uridinediphosphate-glucuronosyl-transferase. PCP exposure did not influence the transcription of the transthyretin (TTR) gene. The results indicate that PCP potentially disrupts the thyroid endocrine system both in vitro and in vivo. Copyright © 2013 Elsevier B.V. All rights reserved.

Simplifying the human serum proteome for discriminating patients with bipolar disorder of other psychiatry conditions.

PubMed

de Jesus, Jemmyson Romário; Galazzi, Rodrigo Moretto; de Lima, Tatiani Brenelli; Banzato, Cláudio Eduardo Muller; de Almeida Lima E Silva, Luiz Fernando; de Rosalmeida Dantas, Clarissa; Gozzo, Fábio Cézar; Arruda, Marco Aurélio Zezzi

2017-12-01

An exploratory analysis using proteomic strategies in blood serum of patients with bipolar disorder (BD), and with other psychiatric conditions such as Schizophrenia (SCZ), can provide a better understanding of this disorder, as well as their discrimination based on their proteomic profile. The proteomic profile of blood serum samples obtained from patients with BD using lithium or other drugs (N=14), healthy controls, including non-family (HCNF; N=3) and family (HCF; N=9), patients with schizophrenia (SCZ; N=23), and patients using lithium for other psychiatric conditions (OD; N=4) were compared. Four methods for simplifying the serum samples proteome were evaluated for both removing the most abundant proteins and for enriching those of lower-abundance: protein depletion with acetonitrile (ACN), dithiothreitol (DTT), sequential depletion using DTT and ACN, and protein equalization using commercial ProteoMiner® kit (PM). For proteomic evaluation, 2-D DIGE and nanoLC-MS/MS analysis were employed. PM method was the best strategy for removing proteins of high abundance. Through 2-D DIGE gel image comparison, 37 protein spots were found differentially abundant (p<0.05, Student's t-test), which exhibited ≥2.0-fold change of the average value of normalized spot intensities in the serum of SCZ, BD and OD patients compared to subject controls (HCF and HCNF). From these spots detected, 13 different proteins were identified: ApoA1, ApoE, ApoC3, ApoA4, Samp, SerpinA1, TTR, IgK, Alb, VTN, TR, C4A and C4B. Proteomic analysis allowed the discrimination of patients with BD from patients with other mental disorders, such as SCZ. The findings in this exploratory study may also contribute for better understanding the pathophysiology of these disorders and finding potential serum biomarkers for these conditions. Copyright © 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Hardware test program for evaluation of baseline range/range rate sensor concept

NASA Technical Reports Server (NTRS)

Pernic, E.

1985-01-01

The test program Phase II effort provides additional design information in terms of range and range rate (R/R) sensor performance when observing and tracking a typical spacecraft target. The target used in the test program was a one-third scale model of the Hubble Space Telescope (HST) available at the MSFC test site where the tests were performed. A modified Bendix millimeter wave radar served as the R/R sensor test bed for evaluation of range and range rate tracking performance, and generation of radar signature characteristics of the spacecraft target. A summary of program test results and conclusions are presented along with detailed description of the Bendix test bed radar with accompaning instrumentation. The MSFC test site and facilities are described. The test procedures used to establish background levels, and the calibration procedures used in the range accuracy tests and RCS (radar cross section) signature measurements, are presented and a condensed version of the daily log kept during the 5 September through 17 September test period is also presented. The test program results are given starting with the RCS signature measurements, then continuing with range measurement accuracy test results and finally the range and range rate tracking accuracy test results.

Tonopah Test Range - Index

Science.gov Websites

Capabilities Test Operations Center Test Director Range Control Track Control Communications Tracking Radars Us Range Videos/Photos Range Capabilities Test Operations Center Test Director Range Control Track Control Communications Tracking Radars Optical Systems Cinetheodolites Telescopes R&D Telescopes

Structural and thermodynamic study of dicesium molybdate Cs2Mo2O7: Implications for fast neutron reactors

NASA Astrophysics Data System (ADS)

Smith, A. L.; Kauric, G.; van Eijck, L.; Goubitz, K.; Wallez, G.; Griveau, J.-C.; Colineau, E.; Clavier, N.; Konings, R. J. M.

2017-09-01

The structure of α-Cs2Mo2O7 (monoclinic in space group P21 / c), which can form during irradiation in fast breeder reactors in the space between nuclear fuel and cladding, has been refined in this work at room temperature from neutron diffraction data. Furthermore, the compounds' thermal expansion and polymorphism have been investigated using high temperature X-ray diffraction combined with high temperature Raman spectroscopy. A phase transition has been observed at Ttr(α → β)=(621.9±0.8) K using Differential Scanning Calorimetry, and the structure of the β-Cs2Mo2O7 phase, orthorhombic in space group Pbcm, has been solved ab initio from the high temperature X-ray diffraction data. Furthermore, the low temperature heat capacity of α-Cs2Mo2O7 has been measured in the temperature range T=(1.9-313.2) K using a Quantum Design PPMS (Physical Property Measurement System) calorimeter. The heat capacity and entropy values at T=298.15 K have been derived as Cp,mo (Cs2Mo2O7 , cr , 298.15 K) = (211.9 ± 2.1) J K-1mol-1 and Smo (Cs2Mo2O7 , cr , 298.15 K) = (317.4 ± 4.3) J K-1mol-1 . When combined with the enthalpy of formation reported in the literature, these data yield standard entropy and Gibbs energy of formation as Δf Smo (Cs2Mo2O7 , cr , 298.15 K) = - (628.2 ± 4.4) J K-1mol-1 and Δf Gmo (Cs2Mo2O7 , cr , 298.15 K) = - (2115.1 ± 2.5) kJmol-1 . Finally, the cesium partial pressure expected in the gap between fuel and cladding following the disproportionation reaction 2Cs2MoO4=Cs2Mo2O7+2Cs(g)+ 1/2 O2(g) has been calculated from the newly determined thermodynamic functions.

Effects of titanium dioxide nanoparticles on lead bioconcentration and toxicity on thyroid endocrine system and neuronal development in zebrafish larvae.

PubMed

Miao, Wei; Zhu, Biran; Xiao, Xiaohong; Li, Ying; Dirbaba, Niguse Bekele; Zhou, Bingsheng; Wu, Hongjuan

2015-04-01

Nanoparticles (NPs) have attracted considerable attention because of their wide range of applications. Interactions between heavy metals (e.g., Pb) and NPs in aquatic environments may modify the bioavailability and toxicity of heavy metals. Therefore, this study investigated the influence of NPs (e.g., nano-TiO2) on the bioavailability and toxicity of Pb and its effects in the thyroid endocrine and nervous systems of zebrafish (Danio rerio) larvae. Zebrafish embryos (2-h post-fertilization) were exposed to five concentrations of Pb alone (0, 5, 10, 20, and 30μg/L) or in combination with nano-TiO2 (0.1mg/L) until 6 days post-fertilization. Results showed that the bioconcentration of Pb was significantly enhanced when combined with nano-TiO2 than when used alone. Zebrafish exposure to Pb alone at 30μg/L significantly decreased the thyroid hormone levels (T4 and T3), whereas nano-TiO2 treatment alone did not produce detectable changes. The levels of T4 and T3 were further decreased when Pb was combined with nano-TiO2 than when used alone. The transcription of the thyroid hormone-related factor tg gene was remarkably down-regulated by Pb treatment alone but up-regulated when Pb was combined with nano-TiO2. The significant up-regulation of tshβ gene and the down-regulation of TTR gene expression in the hypothalamic-pituitary-thyroid were observed in Pb with or without nano-TiO2 treatment groups. In addition, the transcription of genes involved in central nervous system (CNS) development (α-tubulin, mbp, gfap and shha) were significantly down-regulated by Pb and nano-TiO2 co-exposure as compared with Pb exposure alone. The locomotion activity analyzes confirmed that nano-TiO2 might enhance the toxicity of Pb to CNS development. These results suggest that nano-TiO2 increase bioconcentration of lead, which lead to the disruption of thyroid endocrine and neuronal system in zebrafish larvae. Copyright © 2015 Elsevier B.V. All rights reserved.

Developmental toxicity and thyroid hormone-disrupting effects of 2,4-dichloro-6-nitrophenol in Chinese rare minnow (Gobiocypris rarus).

PubMed

Chen, Rui; Yuan, Lilai; Zha, Jinmiao; Wang, Zijian

2017-04-01

In the present study, to evaluate embryonic toxicity and the thyroid-disrupting effects of 2,4-dichloro-6-nitrophenol (DCNP), embryos and adults of Chinese rare minnow (Gobiocypris rarus) were exposed to 2, 20, and 200μg/L DCNP. In the embryo-larval assay, increased percentages of mortality and occurrence of malformations, decreased percentage of hatching, and decreased body length and body weight were observed after DCNP treatment. Moreover, the whole-body T3 levels were significantly increased at 20 and 200μg/L treatments, whereas the T4 levels were markedly decreased significantly (p<0.05) for all DCNP concentrations. In the adult fish assay, plasma T3 levels were significantly increased whereas plasma T4 levels were significantly reduced in the fish treated with 20 and 200μg/L (p<0.05). In addition, DCNP exposure significantly changed the transcription levels of thyroid system related genes, including dio1, dio2, me, nis, tr, and ttr. The increased responsiveness of thyroid hormone and mRNA expression levels of thyroid system related genes suggested that DCNP could disrupt the thyroid hormone synthesis and transport pathways. Therefore, our findings provide new insights of DCNP as a thyroid hormone-disrupting chemical. Copyright © 2017 Elsevier B.V. All rights reserved.

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.

Forced expression of Hnf4a induces hepatic gene activation through directed differentiation.

PubMed

Yahoo, Neda; Pournasr, Behshad; Rostamzadeh, Jalal; Fathi, Fardin

2016-08-05

Embryonic stem (ES) cells are capable of unlimited self-renewal and have a diverse differentiation potential. These unique features make ES cells as an attractive source for developmental biology studies. Having the mature hepatocyte in the lab with functional activities is valuable in drug discovery studies. Overexpression of hepatocyte lineage-specific transcription factors (TFs) becomes a promising approach in pluripotent cell differentiation toward liver cells. Many studies generate transgenic ES cell lines to examine the effects of specific TFs overexpression in cell differentiation. In the present report, we have addressed whether a suspension or adherent model of differentiation is an appropriate way to study the role of Hnf4a overexpression. We generated ES cells that carried a doxycycline (Dox)-inducible Hnf4a using lentiviral vectors. The transduced cells were subjected to induced Hnf4a overexpression through both spontaneous and directed differentiation methods. Gene expression analysis showed substantially increased expression of hepatic gene markers, particularly Ttr and endogenous Hnf4a, in transduced cells differentiated by the directed approach. These results demonstrated that forced expression of TFs during directed differentiation would be an appropriate way to study relevant gene activation and the effects of overexpression in the context of hepatic differentiation. Copyright © 2016 Elsevier Inc. All rights reserved.

Culture versus PCR for Salmonella Species Identification in Some Dairy Products and Dairy Handlers with Special Concern to Its Zoonotic Importance.

PubMed

Gwida, Mayada M; Al-Ashmawy, Maha A M

2014-01-01

A total of 200 samples of milk and dairy products as well as 120 samples of dairy handlers were randomly collected from different dairy farms and supermarkets in Dakahlia Governorate, Egypt. The conventional cultural and serotyping methods for detection of Salmonella in dairy products were applied and the results were compared with those obtained by molecular screening assay using (ttr sequence). The obtained results revealed that 21% of milk and dairy products (42/200) were positive for Salmonella species using enrichment culture-based PCR method, while 12% of different dairy samples (24/200) were found to be positive for Salmonella species by using the conventional culture methods. Two stool specimens out of 40 apparently healthy dairy handlers were positive by the PCR method. Serotyping of Salmonella isolates revealed that 58.3% (14/24) from different dairy products were contaminated with Salmonella Typhimurium. We conclude that the enrichment culture-based PCR assay has high sensitivity and specificity for detection of Salmonella species in dairy products and handlers. High incidence of Salmonella Typhimurium in the examined dairy samples highlights the important role played by milk and dairy products as a vehicle in disease prevalence. Great effort should be applied for reducing foodborne risk for consumers.

Tonopah test range - outpost of Sandia National Laboratories

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

Johnson, L.

Tonopah Test Range is a unique historic site. Established in 1957 by Sandia Corporation, Tonopah Test Range in Nevada provided an isolated place for the Atomic Energy Commission to test ballistics and non-nuclear features of atomic weapons. It served this and allied purposes well for nearly forty years, contributing immeasurably to a peaceful conclusion to the long arms race remembered as the Cold War. This report is a brief review of historical highlights at Tonopah Test Range. Sandia`s Los Lunas, Salton Sea, Kauai, and Edgewood testing ranges also receive abridged mention. Although Sandia`s test ranges are the subject, the centralmore » focus is on the people who managed and operated the range. Comments from historical figures are interspersed through the narrative to establish this perspective, and at the end a few observations concerning the range`s future are provided.« less

The X-33 Extended Flight Test Range

NASA Technical Reports Server (NTRS)

Mackall, Dale A.; Sakahara, Robert; Kremer, Steven E.

1998-01-01

Development of an extended test range, with range instrumentation providing continuous vehicle communications, is required to flight-test the X-33, a scaled version of a reusable launch vehicle. The extended test range provides vehicle communications coverage from California to landing at Montana or Utah. This paper provides an overview of the approaches used to meet X-33 program requirements, including using multiple ground stations, and methods to reduce problems caused by reentry plasma radio frequency blackout. The advances used to develop the extended test range show other hypersonic and access-to-space programs can benefit from the development of the extended test range.

Space-Based Range Safety and Future Space Range Applications

NASA Technical Reports Server (NTRS)

Whiteman, Donald E.; Valencia, Lisa M.; Simpson, James C.

2005-01-01

The National Aeronautics and Space Administration (NASA) Space-Based Telemetry and Range Safety (STARS) study is a multiphase project to demonstrate the performance, flexibility and cost savings that can be realized by using space-based assets for the Range Safety [global positioning system (GPS) metric tracking data, flight termination command and range safety data relay] and Range User (telemetry) functions during vehicle launches and landings. Phase 1 included flight testing S-band Range Safety and Range User hardware in 2003 onboard a high-dynamic aircraft platform at Dryden Flight Research Center (Edwards, California, USA) using the NASA Tracking and Data Relay Satellite System (TDRSS) as the communications link. The current effort, Phase 2, includes hardware and packaging upgrades to the S-band Range Safety system and development of a high data rate Ku-band Range User system. The enhanced Phase 2 Range Safety Unit (RSU) provided real-time video for three days during the historic Global Flyer (Scaled Composites, Mojave, California, USA) flight in March, 2005. Additional Phase 2 testing will include a sounding rocket test of the Range Safety system and aircraft flight testing of both systems. Future testing will include a flight test on a launch vehicle platform. This paper discusses both Range Safety and Range User developments and testing with emphasis on the Range Safety system. The operational concept of a future space-based range is also discussed.

Space-Based Range Safety and Future Space Range Applications

NASA Technical Reports Server (NTRS)

Whiteman, Donald E.; Valencia, Lisa M.; Simpson, James C.

2005-01-01

The National Aeronautics and Space Administration Space-Based Telemetry and Range Safety study is a multiphase project to demonstrate the performance, flexibility and cost savings that can be realized by using space-based assets for the Range Safety (global positioning system metric tracking data, flight termination command and range safety data relay) and Range User (telemetry) functions during vehicle launches and landings. Phase 1 included flight testing S-band Range Safety and Range User hardware in 2003 onboard a high-dynamic aircraft platform at Dryden Flight Research Center (Edwards, California) using the NASA Tracking and Data Relay Satellite System as the communications link. The current effort, Phase 2, includes hardware and packaging upgrades to the S-band Range Safety system and development of a high data rate Ku-band Range User system. The enhanced Phase 2 Range Safety Unit provided real-time video for three days during the historic GlobalFlyer (Scaled Composites, Mojave, California) flight in March, 2005. Additional Phase 2 testing will include a sounding rocket test of the Range Safety system and aircraft flight testing of both systems. Future testing will include a flight test on a launch vehicle platform. This report discusses both Range Safety and Range User developments and testing with emphasis on the Range Safety system. The operational concept of a future space-based range is also discussed.

DEVELOPMENT OF AN INSOLUBLE SALT SIMULANT TO SUPPORT ENHANCED CHEMICAL CLEANING TESTS

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

Eibling, R

The closure process for high level waste tanks at the Savannah River Site will require dissolution of the crystallized salts that are currently stored in many of the tanks. The insoluble residue from salt dissolution is planned to be removed by an Enhanced Chemical Cleaning (ECC) process. Development of a chemical cleaning process requires an insoluble salt simulant to support evaluation tests of different cleaning methods. The Process Science and Engineering section of SRNL has been asked to develop an insoluble salt simulant for use in testing potential ECC processes (HLE-TTR-2007-017). An insoluble salt simulant has been developed based uponmore » the residues from salt dissolution of saltcake core samples from Tank 28F. The simulant was developed for use in testing SRS waste tank chemical cleaning methods. Based on the results of the simulant development process, the following observations were developed: (1) A composition based on the presence of 10.35 grams oxalate and 4.68 grams carbonate per 100 grams solids produces a sufficiently insoluble solids simulant. (2) Aluminum observed in the solids remaining from actual waste salt dissolution tests is probably precipitated from sodium aluminate due to the low hydroxide content of the saltcake. (3) In-situ generation of aluminum hydroxide (by use of aluminate as the Al source) appears to trap additional salts in the simulant in a manner similar to that expected for actual waste samples. (4) Alternative compositions are possible with higher oxalate levels and lower carbonate levels. (5) The maximum oxalate level is limited by the required Na content of the insoluble solids. (6) Periodic mixing may help to limit crystal growth in this type of salt simulant. (7) Long term storage of an insoluble salt simulant is likely to produce a material that can not be easily removed from the storage container. Production of a relatively fresh simulant is best if pumping the simulant is necessary for testing purposes. The insoluble salt simulant described in this report represents the initial attempt to represent the material which may be encountered during final waste removal and tank cleaning. The final selected simulant was produced by heating and evaporation of a salt slurry sample to remove excess water and promote formation and precipitation of solids with solubility characteristics which are consistent with actual tank insoluble salt samples. The exact anion composition of the final product solids is not explicitly known since the chemical components in the final product are distributed between the solid and liquid phases. By combining the liquid phase analyses and total solids analysis with mass balance requirements a calculated composition of assumed simple compounds was obtained and is shown in Table 0-1. Additional improvements to and further characterization of the insoluble salt simulant are possible. During the development of these simulants it was recognized that: (1) Additional waste characterization on the residues from salt dissolution tests with actual waste samples to determine the amount of species such as carbonate, oxalate and aluminosilicate would allow fewer assumptions to be made in constructing an insoluble salt simulant. (2) The tank history will impact the amount and type of insoluble solids that exist in the salt dissolution solids. Varying the method of simulant production (elevated temperature processing time, degree of evaporation, amount of mixing (shear) during preparation, etc.) should be tested.« less

Testing for clustering at many ranges inflates family-wise error rate (FWE).

PubMed

Loop, Matthew Shane; McClure, Leslie A

2015-01-15

Testing for clustering at multiple ranges within a single dataset is a common practice in spatial epidemiology. It is not documented whether this approach has an impact on the type 1 error rate. We estimated the family-wise error rate (FWE) for the difference in Ripley's K functions test, when testing at an increasing number of ranges at an alpha-level of 0.05. Case and control locations were generated from a Cox process on a square area the size of the continental US (≈3,000,000 mi2). Two thousand Monte Carlo replicates were used to estimate the FWE with 95% confidence intervals when testing for clustering at one range, as well as 10, 50, and 100 equidistant ranges. The estimated FWE and 95% confidence intervals when testing 10, 50, and 100 ranges were 0.22 (0.20 - 0.24), 0.34 (0.31 - 0.36), and 0.36 (0.34 - 0.38), respectively. Testing for clustering at multiple ranges within a single dataset inflated the FWE above the nominal level of 0.05. Investigators should construct simultaneous critical envelopes (available in spatstat package in R), or use a test statistic that integrates the test statistics from each range, as suggested by the creators of the difference in Ripley's K functions test.

Addendum to the Corrective Action Decision Document/Closure Report for Corrective Action Unit 406: Area 3 Building 03-74 & Building 03-58 Underground Discharge Points and Corrective Action Unit 429: Area 3 Building 03-55 & Area 9 Building 09-52 Underground Discharge Points, Tonopah Test Range, Nevada, Revision 0

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

Lynn Kidman

This document constitutes an addendum to the March 2000, Corrective Action Decision Document / Closure Report for Corrective Action Unit 406: Area 3 Building 03-74 & 03-58 Underground Discharge Points and Corrective Action Unit 429: Area 3 Building 03-55 & Area 9 Building 09-52 Underground Discharge Points (TTR) as described in the document Recommendations and Justifications for Modifications for Use Restrictions Established under the U.S. Department of Energy, National Nuclear Security Administration Nevada Site Office Federal Facility Agreement and Consent Order (UR Modification document) dated February 2008. The UR Modification document was approved by NDEP on February 26, 2008. Themore » approval of the UR Modification document constituted approval of each of the recommended UR modifications. In conformance with the UR Modification document, this addendum consists of: • This cover page that refers the reader to the UR Modification document for additional information • The cover and signature pages of the UR Modification document • The NDEP approval letter • The corresponding section of the UR Modification document This addendum provides the documentation justifying the cancellation of the UR for CAS 03-51-001-0355 – Photo Shop UDP, Drains in CAU 429. It should be noted that there are no changes to CAU 406. This UR was established as part of a Federal Facility Agreement and Consent Order (FFACO) corrective action and is based on the presence of contaminants at concentrations greater than the action levels established at the time of the initial investigation (FFACO, 1996; as amended August 2006). Since this UR was established, practices and procedures relating to the implementation of risk-based corrective actions (RBCA) have changed. Therefore, this UR was re-evaluated against the current RBCA criteria as defined in the Industrial Sites Project Establishment of Final Action Levels (NNSA/NSO, 2006c). This re-evaluation consisted of comparing the original data (used to define the need for the UR) to risk-based final action levels (FALs) developed using the current Industrial Sites RBCA process. The re-evaluation resulted in a recommendation to remove the UR because contamination is not present at the site above the risk-based FALs. Requirements for inspecting and maintaining this UR will be canceled, and the postings and signage at this site will be removed. Fencing and posting may be present at this site that are unrelated to the FFACO UR such as for radiological control purposes as required by the NV/YMP Radiological Control Manual (NNSA/NSO, 2004f). This modification will not affect or modify any non-FFACO requirements for fencing, posting, or monitoring at this site.« less

Test technology on divergence angle of laser range finder based on CCD imaging fusion

NASA Astrophysics Data System (ADS)

Shi, Sheng-bing; Chen, Zhen-xing; Lv, Yao

2016-09-01

Laser range finder has been equipped with all kinds of weapons, such as tank, ship, plane and so on, is important component of fire control system. Divergence angle is important performance and incarnation of horizontal resolving power for laser range finder, is necessary appraised test item in appraisal test. In this paper, based on high accuracy test on divergence angle of laser range finder, divergence angle test system is designed based on CCD imaging, divergence angle of laser range finder is acquired through fusion technology for different attenuation imaging, problem that CCD characteristic influences divergence angle test is solved.

Test techniques for determining laser ranging system performance

NASA Technical Reports Server (NTRS)

Zagwodzki, T. W.

1981-01-01

Procedures and results of an on going test program intended to evaluate laser ranging system performance levels in the field as well as in the laboratory are summarized. Tests show that laser ranging system design requires consideration of time biases and RMS jitters of individual system components. All simple Q switched lasers tested were found to be inadequate for 10 centimeter ranging systems. Timing discriminators operating over a typical 100:1 dynamic signal range may introduce as much as 7 to 9 centimeters of range bias. Time interval units commercially available today are capable of half centimeter performance and are adequate for all field systems currently deployed. Photomultipliers tested show typical tube time biases of one centimeter with single photoelectron transit time jitter of approximately 10 centimeters. Test results demonstrate that NASA's Mobile Laser Ranging System (MOBLAS) receiver configuration is limiting system performance below the 100 photoelectron level.

DebriSat Pre Preshot Laboratory Analyses

DTIC Science & Technology

2015-03-27

plate on up range side. MLI Down range Up range SBU Marking Witness Plates: Post Test (protected) 17 Surfaces of samples under Whipple plates are...s SBU Marking Witness Plates Post Test : Whipple Plates 59 Bottom Middle Top Up range is to the right – note sharp band of deposits on up range side...Marking Hold down plates: Post test 63 Up range Note larger deposit fragments on the down range plate. Similar larger deposits were observed on

Soy isoflavones interfere with thyroid hormone homeostasis in orchidectomized middle-aged rats

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

Šošić-Jurjević, Branka, E-mail: brankasj@ibiss.bg.ac.rs; Filipović, Branko; Wirth, Eva Katrin

We previously reported that genistein (G) and daidzein (D) administered subcutaneously (10 mg/kg) induce changes in the angio-follicular units of the thyroid gland, reduce concentration of total thyroid hormones (TH) and increase thyrotropin (TSH) in serum of orchidectomized middle-aged (16-month-old) rats. To further investigate these effects, we now examined expression levels of the thyroglobulin (Tg), thyroperoxidase (Tpo), vascular endothelial growth factor A (Vegfa) and deiodinase type 1 (Dio 1) genes in the thyroid; in the pituitary, genes involved in TH feedback control (Tsh β, Dio 1, Dio 2, Trh receptor); and in the liver and kidney, expression of T{sub 3}-activatedmore » genes Dio 1 and Spot 14, as well as transthyretin (Ttr), by quantitative real-time PCR. We also analyzed TPO-immunopositivity and immunofluorescence of T{sub 4} bound to Tg, determined thyroid T{sub 4} levels and measured deiodinase enzyme activities in examined organs. Decreased expression of Tg and Tpo genes (p < 0.05) correlated with immunohistochemical staining results, and together with decreased serum total T{sub 4} levels, indicates decreased Tg and TH synthesis following treatments with both isoflavones. However, expression of Spot 14 (p < 0.05) gene in liver and kidney was up-regulated, and liver Dio 1 expression and activity (p < 0.05) increased. At the level of pituitary, no significant change in gene expression levels, or Dio 1 and 2 enzyme activities was observed. In conclusion, both G and D impaired Tg and TH synthesis, but at the same time increased tissue availability of TH in peripheral tissues of Orx middle-aged rats. - Highlights: • We tested how genistein and daidzein interfere with thyroid hormone homeostasis. • Thyroid: decreased expression of Tg and TPO genes correlated with IHC results. • Serum: total T{sub 4} reduced and TSH increased. • Liver and kidney: expression of Spot 14 and liver Dio 1 activity increased. • Pituitary: expression of T{sub 3}-regulated genes and Dio 1 and 2 activities unchanged.« less

Systematic Determination of Replication Activity Type Highlights Interconnections between Replication, Chromatin Structure and Nuclear Localization

PubMed Central

Polten, Andreas; Hezroni, Hadas; Eldar, Yonina C.; Meshorer, Eran; Yakhini, Zohar; Simon, Itamar

2012-01-01

DNA replication is a highly regulated process, with each genomic locus replicating at a distinct time of replication (ToR). Advances in ToR measurement technology enabled several genome-wide profiling studies that revealed tight associations between ToR and general genomic features and a remarkable ToR conservation in mammals. Genome wide studies further showed that at the hundreds kb-to-megabase scale the genome can be divided into constant ToR regions (CTRs) in which the replication process propagates at a faster pace due to the activation of multiple origins and temporal transition regions (TTRs) in which the replication process propagates at a slower pace. We developed a computational tool that assigns a ToR to every measured locus and determines its replication activity type (CTR versus TTR). Our algorithm, ARTO (Analysis of Replication Timing and Organization), uses signal processing methods to fit a constant piece-wise linear curve to the measured raw data. We tested our algorithm and provide performance and usability results. A Matlab implementation of ARTO is available at http://bioinfo.cs.technion.ac.il/people/zohar/ARTO/. Applying our algorithm to ToR data measured in multiple mouse and human samples allowed precise genome-wide ToR determination and replication activity type characterization. Analysis of the results highlighted the plasticity of the replication program. For example, we observed significant ToR differences in 10–25% of the genome when comparing different tissue types. Our analyses also provide evidence for activity type differences in up to 30% of the probes. Integration of the ToR data with multiple aspects of chromosome organization characteristics suggests that ToR plays a role in shaping the regional chromatin structure. Namely, repressive chromatin marks, are associated with late ToR both in TTRs and CTRs. Finally, characterization of the differences between TTRs and CTRs, with matching ToR, revealed that TTRs are associated with compact chromatin and are located significantly closer to the nuclear envelope. Supplementary material is available. Raw and processed data were deposited in Geo (GSE17236). PMID:23145042

Interest and limits of glomerular filtration rate (GFR) estimation with formulae using creatinine or cystatin C in the malnourished elderly population.

PubMed

Fabre, Emmanuelle E; Raynaud-Simon, Agathe; Golmard, Jean-Louis; Gourgouillon, Nadège; Beaudeux, Jean-Louis; Nivet-Antoine, Valérie

2010-01-01

Renal function is often altered in elderly patients. A lot of formulae are proposed to estimate GFR to adjust drug posology. French guidelines recommend the Cockcroft-Gault formula corrected with the body surface area (cCG), but the initially described unadjusted Cockcroft-Gault equation (CG) is mainly used in geriatric clinical practice. International recommendations have proposed the modification of diet in renal disease (MDRD) formula, since several authors recommended the Rule formula using cystatin C (cystC) in particular population. To appreciate the most accurate GFR estimation for posology adaptation in an elderly polypathological population, a cross-sectional study with prospective inclusion was carried out in Charles Foix Hospital. Plasma glucose levels (PGL), creatinine (CREA) levels and serum cystC, albumin (ALB), transthyretin (TTR), C-reactive protein (CRP), orosomucoid (ORO) total cholesterol (tCHOL) levels were determined among 193 elderly patients aged 70 and older. The results showed that in a malnourished, inflamed old population, CG, MDRD and Rule formulae resulted in different estimations of GFR, depending on nutritional and inflammatory parameters. Only cCG estimation was shown to be independent from these parameters. To conclude, cCG seems to be the most accurate and appropriate formula in a polypathological elderly population to evaluate renal function in order to adapt drug posology. Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.

Monoclonal gammopathy of undetermined significance in systemic transthyretin amyloidosis (ATTR).

PubMed

Phull, Pooja; Sanchorawala, Vaishali; Connors, Lawreen H; Doros, Gheorghe; Ruberg, Frederick L; Berk, John L; Sarosiek, Shayna

2018-03-01

To identify the prevalence of monoclonal gammopathy of undetermined significance (MGUS) in patients with transthyretin (ATTR) amyloidosis. We performed a retrospective analysis of patients with biopsy-proven ATTRwt (wild-type transthyretin amyloid protein) and genopositive ATTR V122I (valine-to-isoleucine substitution at position 122 of the TTR gene) amyloidosis evaluated at the Amyloidosis Center at Boston University and Boston Medical Center between 1 January 2003 and 31 December 2016. There were a total of 226 patients with ATTRwt and ATTR V122I amyloidosis evaluated during the specified time frame with 155 and 71 patients in each cohort, respectively. Those with complete medical records, 140 patients with ATTRwt and 57 V1221 ATTRm subjects, were included in the analyses. Fifty-five patients (39%) in the ATTRwt cohort and 28 patients (49%) in the ATTR V122I cohort had an MGUS, as indicated by an abnormality in the serum-free light-chain ratio and/or serum immunofixation electrophoresis. These data confirm the high prevalence of coexistent MGUS with ATTR amyloidosis in this patient population, with an MGUS rate that is higher than the general population. These findings also highlight the importance of a thorough diagnostic evaluation in patients with amyloidosis to determine the precursor protein, as the clinical course and treatment of AL (light-chain amyloid protein) and ATTR amyloidosis are distinct.

Functional characterization of Arabidopsis thaliana transthyretin-like protein.

PubMed

Pessoa, João; Sárkány, Zsuzsa; Ferreira-da-Silva, Frederico; Martins, Sónia; Almeida, Maria R; Li, Jianming; Damas, Ana M

2010-02-18

Arabidopsis thaliana transthyretin-like (TTL) protein is a potential substrate in the brassinosteroid signalling cascade, having a role that moderates plant growth. Moreover, sequence homology revealed two sequence domains similar to 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline (OHCU) decarboxylase (N-terminal domain) and 5-hydroxyisourate (5-HIU) hydrolase (C-terminal domain). TTL is a member of the transthyretin-related protein family (TRP), which comprises a number of proteins with sequence homology to transthyretin (TTR) and the characteristic C-terminal sequence motif Tyr-Arg-Gly-Ser. TRPs are single domain proteins that form tetrameric structures with 5-HIU hydrolase activity. Experimental evidence is fundamental for knowing if TTL is a tetrameric protein, formed by the association of the 5-HIU hydrolase domains and, in this case, if the structural arrangement allows for OHCU decarboxylase activity. This work reports about the biochemical and functional characterization of TTL. The TTL gene was cloned and the protein expressed and purified for biochemical and functional characterization. The results show that TTL is composed of four subunits, with a moderately elongated shape. We also found evidence for 5-HIU hydrolase and OHCU decarboxylase activities in vitro, in the full-length protein. The Arabidopsis thaliana transthyretin-like (TTL) protein is a tetrameric bifunctional enzyme, since it has 5-HIU hydrolase and OHCU decarboxylase activities, which were simultaneously observed in vitro.

Characterization and Thermodynamic Relationship of Three Polymorphs of a Xanthine Oxidase Inhibitor, Febuxostat.

PubMed

Patel, Jinish; Jagia, Moksh; Bansal, Arvind Kumar; Patel, Sarsvatkumar

2015-11-01

Febuxostat (FXT), a xanthine oxidase inhibitor, is an interesting and unique molecule, which exhibits extensive polymorphism, with over 15 polymorphic forms reported to date. The primary purpose of the study was to characterize the three polymorphic forms with respect to their thermodynamic quantities and establish thermodynamic relationship between them. The polymorphs were characterized by thermal and powder X-ray diffraction methods. Three different methods were used to calculate the transition temperatures (Ttr) and thereby their thermodynamic relationships. Although the first and second method used calorimetric data (melting point and heat of fusion), the third method employed the use of configurational free energy phase diagram. The onset melting points of three polymorphic forms were found to be 482.89 ± 0.37 K for form I, 476.30 ± 1.21 K for form II, and 474.19 ± 0.11 K for form III. Moreover, the powder X-ray diffraction patterns for each form were also unique. The polymorphic pair of form I and II and of form I and III was found to be enantiotropic, whereas pair of form II and III was monotropic. Besides the relative thermodynamic aspects (free energy differences, enthalpy, entropy contributions) using different methods, the pharmaceutical implications and phase transformation aspects have also been covered. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Clinical Implementation of Integrated Genomic Profiling in Patients with Advanced Cancers.

PubMed

Borad, Mitesh J; Egan, Jan B; Condjella, Rachel M; Liang, Winnie S; Fonseca, Rafael; Ritacca, Nicole R; McCullough, Ann E; Barrett, Michael T; Hunt, Katherine S; Champion, Mia D; Patel, Maitray D; Young, Scott W; Silva, Alvin C; Ho, Thai H; Halfdanarson, Thorvardur R; McWilliams, Robert R; Lazaridis, Konstantinos N; Ramanathan, Ramesh K; Baker, Angela; Aldrich, Jessica; Kurdoglu, Ahmet; Izatt, Tyler; Christoforides, Alexis; Cherni, Irene; Nasser, Sara; Reiman, Rebecca; Cuyugan, Lori; McDonald, Jacquelyn; Adkins, Jonathan; Mastrian, Stephen D; Valdez, Riccardo; Jaroszewski, Dawn E; Von Hoff, Daniel D; Craig, David W; Stewart, A Keith; Carpten, John D; Bryce, Alan H

2016-12-23

DNA focused panel sequencing has been rapidly adopted to assess therapeutic targets in advanced/refractory cancer. Integrated Genomic Profiling (IGP) utilising DNA/RNA with tumour/normal comparisons in a Clinical Laboratory Improvement Amendments (CLIA) compliant setting enables a single assay to provide: therapeutic target prioritisation, novel target discovery/application and comprehensive germline assessment. A prospective study in 35 advanced/refractory cancer patients was conducted using CLIA-compliant IGP. Feasibility was assessed by estimating time to results (TTR), prioritising/assigning putative therapeutic targets, assessing drug access, ascertaining germline alterations, and assessing patient preferences/perspectives on data use/reporting. Therapeutic targets were identified using biointelligence/pathway analyses and interpreted by a Genomic Tumour Board. Seventy-five percent of cases harboured 1-3 therapeutically targetable mutations/case (median 79 mutations of potential functional significance/case). Median time to CLIA-validated results was 116 days with CLIA-validation of targets achieved in 21/22 patients. IGP directed treatment was instituted in 13 patients utilising on/off label FDA approved drugs (n = 9), clinical trials (n = 3) and single patient IND (n = 1). Preliminary clinical efficacy was noted in five patients (two partial response, three stable disease). Although barriers to broader application exist, including the need for wider availability of therapies, IGP in a CLIA-framework is feasible and valuable in selection/prioritisation of anti-cancer therapeutic targets.

In vitro modelling of familial amyloidotic polyneuropathy allows quantitative detection of transthyretin amyloid fibril-like structures in hepatic derivatives of patient-specific induced pluripotent stem cells.

PubMed

Hoepfner, Jeannine; Kleinsorge, Mandy; Papp, Oliver; Alfken, Susanne; Heiringhoff, Robin; Pich, Andreas; Sauer, Vanessa; Zibert, Andree; Göhring, Gudrun; Schmidt, Hartmut; Sgodda, Malte; Cantz, Tobias

2017-07-26

The transthyretin protein is thermodynamically destabilised by mutations in the transthyretin gene, promoting the formation of amyloid fibrils in various tissues. Consequently, impaired autonomic organ function is observed in patients suffering from transthyretin-related familial amyloidotic polyneuropathy (FAP). The influence of individual genetic backgrounds on fibril formation as a potential cause of genotype-phenotype variations needs to be investigated in order to ensure efficient patient-specific therapies. We reprogrammed FAP patient fibroblasts to induced pluripotent stem (iPS) cells and differentiated these cells into transthyretin-expressing hepatocyte-like cells (HLCs). HLCs differentiated from FAP iPS cells and healthy control iPS cells secreted the transthyretin protein in similar concentrations. Mass spectrometry revealed the presence of mutant transthyretin protein in FAP HLC supernatants. In comparison to healthy control iPS cells, we demonstrated the formation of transthyretin amyloid fibril-like structures in FAP HLC supernatants using the amyloid-specific dyes Congo red and thioflavin T. These dyes were also applicable for the quantitative determination of in vitro formed transthyretin fibril-like structures. Moreover, we confirmed the inhibition of fibril formation by the TTR kinetic stabiliser diclofenac. Thioflavin T fluorescence intensity measurements even allowed the quantification of amyloid fibril-like structures in 96-well plate formats as a prerequisite for patient-specific drug screening approaches.

Impact of antibodies against amyloidogenic transthyretin (ATTR) on phenotypes of patients with familial amyloidotic polyneuropathy (FAP) ATTR Valine30Methionine.

PubMed

Obayashi, Konen; Tasaki, Masayoshi; Jono, Hirofumi; Ueda, Mitsuharu; Shinriki, Satoru; Misumi, Yohei; Yamashita, Taro; Oshima, Toshinori; Nakamura, Teruya; Ikemizu, Shinji; Anan, Intissar; Suhr, Ole; Ando, Yukio

2013-04-18

This study investigated whether a relationship exists between the presence of de novo antibodies and the clinical manifestations of familial amyloidotic polyneuropathy (FAP). Serum samples were collected from 25 Japanese and 6 Swedish FAP amyloidogenic transthyretin (ATTR) Valine30Methionine (V30M) patients, 4 asymptomatic Japanese ATTR V30M gene carriers, and 24 Japanese healthy volunteers. Study methods included enzyme-linked immunosorbent assay (ELISA) and mass spectrometry. Three Japanese and 5 Swedish patients had significantly higher levels of antibodies against ATTR than did healthy volunteers and asymptomatic gene carriers (P<0.05). All 8 patients with higher antibody levels were late-onset cases. The ratio of wild-type TTR to ATTR V30M in serum from the high-antibody group was higher than that of the low-antibody group. ELISA results revealed two epitopes at positions 24-35 and 105-115 of ATTR V30M. We found a significant positive correlation between levels of the antibody at positions 24-35 and the age at FAP onset (r=0.751, P<0.05). An age-dependent increase in the occurrence of antibodies was observed in these patients with an epitope at positions 24-35. These findings may help explain the differences in early- and late-onset FAP and/or the progression of FAP. Copyright © 2013 Elsevier B.V. All rights reserved.

33 CFR 159.115 - Temperature range test.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 33 Navigation and Navigable Waters 2 2011-07-01 2011-07-01 false Temperature range test. 159.115 Section 159.115 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) POLLUTION MARINE SANITATION DEVICES Design, Construction, and Testing § 159.115 Temperature range test. (a...

Modelling the cost-effectiveness of pharmacist-managed anticoagulation service for older adults with atrial fibrillation in Singapore.

PubMed

Chua, Wen Bing Brandon; Cheen, Hua Heng McVin; Kong, Ming Chai; Chen, Li Li; Wee, Hwee Lin

2016-10-01

Background Oral anticoagulation with warfarin is the cornerstone therapy in atrial fibrillation (AF) for stroke prevention. Multi-disciplinary anticoagulation management services have been shown to be cost-effective in the United States, Hong Kong and Thailand, but the findings are not readily generalizable to Singapore's healthcare system. Objective This study aimed to evaluate the cost-effectiveness of pharmacist-managed anticoagulation clinic (ACC) compared with usual care (UC) for the management of older adults with AF receiving oral anticoagulation with warfarin. Setting Pharmacist-managed ACC in an academic medical centre. Method A Markov model with 3-month cycle length and 30-year time horizon compared costs and quality-adjusted life-years (QALYs) of ACC and UC from the patient's and healthcare provider's perspectives. Four pathways based on time in therapeutic range (TTR) were: ACC TTR < 70 %, ACC TTR ≥ 70 %, UC TTR < 70 % and UC TTR ≥ 70 %. A hypothetical cohort of 70-year-old Singaporean AF patients receiving warfarin was utilised. Local data from national disease registries, patient surveys and hospital databases were used. When local data was not available, published studies on Asian populations were utilized when available. One-way sensitivity analyses and probabilistic sensitivity analyses were performed to account for uncertainties. Costs and QALYs were discounted annually by 3 %. Main outcome measure Costs and QALYs of ACC and UC. Results Pharmacist-managed ACC was found to dominate UC in all comparisons. It improved effectiveness by 0.19 and 0.13 QALYs at TTR < 70 % and TTR ≥ 70 % respectively compared with UC. From the patient's perspective, ACC reduced costs by SG$1222.67 (€1110.24) for TTR < 70 % and SG$1008.16 (€915.46) for TTR ≥ 70 %. Similar trends were observed from the healthcare provider's perspective, with ACC reducing costs by SG$1444.79 (€1311.94) for TTR < 70 % and SG$1269.17 (€1152.46) for TTR ≥ 70 % compared with UC. The results were robust to variations of the parameters over their plausible ranges in one-way sensitivity analyses. Probabilistic sensitivity analyses demonstrated that ACC was cost-effective more than 79 % of the time from both perspectives at a willingness-to-pay threshold of SG$69,050 (€62,701) per QALY. Conclusion Pharmacist-managed ACC is more effective and less costly compared with UC regardless of the quality of anticoagulation therapy. The findings support the current body of evidence demonstrating the cost-effectiveness of ACC.

Management and Capability ot the Major Range and Test Facility Bases

DTIC Science & Technology

1995-07-27

The audit objective was to evaluate management oversight provided to the test ranges and determine whether management oversight could be streamlined... The audit also evaluated whether program managers were procuring test resources that already existed at the test ranges. Management controls related to the objectives were also evaluated.

33 CFR 159.115 - Temperature range test.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 33 Navigation and Navigable Waters 2 2014-07-01 2014-07-01 false Temperature range test. 159.115...) POLLUTION MARINE SANITATION DEVICES Design, Construction, and Testing § 159.115 Temperature range test. (a) The device must be held at a temperature of 60 °C or higher for a period of 16 hours. (b) The device...

33 CFR 159.115 - Temperature range test.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 33 Navigation and Navigable Waters 2 2013-07-01 2013-07-01 false Temperature range test. 159.115...) POLLUTION MARINE SANITATION DEVICES Design, Construction, and Testing § 159.115 Temperature range test. (a) The device must be held at a temperature of 60 °C or higher for a period of 16 hours. (b) The device...

33 CFR 159.115 - Temperature range test.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 33 Navigation and Navigable Waters 2 2012-07-01 2012-07-01 false Temperature range test. 159.115...) POLLUTION MARINE SANITATION DEVICES Design, Construction, and Testing § 159.115 Temperature range test. (a) The device must be held at a temperature of 60 °C or higher for a period of 16 hours. (b) The device...

33 CFR 159.115 - Temperature range test.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 33 Navigation and Navigable Waters 2 2010-07-01 2010-07-01 false Temperature range test. 159.115...) POLLUTION MARINE SANITATION DEVICES Design, Construction, and Testing § 159.115 Temperature range test. (a) The device must be held at a temperature of 60 °C or higher for a period of 16 hours. (b) The device...

A multiwave range test for obstacle reconstructions with unknown physical properties

NASA Astrophysics Data System (ADS)

Potthast, Roland; Schulz, Jochen

2007-08-01

We develop a new multiwave version of the range test for shape reconstruction in inverse scattering theory. The range test [R. Potthast, et al., A `range test' for determining scatterers with unknown physical properties, Inverse Problems 19(3) (2003) 533-547] has originally been proposed to obtain knowledge about an unknown scatterer when the far field pattern for only one plane wave is given. Here, we extend the method to the case of multiple waves and show that the full shape of the unknown scatterer can be reconstructed. We further will clarify the relation between the range test methods, the potential method [A. Kirsch, R. Kress, On an integral equation of the first kind in inverse acoustic scattering, in: Inverse Problems (Oberwolfach, 1986), Internationale Schriftenreihe zur Numerischen Mathematik, vol. 77, Birkhauser, Basel, 1986, pp. 93-102] and the singular sources method [R. Potthast, Point sources and multipoles in inverse scattering theory, Habilitation Thesis, Gottingen, 1999]. In particular, we propose a new version of the Kirsch-Kress method using the range test and a new approach to the singular sources method based on the range test and potential method. Numerical examples of reconstructions for all four methods are provided.

Tonopah Test Range Post-Closure Inspection Annual Report, Tonopah Test Range, Nevada, Calendar Year 2003

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

U.S. Department of Energy, National Nuclear Security Administration Nevada Site Office; Bechtel Nevada

This post-closure inspection report provides documentation of the semiannual inspection activities, maintenance and repair activities, and conclusions and recommendations for calendar year 2003 for eight corrective action units located on the Tonopah Test Range, Nevada.

Aerothermodynamic Testing of Aerocapture and Planetary Probe Geometries in Hypersonic Ballistic-Range Environments

NASA Technical Reports Server (NTRS)

Wilder, M. C.; Reda, D. C.; Bogdanoff, D. W.; Olejniczak, J.

2005-01-01

A viewgraph presentation on aerothermodynamic testing of aerocapture and planetary probe design methods in hypersonic ballistic range environments is shown. The topics include: 1) Ballistic Range Testing; 2) NASA-Ames Hypervelocity Free Flight Facility; and 3) Representative Results.

GPS test range mission planning

NASA Astrophysics Data System (ADS)

Roberts, Iris P.; Hancock, Thomas P.

The principal features of the Test Range User Mission Planner (TRUMP), a PC-resident tool designed to aid in deploying and utilizing GPS-based test range assets, are reviewed. TRUMP features time history plots of time-space-position information (TSPI); performance based on a dynamic GPS/inertial system simulation; time history plots of TSPI data link connectivity; digital terrain elevation data maps with user-defined cultural features; and two-dimensional coverage plots of ground-based test range assets. Some functions to be added during the next development phase are discussed.

Hardware test program for evaluation of baseline range/range rate sensor concept

NASA Technical Reports Server (NTRS)

1985-01-01

The Hardware Test Program for evaluation of the baseline range/range rate sensor concept was initiated 11 September 1984. This ninth report covers the period 12 May through 11 June 1885. A contract amendment adding a second phase has extended the Hardware Test Program through 10 December 1985. The objective of the added program phase is to establish range and range measurement accuracy and radar signature characteristics for a typical spacecraft target. Phase I of the Hardware Test Program was designed to reduce the risks associated with the Range/Range Rate (R/R) Sensor baseline design approach. These risks are associated with achieving the sensor performance required for the two modes of operation, the Interrupted CW (ICW) mode for initial acquisition and tracking to close-in ranges, and the CW mode, providing coverage during the final docking maneuver. The risks associated with these modes of operation have to do with the realization of adequate sensitivity to operate to their individual maximum ranges.

Stability of scores for the Slosson Full-Range Intelligence Test.

PubMed

Williams, Thomas O; Eaves, Ronald C; Woods-Groves, Suzanne; Mariano, Gina

2007-08-01

The test-retest stability of the Slosson Full-Range Intelligence Test by Algozzine, Eaves, Mann, and Vance was investigated with test scores from a sample of 103 students. With a mean interval of 13.7 mo. and different examiners for each of the two test administrations, the test-retest reliability coefficients for the Full-Range IQ, Verbal Reasoning, Abstract Reasoning, Quantitative Reasoning, and Memory were .93, .85, .80, .80, and .83, respectively. Mean differences from the test-retest scores were not statistically significantly different for any of the scales. Results suggest that Slosson scores are stable over time even when different examiners administer the test.

Complete Host Range Testing on Common Reed with Potential Biological Control Agents and Investigation into Biological Control for Flowering Rush

DTIC Science & Technology

2016-07-01

ER D C/ EL C R- 16 -5 Aquatic Plant Control Research Program Complete Host Range Testing on Common Reed with Potential Biological...client/default. Aquatic Plant Control Research Program ERDC/EL CR-16-5 July 2016 Complete Host Range Testing on Common Reed with Potential...and started with sequential no-choice oviposition tests. So far, no eggs were found on any of the 22 test plants offered. The authors also found the

White Sands Missile Range Overview & Introduction: Test Capabilities Briefing

DTIC Science & Technology

2011-11-07

PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) Army Test and Evaluation Command (ATEC),White Sands Missile Range,White Sands Missile Range,NM,88002...5000 8. PERFORMING ORGANIZATION REPORT NUMBER 9. SPONSORING/MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR’S ACRONYM(S) 11. SPONSOR...solar radiation, icing, salt fog, etc. • Instrumented for system performance / diagnostics  Climatics testing capabilities • Fixed and mobile test

Mission Information and Test Systems Summary of Accomplishments, 2012-2013

NASA Technical Reports Server (NTRS)

McMorrow, Sean; Sherrard, Roberta; Gibbs, Yvonne

2015-01-01

This annual report covers the activities of the NASA Dryden Flight Research Center's Mission Information and Test Systems directorate, which include the Western Aeronautical Test Range (Range Engineering and Range Operations), the Simulation Engineering Branch, and Information Services. This report contains highlights, current projects, and various awards achieved throughout 2012 and 2013.

Transmitted wavefront testing with large dynamic range based on computer-aided deflectometry

NASA Astrophysics Data System (ADS)

Wang, Daodang; Xu, Ping; Gong, Zhidong; Xie, Zhongmin; Liang, Rongguang; Xu, Xinke; Kong, Ming; Zhao, Jun

2018-06-01

The transmitted wavefront testing technique is demanded for the performance evaluation of transmission optics and transparent glass, in which the achievable dynamic range is a key issue. A computer-aided deflectometric testing method with fringe projection is proposed for the accurate testing of transmitted wavefronts with a large dynamic range. Ray tracing of the modeled testing system is carried out to achieve the virtual ‘null’ testing of transmitted wavefront aberrations. The ray aberration is obtained from the ray tracing result and measured slope, with which the test wavefront aberration can be reconstructed. To eliminate testing system modeling errors, a system geometry calibration based on computer-aided reverse optimization is applied to realize accurate testing. Both numerical simulation and experiments have been carried out to demonstrate the feasibility and high accuracy of the proposed testing method. The proposed testing method can achieve a large dynamic range compared with the interferometric method, providing a simple, low-cost and accurate way for the testing of transmitted wavefronts from various kinds of optics and a large amount of industrial transmission elements.

Current Testing Capabilities at the NASA Ames Ballistic Ranges

NASA Technical Reports Server (NTRS)

Ramsey, Alvin; Tam, Tim; Bogdanoff, David; Gage, Peter

1999-01-01

Capabilities for designing and performing ballistic range tests at the NASA Ames Research Center are presented. Computational tools to assist in designing and developing ballistic range models and to predict the flight characteristics of these models are described. A CFD code modeling two-stage gun performance is available, allowing muzzle velocity, maximum projectile base pressure, and gun erosion to be predicted. Aerodynamic characteristics such as drag and stability can be obtained at speeds ranging from 0.2 km/s to 8 km/s. The composition and density of the test gas can be controlled, which allows for an assessment of Reynolds number and specific heat ratio effects under conditions that closely match those encountered during planetary entry. Pressure transducers have been installed in the gun breech to record the time history of the pressure during launch, and pressure transducers have also been installed in the walls of the range to measure sonic boom effects. To illustrate the testing capabilities of the Ames ballistic ranges, an overview of some of the recent tests is given.

A New Clinical Pain Knowledge Test for Nurses: Development and Psychometric Evaluation.

PubMed

Bernhofer, Esther I; St Marie, Barbara; Bena, James F

2017-08-01

All nurses care for patients with pain, and pain management knowledge and attitude surveys for nurses have been around since 1987. However, no validated knowledge test exists to measure postlicensure clinicians' knowledge of the core competencies of pain management in current complex patient populations. To develop and test the psychometric properties of an instrument designed to measure pain management knowledge of postlicensure nurses. Psychometric instrument validation. Four large Midwestern U.S. hospitals. Registered nurses employed full time and part time August 2015 to April 2016, aged M = 43.25 years; time as RN, M = 16.13 years. Prospective survey design using e-mail to invite nurses to take an electronic multiple choice pain knowledge test. Content validity of initial 36-item test "very good" (95.1% agreement). Completed tests that met analysis criteria, N = 747. Mean initial test score, 69.4% correct (range 27.8-97.2). After revision/removal of 13 unacceptable questions, mean test score was 50.4% correct (range 8.7-82.6). Initial test item percent difficulty range was 15.2%-98.1%; discrimination values range, 0.03-0.50; final test item percent difficulty range, 17.6%-91.1%, discrimination values range, -0.04 to 1.04. Split-half reliability final test was 0.66. A high decision consistency reliability was identified, with test cut-score of 75%. The final 23-item Clinical Pain Knowledge Test has acceptable discrimination, difficulty, decision consistency, reliability, and validity in the general clinical inpatient nurse population. This instrument will be useful in assessing pain management knowledge of clinical nurses to determine gaps in education, evaluate knowledge after pain management education, and measure research outcomes. Copyright © 2017 American Society for Pain Management Nursing. Published by Elsevier Inc. All rights reserved.

The Effect of Acute and Chronic Social Stress on the Hippocampal Transcriptome in Mice.

PubMed

Stankiewicz, Adrian M; Goscik, Joanna; Majewska, Alicja; Swiergiel, Artur H; Juszczak, Grzegorz R

2015-01-01

Psychogenic stress contributes to the formation of brain pathology. Using gene expression microarrays, we analyzed the hippocampal transcriptome of mice subjected to acute and chronic social stress of different duration. The longest period of social stress altered the expression of the highest number of genes and most of the stress-induced changes in transcription were reversible after 5 days of rest. Chronic stress affected genes involved in the functioning of the vascular system (Alas2, Hbb-b1, Hba-a2, Hba-a1), injury response (Vwf, Mgp, Cfh, Fbln5, Col3a1, Ctgf) and inflammation (S100a8, S100a9, Ctla2a, Ctla2b, Lcn2, Lrg1, Rsad2, Isg20). The results suggest that stress may affect brain functions through the stress-induced dysfunction of the vascular system. An important issue raised in our work is also the risk of the contamination of brain tissue samples with choroid plexus. Such contamination would result in a consistent up- or down-regulation of genes, such as Ttr, Igf2, Igfbp2, Prlr, Enpp2, Sostdc1, 1500015O10RIK (Ecrg4), Kl, Clic6, Kcne2, F5, Slc4a5, and Aqp1. Our study suggests that some of the previously reported, supposedly specific changes in hippocampal gene expression, may be a result of the inclusion of choroid plexus in the hippocampal samples.

The Addition of Postoperative Chemotherapy is Associated with Improved Survival in Patients with Pancreatic Cancer Treated with Preoperative Therapy.

PubMed

Roland, Christina L; Katz, Matthew H G; Tzeng, Ching-Wei D; Lin, Heather; Varadhachary, Gauri R; Shroff, Rachna; Javle, Milind; Fogelman, David; Wolff, Robert A; Vauthey, Jean N; Crane, Christopher H; Lee, Jeffrey E; Fleming, Jason B

2015-12-01

Preoperative/neoadjuvant therapy (NT) is increasingly utilized for the treatment of pancreatic ductal adenocarcinoma (PDAC). However, little data exist regarding information on the use of additional postoperative therapy following NT. The lymph node ratio (LNR) is a prognostic marker of oncologic outcomes after NT and resection. In this study, we evaluated the effectiveness of postoperative therapy following NT, stratified by LNR. A prospective tumor registry database was queried to identify patients with PDAC who underwent resection following NT from 1990 to 2008. Clinicopathologic factors were compared to identify associations with overall survival (OS) and time to recurrence (TTR) based on postoperative chemotherapy status. Thirty-six (14 %) of the 263 patients received additional postoperative therapy. No differences were observed in the pathologic characteristics between patients who received postoperative chemotherapy and those who did not. The median LNR was 0.12 for patients with N + disease. Following NT, the administration of postoperative therapy was associated with improved median OS (72 vs. 33 months; p = 0.008) for patients with an LNR < 0.15. There was no association between postoperative chemotherapy and OS for patients with LNR ≥ 0.15. Multivariate analysis demonstrated that the administration of postoperative systemic therapy in patients with a low LNR was associated with a reduced risk of death (hazard ratio 0.49; p = 0.02). Postoperative chemotherapy after NT in patients with low LNR is associated with improved oncologic outcomes.

Intact stable isotope labeled plasma proteins from the SILAC-labeled HepG2 secretome.

PubMed

Mangrum, John B; Martin, Erika J; Brophy, Donald F; Hawkridge, Adam M

2015-09-01

The plasma proteome remains an attractive biospecimen for MS-based biomarker discovery studies. The success of these efforts relies on the continued development of quantitative MS-based proteomics approaches. Herein we report the use of the SILAC-labeled HepG2 secretome as a source for stable isotope labeled plasma proteins for quantitative LC-MS/MS measurements. The HepG2 liver cancer cell line secretes the major plasma proteins including serum albumin, apolipoproteins, protease inhibitors, coagulation factors, and transporters that represent some of the most abundant proteins in plasma. The SILAC-labeled HepG2 secretome was collected, spiked into human plasma (1:1 total protein), and then processed for LC-MS/MS analysis. A total of 62 and 56 plasma proteins were quantified (heavy:light (H/L) peptide pairs) from undepleted and depleted (serum albumin and IgG), respectively, with log2 H/L = ± 6. Major plasma proteins quantified included albumin, apolipoproteins (e.g., APOA1, APOA2, APOA4, APOB, APOC3, APOE, APOH, and APOM), protease inhibitors (e.g., A2M and SERPINs), coagulation factors (e.g., Factor V, Factor X, fibrinogen), and transport proteins (e.g., TTR). The average log2 H/L values for shared plasma proteins in both undepleted and depleted plasma samples were 0.43 and 0.44, respectively. This work further expands the SILAC strategy into MS-based biomarker discovery of clinical biospecimens. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Comparison of in vitro and in vivo bioassays to measure thyroid hormone disrupting activity in water extracts.

PubMed

Leusch, Frederic D L; Aneck-Hahn, Natalie H; Cavanagh, Jo-Anne E; Du Pasquier, David; Hamers, Timo; Hebert, Armelle; Neale, Peta A; Scheurer, Marco; Simmons, Steven O; Schriks, Merijn

2018-01-01

Environmental chemicals can induce thyroid disruption through a number of mechanisms including altered thyroid hormone biosynthesis and transport, as well as activation and inhibition of the thyroid receptor. In the current study six in vitro bioassays indicative of different mechanisms of thyroid disruption and one whole animal in vivo assay were applied to 9 model compounds and 4 different water samples (treated wastewater, surface water, drinking water and ultra-pure lab water; both unspiked and spiked with model compounds) to determine their ability to detect thyroid active compounds. Most assays correctly identified and quantified the model compounds as agonists or antagonists, with the reporter gene assays being the most sensitive. However, the reporter gene assays did not detect significant thyroid activity in any of the water samples, suggesting that activation or inhibition of the thyroid hormone receptor is not a relevant mode of action for thyroid endocrine disruptors in water. The thyroperoxidase (TPO) inhibition assay and transthyretin (TTR) displacement assay (FITC) detected activity in the surface water and treated wastewater samples, but more work is required to assess if this activity is a true measure of thyroid activity or matrix interference. The whole animal Xenopus Embryonic Thyroid Assay (XETA) detected some activity in the unspiked surface water and treated wastewater extracts, but not in unspiked drinking water, and appears to be a suitable assay to detect thyroid activity in environmental waters. Copyright © 2017 Elsevier Ltd. All rights reserved.

Measurement of xenon diffusing capacity in the rat lung by hyperpolarized 129Xe MRI and dynamic spectroscopy in a single breath-hold.

PubMed

Abdeen, Nishard; Cross, Albert; Cron, Gregory; White, Steven; Rand, Thomas; Miller, David; Santyr, Giles

2006-08-01

We used the dual capability of hyperpolarized 129Xe for spectroscopy and imaging to develop new measures of xenon diffusing capacity in the rat lung that (analogously to the diffusing capacity of carbon monoxide or DLCO) are calculated as a product of total lung volume and gas transfer rate constants divided by the pressure gradient. Under conditions of known constant pressure breath-hold, the volume is measured by hyperpolarized 129Xe MRI, and the transfer rate is measured by dynamic spectroscopy. The new quantities (xenon diffusing capacity in lung parenchyma (DLXeLP)), xenon diffusing capacity in RBCs (DLXeRBC), and total lung xenon diffusing capacity (DLXe)) were measured in six normal rats and six rats with lung inflammation induced by instillation of fungal spores of Stachybotrys chartarum. DLXeLP, DLXeRBC, and DLXe were 56 +/- 10 ml/min/mmHg, 64 +/- 35 ml/min/mmHg, and 29 +/- 9 ml/min/mmHg, respectively, for normal rats, and 27 +/- 9 ml/min/mmHg, 42 +/- 27 ml/min/mmHg, and 16 +/- 7 ml/min/mmHg, respectively, for diseased rats. Lung volumes and gas transfer times for LP (TtrLP) were 16 +/- 2 ml and 22 +/- 3 ms, respectively, for normal rats and 12 +/- 2 ml and 35 +/- 8 ms, respectively, for diseased rats. Xenon diffusing capacities may be useful for measuring changes in gas exchange associated with inflammation and other lung diseases. Copyright 2006 Wiley-Liss, Inc.

Intermediate Temperature Water Heat Pipe Tests

NASA Technical Reports Server (NTRS)

Devarakonda, Angirasa; Xiong, Da-Xi; Beach, Duane E.

2005-01-01

Heat pipes are among the most promising technologies for space radiator systems. Water heat pipes are explored in the intermediate temperature range of 400 to above 500 K. The thermodynamic and thermo-physical properties of water are reviewed in this temperature range. Test data are reported for a copper-water heat pipe. The heat pipe was tested under different orientations. Water heat pipes show promise in this temperature range. Fabrication and testing issues are being addressed.

Spin-dependent heat transport and thermal boundary resistance

NASA Astrophysics Data System (ADS)

Jeong, Taehee

In this thesis, thermal conductivity change depending on the magnetic configurations has been studied. In order to make different magnetic configurations, we developed a spin valve structure, which has high MR ratio and low saturation field. The high MR ratio was achieved using Co/Cu multilayer and 21A or 34A thick Cu layer. The low saturation field was obtained by implementing different coercivities of the successive ferromagnetic layers. For this purpose, Co/Cu/Cu tri-layered structure was used with the thicknesses of the Co layers; 15 A and 30 A. For the thermal conductivity measurement, a three-omega method was employed with a thermally isolated microscale rod. We fabricated the microscale rod using optical lithography and MEMS process. Then the rod was wire-bonded to a chip-carver for further electrical measurement. For the thermal conductivity measurement, we built the three-omega measurement system using two lock-in amplifiers and two differential amplifiers. A custom-made electromagnet was added to the system to investigate the impact of magnetic field. We observed titanic thermal conductivity change depending on the magnetic configurations of the Co/Cu/Co multilayer. The thermal conductivity change was closely correlated with that of the electric conductivity in terms of the spin orientation, but the thermal conductivity was much more sensitive than that of the electric conductivity. The relative thermal conductivity change was 50% meanwhile that of electric resistivity change was 8.0%. The difference between the two ratios suggests that the scattering mechanism for charge and heat transport in the Co/Cu/Co multilayer is different. The Lorentz number in Weidemann-Franz law is also spin-dependent. Thermal boundary resistance between metal and dielectrics was also studied in this thesis. The thermal boundary resistance becomes critical for heat transport in a nanoscale because the thermal boundary resistance can potentially determine overall heat transport in thin film structures. A transient theraroreflectance (TTR) technique can be used for measuring the thermal conductivity of thin films in cross-sectional direction. In this study, a pump-probe scheme was employed for the TTR technique. We built an optical pump-probe system by using a nanosecond pulse laser for pumping and a continuous-wave laser for probing. A short-time heating event occured at the surface of a sample by shining a laser pulse on the surface. Then the time-resolved thermoreflectance signals were detected using a photodetector and an oscilloscope. The increased temperature decreases slowly and its thermal decay depends on the thermal properties of a sample. Since the reflectivity is linearly proportional to the temperature, the time-resolved thermoreflectance signals have the information of the thermal properties of a sample. In order to extract the thermal properties of a sample, a thermal analysis was performed by fitting the experimental data with thermal models. We developed 2-layered and 3-layered thermal models using the analogies between thermal conduction and electric conduction and a transmission-line concept. We used two sets of sample structures: Au/SiNx/Si substrate and Au/CoFe/SiNx/Si substrate with various thickness of SiN x layer. Using the pump-probe system, we measured the time-resolved thermoreflectance signals for each sample. Then, the thermal conductivity and thermal boundary resistance were obtained by fitting the experimental data with the thermal models. The thermal conductivity of SiNx films was measured to be 2.0 W/mK for both structures. In the case of the thermal boundary resistance, it was 0.81x10-5 m 2K/W at the Au/SiNx interface and 0.54x10 -5 m2K/W at the CoFe/SiNx interface, respectively. The difference of the thermal boundary resistance between Au/SiNx and CoFe/SiNx might be came from the different phonon dispersion of Au and CoFe. The thermal conductivity did not depend on the thickness of SiNx films in the thickness range of 50-200nm. However, the thermal boundary resistance at metal/SiNx interfaces will impact overall thermal conduction when the thickness of SiNx thin films is in a nanometer order. For example, apparent thermal conductivity of SiN x film becomes half of the intrinsic thermal conductivity when the thickness decreases to 16nm. Therefore, it is advised that the thermal boundary resistance between metal and dielectrics should be counted in nano-scale electronic devices. (Abstract shortened by UMI.)

Exploring a Source of Uneven Score Equity across the Test Score Range

ERIC Educational Resources Information Center

Huggins-Manley, Anne Corinne; Qiu, Yuxi; Penfield, Randall D.

2018-01-01

Score equity assessment (SEA) refers to an examination of population invariance of equating across two or more subpopulations of test examinees. Previous SEA studies have shown that score equity may be present for examinees scoring at particular test score ranges but absent for examinees scoring at other score ranges. No studies to date have…

Ranking protective coatings: Laboratory vs. field experience

NASA Astrophysics Data System (ADS)

Conner, Jeffrey A.; Connor, William B.

1994-12-01

Environmentally protective coatings are used on a wide range of gas turbine components for survival in the harsh operating conditions of engines. A host of coatings are commercially available to protect hot-section components, ranging from simple aluminides to designer metallic overlays and ceramic thermal barrier coatings. A variety of coating-application processes are available, and they range from simple pack cementation processing to complex physical vapor deposition, which requires multimillion dollar facilities. Detailed databases are available for most coatings and coating/process combinations for a range of laboratory tests. Still, the analysis of components actually used in engines often yields surprises when compared against predicted coating behavior from laboratory testing. This paper highlights recent work to develop new laboratory tests that better simulate engine environments. Comparison of in-flight coating performance as well as industrial and factory engine testing on a range of hardware is presented along with laboratory predictions from standard testing and from recently developed cyclic burner-rig testing.

Testing Fundamental Gravity with Interplanetary Laser Ranging

NASA Astrophysics Data System (ADS)

Turyshev, S. G.; Shao, M.; Hahn, I.

2018-02-01

Very accurate range measurements with the Interplanetary Laser Ranging Terminal (ILRT) will push high-precision tests of astrophysics/gravitation into a new regime. It could be used for navigation and investigations in planetary/lunar science.

Design Guide for Aerodynamics Testing of Earth and Planetary Entry Vehicles in a Ballistic Range

NASA Technical Reports Server (NTRS)

Bogdanoff, David W.

2017-01-01

The purpose of this manual is to aid in the design of an aerodynamics test of an earth or planetary entry capsule in a ballistic range. In this manual, much use is made of the results and experience gained in 50 years of ballistic range aerodynamics testing at the NASA Ames Research Center, and in particular, that gained in the last 27 years, while the author was working at NASA Ames. The topics treated herein include: Data to be obtained; flight data needed to design test; Reynolds number and dynamic similarity of flight trajectory and ballistic range test; capabilities of various ballistic ranges; Calculations of swerves due to average and oscillating lift and of drag-induced velocity decreases; Model and sabot design; materials, weights and stresses; Sabot separation; Launches at angle of attack and slapping with paper to produce pitch/yaw oscillations.

Developmental prosopagnosia and the Benton Facial Recognition Test.

PubMed

Duchaine, Bradley C; Nakayama, Ken

2004-04-13

The Benton Facial Recognition Test is used for clinical and research purposes, but evidence suggests that it is possible to pass the test with impaired face discrimination abilities. The authors tested 11 patients with developmental prosopagnosia using this test, and a majority scored in the normal range. Consequently, scores in the normal range should be interpreted cautiously, and testing should always be supplemented by other face tests.

33 CFR 334.650 - Gulf of Mexico, south of St. George Island, Fla.; test firing range.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 33 Navigation and Navigable Waters 3 2012-07-01 2012-07-01 false Gulf of Mexico, south of St. George Island, Fla.; test firing range. 334.650 Section 334.650 Navigation and Navigable Waters CORPS OF....650 Gulf of Mexico, south of St. George Island, Fla.; test firing range. (a) The danger zone. A fan...

33 CFR 334.650 - Gulf of Mexico, south of St. George Island, Fla.; test firing range.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 33 Navigation and Navigable Waters 3 2013-07-01 2013-07-01 false Gulf of Mexico, south of St. George Island, Fla.; test firing range. 334.650 Section 334.650 Navigation and Navigable Waters CORPS OF....650 Gulf of Mexico, south of St. George Island, Fla.; test firing range. (a) The danger zone. A fan...

33 CFR 334.650 - Gulf of Mexico, south of St. George Island, Fla.; test firing range.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 33 Navigation and Navigable Waters 3 2014-07-01 2014-07-01 false Gulf of Mexico, south of St. George Island, Fla.; test firing range. 334.650 Section 334.650 Navigation and Navigable Waters CORPS OF....650 Gulf of Mexico, south of St. George Island, Fla.; test firing range. (a) The danger zone. A fan...

Streamlined Approach for Environmental Restoration Plan for Corrective Action Unit 489: WWII UXO Sites, Tonopah Test Range, Nevada; May 2005

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

Bechtel Nevada; U.S. Department of Energy, National Nuclear Security Administration Nevada Site Office

2005-05-01

This Streamlined Approach for Environmental Restoration Plan provides the details for the closure of Corrective Action Unit (CAU) 489: WWII UXO Sites, Tonopah Test Range. CAU 489 is located at the Tonopah Test Range and is currently listed in Appendix III of the Federal Facility Agreement and Consent Order of 1996.

Detection and zoonotic potential of Trichinella spp. from free-range pig farming in Greece.

PubMed

Papatsiros, V G; Boutsini, S; Ntousi, D; Stougiou, D; Mintza, D; Bisias, A

2012-06-01

Trichinellosis is a serious parasitic zoonosis, which is widely distributed around the world. Pork meat is still the predominant source of outbreaks of human trichinellosis in many countries. The aim of this study is to examine the impact of Trichinella spp. as an important risk factor on the free-range pig farming sector in Greece. In 2009, during routine testing for the detection of Trichinella larvae at slaughterhouses and the National Reference Laboratory for Parasites (NRL), a total of 826,426 pigs were tested with the magnetic stirrer method for Trichinella spp. at slaughterhouses, including 2,892 samples from free-range pigs. Two positive samples were detected: one positive for Trichinella britovi and one positive for Trichinella spp. (unspecified) in the samples from wild farmed free-range pigs. It is alarming that one of these cases was connected with clinical signs of trichinellosis in five persons of the same family in northeastern Greece, who consumed undercooked pork meat from a free-range pig farm. During 2010, a total number of 1,295,034 pigs were tested with same method, including 4,159 samples from free-range pig farms. Five positive samples for Trichinella spp. (unspecified) were detected from 4,159 free-range pigs tested by the Greek NRL. Moreover, 363 serum samples from free-range pigs were serologically tested with enzyme-linked immunosorbent assay (ELISA). Moreover, 363 serum samples from farmed free-range pigs were serologically tested with ELISA, and 15 samples were found positive. Finally, the present study is the first report of detection of T. britovi in Greece. In conclusion, based on the results of the present study, Trichinella spp. is a high-risk factor for the free-range pig farming in Greece.

A new airborne laser rangefinder dynamic target simulator for non-stationary environment

NASA Astrophysics Data System (ADS)

Ma, Pengge; Pang, Dongdong; Yi, Yang

2017-11-01

For the non-stationary environment simulation in laser range finder product testing, a new dynamic target simulation system is studied. First of all, the three-pulsed laser ranging principle, laser target signal composition and mathematical representation are introduced. Then, the actual nonstationary working environment of laser range finder is analyzed, and points out that the real sunshine background light clutter and target shielding effect in laser echo become the main influencing factors. After that, the dynamic laser target signal simulation method is given. Eventlly, the implementation of automatic test system based on arbitrary waveform generator is described. Practical application shows that the new echo signal automatic test system can simulate the real laser ranging environment of laser range finder, and is suitable for performance test of products.

Validation of a virtual reality-based simulator for shoulder arthroscopy.

PubMed

Rahm, Stefan; Germann, Marco; Hingsammer, Andreas; Wieser, Karl; Gerber, Christian

2016-05-01

This study was to determine face and construct validity of a new virtual reality-based shoulder arthroscopy simulator which uses passive haptic feedback. Fifty-one participants including 25 novices (<20 shoulder arthroscopies) and 26 experts (>100 shoulder arthroscopies) completed two tests: for assessment of face validity, a questionnaire was filled out concerning quality of simulated reality and training potential using a 7-point Likert scale (range 1-7). Construct validity was tested by comparing simulator metrics (operation time in seconds, camera and grasper pathway in centimetre and grasper openings) between novices and experts test results. Overall simulated reality was rated high with a median value of 5.5 (range 2.8-7) points. Training capacity scored a median value of 5.8 (range 3-7) points. Experts were significantly faster in the diagnostic test with a median of 91 (range 37-208) s than novices with 1177 (range 81-383) s (p < 0.0001) and in the therapeutic test 102 (range 58-283) s versus 229 (range 114-399) s (p < 0.0001). Similar results were seen in the other metric values except in the camera pathway in the therapeutic test. The tested simulator achieved high scores in terms of realism and training capability. It reliably discriminated between novices and experts. Further improvements of the simulator, especially in the field of therapeutic arthroscopy, might improve its value as training and assessment tool for shoulder arthroscopy skills. II.

[Statistical approach to evaluate the occurrence of out-of acceptable ranges and accuracy for antimicrobial susceptibility tests in inter-laboratory quality control program].

PubMed

Ueno, Tamio; Matuda, Junichi; Yamane, Nobuhisa

2013-03-01

To evaluate the occurrence of out-of acceptable ranges and accuracy of antimicrobial susceptibility tests, we applied a new statistical tool to the Inter-Laboratory Quality Control Program established by the Kyushu Quality Control Research Group. First, we defined acceptable ranges of minimum inhibitory concentration (MIC) for broth microdilution tests and inhibitory zone diameter for disk diffusion tests on the basis of Clinical and Laboratory Standards Institute (CLSI) M100-S21. In the analysis, more than two out-of acceptable range results in the 20 tests were considered as not allowable according to the CLSI document. Of the 90 participating laboratories, 46 (51%) experienced one or more occurrences of out-of acceptable range results. Then, a binomial test was applied to each participating laboratory. The results indicated that the occurrences of out-of acceptable range results in the 11 laboratories were significantly higher when compared to the CLSI recommendation (allowable rate < or = 0.05). The standard deviation indices(SDI) were calculated by using reported results, mean and standard deviation values for the respective antimicrobial agents tested. In the evaluation of accuracy, mean value from each laboratory was statistically compared with zero using a Student's t-test. The results revealed that 5 of the 11 above laboratories reported erroneous test results that systematically drifted to the side of resistance. In conclusion, our statistical approach has enabled us to detect significantly higher occurrences and source of interpretive errors in antimicrobial susceptibility tests; therefore, this approach can provide us with additional information that can improve the accuracy of the test results in clinical microbiology laboratories.

A collection of articles on S/X-band experiment zero delay ranging tests, volume 1

NASA Technical Reports Server (NTRS)

Otoshi, T. Y. (Editor)

1975-01-01

Articles are presented which are concerned with the development of special test equipment and a dual-frequency zero delay device (ZDD) that were required for range tests and the measurement of ground station delays for the Mariner-Venus-Mercury 1973 S/X-band experiment. Test data obtained at DSS 14 after installation of the ZDD on the 64-m antenna are given. It is shown that large variations of range were observed as a function of antenna elevation angle and were sensitive to antenna location. A ranging calibration configuration that was subsequently developed and a technique for determining the appropriate Z-correction are described. Zero delay test data at DSS 14 during the Mariner 10 Venus-Mercury-Encounter periods (1974 days 12-150) are presented. The theoretical analysis and experimental verifications are included of the effects of multipath and effects of discontinuities on range delay measurements. A movable subreflector technique and the multipath theory were used to isolate principal multipath errors on the 64-m antenna and to enable a more accurate determination of the actual ground station range delay.

DC to DC Converter Testing for Space Applications: Use of EMI Filters and Thermal Range of Operation

NASA Technical Reports Server (NTRS)

Leon, Rosa

2008-01-01

Several tests were performed on Interpoint and International Rectifier (IR) direct current (DC) to DC converters to evaluate potential performance and reliability issues in space use of DC to DC converters and to determine if the use of electromagnetic interference (EMI) filters mitigates concerns observed during previous tests. Test findings reported here include those done up until September - October 2008. Tests performed include efficiency, regulation, cross-regulation, power consumption with inhibit on, load transient response, synchronization, and turn-on tests. Some of the test results presented here span the thermal range -55 C to 125 C. Lower range was extended to -120 C in some tested converters. Determination of failure root cause in DC/DC converters that failed at thermal extremes is also included.

Force test of a 0.88 percent scale 142-inch diameter solid rocket booster (MSFC model number 461) in the NASA/MSFC high Reynolds number wind tunnel (SA13F)

NASA Technical Reports Server (NTRS)

Johnson, J. D.; Winkler, G. W.

1976-01-01

The results are presented of a force test of a .88 percent scale model of the 142 inch solid rocket booster without protuberances, conducted in the MSFC high Reynolds number wind tunnel. The objective of this test was to obtain aerodynamic force data over a large range of Reynolds numbers. The test was conducted over a Mach number range from 0.4 to 3.5. Reynolds numbers based on model diameter (1.25 inches) ranged from .75 million to 13.5 million. The angle of attack range was from 35 to 145 degrees.

Role Of High Speed Photography In The Testing Capabilities Of The Arnold Engineering Development Center (AEDC) Range And Track Facilities

NASA Astrophysics Data System (ADS)

Hendrix, Roy E.; Dugger, Paul H.

1983-03-01

Since the onset of user testing in the AEDC aeroballistic ranges in 1961, concentrated efforts in such areas as model launching techniques, test environment simulation, and specialized instrumentation have been made to enhance the usefulness of these test facilities. A wide selection of specialized instrumentation has been developed over the years to provide, among other features, panoramic photographic coverage of test models during flight. Pulsed ruby lasers, xenon flash lamps, visible-light spark sources, and flash X-ray systems are employed as short-duration radiation sources in various front-light and back-light photographic systems. Visible-light and near infrared image intensifier diodes are used to achieve high-speed shuttering in photographic pyrometry systems that measure surface temperatures of test models in flight. Turbine-driven framing cameras are used to provide multiframe photography of such high-speed phenomena as impact debris formation and model encounter with erosive fields. As a result, the capabilities of these ballistic range test units have increased significantly in regard to the types of tests that can be accommodated and to the quality and quantity of data that can be provided. Presently, five major range and companion track facilities are active in conducting hypervelocity testing in AEDC's von K6rman Gas Dynamics Facility (VKF): Ranges G, K, and S-1 and Tracks G and K. The following types of tests are conducted in these test units: ablation/erosion, transpiration-cooled nosetip (TCNT), nosetip transition, heat transfer, aerodynamic, cannon projectile, rocket contrail, reentry physics, and hypervelocity impact. The parallel achievements in high-speed photography and testing capabilities are discussed, and the significant role of photographic systems in the development of the overall testing capabilities of the AEDC range and track facilities is illustrated in numerous examples of photographic results.

Largo hot water system long range thermal performance test report, addendum

NASA Technical Reports Server (NTRS)

1978-01-01

The test procedure used and the test results obtained during the long range thermal performance tests of the LARGO Solar Hot Water System under natural environmental conditions are presented. Objectives of these tests were to determine the amount of energy collected, the amount of power required for system operation, system efficiency, temperature distribution, and system performance degradation.

40 CFR Table C-1 to Subpart C of... - Test Concentration Ranges, Number of Measurements Required, and Maximum Discrepancy Specifications

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 6 2014-07-01 2014-07-01 false Test Concentration Ranges, Number of Measurements Required, and Maximum Discrepancy Specifications C Table C-1 to Subpart C of Part 53 Protection of... Reference Methods Pt. 53, Subpt. C, Table C-1 Table C-1 to Subpart C of Part 53—Test Concentration Ranges...

40 CFR Table C-1 to Subpart C of... - Test Concentration Ranges, Number of Measurements Required, and Maximum Discrepancy Specifications

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 6 2012-07-01 2012-07-01 false Test Concentration Ranges, Number of Measurements Required, and Maximum Discrepancy Specifications C Table C-1 to Subpart C of Part 53 Protection of... Reference Methods Pt. 53, Subpt. C, Table C-1 Table C-1 to Subpart C of Part 53—Test Concentration Ranges...

40 CFR Table C-1 to Subpart C of... - Test Concentration Ranges, Number of Measurements Required, and Maximum Discrepancy Specifications

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 6 2013-07-01 2013-07-01 false Test Concentration Ranges, Number of Measurements Required, and Maximum Discrepancy Specifications C Table C-1 to Subpart C of Part 53 Protection of... Reference Methods Pt. 53, Subpt. C, Table C-1 Table C-1 to Subpart C of Part 53—Test Concentration Ranges...

40 CFR Table C-1 to Subpart C of... - Test Concentration Ranges, Number of Measurements Required, and Maximum Discrepancy Specifications

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 5 2011-07-01 2011-07-01 false Test Concentration Ranges, Number of Measurements Required, and Maximum Discrepancy Specifications C Table C-1 to Subpart C of Part 53 Protection of... Reference Methods Pt. 53, Subpt. C, Table C-1 Table C-1 to Subpart C of Part 53—Test Concentration Ranges...

Results of baseline tests of the EVA metro sedan, citi-car, jet industries electra-van, CDA town car, and OTIS P-500 van

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

Stenger, F.J.; Bozek, J.M.; Soltis, R.F.

1976-10-01

Five electric vehicles were tested at vehicle test tracks using the SAE. The tests provide range data at steady speeds and for several driving cycles. Most tests were conducted with lead-acid traction batteries. The Otis Van and the Copper Electric Town Car were also tested with lead-acid and nickel-zinc batteries. The tests showed a range increase of from 82 to 101 percent depending on vehicle, speed, and test cycle.

Results of baseline tests of the EVA Metro sedan, Citi-car, Jet Industries Electra-van, CDA town car, and Otis P-500 van

NASA Technical Reports Server (NTRS)

Stenger, F. J.; Bozek, J. M.; Soltis, R. F.

1976-01-01

Five electric vehicles were tested at vehicle test tracks using the SAE. The tests provide range data at steady speeds and for several driving cycles. Most tests were conducted with lead-acid traction batteries. The Otis Van and the Copper Electric Town Car were also tested with lead-acid and nickel-zinc batteries. The tests showed a range increase of from 82 to 101 percent depending on vehicle, speed, and test cycle.