scholarly journals Determination of receptor occupancy in the presence of mass dose: [11C]GSK189254 PET imaging of histamine H3 receptor occupancy by PF-03654746

2016 ◽  
Vol 37 (3) ◽  
pp. 1095-1107 ◽  
Author(s):  
Jean-Dominique Gallezot ◽  
Beata Planeta ◽  
Nabeel Nabulsi ◽  
Donna Palumbo ◽  
Xiaoxi Li ◽  
...  
Keyword(s):  
Binding Sites ◽  
Human Subjects ◽  
Receptor Occupancy ◽  
Healthy Human ◽  
Positron Emission ◽  
Relationship Of ◽  
The Relationship ◽  
Pet Scans

Measurements of drug occupancies using positron emission tomography (PET) can be biased if the radioligand concentration exceeds “tracer” levels. Negative bias would also arise in successive PET scans if clearance of the radioligand is slow, resulting in a carryover effect. We developed a method to (1) estimate the in vivo dissociation constant Kd of a radioligand from PET studies displaying a non-tracer carryover (NTCO) effect and (2) correct the NTCO bias in occupancy studies taking into account the plasma concentration of the radioligand and its in vivo Kd. This method was applied in a study of healthy human subjects with the histamine H3 receptor radioligand [11C]GSK189254 to measure the PK-occupancy relationship of the H3 antagonist PF-03654746. From three test/retest studies, [11C]GSK189254 Kd was estimated to be 9.5 ± 5.9 pM. Oral administration of 0.1 to 4 mg of PF-03654746 resulted in occupancy estimates of 71%–97% and 30%–93% at 3 and 24 h post-drug, respectively. NTCO correction adjusted the occupancy estimates by 0%–15%. Analysis of the relationship between corrected occupancies and PF-03654746 plasma levels indicated that PF-03654746 can fully occupy H3 binding sites ( ROmax = 100%), and its IC50 was estimated to be 0.144 ± 0.010 ng/mL. The uncorrected IC50 was 26% higher.

scholarly journals Determination of [11C]PBR28 Binding Potential in vivo: A First Human TSPO Blocking Study

2014 ◽  
Vol 34 (6) ◽  
pp. 989-994 ◽  
Author(s):  
David R Owen ◽  
Qi Guo ◽  
Nicola J Kalk ◽  
Alessandro Colasanti ◽  
Dimitra Kalogiannopoulou ◽  
...  
Keyword(s):  
Volume Of Distribution ◽  
Translocator Protein ◽  
Binding Potential ◽  
Healthy Human ◽  
Positron Emission ◽  
Dose Dependent ◽  
In Vitro Data

Positron emission tomography (PET) targeting the 18 kDa translocator protein (TSPO) is used to quantify neuroinflammation. Translocator protein is expressed throughout the brain, and therefore a classical reference region approach cannot be used to estimate binding potential ( BP ND). Here, we used blockade of the TSPO radioligand [11C]PBR28 with the TSPO ligand XBD173, to determine the non-displaceable volume of distribution ( V ND), and hence estimate the BP ND. A total of 26 healthy volunteers, 16 high-affinity binders (HABs) and 10 mixed affinity binders (MABs) underwent a [11C]PBR28 PET scan with arterial sampling. Six of the HABs received oral XBD173 (10 to 90 mg), 2 hours before a repeat scan. In XBD173-dosed subjects, V ND was estimated via the occupancy plot. Values of BP ND for all subjects were calculated using this V ND estimate. Total volume of distribution ( V T) of MABs (2.94 ± 0.31) was lower than V T of HABs (4.33 ± 0.29) ( P<0.005). There was dose-dependent occupancy of TSPO by XBD173 (ED50 = 0.34 ± 0.13 mg/kg). The occupancy plot provided a V ND estimate of 1.98 (1.69, 2.26). Based on these V ND estimates, BP ND for HABs is approximately twice that of MABs, consistent with predictions from in vitro data. Our estimates of [11C]PBR28 V ND and hence BP ND in the healthy human brain are consistent with in vitro predictions. XBD173 blockade provides a practical means of estimating V ND for TSPO targeting radioligands.

The relationship of in vivo central CB1 receptor occupancy to changes in cortical monoamine release and feeding elicited by CB1 receptor antagonists in rats

2005 ◽  
Vol 184 (1) ◽  
pp. 26-35 ◽  
Author(s):  
Anne B. Need ◽  
Richard J. Davis ◽  
Jesline T. Alexander-Chacko ◽  
Brian Eastwood ◽  
Eyassu Chernet ◽  
...  
Keyword(s):  
Receptor Occupancy ◽  
Cb1 Receptor ◽  
Receptor Antagonists ◽  
Monoamine Release ◽  
Relationship Of ◽  
The Relationship ◽  
Cb1 Receptor Antagonists

Calculating the aerodynamics of vertical axis wind turbines

2012 ◽  
Vol 34 (3) ◽  
pp. 169-184 ◽  
Author(s):  
Hoang Thi Bich Ngoc
Keyword(s):  
Wind Turbine ◽  
Incidence Angle ◽  
Vertical Axis ◽  
Rotor Blades ◽  
Vertical Axis Wind Turbine ◽  
Horizontal Axis Wind Turbine ◽  
Velocity Triangle ◽  
Relationship Of ◽  
The Relationship

Vertical axis wind turbine technology has been applied last years, very long after horizontal axis wind turbine technology. Aerodynamic problems of vertical axis wind machines are discussible. An important problem is the determination of the incidence law in the interaction between wind and rotor blades. The focus of the work is to establish equations of the incidence depending on the blade azimuth, and to solve them. From these results, aerodynamic torques and power can be calculated. The incidence angle is a parameter of velocity triangle, and both the factors depend not only on the blade azimuth but also on the ratio of rotational speed and horizontal speed. The built computational program allows theoretically selecting the relationship of geometric parameters of wind turbine in accordance with requirements on power, wind speed and installation conditions.

Tire Treadwear — A Comprehensive Evaluation of the Factors: Generic Type, Aspect Ratio, Tread Pattern, and Tread Composition Part I: Introduction and Details on the Organization of the Program

1986 ◽  
Vol 14 (4) ◽  
pp. 201-218 ◽  
Author(s):  
A. G. Veith
Keyword(s):  
Aspect Ratio ◽  
Comprehensive Evaluation ◽  
Test Method ◽  
Interactive Effects ◽  
Data Analyses ◽  
Main Effect ◽  
Systematic Determination ◽  
Relationship Of ◽  
The Relationship

Abstract This four-part series of papers addresses the problem of systematic determination of the influence of several tire factors on tire treadwear. Both the main effect of each factor and some of their interactive effects are included. The program was also structured to evaluate the influence of some external-to-tire conditions on the relationship of tire factors to treadwear. Part I describes the experimental design used to evaluate the effects on treadwear of generic tire type, aspect ratio, tread pattern (groove or void level), type of pattern (straight rib or block), and tread compound. Construction procedures and precautions used to obtain a valid and functional test method are included. Two guiding principles to be used in the data analyses of Parts II and III are discussed. These are the fractional groove and void concept, to characterize tread pattern geometry, and a demonstration of the equivalence of wear rate for identical compounds on whole tread or multi-section tread tires.

Pharmacological treatment with L-DOPA may reduce striatal dopamine transporter binding in in vivo imaging studies

2016 ◽  
Vol 55 (01) ◽  
pp. 21-28 ◽  
Author(s):  
C. Antke ◽  
H. Hautzel ◽  
H.-W. Mueller ◽  
S. Nikolaus
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Binding Sites ◽  
Human Subjects ◽  
Synaptic Cleft ◽  
Presynaptic Terminal ◽  
Imaging Studies ◽  
Psychiatric Conditions ◽  
Da Release

SummaryNumerous neurologic and psychiatric conditions are treated with pharmacological compounds, which lead to an increase of synaptic dopamine (DA) levels. One example is the DA precursor L-3,4-dihydroxyphenylalanine (L-DOPA), which is converted to DA in the presynaptic terminal. If the increase of DA concentrations in the synaptic cleft leads to competition with exogenous radioligands for presynaptic binding sites, this may have implications for DA transporter (DAT) imaging studies in patients under DAergic medication.This paper gives an overview on those findings, which, so far, have been obtained on DAT binding in human Parkinson’s disease after treatment with L-DOPA. Findings, moreover, are related to results obtained on rats, mice or non-human primates. Results indicate that DAT imaging may be reduced in the striata of healthy animals, in the unlesioned striata of animal models of unilateral Parkinson’s disease and in less severly impaired striata of Parkinsonian patients, if animal or human subjects are under acute or subchronic treatment with L-DOPA. If also striatal DAT binding is susceptible to alterations of synaptic DA levels, this may allow to quantify DA reuptake in analogy to DA release by assessing the competition between endogenous DA and the administered exogenous DAT radioligand.

scholarly journals Actin and Microtubules Differently Contribute to Vacuolar Targeting Specificity during the Export from the ER

Membranes ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 299
Author(s):  
Monica De Caroli ◽  
Fabrizio Barozzi ◽  
Luciana Renna ◽  
Gabriella Piro ◽  
Gian-Pietro Di Sansebastiano
Keyword(s):  
Spatial Targeting ◽  
Traffic Regulation ◽  
Emergent Features ◽  
Vacuolar Sorting ◽  
Er Export ◽  
Golgi Network ◽  
Relationship Of ◽  
The Relationship ◽  
Fine Tune

Plants rely on both actin and microtubule cytoskeletons to fine-tune sorting and spatial targeting of membranes during cell growth and stress adaptation. Considerable advances have been made in recent years in the comprehension of the relationship between the trans-Golgi network/early endosome (TGN/EE) and cytoskeletons, but studies have mainly focused on the transport to and from the plasma membrane. We address here the relationship of the cytoskeleton with different endoplasmic reticulum (ER) export mechanisms toward vacuoles. These emergent features of the plant endomembrane traffic are explored with an in vivo approach, providing clues on the traffic regulation at different levels beyond known proteins’ functions and interactions. We show how traffic of vacuolar markers, characterized by different vacuolar sorting determinants, diverges at the export from the ER, clearly involving different components of the cytoskeleton.

scholarly journals Harnessing PET to track micro- and nanoplastics in vivo

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Outi Keinänen ◽  
Eric J. Dayts ◽  
Cindy Rodriguez ◽  
Samantha M. Sarrett ◽  
James M. Brennan ◽  
...  
Keyword(s):  
Sea Water ◽  
Accurate Determination ◽  
Nuclear Imaging ◽  
Imaging Data ◽  
Biodistribution Studies ◽  
Positron Emission ◽  
20 Nm ◽  
Pharmacokinetic Behavior

AbstractThe proliferation of plastics in the environment continues at an alarming rate. Plastic particles have been found to be persistent and ubiquitous pollutants in a variety of environments, including sea water, fresh water, soil, and air. In light of this phenomenon, the scientific and medical communities have become increasingly wary of the dangers posed to human health by chronic exposure to microplastics (< 5 mm diameter) and nanoplastics (< 100 nm diameter). A critical component of the study of the health effects of these pollutants is the accurate determination of their pharmacokinetic behavior in vivo. Herein, we report the first use of molecular imaging to track polystyrene (PS) micro- and nanoplastic particles in mammals. To this end, we have modified PS particles of several sizes—diameters of 20 nm, 220 nm, 1 µm, and 6 µm—with the chelator desferrioxamine (DFO) and radiolabeled these DFO-bearing particles with the positron-emitting radiometal zirconium-89 (89Zr; t1/2 ~ 3.3 d). Subsequently, positron emission tomography (PET) was used to visualize the biodistribution of these radioplastics in C57BL/6J mice at 6, 12, 24, and 48 h after ingestion. The imaging data reveal that the majority of the radioplastics remain in the gastrointestinal tract and are eliminated through the feces by 48 h post-ingestion, a result reinforced by acute biodistribution studies. Ultimately, this work suggests that nuclear imaging—and PET in particular—can be a sensitive and effective tool in the urgent and rapidly growing effort to study the in vivo behavior and potential toxicity of micro- and nanoplastics.

Determination of cerebral glucose transport and metabolic kinetics by dynamic MR spectroscopy

1997 ◽  
Vol 273 (6) ◽  
pp. E1216-E1227 ◽  
Author(s):  
P. C. M. Van Zijl ◽  
D. Davis ◽  
S. M. Eleff ◽  
C. T. W. Moonen ◽  
R. J. Parker ◽  
...  
Keyword(s):  
Glucose Transport ◽  
Kinetic Equations ◽  
Direct Determination ◽  
Life Time ◽  
Compartment Model ◽  
Brain Extract ◽  
Influx Rate ◽  
Positron Emission

A new in vivo nuclear magnetic resonance (NMR) spectroscopy method is introduced that dynamically measures cerebral utilization of magnetically labeled [1-13C]glucose from the change in total brain glucose signals on infusion. Kinetic equations are derived using a four-compartment model incorporating glucose transport and phosphorylation. Brain extract data show that the glucose 6-phosphate concentration is negligible relative to glucose, simplifying the kinetics to three compartments and allowing direct determination of the glucose-utilization half-life time [ t ½ = ln2/( k 2 + k 3)] from the time dependence of the NMR signal. Results on isofluorane ( n = 5)- and halothane ( n = 7)- anesthetized cats give a hyperglycemic t ½ = 5.10 ± 0.11 min−1 (SE). Using Michaelis-Menten kinetics and an assumed half-saturation constant Kt = 5 ± 1 mM, we determined a maximal transport rate T max = 0.83 ± 0.19 μmol ⋅ g−1 ⋅ min−1, a cerebral metabolic rate of glucose CMRGlc = 0.22 ± 0.03 μmol ⋅ g−1 ⋅ min−1, and a normoglycemic cerebral influx rate CIRGlc = 0.37 ± 0.05 μmol ⋅ g−1 ⋅ min−1. Possible extension of this approach to positron emission tomography and proton NMR is discussed.

Knowledge management implementation in Indian automobile ancillary industries

2016 ◽  
Vol 11 (3) ◽  
pp. 802-810 ◽  
Author(s):  
Nitin Yashwant Patil ◽  
Ravi M. Warkhedkar
Keyword(s):  
Knowledge Management ◽  
Industrial Area ◽  
Total Quality ◽  
Limited Data ◽  
Interpretive Structural Modeling ◽  
Content Type ◽  
Relationship Of ◽  
Power And Dependence ◽  
The Relationship

Purpose In the past decade, much has been written about knowledge management (KM) in the manufacturing; however, less attention has been paid to the Indian automobile ancillary industries located in Chinchwad, Pune. It is suitable to find out the relationship of the factors of the study. It helps in identifying the hierarchy of factors to be taken, and interlinking of production department with KM improves the productivity of the industries. Categorization of these principles based on their driving power (principles which hold other principles) and dependence (principles which are dependent on other principles) has also been examined for KM implementation to study the driving power and dependence power of these principles. This paper aims to determine the roadmap of KM implementation and categorize KM principles based on their driving power for manufacturing industries with the use of the interpretive structural modeling (ISM)-based model. The results indicate that the principles possessing higher driving power, such as KM, inventory control, quality control, productivity and scheduling and their interlinking. The major contribution of this research lies in the development of contextual relationship among various identified factors of KM and determination of their driving and dependence power through a single systemic framework. Design/methodology/approach In this paper, author find out the suitability ISM for Indian Automobile industries to find the relation among the variables. Findings ISM model has been developed for the hierarchy of the identified KM. As ISM model results a hypothetical hierarchy which needs a proper quantitative analysis to evaluate their percentage effectiveness in the hierarchy. Research limitations/implications It is applied to automobile industries with limited number of variables that will show the dependence variable and driving variables and their interrelations. It can be applied other fields to fine the relationship of variables. Practical implications The ISM may be used in supply chain management and total quality management to find interlinking between the variables. Originality/value The limited data collected from Pimpri Chinchwad industrial area of Pune from Maharashtra state (India).

Genetic variation and relationship of ultrasonic measures and carcass composition in Suffolk cross lambs

1996 ◽  
Vol 1996 ◽  
pp. 111-111
Author(s):  
V.C. Flamarique ◽  
R.M. Lewis ◽  
G. Simm
Keyword(s):  
Genetic Variation ◽  
Selection Criteria ◽  
Live Weight ◽  
Ultrasonic Measurement ◽  
Carcass Composition ◽  
Selection Indices ◽  
Terminal Sire ◽  
Relationship Of ◽  
The Relationship

Excess fat in lamb is regarded as an important reason for less lamb meat being purchased by consumers. This has encouraged the development and use (particularly in Terminal Sire breeds) of selection indices that can identify animals that will sire leaner progeny. These indices usually include live weight and in vivo predictors of body composition, such as an ultrasonic measurement of muscle and fat depth, as selection criteria (Simm and Dingwall, 1989). But the usefulness of such in vivo measurements as predictors of carcass composition depends on the correlation between, and the variation in, live and carcass measures. The objectives of this study were to determine the strength of the relationship between ultrasound and dissection measures of carcass composition, and the degree of genetic variation in these measures, in crossbred progeny of Suffolk rams.

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