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Alzheimer's Research & Therapy 2012Therapeutic products that depend on the use of an in vitro diagnostic biomarker test to confirm their effectiveness are increasingly being developed. Use of biomarkers... (Review)
Review
Therapeutic products that depend on the use of an in vitro diagnostic biomarker test to confirm their effectiveness are increasingly being developed. Use of biomarkers is particularly meaningful in the context of selecting the patient population where the therapeutic treatment is believed to be efficacious (patient enrichment). Currently available 'research-use-only' assays for Alzheimer's disease diagnosis all suffer from non-analyte and analyte-specific interferences. The impact of these interferences on the outcome of the assays is not well understood. The confounding factors are hampering correct value determination in biological samples and are intrinsic to the assay concept, the assay design, the presence in the sample of heterophilic antibodies and auto-antibodies, or might be the result of the therapeutic approach. This review focuses on the importance of assay interferences and considers how these might be minimized with the final aim of making the assays more acceptable as in vitro diagnostic biomarker tests for theranostic use.
PubMed: 23082750
DOI: 10.1186/alzrt142 -
PLoS Computational Biology Apr 2018The peregrine falcon Falco peregrinus is renowned for attacking its prey from high altitude in a fast controlled dive called a stoop. Many other raptors employ a similar...
The peregrine falcon Falco peregrinus is renowned for attacking its prey from high altitude in a fast controlled dive called a stoop. Many other raptors employ a similar mode of attack, but the functional benefits of stooping remain obscure. Here we investigate whether, when, and why stooping promotes catch success, using a three-dimensional, agent-based modeling approach to simulate attacks of falcons on aerial prey. We simulate avian flapping and gliding flight using an analytical quasi-steady model of the aerodynamic forces and moments, parametrized by empirical measurements of flight morphology. The model-birds' flight control inputs are commanded by their guidance system, comprising a phenomenological model of its vision, guidance, and control. To intercept its prey, model-falcons use the same guidance law as missiles (pure proportional navigation); this assumption is corroborated by empirical data on peregrine falcons hunting lures. We parametrically vary the falcon's starting position relative to its prey, together with the feedback gain of its guidance loop, under differing assumptions regarding its errors and delay in vision and control, and for three different patterns of prey motion. We find that, when the prey maneuvers erratically, high-altitude stoops increase catch success compared to low-altitude attacks, but only if the falcon's guidance law is appropriately tuned, and only given a high degree of precision in vision and control. Remarkably, the optimal tuning of the guidance law in our simulations coincides closely with what has been observed empirically in peregrines. High-altitude stoops are shown to be beneficial because their high airspeed enables production of higher aerodynamic forces for maneuvering, and facilitates higher roll agility as the wings are tucked, each of which is essential to catching maneuvering prey at realistic response delays.
Topics: Altitude; Animals; Biophysical Phenomena; Computational Biology; Computer Simulation; Falconiformes; Flight, Animal; Models, Biological; Predatory Behavior; Starlings; Vision, Ocular
PubMed: 29649207
DOI: 10.1371/journal.pcbi.1006044 -
Proceedings. Mathematical, Physical,... May 2017We investigate how thin structures change their shape in response to non-mechanical stimuli that can be interpreted as variations in the structure's natural curvature....
We investigate how thin structures change their shape in response to non-mechanical stimuli that can be interpreted as variations in the structure's natural curvature. Starting from the theory of non-Euclidean plates and shells, we derive an effective model that reduces a three-dimensional stimulus to the natural fundamental forms of the mid-surface of the structure, incorporating expansion, or growth, in the thickness. Then, we apply the model to a variety of thin bodies, from flat plates to spherical shells, obtaining excellent agreement between theory and numerics. We show how cylinders and cones can either bend more or unroll, and eventually snap and rotate. We also study the nearly isometric deformations of a spherical shell and describe how this shape change is ruled by the geometry of a spindle. As the derived results stem from a purely geometrical model, they are general and scalable.
PubMed: 28588415
DOI: 10.1098/rspa.2017.0087 -
Drug and Alcohol Dependence Nov 2018Despite extensive efforts to develop effective smoking cessation interventions, 70-85% of American cigarette smokers who quit relapse within one year. Exercise has shown...
INTRODUCTION
Despite extensive efforts to develop effective smoking cessation interventions, 70-85% of American cigarette smokers who quit relapse within one year. Exercise has shown promise as an intervention; however, many results have been equivocal. This study explored how exercise is associated with smoking-related symptomatology, smoking behavior and impulsivity in male and female smokers.
METHODS
Participants were recruited throughout the United States using the on-line crowdsourcing platform, Amazon's Mechanical Turk. They completed a survey with self-report measures assessing exercise, smoking-related symptomatology, smoking behavior and impulsivity. Differences between men and women were tested using t- and chi-square tests. Regression analyses tested for associations between exercise and smoking-related symptomatology, smoking behavior and impulsivity.
RESULTS
Participants (N = 604) were, on average, 32 (SD = 6.2) years old, mostly Caucasian, with at least some college education and approximately half were women. Women exercised slightly less than men and had more negative affect, craving, physical symptoms and withdrawal. Women smoked more cigarettes per day, had greater nicotine dependency and more years of smoking. Positive affect was positively associated with exercise for both men and women; however, this association was significantly stronger in women. Negative affect and withdrawal were inversely associated with exercise for women only. Impulsivity was inversely associated with exercise for both men and women.
CONCLUSION
Exercise was significantly associated with several smoking-related symptomatology, smoking behavior and impulsivity variables for both men and women, suggesting that exercise may be a useful intervention for smoking cessation. Future prospective research should determine how exercise directly impacts smoking cessation.
Topics: Adult; Cigarette Smoking; Craving; Cross-Sectional Studies; Exercise; Female; Humans; Impulsive Behavior; Male; Prospective Studies; Smoking Cessation; Surveys and Questionnaires; Tobacco Use Disorder; Young Adult
PubMed: 30199844
DOI: 10.1016/j.drugalcdep.2018.07.022 -
BioRxiv : the Preprint Server For... Mar 2023Rho-GTPases are central regulators within a complex signaling network that controls the cytoskeletal organization and cell movement. This network includes multiple...
Rho-GTPases are central regulators within a complex signaling network that controls the cytoskeletal organization and cell movement. This network includes multiple GTPases, such as the most studied Rac1, Cdc42, and RhoA, and their numerous effectors that provide mutual regulation and feedback loops. Here we investigate the temporal and spatial relationship between Rac1 and Cdc42 during membrane ruffling using a simulation model which couples GTPase signaling with cell morphodynamics to capture the GTPase behavior observed with FRET-based biosensors. We show that membrane velocity is regulated by the kinetic rate of GTPase activation rather than the concentration of active GTPase. Our model captures both uniform and polarized ruffling. We also show that cell-type specific time delays between Rac1 and Cdc42 activation can be reproduced with a single signaling motif, in which the delay is controlled by feedback from Cdc42 to Rac1. The resolution of our simulation output matches those of the time-lapsed recordings of cell dynamics and GTPase activity. This approach allows us to validate simulation results with quantitative precision using the same pipeline for the analysis of simulated and experimental data.
PubMed: 37034645
DOI: 10.1101/2023.03.31.535147 -
Experimental and Clinical... Dec 2008Drug self-administration methodologies have been developed for use in humans to model naturalistic stimulant drug-taking behaviors. These methodologies use a number of... (Review)
Review
Drug self-administration methodologies have been developed for use in humans to model naturalistic stimulant drug-taking behaviors. These methodologies use a number of schedules of reinforcement, including progressive-ratio schedules. As the name implies, in a progressive-ratio schedule, the response requirement for each subsequent delivery of drug increases, and the primary outcome variable is often the break point (i.e., the last ratio completed to receive a drug delivery). These schedules have been used in a number of human laboratory studies evaluating the reinforcing effects of stimulants. The results of these studies have demonstrated that progressive-ratio schedules are sensitive to manipulation of a pharmacological variable, dose, and to nonpharmacological variables contributing to stimulant drug effects. In addition, findings with progressive-ratio schedules are largely concordant with clinical findings, suggesting that drug self-administration under these schedules has predictive validity in terms of drug abuse and dependence. Future research is necessary, however, to understand better how pharmacological factors like route of administration, onset of effects, and pretreatment influence the reinforcing effects of stimulants under progressive-ratio schedules.
Topics: Central Nervous System Stimulants; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Reinforcement Schedule; Research Design; Self Administration; Substance-Related Disorders
PubMed: 19086771
DOI: 10.1037/a0013657 -
Musculoskeletal Science & Practice Aug 2017The methodological quality of controlled clinical trials (CCTs) of physiotherapeutic treatment modalities for myofascial trigger points (MTrP) has not been investigated... (Review)
Review
BACKGROUND
The methodological quality of controlled clinical trials (CCTs) of physiotherapeutic treatment modalities for myofascial trigger points (MTrP) has not been investigated yet.
OBJECTIVES
To detect the methodological quality of CCTs for physiotherapy treatments of MTrPs and demonstrating the possible increase over time.
DESIGN
Systematic review.
METHODS
A systematic search was conducted in two databases, Physiotherapy Evidence Database (PEDro) and Medicine Medical Literature Analysis and Retrieval System online (MEDLINE), using the same keywords and selection procedure corresponding to pre-defined inclusion criteria. The methodological quality, assessed by the 11-item PEDro scale, served as outcome measure. The CCTs had to compare at least two interventions, where one intervention had to lay within the scope of physiotherapy. Participants had to be diagnosed with myofascial pain syndrome or trigger points (active or latent).
RESULTS
A total of n = 230 studies was analysed. The cervico-thoracic region was the most frequently treated body part (n = 143). Electrophysical agent applications was the most frequent intervention. The average methodological quality reached 5.5 on the PEDro scale. A total of n = 6 studies scored the value of 9. The average PEDro score increased by 0.7 points per decade between 1978 and 2015.
CONCLUSIONS
The average PEDro score of CCTs for MTrP treatments does not reach the cut-off of 6 proposed for moderate to high methodological quality. Nevertheless, a promising trend towards an increase of the average methodological quality of CCTs for MTrPs was recorded. More high-quality CCT studies with thorough research procedures are recommended to enhance methodological quality.
Topics: Clinical Trials as Topic; Electrophysiological Phenomena; Forecasting; Humans; Myofascial Pain Syndromes; Physical Therapy Modalities; Trigger Points
PubMed: 28448859
DOI: 10.1016/j.msksp.2017.04.009 -
Journal of Movement Disorders Sep 2018The current body of literature contains 5 reports of myotonic dystrophy (DM) with parkinsonism: 4 reports of DM type 2 and 1 report of clinically suspected DM type 1. To...
The current body of literature contains 5 reports of myotonic dystrophy (DM) with parkinsonism: 4 reports of DM type 2 and 1 report of clinically suspected DM type 1. To date, there have been no genetically proven cases of DM type 1 with parkinsonism. Here, we report the first case of genetically proven DM type 1 and parkinsonism that developed ahead of muscle symptoms with bilateral putaminal, presynaptic dopaminergic deficits on imaging. A 54-year-old female patient presented with bradykinesia, axial and bilateral limb rigidity, stooped posture, and hypomimia, which did not respond to levodopa. At age 56, she developed neck flexion weakness. Examination showed bilateral facial weakness, percussion and grip myotonia, and electromyography confirmed myotonic discharges. A genetic study of DM type 1 showed a DMPK mutation. At age 58, gait freezing, postural instability, and frequent falling developed and did not respond to increasing doses of levodopa. At age 59, the patient died from asphyxia.
PubMed: 30304928
DOI: 10.14802/jmd.18028 -
PloS One 2017The objectives were to analyze the knowledge about overdose prevention, the use of naloxone, and the number of fatal overdoses after the implementation of Systematic...
The objectives were to analyze the knowledge about overdose prevention, the use of naloxone, and the number of fatal overdoses after the implementation of Systematic Training in Overdose Prevention (STOOP) program. We conducted a quasi-experimental study, and held face-to-face interviews before (n = 725) and after (n = 722) implementation of systematic training in two different samples of people who injected opioids attending harm reduction centers. We asked participants to list the main causes of overdose and the main actions that should be taken when witnessing an overdose. We created two dependent variables, the number of (a) correct and (b) incorrect answers. The main independent variable was Study Group: Intervention Group (IG), Comparison Group (CG), Pre-Intervention Group With Sporadic Training in Overdose Prevention (PREIGS), or Pre-Intervention Group Without Training in Overdose Prevention (PREIGW). The relationship between the dependent and independent variables was assessed using a multivariate Poisson regression analysis. Finally, we conducted an interrupted time series analysis of monthly fatal overdoses before and after the implementation of systematic program during the period 2006-2015. Knowledge of overdose prevention increased after implementing systematic training program. Compared to the PREIGW, the IG gave more correct answers (IRR = 1.40;95%CI:1.33-1.47), and fewer incorrect answers (IRR = 0.33;95%CI:0.25-0.44). Forty percent of people who injected opioids who received a naloxone kit had used the kit in response to an overdose they witnessed. These courses increase knowledge of overdose prevention in people who use opioids, give them the necessary skills to use naloxone, and slightly diminish the number of fatal opioid overdoses in the city of Barcelona.
Topics: Adult; Analgesics, Opioid; Drug Overdose; Female; Harm Reduction; Health Education; Health Knowledge, Attitudes, Practice; Humans; Interviews as Topic; Male; Multivariate Analysis; Naloxone; Narcotic Antagonists; Opioid-Related Disorders; Program Evaluation; Regression Analysis; Risk Factors; Spain
PubMed: 29088247
DOI: 10.1371/journal.pone.0186833 -
Alzheimer's Research & Therapy Dec 2020Blood-based amyloid biomarkers may provide a non-invasive, cost-effective and scalable manner for detecting cerebral amyloidosis in early disease stages.
BACKGROUND
Blood-based amyloid biomarkers may provide a non-invasive, cost-effective and scalable manner for detecting cerebral amyloidosis in early disease stages.
METHODS
In this prospective cross-sectional study, we quantified plasma Aβ/Aβ ratios with both routinely available ELISAs and novel SIMOA Amyblood assays, and provided a head-to-head comparison of their performances to detect cerebral amyloidosis in a nondemented elderly cohort (n = 199). Participants were stratified according to amyloid-PET status, and the performance of plasma Aβ/Aβ to detect cerebral amyloidosis was assessed using receiver operating characteristic analysis. We additionally investigated the correlations of plasma Aβ ratios with amyloid-PET and CSF Alzheimer's disease biomarkers, as well as platform agreement using Passing-Bablok regression and Bland-Altman analysis for both Aβ isoforms.
RESULTS
ELISA and SIMOA plasma Aβ/Aβ detected cerebral amyloidosis with identical accuracy (ELISA: area under curve (AUC) 0.78, 95% CI 0.72-0.84; SIMOA: AUC 0.79, 95% CI 0.73-0.85), and both increased the performance of a basic demographic model including only age and APOE-ε4 genotype (p ≤ 0.02). ELISA and SIMOA had positive predictive values of respectively 41% and 36% in cognitively normal elderly and negative predictive values all exceeding 88%. Plasma Aβ/Aβ correlated similarly with amyloid-PET for both platforms (Spearman ρ = - 0.32, p < 0.0001), yet correlations with CSF Aβ/t-tau were stronger for ELISA (ρ = 0.41, p = 0.002) than for SIMOA (ρ = 0.29, p = 0.03). Plasma Aβ levels demonstrated poor agreement between ELISA and SIMOA with concentrations of both Aβ and Aβ measured by SIMOA consistently underestimating those measured by ELISA.
CONCLUSIONS
ELISA and SIMOA demonstrated equivalent performances in detecting cerebral amyloidosis through plasma Aβ/Aβ, both with high negative predictive values, making them equally suitable non-invasive prescreening tools for clinical trials by reducing the number of necessary PET scans for clinical trial recruitment.
TRIAL REGISTRATION
EudraCT 2009-014475-45 (registered on 23 Sept 2009) and EudraCT 2013-004671-12 (registered on 20 May 2014, https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-004671-12/BE ).
Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Amyloidosis; Biomarkers; Cross-Sectional Studies; Enzyme-Linked Immunosorbent Assay; Humans; Peptide Fragments; Prospective Studies
PubMed: 33278904
DOI: 10.1186/s13195-020-00728-w