Assessing Leg Blood Flow and Cardiac Output During Running Using Thermodilution.

Cardiac output (Q̇C) and leg blood flow (Q̇LEG) can be measured simultaneously with high accuracy using transpulmonary and femoral vein thermodilution with a single-bolus injection. The invasive measure has offered important insight into leg hemodynamics and blood flow distribution during exercise. Despite being the natural modality of exercise in humans, there has been no direct measure of Q̇LEG while running in humans. We sought to determine the feasibility of the thermodilution technique for measuring Q̇LEG and conductance during high-intensity running, in an exploratory case study. A trained runner (30 years male) completed two maximal incremental tests on a cycle ergometer and motorized treadmill. Q̇LEG and Q̇C were determined using the single-bolus thermodilution technique. Arterial and venous blood were sampled throughout exercise, with continuous monitoring of metabolism, intra-arterial and venous pressure, and temperature. The participant reached a greater peak oxygen uptake (V̇O2peak) during running relative to cycling (74 vs. 68 mL/kg/min) with comparable Q̇LEG (19.0 vs. 19.5 L/min) and Q̇C (27.4 vs. 26.2 L/min). Leg vascular conductance was greater during high-intensity running relative to cycling (82 vs. 70 mL/min/mmHg @ ~80% V̇O2peak). The "beat phenomenon" was apparent in femoral flow while running, producing large gradients in conductance (62-90 mL/min/mmHg @ 70% V̇O2peak). In summary, we present the first direct measure of Q̇LEG and conductance in a running human. Our findings corroborate several assumptions about Q̇LEG during running compared with cycling. Importantly, we demonstrate that using thermodilution in running exercise can be completed effectively and safely.

The Effect of Passive Dehydration on Phase Angle and Body Composition: A Bioelectrical Impedance Analysis.

Bioelectrical impedance analysis (BIA) is a method used to estimate body composition, and it relies mainly on the body's water content. Insufficient body water can introduce bias to body composition scores. PURPOSE: To determine the effect of body weight loss elicited by passive dehydration on body composition scores, including phase angle (PhA). METHODS: Twenty-five euhydrated apparently healthy and physically active men's (age = 22.6 ± 3.3 yr.; body mass = 76.7 ± 15.9 kg; height = 172.0 ± 6.3 cm) body composition variables and PhA were measured before and after sitting quietly for 5 h in a controlled environment (26.6 ± 1.7 °C, 72 ± 4.9%RH). RESULTS: It was found that five hours of passive dehydration caused a loss in body weight (Δ = 0.76 ± 0.34 kg, p < 0.05) and a decrease in body fat estimation (Δ = 0.90 ± 0.87 kg, p < 0.001). Additionally, an increase in ECW (Δ = 0.12 ± 0.30 L, p < 0.021) and PhA (Δ = 0.10 ± 0.15°, p < 0.005) was observed. CONCLUSION: Body weight loss due to passive dehydration decreased BIA-derived fat mass, and increased extracellular water and PhA in physically active and apparently healthy men. Nonetheless, these changes had a negligible effect on the accuracy of the equipment, rendering them clinically insignificant.

The Fluorescent Cell Line SW620-GFP Is a Valuable Model to Monitor Magnetic Hyperthermia.

In this work, the cell line SW620-GFP has been used in a complete magnetic hyperthermia assay, from the preparation of the ferrofluid with folate-coated iron oxide nanoparticles to in vivo experiments. The physical and chemical characterization of the nanoparticles evidenced their superparamagnetic behaviour, an average diameter of 12 ± 4 nm, a 2 nm coat thickness, and a high-power loss density. The main innovation of the work is the exclusive capability of viable SW620-GFP cells to emit fluorescence, enabling fast analysis of both, cell viability in vitro with an epifluorescence microscope and tumour size and shape in vivo in a non-invasive manner using the iBox technology. Moreover, with this imaging technique, it was possible to demonstrate the successful tumour size reduction in mice applying magnetic hyperthermia three times a week over 3 weeks.

Computational approaches for lead compound discovery in dipeptidyl peptidase-4 inhibition using machine learning and molecular dynamics techniques.

The prediction of possible lead compounds from already-known drugs that may present DPP-4 inhibition activity imply a advantage in the drug development in terms of time and cost to find alternative medicines for the treatment of Type 2 Diabetes Mellitus (T2DM). The inhibition of dipeptidyl peptidase-4 (DPP-4) has been one of the most explored strategies to develop potential drugs against this condition. A diverse dataset of molecules with known experimental inhibitory activity against DPP-4 was constructed and used to develop predictive models using different machine-learning algorithms. Model M36 is the most promising one based on the internal and external performance showing values of Q2CV = 0.813, and Q2EXT = 0.803. The applicability domain evaluation and Tropsha's analysis were conducted to validate M36, indicating its robustness and accuracy in predicting pIC50 values for organic molecules within the established domain. The physicochemical properties of the ligands, including electronegativity, polarizability, and van der Waals volume were relevant to predict the inhibition process. The model was then employed in the virtual screening of potential DPP4 inhibitors, finding 448 compounds from the DrugBank and 9 from DiaNat with potential inhibitory activity. Molecular docking and molecular dynamics simulations were used to get insight into the ligand-protein interaction. From the screening and the favorable molecular dynamic results, several compounds including Skimmin (pIC50 = 3.54, Binding energy = -8.86 kcal/mol), bergenin (pIC50 = 2.69, Binding energy = -13.90 kcal/mol), and DB07272 (pIC50 = 3.97, Binding energy = -25.28 kcal/mol) seem to be promising hits to be tested and optimized in the treatment of T2DM. This results imply a important reduction in cost and time on the application of this drugs because all the information about the its metabolism is already available.

NITIRSOIL: A model that balances complexity with prediction uncertainty for improving nitrogen fertilization in agriculture.

Mismanagement of the nitrogen (N) fertilization in agriculture leads to low N use efficiency (NUE) and therefore pollution of waters and atmosphere due to NO3- leaching, and N2O and NH3 emissions. The use of N simulation models of the soil-plant system can help improve the N fertilizer management increasing NUE and decreasing N pollution issues. However, many N simulation models lack balance between complexity and uncertainty with the result that they are not applied in actual practice. The NITIRSOIL is a one-dimensional transient-state model with a monthly time step that aims at addressing this lack in the estimation of, mainly, dry matter yield (DMY), crop N uptake (Nupt), soil mineral N (Nmin), and NO3- leaching in agricultural fields. According to its global sensitivity analysis for horticulture, the NITIRSOIL simulations of the aforementioned outputs mostly depend on the critical N dilution curve, harvest index, dry matter fraction, potential fresh yield and nitrification coefficients. According to its validation for 35 nitrogen fertilization trials with 11 vegetables under semi-arid Mediterranean climate in Eastern Spain, the NITIRSOIL presents indices of agreement between 0.87 and 0.97 for the prediction of total dry matter, DMY, Nupt, NO3- leaching and soil Nmin at crop season end. Therefore, the NITIRSOIL model can be used in actual practice to improve the sustainability of the N management in, particularly horticulture, due to the balance it features between complexity and prediction uncertainty. For this aim, the NITRISOIL can be used either on its own, or in combination with "Nmin" on-site N fertilization recommendation methods, or even could be implemented as the calculation core of decision support systems.

Novel Biomarkers for the diagnosis of diabetic nephropathy.

Diabetes mellitus and its complications are a known public health problem nowadays. Diabetic nephropathy is one of the main complications and the result of multiple mechanisms, including: activation of the renin-angiotensin-aldosterone system, formation of advanced glycation end products and chronic inflammation that led to glomerular and tubulo-interstitial damage producing mesangial expansion and glomerulosclerosis, which finally results in chronic kidney disease. Early detection of diabetic nephropathy is essential for adequate intervention to stop, or at least slow down its progression. Multiple markers have been described, not only the classic ones such as serum creatinine, urea, and albuminuria, but at this point also novel biomarkers such as neutrophil gelatinase-associated lipocalin, tumor necrosis factor 1 receptor and monocyte chemoattractant protein-1, among others. The aim of this article was to provide an update review of the role of biomarkers in the diagnosis of diabetic nephropathy.

Assessing the relationship between lipoprotein(a) levels and blood pressure among hypertensive patients beyond conventional measures. An observational study.

High lipoprotein(a) (Lp(a)) levels are associated with an increased risk of arterial hypertension (AHT) and atherosclerotic cardiovascular disease. However, little is known about the detailed profile of AHT based on Lp(a) levels. This observational study focused on elucidating the relationship between Lp(a) concentrations and specific indices obtained from 24-h ambulatory blood pressure (BP) monitoring in hypertensive patients over 18 years of age. We gathered and analyzed data on BP indices along with demographic, epidemiological, clinical, and laboratory variables from 227 hypertensive patients, median age 56 years, including 127 women (56%). After comparing hypertensive patients with Lp(a) levels above and below 125 nmol/L, we found that a 10 mmHg increase in nocturnal systolic BP and all pulse pressure indices (24-h, daytime, and night-time) was associated with an increased risk of high Lp(a) levels by more than 20% and 40%, respectively. Similarly, each 10% increase in the area under the function over time of nocturnal diastolic BP dipping was associated with more than a 30% decrease in the odds of belonging to the elevated Lp(a) levels category. Additionally, Lp(a) levels above 125 nmol/L were associated with higher 24-h, daytime, and night-time systolic BP and pulse pressure load. The relationship between Lp(a) and AHT appears to extend beyond conventional BP measurements, which may be relevant given the prognostic implications of nocturnal BP and pulse pressure indices.

Morphological, Biological, and Molecular Characterization of Type I Granuloviruses of Spodoptera frugiperda.

Granuloviruses (GVs) Betabaculovirus associated with the fall armyworm (FAW), Spodoptera frugiperda (J.E. Smith) (Lepidoptera: Noctuidae), especially those of the type I, have scarcely been studied. These GVs might be an effective alternative for the biocontrol of this insect. In this study, the native GVs SfGV-CH13 and SfGV-CH28 were isolated from FAW larvae and characterized for morphology, molecular traits, and insecticidal activity. The elapsed time between symptomatic infection of larvae and stop feeding as well as the weight of larvae before death or prior to pupation were also evaluated. Both GVs had ovoid shape and a length of 0.4 µm. They had the same DNA restriction profiles and their genome sizes were about 126 kb. The symptomatic infection with the tested GVs mainly caused flaccidity of larva body and discoloration of integument. The integument lysis was only observed in 8% of infected larvae. Infected larvae gradually stopped feeding. Overall, these symptoms are characteristic of infections caused by type I GVs, which are known as monoorganotropic or slow-killing GVs. The median lethal dose (LD50) values for SfGV-CH13 and SfGV-CH28 isolates were 5.4 × 102 and 1.1 × 103 OBs/larva, respectively. The median lethal time (LT50) ranged from 17 to 24 days. LT50 values decreased as the viral dose was increased. The elapsed time from symptomatic infection until pupation and body weight of larvae (third instar) were higher with SfGV-CH28 than SfGV-CH13. Both granulovirus isolates were able to kill the FAW larvae from the 12th day.

Synthesis, Photophysical Properties, Theoretical Studies, and Living Cancer Cell Imaging Applications of New 7-(Diethylamino)quinolone Chalcones.

In this article, three unsymmetrical 7-(diethylamino)quinolone chalcones with D-π-A-D and D-π-A-π-D type push-pull molecular arrangements were synthesized via a Claisen-Schmidt reaction. Using 7-(diethylamino)quinolone and vanillin as electron donor (D) moieties, these were linked together through the α,ß-unsaturated carbonyl system acting as a linker and an electron acceptor (A). The photophysical properties were studied, revealing significant Stokes shifts and strong solvatofluorochromism caused by the ICT and TICT behavior produced by the push-pull effect. Moreover, quenching caused by the population of the TICT state in THF-H2O mixtures was observed, and the emission in the solid state evidenced a red shift compared to the emission in solution. These findings were corroborated by density functional theory (DFT) calculations employing the wb97xd/6-311G(d,p) method. The cytotoxic activity of the synthesized compounds was assessed on BHK-21, PC3, and LNCaP cell lines, revealing moderate activity across all compounds. Notably, compound 5b exhibited the highest activity against LNCaP cells, with an LC50 value of 10.89 µM. Furthermore, the compounds were evaluated for their potential as imaging agents in living prostate cells. The results demonstrated their favorable cell permeability and strong emission at 488 nm, positioning them as promising candidates for cancer cell imaging applications.

Theoretical Study of Cyanidin-Resveratrol Copigmentation by the Functional Density Theory.

Anthocyanins are colored water-soluble plant pigments. Upon consumption, anthocyanins are quickly absorbed and can penetrate the blood-brain barrier (BBB). Research based on population studies suggests that including anthocyanin-rich sources in the diet lowers the risk of neurodegenerative diseases. The copigmentation caused by copigments is considered an effective way to stabilize anthocyanins against adverse environmental conditions. This is attributed to the covalent and noncovalent interactions between colored forms of anthocyanins (flavylium ions and quinoidal bases) and colorless or pale-yellow organic molecules (copigments). The present work carried out a theoretical study of the copigmentation process between cyanidin and resveratrol (CINRES). We used three levels of density functional theory: M06-2x/6-31g+(d,p) (d3bj); ωB97X-D/6-31+(d,p); APFD/6-31+(d,p), implemented in the Gaussian16W package. In a vacuum, the CINRES was found at a copigmentation distance of 3.54 Å between cyanidin and resveratrol. In water, a binding free energy ∆G was calculated, rendering -3.31, -1.68, and -6.91 kcal/mol, at M06-2x/6-31g+(d,p) (d3bj), ωB97X-D/6-31+(d,p), and APFD/6-31+(d,p) levels of theory, respectively. A time-dependent density functional theory (TD-DFT) was used to calculate the UV spectra of the complexes and then compared to its parent molecules, resulting in a lower energy gap at forming complexes. Excited states' properties were analyzed with the ωB97X-D functional. Finally, Shannon aromaticity indices were calculated and isosurfaces of non-covalent interactions were evaluated.

68Ga-DOTA-D-Alanine-BoroPro Radiotracer for Imaging of the Fibroblast Activation Protein in Malignant and Non-Malignant Diseases.

Recently, we reported a new fibroblast activation protein (FAP) inhibitor radiopharmaceutical based on the 99mTc-((R)-1-((6-hydrazinylnicotinoyl)-D-alanyl) pyrrolidin-2-yl) boronic acid (99mTc-HYNIC-D-Alanine-BoroPro)(99mTc-HYNIC-iFAP) structure for tumor microenvironment SPECT imaging. This research aimed to synthesize 68Ga-[2,2',2″,2‴-(2-(4-(2-(5-(((S)-1-((S)-2-boronopyrrolidin-1-yl)-1-oxopropan-2-yl)carbamoyl)pyridin-2-yl)hydrazine-1-carbothioamido)benzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid] (68Ga-DOTA-D-Alanine-BoroPro)(68Ga-iFAP) as a novel radiotracer for PET imaging and evaluate its usefulness for FAP expression in malignant and non-malignant tissues. The coupling of p-SCN-benzene DOTA with HYNIC-iFAP was used for the chemical synthesis and further labeling with 68Ga. Radiochemical purity was verified by radio-HPLC. The specificity of 68Ga-iFAP was evaluated in HCT116 cells, in which FAP expression was verified by immunofluorescence and Western blot. Biodistribution and biokinetic studies were performed in murine models. 68Ga-iFAP uptake at the myocardial level was assessed in mice with induced infarction. First-in-human images of 68Ga-iFAP in healthy subjects and patients with myocardial infarction, glioblastoma, prostate cancer, and breast cancer were also obtained. DOTA-D-Alanine BoroPro was prepared with a chemical purity of 98% and was characterized by UPLC mass spectroscopy, FT-IR, and UV-vis. The 68Ga-iFAP was obtained with a radiochemical purity of >95%. In vitro and in vivo studies demonstrated 68Ga-iFAP-specific recognition for FAP, rapid renal elimination, and adequate visualization of the glioblastoma, breast tumor, prostate cancer, and myocardial infarction sites. The results of this research justify further dosimetry and clinical trials to establish the specificity and sensitivity of 68Ga-iFAP PET for FAP expression imaging.

The 2-Minutes Walking Test Is Not Correlated with Aerobic Fitness Indices but with the 5-Times Sit-to-Stand Test Performance in Apparently Healthy Older Adults.

The 2-minutes walking test (2-MWT) is a valid and reliable test that has a high correlation with the distance walked in the 6-minutes walking test (6-MWT). However, to date, no study has determined the relationship between 2-MWT performance and the aerobic fitness indices obtained during a maximal incremental test to confirm if this test is a valid surrogate of aerobic fitness in apparently healthy older adults. The main objective of this work was to identify the factors associated to the performance in the 2-MWT, including aerobic fitness, functional and spatial-temporal gait parameters. Seventeen elderly adults performed a maximal incremental cycling test to determine maximum oxygen consumption (VO2max) and ventilatory thresholds (VT1 and VT2), two static standing balance tests with open and close eyes, a 5-times sit-to-stand test (5-TSTS), a handgrip test, and a 2-MWT on three different days over 2 weeks. No correlations were found between aerobic fitness indices and the distance covered in 2-MWT, but significant moderate correlations were found between the distance covered in 2-MWT and the time to perform the 5-TSTS (rho = -0.49) and with stride length (rho = 0.52) during the test. In conclusion, the 2-MWT does not seem a good test to assess aerobic capacity while it showed to be associated to the 5-TSTS performance of the elderly.

Biophysical Analysis of Potential Inhibitors of SARS-CoV-2 Cell Recognition and Their Effect on Viral Dynamics in Different Cell Types: A Computational Prediction from In Vitro Experimental Data.

Recent reports have suggested that the susceptibility of cells to SARS-CoV-2 infection can be influenced by various proteins that potentially act as receptors for the virus. To investigate this further, we conducted simulations of viral dynamics using different cellular systems (Vero E6, HeLa, HEK293, and CaLu3) in the presence and absence of drugs (anthelmintic, ARBs, anticoagulant, serine protease inhibitor, antimalarials, and NSAID) that have been shown to impact cellular recognition by the spike protein based on experimental data. Our simulations revealed that the susceptibility of the simulated cell systems to SARS-CoV-2 infection was similar across all tested systems. Notably, CaLu3 cells exhibited the highest susceptibility to SARS-CoV-2 infection, potentially due to the presence of receptors other than ACE2, which may account for a significant portion of the observed susceptibility. Throughout the study, all tested compounds showed thermodynamically favorable and stable binding to the spike protein. Among the tested compounds, the anticoagulant nafamostat demonstrated the most favorable characteristics in terms of thermodynamics, kinetics, theoretical antiviral activity, and potential safety (toxicity) in relation to SARS-CoV-2 spike protein-mediated infections in the tested cell lines. This study provides mathematical and bioinformatic models that can aid in the identification of optimal cell lines for compound evaluation and detection, particularly in studies focused on repurposed drugs and their mechanisms of action. It is important to note that these observations should be experimentally validated, and this research is expected to inspire future quantitative experiments.

In vivo functional phenotypes from a computational epistatic model of evolution.

Computational models of evolution are valuable for understanding the dynamics of sequence variation, to infer phylogenetic relationships or potential evolutionary pathways and for biomedical and industrial applications. Despite these benefits, few have validated their propensities to generate outputs with in vivo functionality, which would enhance their value as accurate and interpretable evolutionary algorithms. We demonstrate the power of epistasis inferred from natural protein families to evolve sequence variants in an algorithm we developed called sequence evolution with epistatic contributions (SEEC). Utilizing the Hamiltonian of the joint probability of sequences in the family as fitness metric, we sampled and experimentally tested for in vivo [Formula: see text]-lactamase activity in Escherichia coli TEM-1 variants. These evolved proteins can have dozens of mutations dispersed across the structure while preserving sites essential for both catalysis and interactions. Remarkably, these variants retain family-like functionality while being more active than their wild-type predecessor. We found that depending on the inference method used to generate the epistatic constraints, different parameters simulate diverse selection strengths. Under weaker selection, local Hamiltonian fluctuations reliably predict relative changes to variant fitness, recapitulating neutral evolution. SEEC has the potential to explore the dynamics of neofunctionalization, characterize viral fitness landscapes, and facilitate vaccine development.

Cost benefit analysis of diversified farming systems across Europe: Incorporating non-market benefits of ecosystem services.

Crop diversification can enhance farm economic sustainability while reducing the negative impact on the environment and ecosystem services related. Despite the market and non-market benefits of crop diversification, monocropping is a widely used dominant practice in Europe. In this context, this works aims to assess the overall economic impact of several crop diversification systems across Europe and compared it to the monocropping system. For this purpose, an economic valuation by integrating market and non-market values for eight case studies distributed across three different European pedoclimatic regions (Southern Mediterranean, Northern Mediterranean and Boreal) is proposed. The economic valuation was conducted both in the short and medium-long term. For the short-term we conducted a social gross margin analysis, while for the medium-long term a cost-benefit analysis is developed. The results show an improvement in social gross margins for most of the diversification scenarios assessed when environmental and socio-cultural benefits are considered in the short-term. In the medium and long-term the transformation of cropping towards a more diversified agriculture is encouraged by greater economic benefits. These results provide a first insight in global economic performance of diversified cropping systems, whose main contribution relies on the integration of market and non-market values of ecosystem services from crop diversification. They are expected to be useful for guiding policy makers to promote crop diversification practices as a key instrument for building resilience in farming systems for an adaptive management to climate change.

Staging Parkinson's disease according to the MNCD classification correlates with caregiver burden.

BACKGROUND AND OBJECTIVE: Recently, we demonstrated that staging Parkinson's disease (PD) with a novel simple classification called MNCD, based on four axes (motor, non-motor, cognition, and dependency) and five stages, correlated with disease severity and patients' quality of life. Here, we analyzed the correlation of MNCD staging with PD caregiver's status. PATIENTS AND METHODS: Data from the baseline visit of PD patients and their principal caregiver recruited from 35 centers in Spain from the COPPADIS cohort from January 2016 to November 2017 were used to apply the MNCD total score (from 0 to 12) and MNCD stages (from 1 to 5) in this cross-sectional analysis. Caregivers completed the Zarit Caregiver Burden Inventory (ZCBI), Caregiver Strain Index (CSI), Beck Depression Inventory-II (BDI-II), PQ-10, and EUROHIS-QOL 8-item index (EUROHIS-QOL8). RESULTS: Two hundred and twenty-four PD patients (63 ± 9.6 years old; 61.2% males) and their caregivers (58.5 ± 12.1 years old; 67.9% females) were included. The frequency of MNCD stages was 1, 7.6%; 2, 58.9%; 3, 31.3%; and 4-5, 2.2%. A more advanced MNCD stage was associated with a higher score on the ZCBI (p < .0001) and CSI (p < .0001), and a lower score on the PQ-10 (p = .001), but no significant differences were observed in the BDI-II (p = .310) and EUROHIS-QOL8 (p = .133). Moderate correlations were observed between the MNCD total score and the ZCBI (r = .496; p < .0001), CSI (r = .433; p < .0001), and BDI-II (r = .306; p < .0001) in caregivers. CONCLUSION: Staging PD according to the MNCD classification is correlated with caregivers' strain and burden.

Acute effects of isotonic eccentric exercise on the neuromuscular function of knee extensors vary according to the motor task: impact on muscle strength profiles, proprioception and balance.

Introduction: Eccentric exercise has often been reported to result in muscle damage, limiting the muscle potential to produce force. However, understanding whether these adverse consequences extend to a broader, functional level is of apparently less concern. In this study, we address this issue by investigating the acute and delayed effects of supramaximal isotonic eccentric exercise on neuromuscular function and motor performance of knee extensors during tasks involving a range of strength profiles, proprioception, and balance. Methods: Fifteen healthy volunteers (23.2 ± 2.9 years old) performed a unilateral isotonic eccentric exercise of the knee extensors of their dominant lower limb (4 × 10 reps at 120% of one Repetition Maximum (1RM)). The maximum voluntary isometric contraction (MVC), rate of force development (RFD), force steadiness of the knee extensors, as well as knee joint position sense and mediolateral (MLI) and anteroposterior stability (API) of the dominant lower limb, were measured pre-, immediately, and 24 h after the eccentric exercise. The EMG amplitude of the vastus medialis (VM) and biceps femoris (BF) were concomitantly evaluated. Results: MVC decreased by 17.9% immediately after exercise (P < 0.001) and remained reduced by 13.6% 24 h following exercise (P < 0.001). Maximum RFD decreased by 20.4% immediately after exercise (P < 0.001) and remained reduced by 15.5% at 24 h (P < 0.001). During the MVC, EMG amplitude of the VM increased immediately after exercise while decreasing during the RFD task. Both values returned to baseline 24 h after exercise. Compared to baseline, force steadiness during submaximal isometric tasks reduced immediately after exercise, and it was accompanied by an increase in the EMG amplitude of the VM. MLI and knee joint position sense were impaired immediately after isotonic eccentric exercise (P < 0.05). While MLI returned to baseline values 24 h later, the absolute error in the knee repositioning task did not. Discussion: Impairments in force production tasks, particularly during fast contractions and in the knee joint position sense, persisted 24 h after maximal isotonic eccentric training, revealing that neuromuscular functional outputs were affected by muscle fatigue and muscle damage. Conversely, force fluctuation and stability during the balance tasks were only affected by muscle fatigue since fully recovered was observed 24 h following isotonic eccentric exercise.

Synthesis and interaction with growth factors of sulfated oligosaccharides containing an anomeric fluorinated tail.

Compounds that mimic the biological properties of glycosaminoglycans (GAGs) and can be more easily prepared than the native GAG oligosaccharides are highly demanded. Here, we present the synthesis of sulfated oligosaccharides displaying a perfluorinated aliphatic tag at the reducing end as GAG mimetics. The preparation of these molecules was greatly facilitated by the presence of the fluorinated tail since the reaction intermediates were isolated by simple fluorous solid-phase extraction. Fluorescence polarization competition assays indicated that the synthesized oligosaccharides interacted with two heparin-binding growth factors, midkine (MK) and FGF-2, showing higher binding affinities than the natural oligosaccharides, and can be therefore considered as useful GAG mimetics. Moreover, NMR experiments showed that the 3D structure of these compounds is similar to that of the native sequences, in terms of sugar ring and glycosidic linkage conformations. Finally, we also demonstrated that these derivatives are able to block the MK-stimulating effect on NIH3T3 cells growth.

Response to levodopa in Parkinson's disease over time. A 4-year follow-up study.

BACKGROUND AND OBJECTIVE: A good response to levodopa is a key factor to indicate device-aided therapies in people with Parkinson's disease (PwPD). The aim of the present study was to analyze the response to levodopa in PwPD with motor fluctuations followed for 4 years. PATIENTS AND METHODS: PwPD with motor fluctuations recruited from January 2016 to November 2017 from the COPPADIS cohort and assessed annually (from baseline to 4-year follow-up) during the OFF and ON states were included in this analysis. At each visit, the Unified Parkinson's Disease Rating Scale - part III (UPDRS-III) was applied during the OFF state (without medication during the last 12 h) and during the ON state. General linear model repeated measures were used to test for changes in the mean UPDRS-III-OFF, UPDRS-III-ON, and ΔUPDRS-III (UPDRS-III-OFF - UPDRS-III-ON) between visits. Levodopa equivalent daily dose (LEDD) was included as covariate. RESULTS: Sixty-three patients (63.94 ± 8.42 years old; 68.3% males) were included. Mean disease duration was 7.81 ± 3.64 years. From baseline to 4-year follow-up visit, a significant increase in both the UPDRS-III-OFF (from 27.98 ± 9.58 to 31.75 ± 12.39; p = 0.003) and the UPDRS-III-ON (from 15.92 ± 7.93 to 18.84 ± 8.17; p = 0.006) was observed despite the significant increase in the LEDD (from 896.35 ± 355.65 to 1085.51 ± 488.29; p = 0.003). However, no significant differences were detected between visits in the ΔUPDRS-III. CONCLUSION: In this cohort of PwPD with motor fluctuations, the response to levodopa did not weaken after a 4-year follow-up.