Potentiating Effect Research Articles

Guanidinylated Polymyxins as Outer Membrane Permeabilizers Capable of Potentiating Rifampicin, Erythromycin, Ceftazidime and Aztreonam against Gram-Negative Bacteria.

Polymyxins are considered a last-line treatment against infections caused by multidrug-resistant (MDR) Gram-negative bacteria. In addition to their use as a potent antibiotic, polymyxins have also been utilized as outer membrane (OM) permeabilizers, capable of augmenting the activity of a partner antibiotic. Several polymyxin derivatives have been developed accordingly, with the objective of mitigating associated nephrotoxicity. The conversion of polymyxins to guanidinylated derivatives, whereby the L-γ-diaminobutyric acid (Dab) amines are substituted with guanidines, are described herein. The resulting guanidinylated colistin and polymyxin B (PMB) exhibited reduced antibacterial activity but preserved OM permeabilizing properties that allowed potentiation of several antibiotic classes. Rifampicin, erythromycin, ceftazidime and aztreonam were particularly potentiated against clinically relevant MDR Gram-negative bacteria. The potentiating effects of guanidinylated polymyxins with ceftazidime or aztreonam were further enhanced by adding the β-lactamase inhibitor avibactam.

Long-term durability of improved glycemic control in type 2 diabetes mellitus treated with dasatinib, a second-generation tyrosine kinase inhibitor, for chronic myeloid leukemia: A report of two cases

Dasatinib, a second-generation tyrosine kinas inhibitoris effective against most cases of imatinib-resistant Chronic Myelogenous Leukemia (CML), and this drug has also shown significant glucose-lowering effects. Here, we report two diabetes patients with sudden onset of CML. In Case 1, dasatinib produced mild but clear improvement of hyperglycemia with the same anti-diabetic regimen together with rapid control of CML. In Case 2, initiation of dasatinib resulted inmarked potentiation of insulin-induced glucose-lowering effects in parallel with rapid improvements of CML. In both cases, this favorable diabetes control was well maintained for 5 years under leukemia management with dasatinib

Molecular Bases of Serotonin Reuptake Inhibitor Antidepressant-Attributed Effects in COVID-19: A New Insight on the Role of Bradykinins.

Widely available effective drugs to treat coronavirus disease-2019 (COVID-19) are still limited. Various studies suggested the potential contribution of selective serotonin-reuptake inhibitor (SSRI) antidepressants to alleviate the clinical course of COVID-19. Initially, SSRI antidepressant-attributed anti-COVID-19 activity was attributed to their direct agonistic or indirect serotonin-mediated stimulation of sigma-1 receptors (Sig1-R). Thereafter, attention was drawn to the property of SSRI antidepressants to decrease ceramide production, as functional inhibitors of acid sphingomyelinase. Ceramides are cell membrane waxy lipids formed by sphingosine and a fatty acid, playing a major role in receptor signaling and infection. In COVID-19 patients, ceramide production is increased due to acid sphingomyelinase activation. Here, we aimed to review the relationships between bradykinins and the proposed pathways supporting SSRI antidepressant-attributed effectiveness in COVID-19. In COVID-19 patients, bradykinin receptor-B1 stimulation is enhanced following the downregulation of angiotensin-converting enzyme-2, which is responsible for the inactivation of des-Arg9-bradykinin, a bradykinin metabolite, contrasting with the decrease in bradykinin receptor-B2 (BDKRB2) stimulation, which results from the inhibition of cathepsin L, a kininogenase involved in bradykinin production and present at the infection site. Sig1-R stimulation modulates the inflammatory response by regulating cytokine production and counterbalances COVID-19-attributed BDKRB2 inhibition by potentiating its effects on the cytosolic calcium concentration. Moreover, the beneficial effects obtained with acid sphingomyelinase inhibition are parallel to those expected with BDKRB2 stimulation in COVID-19. Altogether, these findings suggest that one ultimate pathway of SSRI antidepressant-attributed anti-COVID-19 activity is the potentiation of BDKRB2 effects shown to be inhibited in COVID-19. In conclusion, SSRI antidepressants are able to interact positively with the pathophysiological mechanisms involved in COVID-19. However, their exact benefits in preventing morbidities or improving the outcome in COVID-19 patients remain unknown.

An Oleocanthal-Enriched EVO Oil Extract Induces the ROS Production in Gastric Cancer Cells and Potentiates the Effect of Chemotherapy.

Oleocanthal, a minor polar compound in extra-virgin olive (EVO) oil, contains anticancer properties, which should be encouraged in its use in oncology. Gastric Cancer (GC), a very aggressive human cancer, is often diagnosed at advanced stages, when surgery is substituted or supported by chemotherapy (CT). However, CT frequently fails due to the patient’s resistance to the treatment. Thus, the aim of this study is to verify whether an OC-enriched EVO oil extract fraction (OCF) may be useful in order to overcome a resistance to GC. We evaluated the OCF effects on an AGS gastric adenocarcinoma cell line wild type (AGS wt) and on its subpopulations resistant to 5-fluorouracil (5FUr), Paclitaxel (TAXr) or cisplatin (CISr). We found that a 60 µM dose of the OCF acts on the AGS wt, 5FUr and TAXr, leading to the cell cycle inhibition and to a ROS production, but not on CISr cells. Resistance of CISr to the OCF seems to be due to higher levels of antioxidant-enzymes that can counteract the OCF-induced ROS production. Moreover, using the OCF plus 5-fluorouracil, Paclitaxel or cisplatin, we found a potentiating effect compared with a mono-treatment in all resistant GC cells, including CISr. In conclusion, the use of the OCF in the management of GC has shown very interesting advantages, opening-up the possibility to evaluate the efficacy of the OCF in vivo, as a valid adjuvant in the treatment of resistant GC.

The Effect Of Cluster-sets Resistance Priming Training On Delayed Potentiation Of Athletes

Cluster sets (CS) resistance training can induce greater post-activation potentiation (PAP) effects than traditional sets (TS) by reducing fatigue. The neuromuscular performance response demonstrated in delayed potentiation (DLP) effects is similar to that in PAP, they are all based on the relationship between potentiation and fatigue. However, it is not clear whether CS resistance training can induce greater DLP effects. OBJECTIVE The aim of the study was to compare the delayed potentiation (DLP) effects induced by cluster sets (CS) versus traditional sets (TS) resistance priming (RP) training. METHODS Sixteen male collegiate athletes were recruited for the study in a crossover design. All the subjects performed a CS (30s interval between reps, 4 minutes interval between sets) and a TS (no rest between reps, 4 minutes interval between sets) RP training sessions (3 sets of 3 repetitions of barbell back squat at 85%1RM) in random order separated by 72 hours. countermovement jump (CMJ),20-meters sprint, and T-test were evaluated at baseline and 6 hours after the RP training sessions. RESULTS 6 hours after the RP sessions, both the CS and TS significantly improved the CMJ height (CS: 50.44 ± 8.35 cm, ES = 0.48; TS: 48.35 ± 8.05 cm, ES = 0.23), CMJ take-off velocity (CS: 3.21 ± 0.28 m/s, ES = 0.56; TS: 3.16 ± 0.27 m/s, ES = 0.38), CMJ push-off impulse (CS: 237.3 ± 26.99Ns, ES = 0.38; TS: 233.8 ± 24.96Ns, ES = 0.26), 20-meters sprint (CS: 2.967 ± 0.139 s, ES = 0.85; TS: 3.007 ± 0.122 s, ES = 0.58) and T-test (CS:9.805 ± 0.535 s, ES = 0.99; TS: 9.921 ± 0.64 s, ES = 0.73) performance compared with baseline values. The CMJ peak power (64.42 ± 8.92 W/kg, ES = 0.3) were significant better following the CS compared with baseline values. The CMJ height (ES = 0.25), CMJ peak power (ES = 0.2), 20-meters sprint (ES = 0.31) were significant better following the CS compared with the TS training session. No inter-condition significant difference was observed in CMJ take-off velocity (ES = 0.18), CMJ push-off impulse (ES = 0.13), and T-test (ES = 0.2). CONCLUSIONS Compared with TS, CS RP training resulted in greater DLP effects after 6 hours, and significantly improving athletes’ lower limb speed performance and power output.

Communication Theoretical Modeling and Analysis of Tripartite Synapses With Astrocytes in Synaptic Molecular Communication

Astrocytes, the most abundant glial cells in brain, being in physical proximity of pre- and postsynaptic terminals of the chemical synapse, form tripartite synapses. The feedback from astrocytes introduces synaptic plasticity, which modulates information transmission through neurons. Various other synaptic events also cause plasticity, hence combining them in a single model is quite challenging. In this paper, we study the combined effect of short-term depression (STD) and long-term potentiation (LTP) on vesicle release process in a tripartite synapse. STD decreases the release probability due to slower replenishment rates of releasable vesicles, whereas LTP is due to the positive feedback from astrocytes that increases release probability. Thus, we evaluate vesicle release probability and mutual information between input spikes and vesicle release to quantify the effects of STD and LTP on information transmission. Moreover, the effect of different synaptic parameters such as number of releasable vesicles, input spike rate and replenishment rate of the vesicles, is analyzed on information transmission. It is observed that release probability is predominantly affected by LTP, however, presence of STD decreases the achievable average mutual information over time. Furthermore, the synapses with higher number of releasable vesicles are observed to become stronger with time.

Joint Action of Botanicals against Helopeltis theivora Waterhouse and Oligonychus coffeae Nietner

Laboratory experiments to evaluate the combined effect of Chromolaena odorata (Co) and Phlogocanthus thyrsiflorus (Pt) against Oligonychus coffeae and Helopeltis theivora revealed that the methanolic leaf extracts at a combination of 75% LC50 Pt + 25% LC50 Co and 25% LC50 Pt + 75% LC50 Co were the most effective against O. coffeae and H. theivora, respectively. They recorded the highest co-toxicity coefficient and co-toxicity factor values of 206.53 and 63.34 and 398.40 and 100.00, respectively revealing potentiation and synergistic effects. A combination of 50% LC50 Pt + 50% LC50 Co can effectively manage both O. coffeae and H. theivora (76.67% and 100.00% adult mortality, respectively) with the highest co-toxicity coefficient and co-toxicity factors.

Effect of Rumex dentatus on Gastrointestinal Protection and Toxicology in Rodents via Investigating H+/K+-ATPase, Calcium Channels, and PDE Mediated Signaling

This present study aims to delineate Rumex dentatus crude extract (Rd.Cr), n-Hexane, ethyl acetate, aqueous fractions (Rd.n-Hex, Rd.ETAC, and Rd.Aq), and emodin for antidiarrheal, antisecretory effects, anti-spasmodic, gastrointestinal transient time, anti-H. pylori, antiulcer effects, and toxicology. Plant extracts attributed dose-dependent protection against castor oil-induced diarrhea and dose-dependently inhibited intestinal fluid secretions in mice. They decreased the distance transverse by charcoal in the gastrointestinal transit model in rats. In rabbit jejunum preparations, it causes a concentration-dependent relaxation of both spontaneous and K+ (80 mM)-induced contraction, Rd.n-Hex and verapamil were relatively potent against K+-induced contractions and shifted the Ca2+ concentration-response curves (CRCs) to the right, Rd.Cr and Rd.ETAC shifted the isoprenaline-induced inhibitory CRCs to the left, showing potentiating effect similar to papaverine. Rd.n-Hex showed anti-H. pylori effect. Extracts and emodin also show an inhibitory effect against H+/K+-ATPase. Rumex dentatus showed a gastroprotective and antioxidant effect. Histopathological evaluation showed improvement in cellular architecture and decrease in the expression of inflammatory markers such as cyclooxygenase (COX2), tumor necrosis factor (TNF-α), and phosphorylated nuclear factor kappa B (p-NFƙB), validated through immunohistochemistry, ELISA, and western blot techniques. In RT-PCR, it decreases H+/K+-ATPase mRNA levels. Rumex dentatus was analyzed for certain safety aspects and exhibited a relative safety profile as no impairment was observed in kidneys, heart, liver, and brain further assisted by biochemical and hematological analysis. Docking studies revealed that emodin against H+/K+-ATPase pump and voltage gated L-type calcium channel showed E-value of −7.9 and −7.4 kcal/mol, respectively. MD simulations and molecular mechanics Poisson Boltzmann surface area and molecular mechanics Generalized Born surface area MMPBSA/GBSA findings are consistent with the in-vitro, in-vivo, and docking results. In conclusion, Rumex dentatus extracts and its phytoconstituent could be considered a potent antioxidant and anti-inflammatory drug candidates that possess anti-diarrheal, anti-secretary, antispasmodic, anti-H. pylori, and anti-ulcer potential. Toxicity studies were done according to OECD standards 425. It belongs to group 5 (LD50 > 2000 mg/kg), which suggests that it is in the lower toxicity class.

Anesthetics and Cell-Cell Communication: Potential Ca2+-Calmodulin Role in Gap Junction Channel Gating by Heptanol, Halothane and Isoflurane.

Cell–cell communication via gap junction channels is known to be inhibited by the anesthetics heptanol, halothane and isoflurane; however, despite numerous studies, the mechanism of gap junction channel gating by anesthetics is still poorly understood. In the early nineties, we reported that gating by anesthetics is strongly potentiated by caffeine and theophylline and inhibited by 4-Aminopyridine. Neither Ca2+ channel blockers nor 3-isobutyl-1-methylxanthine (IBMX), forskolin, CPT-cAMP, 8Br-cGMP, adenosine, phorbol ester or H7 had significant effects on gating by anesthetics. In our publication, we concluded that neither cytosolic Ca2+i nor pHi were involved, and suggested a direct effect of anesthetics on gap junction channel proteins. However, while a direct effect cannot be excluded, based on the potentiating effect of caffeine and theophylline added to anesthetics and data published over the past three decades, we are now reconsidering our earlier interpretation and propose an alternative hypothesis that uncoupling by heptanol, halothane and isoflurane may actually result from a rise in cytosolic Ca2+ concentration ([Ca2+]i) and consequential activation of calmodulin linked to gap junction proteins.

In Vitro Assessment of the Combination of Antibiotics against Some Integron-Harbouring Enterobacteriaceae from Environmental Sources.

One strategy for combating antimicrobial resistance in many infections is to combine antibacterial compounds to create combinations that outperform each molecule alone. In this study, we examine and study the inhibitory effect of combining two drugs belonging to different antibiotic classes to obtain a possible potentiating effect against some Enterobacteriaceae isolates harbouring integrons recovered from rivers and effluents of hospital and wastewater treatment plants in Eastern Cape Province, South Africa. These integrons could easily enable the isolates to acquire genes that confer additional resistance against conventional antibiotics. The minimum inhibitory concentration of the various antibiotics was determined using the broth microdilution, while the checkerboard method was used to determine the fractional inhibitory concentration indices (FICIs). A total of 26.3% (10/38) of the interactions were categorised as synergistic, while 73.7% (28/38) were indifferent. None of the combinations were antagonistic. The time–kill assays revealed all the synergistic interactions as bactericidal. Therefore, the combinations of gentamicin with tetracycline, ciprofloxacin, and ceftazidime against multidrug-resistant (MDR) Klebsiella pneumoniae, tetracycline–ceftazidime combination against MDR Escherichia coli, colistin combinations with ceftazidime and gentamicin, and tetracycline–gentamicin combinations against MDR Citrobacter freundii may be future therapeutic alternatives. Hence, the synergistic combinations reported in this study must be assessed further in vivo before their clinical applications.

Crosstalk between PI3K/Akt and Wnt/β-catenin pathways promote colorectal cancer progression regardless of mutational status

ABSTRACT The PI3K/Akt and Wnt/β-catenin pathways play an important role in the acquisition of the malignant phenotype in cancer. However, there are few data regarding the role of the interplay between both pathways in colorectal cancer (CRC) progression. The mutational status and the clinicopathological characteristics of PI3K/Akt and Wnt/β-catenin pathways were accessed by bioinformatic analysis whereas that the impact of the interplay between the activity of both pathways to explain tumorigenic potential was performed in vitro using IGF-1 and Wnt3a treatments in CRC cell models. The mutational status of these pathways did not influence the survival of CRC patients, but an association between clinicopathological characteristics in patients with mutations in one, but not in both pathways was observed. A potentiating effect on the activation of both pathways and enhanced cellular migration and proliferation was observed when both pathways were activated simultaneously with IGF-1 and Wnt3a. In addition, these effects were hindered after pretreatment with LY294002, a specific PI3K inhibitor, suggesting some dependence between these two signaling cascades. Our findings show that, regardless of mutational status, there is an interplay between the activity of PI3K/Akt and Wnt/β-catenin pathways that contributes to events related to CRC progression and that the reversal of such events using a PI3K inhibitor highlights the value of targeting these pathways for potential directed therapies in CRC patients.

Cattle effluents, either composted or bio-digested by Black Soldier Fly larvae, in the fertilization of ryegrass in sandy soils

The relative agronomic performance of two organic fertilizers - effluents from intensive cattle farming, after composting either by traditional aerobic methods (compost) or by bio-digestion by larvae of the black soldier fly (Hermetia illucens, BSF) (frass) - in the growth of annual ryegrass (Lolium multiflorum L.) on a sandy soil was evaluated. For this purpose, a pot trial was conducted in a semi-controlled greenhouse. Eight treatments were defined, with four treatments using the compost and four treatments using frass (with a 10% nitroamoniacal nitrogen supplementation in all treatments), in addition to a negative control without fertilization, and a positive control with exclusively chemical nitroamoniacal fertilization. Regarding the biomass production, the BSF frass displayed a higher potential than the compost, with a significantly higher production from an N endowment equivalent to 280 kg ha-1 (252 kg organic N + 28 kg mineral N). While the yields obtained with compost were stable when 350 kg ha-1 (315 kg organic N + 35 kg mineral N) were provided, the yields obtained with BSF frass revealed a tendency to continue to progress with higher doses. This could be justified by the fact that the P2O5 and K2O content of BSF frass is significantly higher than that of the compost, and these nutrients continued to be mineralized over time. Furthermore, the obtained results confirm the potentiating effect of mineral fertilizers in the maximization of biomass production, when associated with organic fertilizers in adequate proportions. In addition, it was verified that the addition of frass enhanced the water use by plants, which was significantly higher than the treatments with compost, regardless of the N endowment. It was concluded that mixing chemical and organic fertilizers positively impacts soil fertility and the sustainability of the production as a whole, by increasing productivities in a sustainable way.

Combined in-silico and in-vitro experiments support acid-base equilibrium as a tool to estimate the localization depth of 4-nitrophenol within a phospholipid bilayer

The interaction and location of 4-nitrophenol (PNP) in biomembranes are relevant in the bioaccumulation and potentiation of the intensive toxic effects of this persistent organic pollutant. In this work, in-silico analyses predicted that, in a fluid phospholipid bilayer, the minimum energy of the protonated (PNPH) and deprotonated (PNP−) species is located within the glycerol and choline region, respectively. This was experimentally confirmed by acid-base equilibrium experiments and theory, allowing the estimation of the mean location of PNP within a bilayer region with a dielectric constant D = 50.6 compatible with the phosphate/choline moiety of egg-yolk phosphatidylcholine unilamellar (EPC) vesicles. The comparison with the D = 43.2 value obtained in Triton X-100 micelles allow predicting a mean surface potential of ψ = 25.37 mV for the EPC-water interface. Changes in the chemical shifts and longitudinal relaxation times of EPC hydrogens by 1H NMR confirm the deeper location of the PNPH within the glycerol region and at the choline region (PNP−) at higher pH. Intermolecular PNP−EPC dipolar interactions within the choline region was also demonstrated at pH 10.2 using ROESY experiments. Additional information was obtained trough 31P NMR, that detected an increase in the anisotropy at the membrane interface after insertion of PNP which probably act as a bridge between choline moieties rigidizing the crystalline structure at that spot. Concluding, here we provide experimental support to the “pH-piston hypothesis” proposed some decades ago in the pharmaceutical field, and that reinforce the importance of the environmental conditions (e.g. pH) to modulate the bioavailability of this highly toxic pollutant.

Analysis of Structural Determinants of Peptide MS 9a-1 Essential for Potentiating of TRPA1 Channel.

The TRPA1 channel is involved in a variety of physiological processes and its activation leads to pain perception and the development of inflammation. Peptide Ms 9a-1 from sea anemone Metridium senile is a positive modulator of TRPA1 and causes significant analgesic and anti-inflammatory effects by desensitization of TRPA1-expressing sensory neurons. For structural and functional analysis of Ms 9a-1, we produced four peptides—Ms 9a-1 without C-terminal domain (abbreviated as N-Ms), short C-terminal domain Ms 9a-1 alone (C-Ms), and two homologous peptides (Ms 9a-2 and Ms 9a-3). All tested peptides possessed a reduced potentiating effect on TRPA1 compared to Ms 9a-1 in vitro. None of the peptides reproduced analgesic and anti-inflammatory properties of Ms 9a-1 in vivo. Peptides N-Ms and C-Ms were able to reduce pain induced by AITC (selective TRPA1 agonist) but did not decrease AITC-induced paw edema development. Fragments of Ms 9a-1 did not effectively reverse CFA-induced thermal hyperalgesia and paw edema. Ms 9a-2 and Ms 9a-3 possessed significant effects and anti-inflammatory properties in some doses, but their unexpected efficacy and bell-shape dose–responses support the hypothesis of other targets involved in their effects in vivo. Therefore, activity comparison of Ms 9a-1 fragments and homologues peptides revealed structural determinants important for TRPA1 modulation, as well as analgesic and anti-inflammatory properties of Ms9a-1.

Disputable questions of statins antitumor effects in hemoblastoses

Antitumor drug treatment of hemoblastoses always takes into account the patient comorbidity. Due to the frequent cardiovascular pathology and atherosclerosis, patients have to take statins along with antitumor treatment. Experimental studies have shown that statins inhibit the cholesterol synthesis (necessary for the vital activity of malignant cells), isoprenylation of the RAS and RHO oncogenes, and the proliferation of leukemic cells. In addition, the potentiation of antitumor drugs effect by statins, sensitization of leukemia and lymphomas cells to their effects were noted. when conducting a meta-analysis, it was found that mortality among patients with hematological malignancies taking statins is lower compared with the group of patients not receiving statins. This fact is probably explained not only by the improvement in cholesterol metabolism, but also by indirect antitumor effects of this group of drugs.

Photo-enhanced upcycling H2O2 into hydroxyl radicals by IR780-embedded Fe3O4@MIL-100 for intense nanocatalytic tumor therapy

Reactive oxygen species (ROS)-based nanocatalytic tumor therapy is alluring owing to the capability to generate highly cytotoxic ∙OH radicals from tumoral H2O2. However, the antitumor efficacy is highly dependent on the radical generation efficiency and challenged by the high levels of antioxidative glutathione (GSH) in cancer cells. Herein, we report an IR-780 decorated, GSH-depleting Fe3O4@MIL-100 (IFM) nanocomposite for photo-enhanced tumor catalytic therapy by extensive production of ∙OH, which is realized by an integration of excellent peroxidase-like activity of IFM, selective upregulation of tumoral H2O2 by β-lapachone, and localized hyperthermia by near infrared light irradiation. IFM shows potentiated antiproliferative effect in 4T1 cancer cells by ∙OH overproduction and glutathione scavenging, inducing intracellular redox dyshomeostasis and cell death by concurrent apoptosis and ferroptosis. In vivo antitumor investigation further demonstrates photoacoustic and fluorescence imaging-guided combinational therapy with a tumor inhibition rate of 96.4%. This study provides a strategy of photo-enhanced nanocatalytic tumor therapy by tumor-specific H2O2 amplification and hyperthermia.

Motor cortical plasticity in adolescents with early onset schizophrenia: A TMS-EMG study assessing the perturbation effect of intermittent and continuous theta burst stimulation.

Neuroplasticity in adolescents is distinct from that of adults. Literature pertaining to neuroplasticity in schizophrenia is limited to adult populations. We aimed to assess baseline (or resting) cortical excitability and cortical plasticity in adolescents with schizophrenia using the transcranial magnetic stimulation-electromyography (TMS-EMG) protocol. Twenty adolescent cases with schizophrenia and 20 age and gender matched healthy controls were studied using a crossover design. Single pulse TMS elicited resting motor threshold (RMT) and motor evoked potentials (MEPs) were assessed. Cortical plasticity was determined by tracking MEPs after a single session continuous theta burst stimulation (cTBS) and intermittent theta burst stimulation (iTBS) up to 120 min at 12 intervals. Baseline (or resting) cortical excitability was found to be significantly lower in cases compared with controls. Response patterns to cTBS and iTBS were similar between the crossover. While cTBS led to inhibitory response, iTBS had an excitatory effect in both the groups. In the cases, while cTBS led to significantly greater initial inhibitory response, iTBS led to significantly lower excitatory response, compared with controls. The time taken to return to baseline excitability was significantly longer after receiving cTBS for cases, compared with controls. iTBS and cTBS lead to excitatory and inhibitory response, representing classical long-term depression and long-term potentiation effects, respectively, in both cases and controls. We conclude that adolescents with schizophrenia have significantly lower baseline (resting) cortical excitability as well as significantly greater inhibitory plasticity; excitatory plasticity is significantly lower.

Associative effect of essential oils, tannins, and sodium monensin on the performance of steers finished in feedlot

The objective was to evaluate the productive performance, ingestive behavior, apparent digestibility of the diet and carcass traits of beef steers finished in feedlot under the effect of including tannins and essential oils (TAN+EO) alone or combined with sodium monensin (MO) in the feed. For this purpose, 30 ½ blood Angus steers from the same herd, with an average age of 12 months and an average initial body weight of 367.8 kg were used. The experimental design was randomized blocks, consisting of three treatments: MO - diet with sodium monensin (25 mg kg DM-1); TAN+EO - diet with tannins and essential oils (1.5 g kg DM-1); and MO+TAN+EO - diet with sodium monensin + tannins and essential oils (25 mg kg DM-1 + 1.5 g kg DM-1), with five repetitions, where each repetition was represented by a stall with two animals. Diets were formulated and consisted of a mixture of 40% corn silage and 60% concentrate, which was fed to the animals twice a day, at 06h00 am and 05h30 pm. There was no difference (P>0.05) in average daily weight gain of animals between treatments, with an average of 1.392 kg day-1. Carcass yield was higher for animals that received the compound of essential oils and tannins (55.72%), compared to animals fed the combination of tannins, essential oils and monensin (54.54%) but did not differ from those supplemented with sodium monensin alone (55.58%). Supplementation with essential oils and tannins improved the apparent digestibility of the diet, however, did not promote changes in the ingestive behavior and carcass traits of steers. The combination of essential oils and tannins with sodium monensin did not show a potentiated effect on animal performance, digestibility of DM, digestive and ingestive behavior and carcass traits of feedlot finished steers compared to the combined use of essential oils with tannins.

Pharmacodynamic Target Assessment and PK/PD Cutoff Determination for Gamithromycin Against Streptococcus suis in Piglets.

Gamithromycin is a long-acting azalide antibiotic that has been developed recently for the treatment of swine respiratory diseases. In this study, the pharmacokinetic/pharmacodynamic (PK/PD) targets, PK/PD cutoff, and optimum dosing regimen of gamithromycin were evaluated in piglets against Streptococcus suis in China, including a subset with capsular serotype 2. Short post-antibiotic effects (PAEs) (0.5–2.6 h) and PA-SMEs (2.4–7.7 h) were observed for gamithromycin against S. suis. The serum matrix dramatically facilitated the intracellular uptake of gamithromycin by S. suis strains, thus contributing to the potentiation effect of serum on their susceptibilities, with a Mueller-Hinton broth (MHB)/serum minimum inhibitory concentration (MIC) ratio of 28.86 for S. suis. Dose-response relationship demonstrated the area under the concentration (AUC)/MIC ratio to be the predictive PK/PD index closely linked to activity (R2 > 0.93). For S. suis infections, the net stasis, 1–log10, and 2–log10 kill effects were achieved at serum AUC24h/MIC targets of 17.9, 49.1, and 166 h, respectively. At the current clinical dose of 6.0 mg/kg, gamithromycin PK/PD cutoff value was determined to be 8 mg/L. A PK/PD-based dose assessment demonstrated that the optimum dose regimen of gamithromycin to achieve effective treatments for the observed wild-type MIC distribution of S. suis in China with a probability of target attainment (PTA) ≥ 90% was 2.53 mg/kg in this study. These results will aid in the development of clinical dose-optimization studies and the establishment of clinical breakpoints for gamithromycin in the treatment of swine respiratory infections due to S. suis.

Effect of post-activation potentiation on the force, power and rate of power and force development of the upper limbs in mixed martial arts (MMA) fighters, taking into account training experience

Introduction. The aim of the study is to determine the optimal load for generating the highest value of force, power and the rate of power and force development (RFD and RPD) in the upper limb of mixed martial arts (MMA) fighters with the use of activation and explosive exercises. The training period of MMA players was included in the research. Material and Methods: Twenty-nine MMA fighters participated in the study and were divided into two groups depending on the length of their training period (under and over 5 years). The subjects did 2 ballistic push-ups before the study and after-wards they performed 5 repetitions of press dumbbells while lying down with an increasing load: 50% 1RM, 65% 1RM and 80% 1RM. The rest was 4 minutes. All ballistic push-ups were performed on ForceDecks, and the data was analysed using the manufacturer’s software. To compare differences between the groups, one-way ANOVA and post-hoc test were used. T-Student test was used to deter-mine the differences within the groups. Results: Amateurs obtained greater force and RPD results after the activation exercise performed at 50% 1RM, while power and RFD at 65% 1RM. For professionals, the highest force was achieved with a load of 80% 1RM, power at 50% 1RM, and RFD and RPD at 80% 1RM. Statistically significant differences between the groups were observed before and after each trial in force and RPD. The power did not statistically differ only after the load of 65% 1RM. In RFD, no statistically significant differences were found between the studied groups. Conclusions: Competitors with longer training experience should use a greater load in an activation exercise than competitors with shorter training experience.