Search

OBJECTIVE Deep brain stimulation (DBS) for pain has largely been implemented in an uncontrolled manner to target the somatosensory component of pain, with research leading to mixed results. We have previously shown that patients with poststroke pain syndrome who were treated with DBS targeting the ventral striatum/anterior limb of the internal capsule (VS/ALIC) demonstrated a significant improvement in measures related to the affective sphere of pain. In this study, we sought to determine how DBS targeting the VS/ALIC modifies brain activation in response to pain. MATERIALS AND METHODS Five patients with poststroke pain syndrome who were blinded to DBS status (ON/OFF) and six age- and sex-matched healthy controls underwent functional magnetic resonance imaging (fMRI) measuring blood oxygen level-dependent activation in a block design. In this design, each participant received heat stimuli to the affected or unaffected wrist area. Statistical comparisons were performed using fMRI z-maps. RESULTS In response to pain, patients in the DBS OFF state showed significant activation (p

The development of molecular and supramolecular optical devices for sensing ionic analytes in solution has emerged as a promissory field in the last decades. In this context, qualitative and quantitative analysis of metal cations based on chromogenic and fluorogenic chemosensors are particularly attractive, especially due to their successfully employment for biological and environmental purposes. In this work, the literature data associated to quinoxaline-based derivatives as chemosensors for metal cations in solution are comprehensively reviewed. Sensing mechanisms, detection limits, solvent effect, work concentration ranges, as well as examples of practical implementation are presented. We believe that the data compilation and pertinent discussion present in this survey should be of interest for researchers of heterocyclic-based chemosensors’ field.

Recent studies have found that hydroxide elimination and the C[double bond, length as m-dash]C bond formation step in base-promoted aldol condensation have a strong influence on the overall rate of the reaction, in contrast to the well-accepted first enolization or C-C bond formation step. Here, applying theoretical models to the prototypical reaction of chalcone formation, the complete free energy profile of Claisen-Schmidt condensation is assessed, revealing how a protic solvent and a slight increase in temperature can induce the second enolization as the rate-controlling step (RCS). It is also observed: i) the nonexistence of a step with a much higher energetic barrier than the others, making the concept of RCS debatable; and ii) that the overall inverse kinetic isotopic effect does not exclude second enolization as a RCS in protic continuum medium. We expect that these results can expand the understanding of the decisive role of physicochemical factors on the choose of the RCS in the aldol condensation.

In the Comment on our paper on the description of the Gibbs Free energy profile of Claisen–Schmidt condensation, it is claimed that our calculations are flawed due to inconsistencies with experimental isotope effects in aqueous acetonitrile. In this Reply, we presented rigorous arguments, ambiguities in the Comment and new calculations confirming the consistency of our results: (i) small differences in the relative energetic barriers in both experimental and theoretical curves make the assignment of the rate-limiting step debatable, making the concept of RCS questionable; (ii) it is shown how the misinterpretation of the elementary steps and of the overall processes rate constants led the Comment to incorrect conclusions about the behavior of the inverse isotopic effect; (iii) neglect in the Comment of the inverse kinetic isotope effect in step R2 due to the hybridization conversion, and of the inverse equilibrium isotopic effect for step R1 to describe an overall iKIE > 1, (iv) an erroneous suggestion in the Comment that the disagreement between experimental kinetic parameters is due to the fact that acetonitrile is not used in previous experimental works, when contradictorily the literature recommends it as being indispensable to allow kinetic accuracy; and (v) new calculations improved by explicit-implicit hybrid treatment again ensure that step R4, and not step R5, can assume the role of RCS in protic solvents. Recognizing that questioning is an excellent path for promoting understanding, we hope that the answers provided here will help to clarify and expand the pertinent topics under discussion.

Objective A recent “bimodal-balance recovery” model suggests that contralesional influence varies based on the amount of ipsilesional reserve: inhibitory when there is a large reserve, but supportive when there is a low reserve. Here, we investigated the relationships between contralesional influence (inter-hemispheric inhibition, IHI) and ipsilesional reserve (corticospinal damage/impairment), and also defined a criterion separating subgroups based on the relationships. Methods Twenty-four patients underwent assessment of IHI using Transcranial Magnetic Stimulation (ipsilateral silent period method), motor impairment using Upper Extremity Fugl-Meyer (UEFM), and corticospinal damage using Diffusion Tensor Imaging and active motor threshold. Assessments of UEFM and IHI were repeated after 5-week rehabilitation (n = 21). Results Relationship between IHI and baseline UEFM was quadratic with criterion at UEFM 43 (95%conference interval: 40–46). Patients less impaired than UEFM = 43 showed stronger IHI with more impairment, whereas patients more impaired than UEFM = 43 showed lower IHI with more impairment. Of those made clinically-meaningful functional gains in rehabilitation (n = 14), more-impaired patients showed further IHI reduction. Conclusions A criterion impairment-level can be derived to stratify patient-subgroups based on the bimodal influence of contralesional cortex. Contralesional influence also evolves differently across subgroups following rehabilitation. Significance The criterion may be used to stratify patients to design targeted, precision treatments.

Poly(lactic acid) (PLA) and poly(e-caprolactone) (PCL) are two immiscible polymers which are biodegradable and bioabsorbable, being therefore widely applied for medical materials. The formation of ...

Objective Neuromodulation for trigeminal pain syndromes such as trigeminal neuropathic pain (TNP) necessitates accurate localization of foramen ovale (FO). The Hartel-type approach is very well-established and safe, ideal for temporary cannulation of the FO for ablative procedures such as balloon microcompression. A key shortcoming of the Hartel approach for placement of neuromodulation leads is the limited opportunity for secure anchoring. The aim of this study is to introduce a novel surgical approach for the treatment of TNP by investigating key osseous landmarks and their spatial relationships to the FO. Materials and methods Sixteen sides of cadaver heads were dissected to investigate a surgical route of the FO via transoral gingival buccal approach. Alveolar arch of the maxilla and zygomaticomaxillary suture were selected to serve as an osseous landmark for the surgical guidance to the FO. Through the intraoral route, a needle simulating electrode was traversed to aim the FO from the inferior lateral to the superior medial direction to target specific fibers of the aimed division of the nerve. Results Visual identification and access to the trigeminal nerve at the external opening of FO was successful in all 16 hemifacial cadavers. A needle successfully targeted different regions of the trigeminal nerve by changing the angle of the trajectory allowing the needle to reach a specific division of the trigeminal nerve. Conclusions This study provides a novel means of approaching the FO via transoral gingival buccal access.

Background: Intrathecal baclofen (ITB) is traditionally reserved for non-ambulatory patients. Objective: To investigate outcomes of ITB in ambulatory multiple sclerosis (MS) patients. Methods: Changes in outcome measures were estimated by a mixed effect model, while the complication rate was calculated using a logistic regression. Predictors of non-ambulatory status were identified by Cox model. Results: In all, 256 patients received an ITB test injection and 170 underwent ITB surgery. Aggregate Modified Ashworth Scale (MAS) scores for the ambulatory ITB cohort decreased from 13.5 ± 6.96 to 4.54 ± 4.18 at 5 years ( p Conclusion: ITB is effective for ambulatory MS patients without compromising short-term walking speed, although a higher complication rate was observed in this cohort.

Sarcopenia is characterized by progressive loss of skeletal muscle mass, which results in decreased muscle strength, functional impairment, and increased risk of death. Few studies have performed a concomitant evaluation of clinical, laboratory, and body composition variables to accurately determine the contribution of each parameter to low muscle mass (LMM) in older subjects. This study aimed to identify risk factors (clinical, laboratory parameters, BMD, and body composition by DXA including visceral fat) for LMM in a prospective cohort of older Brazilian women.A total of 408 women aged ≥65 yr from the São Paulo AgeingHealth study were evaluated with clinical data, laboratory bone tests, BMD, and body composition by DXA using Hologic QDR 4500A equipment. Risk factors were measured at baseline (2005-2007). After a follow-up of 4.3 ± 0.8 yr, subjects were classified according to the LMM definition of the Foundation for the National Institutes of Health criteria. LMM was defined when appendicular lean mass divided by body mass index was less than 0.512. Multivariate logistic regression models were used to identify independent risk factors for LMM.At the end of follow-up, 116 women (28.4%) had LMM. Age averages were 73.3 ± 4.9 yr in the LMM group and 72.5 ± 4.5 yr in the normal group (p = 0.11). Mean BMI was 30.6 ± 5.2 kg/mFalls, high TSH, low creatinine, and high VAT were risk factors for LMM in older women. More attention should be paid to these factors, since they are potentially reversible with adequate intervention.

The current work reports the synthesis and structural investigation of three novel complexes with 2-acetyl-pyridine-N(4)-phenylthiosemicarbazone (HL1), [Ni(L1)Cl] (1), [Pd(L1)Cl] (2) and [Pt(L1)PPh3]Cl•2MeOH (3). The compounds were structurally characterized by means of single-crystal X-ray crystallography and spectroscopic techniques. All three complexes exhibit tetracoordinated metal centers in a square planar fashion with the thiosemicarbazone acting as a tridentate NNS-donor atoms. Intermolecular hydrogen bonds and π···π stacking interactions, building supramolecular assemblies in the complexes, were analyzed using the Hirshfeld surface. Mass spectrometry data showed the presence in solution of the characteristic fragmentation with the [M+H]+ molecular ion for all complexes. The thermochemical data, estimated by computational chemistry, allowed elucidate the relative intensity of the peaks present in the mass spectrum of the compounds investigated. The antitumor activity and selectivity of the free thiosemicarbazone ligand and their M(II) complexes (M = Ni, Pd, Pt) were evaluated against MCF-7, PBMC, and healthy cells. All compounds studied showed the death of cancer cells observing a great selectivity for the Ni(II) complex.

Herein, we report a synthetic route capable of producing superparamagnetic, stable and biocompatible glucosamine (GLU) nanocarriers, composed by colloidal iron oxide nanoparticles (ION, ~6 nm) surface-functionalized with GLU dispersed in physiological media (pH 7.2). The route consists first of the preparation of ION by aqueous alkaline co-precipitation of 1:2 Fe(II)/Fe(III) followed by surface treatment with citric acid, activation of acidic groups via carbodiimide intermediary and further amidation using GLU as the amine reactant. Results from cell viability tests performed with human dental pulp tissue cells suggest that ION–GLU nanocolloids are biocompatible and non-toxic for two different concentrations and several hours of incubation. Moreover, optical microscopy shows that ION–GLU adsorbs at the cells walls and also transposes them, reaching cytoplasm and nucleus as well. All findings point out the promising use of ION–GLU as biocompatible nanocarriers for GLU delivery such as in articulation diseases.

Collision events lead to peculiar morphologies in the intracluster gas of galaxies clusters. That seems to be the case of Abell 1644, a nearby galaxy cluster, composed of three main structures: the southern cluster that exhibits a spiral-like morphology, A1644S; the northern cluster seen in X-ray observations, A1644N1; and the recently discovered substructure, A1644N2. By means of $N$-body hydrodynamical simulations, we attempt to reconstruct the dynamical history of this system. These simulations resulted in two specific scenarios: (i) The collision between A1644S and A1644N2. Our best model has an inclination between the merger plane and the plane of the sky of $30^\circ$, and reaches the best morphology $1.6\,$Gyr after the pericentric passage. At this instant A1644N2 is gas poor, becoming nearly undetectable in X-ray emission. This model shows a good agreement with observations; (ii) The collision between A1644S and A1644N1. This approach did not give rise to results as satisfactory as the first scenario, due to great disturbances in density and mismatching temperature maps. As a complementary study, we perform a three-cluster simulation using as base the best-fitting model to reproduce the current state of A1644 with the three main structures. This scenario presented a good agreement to the global morphology of the observations. Thus, we find that the more likely scenario is a collision between A1644S and the newly discovered A1644N2, where A1644N1 may be present as long as it does not greatly interfere in the formation of the spiral feature., 13 pages, 11 figures, 2 tables. Accepted for publication in MNRAS in 2020 April 16

Background Various multimodal analgesic approaches have been proposed for spine surgery. The authors evaluated the effect of using a combination of four nonopioid analgesics versus placebo on Quality of Recovery, postoperative opioid consumption, and pain scores. Methods Adults having multilevel spine surgery who were at high risk for postoperative pain were double-blind randomized to placebos or the combination of single preoperative oral doses of acetaminophen 1,000 mg and gabapentin 600 mg, an infusion of ketamine 5 µg/kg/min throughout surgery, and an infusion of lidocaine 1.5 mg/kg/h intraoperatively and during the initial hour of recovery. Postoperative analgesia included acetaminophen, gabapentin, and opioids. The primary outcome was the Quality of Recovery 15-questionnaire (0 to 150 points, with 15% considered to be a clinically important difference) assessed on the third postoperative day. Secondary outcomes were opioid use in morphine equivalents (with 20% considered to be a clinically important change) and verbal-response pain scores (0 to 10, with a 1-point change considered important) over the initial postoperative 48 h. Results The trial was stopped early for futility per a priori guidelines. The average duration ± SD of surgery was 5.4 ± 2.1 h. The mean ± SD Quality of Recovery score was 109 ± 25 in the pathway patients (n = 150) versus 109 ± 23 in the placebo group (n = 149); estimated difference in means was 0 (95% CI, –6 to 6, P = 0.920). Pain management within the initial 48 postoperative hours was not superior in analgesic pathway group: 48-h opioid consumption median (Q1, Q3) was 72 (48, 113) mg in the analgesic pathway group and 75 (50, 152) mg in the placebo group, with the difference in medians being –9 (97.5% CI, –23 to 5, P = 0.175) mg. Mean 48-h pain scores were 4.8 ± 1.8 in the analgesic pathway group versus 5.2 ± 1.9 in the placebo group, with the difference in means being –0.4 (97.5% CI; –0.8, 0.1, P = 0.094). Conclusions An analgesic pathway based on preoperative acetaminophen and gabapentin, combined with intraoperative infusions of lidocaine and ketamine, did not improve recovery in patients who had multilevel spine surgery. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Administration of convalescent plasma may serve as an adjunct to supportive treatment to prevent COVID-19 progression and death. We aimed to evaluate the efficacy and safety of 2 volumes of intravenous convalescent plasma (CP) with high antibody titers for the treatment of severe cases of COVID-19.We conducted a Bayesian, randomized, open-label, multicenter, controlled clinical trial in 7 Brazilian hospitals. Adults admitted to hospital with positive RT-PCR for SARS-CoV2, within 10 days of the symptom onset, were eligible. Patients were randomly assigned (1:1:1) to receive standard of care (SoC) alone, or in combination with 200 mL (150-300 mL) of CP (Low-volume), or 400 mL (300-600 mL) of CP (High-volume); infusion had to be performed within 24 h of randomization. Randomization was centralized, stratified by center. The primary outcome was the time until clinical improvement up to day 28, measured by the WHO ten-point scale, assessed in the intention-to-treat population. Interim and terminal analyses were performed in a Bayesian framework. Trial registered at ClinicalTrials.gov: NCT04415086.Between June 2, 2020, and November 18, 2020, 129 patients were enrolled and randomly assigned to SoC (In this prospective, randomized trial of adult hospitalized patients with severe COVID-19, convalescent plasma was not associated with clinical benefits.Brazilian Ministry of Science, Technology and Innovation, Fundação de Amparo à Pesquisa do Estado de São Paulo.

We consider the effect of a nonvanishing fraction of initially infected nodes (seeds) on the susceptible-infected-recovered epidemic model on random networks. This is relevant when the number of arriving infected individuals is large, or to the spread of ideas with publicity campaigns. This model is frequently studied by mapping to a bond percolation problem, in which edges are occupied with the probability p of eventual infection along an edge. This gives accurate measures of the final size of the infection and epidemic threshold in the limit of a vanishingly small seed fraction. We show, however, that when the initial infection occupies a nonvanishing fraction, f, of the network, this method yields ambiguous results, as the correspondence between edge occupation and contagion transmission no longer holds. We propose instead to measure the giant component of recovered individuals within the original contact network. We derive exact equations for the size of the epidemic and the epidemic threshold in the infinite size limit in heterogeneous sparse random networks, and we confirm them with numerical results. We observe that the epidemic threshold correctly depends on f, decreasing as f increases. When the seed fraction tends to zero, we recover the standard results.

We aim to provide a comprehensive review of the current scientific evidence supporting the use of invasive neurostimulation in the treatment of deficits associated with traumatic brain injury (TBI), as well as to identify future directions for research and highlight important questions that remain unaddressed. Neurostimulation is a treatment modality with expanding applications in modern medical practice. Targeted electrical stimulation of specific brain regions has been shown to increase synaptogenesis and enhance structural reorganization of neuronal networks. This underlying therapeutic effect might be of high value for patients suffering from TBI because it could modulate neuronal connectivity and function of areas that are partially or completely spared after injury. The current published literature exploring the application of invasive neurostimulation for the treatment of functional deficits associated with TBI is scarce but promising. Rodent models have shown that targeted stimulation of the hippocampus or connecting structures can result in significant cognitive recovery, while stimulation of the motor cortex and deep cerebellar nuclei is associated with motor improvements. Data from clinical studies are extremely limited; single-patient reports and case series found neurostimulation to be effective in relieving motor symptoms, improving visuospatial memory, and supporting emotional adjustment. Looking forward, it will be important to identify stimulation targets and paradigms that can maximize improvement over multiple functional domains. It will also be important to corroborate the observed behavioral improvements with histological, electrophysiological, and radiological evidence. Finally, the impact of biological variables such as sex and age on the treatment outcomes needs to be explored.

O envelhecimento é um processo natural, marcado por mudanças biopsicossociais relacionadas à passagem do tempo. O objetivo do trabalho foi avaliar a percepção de idosos sobre macronutrientes e alimentos saudáveis na área rural do município de Solânea-PB. A metodologia empregada foi quantitativa e qualitativa e os dados foram coletados por meio de entrevista semiestruturada contendo questões a respeito do conhecimento sobre os macronutrientes e o conceito de alimento saudável. Com relação à idade, 55% tinham entre 60 e 69 anos. Quanto à escolaridade, prevaleceu o Ensino Fundamental incompleto (60%). A respeito da profissão, 100% dos idosos citaram ser agricultores. Relativo ao conceito de alimento saudável, a grande maioria dos idosos elencaram alguns alimentos produzidos por eles, como feijão, milho, verduras e frutas. Com relação ao conceito de carboidratos, 100% dos idosos entrevistados afirmaram não saber ou nunca terem escutado o termo. Já quando questionados sobre o termo açúcar, todos afirmaram saber o que é, destacando-se a resposta: “O açúcar que se coloca no café”. Para o conceito de lipídio, nenhum dos idosos entrevistados tinham conhecimento ou souberam definir esse termo, não fazendo associação com seu homônimo, gordura, onde 100% afirmaram saber o que é, associando a mesma a “gordura de boi”. Quando perguntamos a respeito do termo proteína, 70% dos idosos entrevistados não tinham nenhum conhecimento sobre ele. Para os idosos pesquisados, alimento saudável é aquele produzido no campo por si mesmos, porém, cada vez mais informações rígidas e arcaicas vêm crescendo nessa população.

This paper presents measurements at a mock-up medium voltage network to verify the feasibility of Broadband Power Line Communication (BPLC). We use the data extracted within the frequency range 2 − 30 MHz to characterize a MIMO PLC network using different phase combinations, defining the best and worst use case scenarios. The empirical data shows that not only phases directly connected for input-output can be used, but also that we can exploit the coupling between phases to transmit and receive data, therefore creating a dynamic PLC network which will depend on the characteristics of the power grid. By making use of transmission line theory, we also demonstrate how we can mitigate the reflections by measuring the input impedance of the network to allow better use of the bandwidth available for BPLC operation.

To evaluate the effect of nutritional supplementation with leftover food of dairy cows upon the reproductive response of multiracial female goats fed in open range in northern Mexico (26°N, 104°W), 38 multiparous goats in extensive grazing conditions were randomly assigned to two groups with similar weight (BW; Kg) and body condition score (BCS; scale 1-5). The control group (CG; n=19; BCS 1.7± 0.03; BW 60.42 ± 1.5 Kg, fed only in native vegetation) and supplemented group (SG; n=19; BCS; 1.7± 0.07; BW 60.21± 0.97 Kg) were fed native vegetation plus a nutritional supplementation with a ration fully mixed of leftover dairy feed, which consisted of 96.67 g of corn silage, 54.08 g of alfalfa ground hay, 49.38 of soybean paste, 37.80 g of cottonseed, 124.27 g of rolled corn and 37.80 g of commercial mixture with vitamins and minerals (totaling 400g; 14.5 PC,80% DM). The diet was offered individually daily (before grazing) from day -5 to +15 of the study. All females were subject to the male effect (Day 0; 2/group) for 10 days. By transrectal ultrasonography (Aloka SSD-500; 7.5MHz) were determined: the proportions of females having ovulations (OF: day 8) and pregnant females (PF, day 45). All data were compared using a Chi-square test (IBM SPSS 25). Differences were observed (P< 0.05) for OF (SG:15/19;78.9% vs CG: 9/19; 47.3%), but not for PF (SG:10/19; 52.6% vs CG: 6/19; 31.5%). We conclude that the proportion of ovulating females was greater n SG than in CG, nevertheless, the PF was not different, possibly because the time in which the nutritional supplementation was offered did not influence the period of embryonic implantation, it would be interesting to do an experiment extending the period of nutritional supplement with leftover food.

Functional outcome following traumatic brain injury (TBI) varies greatly, with approximately half of those who survive suffering long-term motor and cognitive deficits despite contemporary rehabilitation efforts. We have previously shown that deep brain stimulation (DBS) of the lateral cerebellar nucleus (LCN) enhances rehabilitation of motor deficits that result from brain injury. The objective of the present study was to evaluate the efficacy of LCN DBS on recovery from rodent TBI that uniquely models the injury location, chronicity and resultant cognitive symptoms observed in most human TBI patients. We used controlled cortical impact (CCI) to produce an injury that targeted the medial prefrontal cortex (mPFC-CCI) bilaterally, resulting in cognitive deficits. Unilateral LCN DBS electrode implantation was performed 6 weeks post-injury. Electrical stimulation started at week eight post-injury and continued for an additional 4 weeks. Cognition was evaluated using baited Y-maze, novel object recognition task and Barnes maze. Post-mortem analyses, including Western Blot and immunohistochemistry, were conducted to elucidate the cellular and molecular mechanisms of recovery. We found that mPFC-CCI produced significant cognitive deficits compared to pre-injury and naïve animals. Moreover, LCN DBS treatment significantly enhanced the long-term memory process and executive functions of applying strategy. Analyses of post-mortem tissues showed significantly greater expression of CaMKIIα, BDNF and p75

This work was supported by the Biotechnology and Biological Sciences Research Council (BBSRC) (Grant BB/M010996/1) via EASTBIO Doctoral Training Partnership studentships to B.J.R. and G.F., and by the Engineering and Physical Sciences Research Council (EPSRC) [grant number EP/L016419/1] via a CRITICAT Centre for Doctoral Training studentship to T.F.G.M. ATP phosphoribosyltransferase (ATPPRT) catalyzes the first step of histidine biosynthesis in bacteria, namely, the condensation of ATP and 5-phospho-α-d-ribosyl-1-pyrophosphate (PRPP) to generate N1-(5-phospho-β-d-ribosyl)-ATP (PRATP) and pyrophosphate. Catalytic (HisGS) and regulatory (HisZ) subunits assemble in a hetero-octamer where HisZ activates HisGS and mediates allosteric inhibition by histidine. In Acinetobacter baumannnii, HisGS is necessary for the bacterium to persist in the lung during pneumonia. Inhibition of ATPPRT is thus a promising strategy for specific antibiotic development. Here, A. baumannii ATPPRT is shown to follow a rapid equilibrium random kinetic mechanism, unlike any other ATPPRT. Histidine noncompetitively inhibits ATPPRT. Binding kinetics indicates histidine binds to free ATPPRT and to ATPPRT:PRPP and ATPPRT:ATP binary complexes with similar affinity following a two-step binding mechanism, but with distinct kinetic partition of the initial enzyme:inhibitor complex. The dipeptide histidine-proline inhibits ATPPRT competitively and likely uncompetitively, respectively, against PRPP and ATP. Rapid kinetics analysis shows His-Pro binds to the ATPPRT:ATP complex via a two-step binding mechanism. A related HisZ that shares 43% sequence identity with A. baumannii HisZ is a tight-binding allosteric inhibitor of A. baumannii HisGS. These findings lay the foundation for inhibitor design against A. baumannii ATPPRT. Postprint

What is the central question of this study? We investigated the effects of intrathecal administration of a novel toxin, CTK 01512-2, in a mouse model of Huntington's disease. We asked whether spinal cord neurons can represent a therapeutic target, given that the spinal cord seems to be involved in motor symptoms of Huntington's disease. Pharmacological approaches focusing on the spinal cord and skeletal muscles might represent a more feasible strategy than a high-risk brain intervention. What is the main finding and its importance? We provided evidence of a novel, local, neuroprotective effect of CTK 01512-2, paving a path for the development of approaches to treat motor symptoms of Huntington's disease beyond the brain.Phα1β is a neurotoxin from the venom of the Phoneutria nigriventer spider, available as CTK 01512-2, a recombinant peptide. Owing to its antinociceptive and analgesic properties, CTK 01512-2 has been described to alleviate neuroinflammatory responses. Despite the diverse actions of CTK 01512-2 on the nervous system, little is known regarding its neuroprotective effect, especially in neurodegenerative conditions such as Huntington's disease (HD), a genetic movement disorder without cure. Here, we investigated whether CTK 01512-2 has a neuroprotective effect in a mouse model of HD. We hypothesized that spinal cord neurons might represent a therapeutic target, because the spinal cord seems to be involved in the motor symptoms of HD (BACHD) mice. We treated BACHD mice with CTK 01512-2 by intrathecal injection and performed in vivo motor behavioural and morphological analyses in the CNS (brain and spinal cord) and muscles. Our data showed that intrathecal injection of CTK 01512-2 significantly improved motor performance in the open field task. CTK 01512-2 protected neurons in the spinal cord (but not in the brain) from death, suggesting a local effect. CTK 01512-2 exerted its neuroprotective effect by inhibiting BACHD neuronal apoptosis, as revealed by a reduction in caspase-3 in the spinal cord. CTK 01512-2 was also able to revert BACHD muscle atrophy. In conclusion, our data suggest a novel role for CTK 01512-2 acting directly in the spinal cord to ameliorate morphofunctional aspects of spinal cord neurons and muscles and improve the performance of BACHD mice in motor behavioural tests. Given that HD shares similar symptoms with many neurodegenerative conditions, the findings presented herein might also be applicable to other disorders.

ATP phosphoribosyltransferase (ATPPRT) catalyzes the first step of histidine biosynthesis in bacteria, namely, the condensation of ATP and 5-phospho-α-d-ribosyl-1-pyrophosphate (PRPP) to generate

The robust, reciprocal anatomic connections between the cerebellum and contralateral sensorimotor cerebral hemisphere underscore the strong physiological interdependence between these two regions in relation to human behavior. Previous studies have shown that damage to sensorimotor cortex can result in a lasting reduction of cerebellar metabolism, the magnitude of which has been linked to poor rehabilitative outcomes. A better understanding of movement-related cerebellar physiology as well as cortico-cerebellar coherence (CCC) in the chronic, poststroke state may be key to developing novel neuromodulatory techniques that promote upper limb motor rehabilitation. As a part of the first in-human phase I trial investigating the effects of deep brain stimulation of the cerebellar dentate nucleus (DN) on chronic poststroke motor rehabilitation, we collected invasive recordings from DN and scalp EEG in participants (both sexes) with middle cerebral artery stroke during a visuo-motor tracking task. We investigated the excitability of ipsilesional cortex, DN, and their interaction as a function of motor impairment and performance. Our results indicate the following: (1) event-related oscillations in the ipsilesional cortex and DN were significantly correlated at movement onset in the low beta band, with moderately and severely impaired participants showing desynchronization and synchronization, respectively; and (2) significant CCC was observed during the isometric hold period in the low beta band, which was critical for maintaining task accuracy. Our findings support a strong coupling between ipsilesional cortex and DN in the low beta band during motor control across all impairment levels, which encourages the exploitation of the cerebello–thalamo–cortical pathway as a neuromodulation target to promote rehabilitation. SIGNIFICANCE STATEMENT Cerebral infarct because of stroke can lead to lasting reduction in cerebellar metabolism, resulting in poor rehabilitative outcomes. Thorough investigation of the cerebellar electrophysiology, as well as cortico-cerebellar connectivity in humans that could provide key insights to facilitate the development of novel neuromodulatory technologies, has been lacking. As a part of the first in-human phase I trial investigating deep brain stimulation of the cerebellar dentate nucleus (DN) for chronic, poststroke motor rehabilitation, we collected invasive recordings from DN and scalp EEG while stroke survivors performed a motor task. Our data indicate strong coupling between ipsilesional sensorimotor cortex and DN in the low beta band across all impairment levels encouraging the exploration of electrical stimulation of the DN.

Three imines comprised of 5-nitrothiophen-2-yl as electron-accepting and phenols as electrondonating groups were synthesized and used as chromogenic chemosensors to detect alkylamines. The compounds are colorless in water, but their deprotonation by the alkylamines generates the corresponding colored phenolates, which can be used to detect those analytes. The addition of cetyltrimethylammonium bromide (CTAB) causes bathochromic shift of the perichromic band of the phenolates, indicating that the compounds are transferred into the micelles. In addition, CTAB lowers the pKa of phenols and increases the stability of the phenolates, improving their performance as chemosensors. Applications were prospected with the chromogenic chemosensors adsorbed on strip papers to detect alkylamines in water and in the vapor phase. The compounds were also used in solution for the quantification of lidocaine in water. Thus, the versatility of the compounds studied allows to think about applications in industrial, environmental, and pharmaceutical areas.

PURPOSE OF REVIEW: This paper reviews the current preclinical and clinical evidence for cerebellar deep brain stimulation for stroke rehabilitation. RECENT FINDINGS: We have demonstrated the effectiveness of cerebellar stimulation for stroke rehabilitation in rodent models, which has been reproduced by other groups. Synaptogenesis, neurogenesis, and vicariation of function in the perilesional cortex likely contribute to the mechanistic underpinnings of the effectiveness of this therapy. A Phase I clinical trial investigating dentate nucleus stimulation for improvement of hemiparesis due to stroke is currently underway, and results thus far are encouraging. SUMMARY: Activation of the rodent cerebellar dentate nucleus promotes functional motor recovery following stroke. Although results of a Phase I clinical trial are pending, substantial preclinical evidence indicates that deep brain stimulation of the dentate nucleus is a promising therapeutic modality.