Hemispheric Differences in Corticospinal Excitability and in Transcallosal Inhibition in Relation to Degree of Handedness

In this study, we examined hemispheric differences in corticospinal excitability and in transcallosal inhibition in a selected group of young adults (n = 34) grouped into three handedness categories (RH: strongly right-handed, n = 17; LH: strongly left-handed, n = 10; MH: mixed-handed, n = 7) based on laterality quotients (LQ) derived from the Edinburgh Handedness Inventory. Performance measures were also used to derive a laterality index reflecting right-left asymmetries in manual dexterity (Dext_li) and in finger tapping speed (Speed_li). Corticospinal excitability was assessed in each hemisphere by means of transcranial magnetic stimulation (TMS) using the first dorsal interosseus as the target muscle. TMS measures consisted of resting motor threshold (rMT), motor evoked potential (MEP) recruitment curve (RC) and the contralateral silent period (cSP) with the accompanying MEP facilitation. Hemispheric interactions were assessed by means of the ipsilateral silent period (iSP) to determine the onset latency and the duration of transcallosal inhibition (i.e., LTI and DTI). Analysis of hemispheric variations in measures of corticospinal excitability revealed no major asymmetries in relation to degrees of laterality or handedness, with the exception of a rightward increase in rMTs in the LH group. Similarly, no clear asymmetries were found when looking at hemispheric variations in measures of transcallosal inhibition. However, a large group effect was detected for LTI measures, which were found to be significantly shorter in the MH group than in either the LH or RH group. MH participants also tended to show longer DTI than the other participants. Further inspection of overall variations in LTI and DTI measures as a function of LQs revealed that both variables followed a non-linear relationship, which was best described by a 2^nd order polynomial function. Overall, these findings provide converging evidence for a link between mixed-handedness and more efficient interhemispheric communication when compared to either right- or left-handedness.     

Changes in the cortical silent period during force control

Purpose: The contribution of gamma-aminobutyric acidergic inhibitory neural circuits in the primary motor cortex, as estimated by the cortical silent period, during weak and strong force output has not been defined. The aim of this study was to investigate whether cortical silent period is modulated with change from weak to strong force control.

Materials and methods: Eleven healthy right-handed adults participated in this study. With the aid of visual feedback, participants were asked to control the force of abduction of the right index finger to 10%, 20%, 40%, 60%, 80%, and 100% of the maximum voluntary contraction. Single pulse transcranial magnetic stimulation was delivered to the left primary motor cortex region during force control tasks. The averaged actual force output level, background electromyography amplitude, and cortical silent period duration were compared between conditions, and correlation analysis was conducted.

Results: There were significant main effects of target force on background electromyography, and cortical silent period duration; with increased force, the actual force output level and background electromyography gradually increased, while cortical silent period duration gradually decreased. There were significant negative correlations between cortical silent period and force and cortical silent period and background electromyography.

Conclusions: These findings indicate that the excitability of gamma-aminobutyric acidergic inhibitory neural circuits in primary motor cortex decreases in response to increased force output, mediated via increased corticospinal and motoneuron excitability. These results may facilitate understanding of the role of the gamma-aminobutyric acidergic circuit in primary motor cortex in force control, as well as of the mechanism underlying motor dysfunction in stroke-induced palsy, dystonia, and cerebellar ataxia.     

Lysophosphatidic acid-stimulated phosphorylation of PKD2 is mediated by PI3K p110β and PKCδ in myoblasts

Abstract

Context: G-protein coupled receptor (GPCR) signaling in skeletal muscle is incompletely understood; in particular, the signaling pathways that regulate GPCR-mediated signaling in skeletal muscle are only beginning to be established. Lysophosphatidic acid (LPA) is a GPCR agonist that has previously been shown to activate protein kinase D (PKD) in non-muscle cells; however, whether PKD is activated in response to LPA in skeletal muscle myoblasts, and the identities of signaling intermediates that regulate this activation, have not been defined. Objective: To determine whether PKD is activated in response to LPA administration in myoblasts, and to define the signaling pathways that mediate LPA-stimulated PKD phosphorylation. Methods: C2C12 myoblasts were treated with LPA and signaling pathways examined by means of Western immunoblotting and real-time PCR (RT-PCR). Pharmacological inhibition and RNA-interference were used to target specific molecules to determine their involvement in LPA-induced PKD phosphorylation. Results: Treatment of myoblasts with exogenous LPA revealed that PI3K p110β mediated PKD phosphorylation at Ser 748 and at Ser 916 through kinase-dependent and kinase-independent mechanisms. Loss of PKCδ, but not the loss of PKCα, prevented LPA-induced PKD phosphorylation. The PKD isoform responsive to LPA treatment was identified as PKD2. Conclusion: These results indicate that LPA-stimulated PKD2 phosphorylation requires PKCδ and non-catalytic actions of PI3K p110β, and provide new information with respect to GPCR-mediated signal transduction in myoblasts.     

PRRT2 Mutations in Paroxysmal Kinesigenic Dyskinesia with Infantile Convulsions in a Taiwanese Cohort

Background

Mutations in the PRRT2 gene have recently been identified in patients with familial paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC) and patients with sporadic PKD/IC from several ethnic groups. To extend these recent genetic reports, we investigated the frequency and identities of PRRT2 mutations in a cohort of Taiwanese patients with PKD/IC.

Methodology and Principal Findings

We screened all 3 coding exons of PRRT2 for mutations in 28 Taiwanese patients with PKD/IC. Among them, 13 had familial PKD/IC and 15 were apparently sporadic cases. In total, 7 disparate mutations were identified in 13 patients, including 8 familial cases and 5 apparently sporadic cases. The mutations were not present in 500 healthy controls. Four mutations were novel. One patient had a missense mutation and all other patients carried PRRT2 mutations putatively resulting in a protein truncation. Haplotype analysis revealed that 5 of the 7 patients with the PRRT2 p.R217Pfs*8 mutation shared the same haplotype linked to the mutation.

Conclusions and Significance

PRRT2 mutations account for 61.5% (8 out of 13) of familial PKD/IC and 33.3% (5 out of 15) of apparently sporadic PKD/IC in the Taiwanese cohort. Most patients with the PRRT2 p.R217Pfs*8 mutation in Taiwan likely descend from a single common ancestor. This study expands the spectrum of PKD/IC-associated PRRT2 mutations, highlights the pathogenic role of PRRT2 mutations in PKD/IC, and suggests genetic heterogeneity within idiopathic PKD.     

The severity of chewing disorders is related to gross motor function and trunk control in children with cerebral palsy

Abstract

Purpose: The frequency of chewing disorders increases with decreasing level of gross motor function in children with cerebral palsy (CP). Besides its frequency, the severity of chewing disorders is also important. The aim of this study was to determine the relationship between chewing performance level and gross motor function, and trunk postural control in children with CP.

Materials and methods: The study included 119 children with CP (age 2–10 years). Chewing performance level was determined by the Karaduman Chewing Performance Scale (KCPS). The Gross Motor Function Classification System (GMFCS) was used to determine the level of gross motor function. Segmental Assessment of Trunk Control (SATCo) was used to measure trunk control.

Results: Children with spastic CP with a median age of 4?years were evaluated, of which 50.4% were male. The percentages of patients classified to GMFCS levels I to V were 43.7%, 6.7%, 9.2%, 5.0%, and 35.3%, respectively. The median KCPS score was 3 (min?=?0, max?=?4). A good correlation was found between KCPS and GMFCS (p?<?.001, r?=?0.70). Negative, excellent correlations between KCPS and SATCo static, SATCo active, and SATCo reactive postural controls were found (p?<?.001, r?=?–0.75, r?=?–0.77, r?=?–0.79; respectively).

Conclusions: The severity of chewing disorders is related to the level of gross motor function and trunk postural control in children with CP.

Clinical trial number: NCT03241160     

Inter-individual variation in reciprocal Ia inhibition is dependent on the descending volleys delivered from corticospinal neurons to Ia interneurons

IntroductionWe investigated the extent to which the corticospinal inputs delivered to Ia inhibitory interneurons influence the strength of disynaptic reciprocal Ia inhibition.MethodsSeventeen healthy subjects participated in this study. The degree of reciprocal Ia inhibition was determined via short-latency (condition-test interval: 1–3 ms) suppression of Sol H-reflex by conditioning stimulation of common peroneal nerve. The effect of corticospinal descending inputs on Ia inhibitory interneurons was assessed by evaluating the conditioning effect of transcranial magnetic stimulation (TMS) on the Sol H-reflex. Then, we determined the relationship between the degree of reciprocal Ia inhibition and the conditioning effect of TMS on the Sol H-reflex.ResultWe found that the degree of reciprocal Ia inhibition and the extent of change in the amplitude of the TMS-conditioned H-reflex, which was measured from short latency facilitation to inhibition, displayed a strong correlation (r = 0.76, p < 0.01) in the resting conditions.ConclusionThe extent of reciprocal Ia inhibition is affected by the corticospinal descending inputs delivered to Ia inhibitory interneurons, which might explain the inter-individual variations in reciprocal Ia inhibition.     

Effectiveness of using an unskilled model in action observation combined with motor imagery training for early motor learning in elderly people: a preliminary study

Abstract

Aim of the study: To investigate a more available model for the early phase of motor learning after action observation combined with motor imagery training in elderly people. To address the purpose, we focused on a slow, unskilled model demonstrating an occasional error.

Materials and methods: A total of 36 elderly people participated in the current study and were assigned to either the unskilled or skilled model observation groups (n?=?12, respectively), or the control group (n?=?12). The participants in the observation groups observed the assigned a video clip of an unskilled or skilled model demonstrating a ball rotation task. During the observation, the participants were instructed to imagine themselves as the person in the video clip. The participants in the control group read a scientific paper during the equivalent period of action observation and motor imagery. We measured ball rotation performance (the time required for five rotations, the number of ball drops) in pre- and post-intervention (observation combined with motor imagery training for intervention groups or reading for control group).

Results: Ball rotation performance (ball rotation speed) significantly improved in the unskilled model observation group compared to the other two groups.

Conclusions: Intervention for action observation using unskilled model combined with motor imagery was effective for improving motor performance during the early phase of motor learning.     

Novel PRRT2 mutations in paroxysmal dyskinesia patients with variant inheritance and phenotypes

Paroxysmal dyskinesias (PDs) are a group of episodic movement disorders with marked variability in clinical manifestation and potential association with epilepsy. PRRT2 has been identified as a causative gene for PDs, but the phenotypes and inheritance patterns of PRRT2 mutations need further clarification. In this study, 10 familial and 21 sporadic cases with PDs and PDs‐related phenotypes were collected. Genomic DNA was screened for PRRT2 mutations by direct sequencing. Seven PRRT2 mutations were identified in nine (90.0%) familial cases and in six (28.6%) sporadic cases. Five mutations are novel: two missense mutations (c.647C>G/p.Pro216Arg and c.872C>T/p.Ala291Val) and three truncating mutations (c.117delA/p.Val41TyrfsX49, c.510dupT/p.Leu171SerfsX3 and c.579dupA/p.Glu194ArgfsX6). Autosomal dominant inheritance with incomplete penetrance was observed in most of the familial cases. In the sporadic cases, inheritance was heterogeneous including recessive inheritance with compound heterozygous mutations, inherited mutations with incomplete parental penetrance and de novo mutation. Variant phenotypes associated with PRRT2 mutations, found in 36.0% of the affected cases, included febrile convulsions, epilepsy, infantile non‐convulsive seizures (INCS) and nocturnal convulsions (NC). All patients with INCS or NC, not reported previously, displayed abnormalities on electroencephalogram (EEG). No EEG abnormalities were recorded in patients with classical infantile convulsions and paroxysmal choreoathetosis (ICCA)/paroxysmal kinesigenic dyskinesia (PKD). Our study further confirms that PRRT2 mutations are the most common cause of familial PDs, displaying both dominant and recessive inheritance. Epilepsy may occasionally occur in ICCA/PKD patients with PRRT2 mutations. Variant phenotypes INCS or NC differ from classical ICCA/PKD clinically and electroencephalographically. They have some similarities with, but not identical to epilepsy, possibly represent an overlap between ICCA/PKD and epilepsy .     

Protein kinase D: A therapeutic target in experimental alcoholic pancreatitis

BackgroundAlcohol abuse, a main cause of pancreatitis, has been known to augment NF-κB activation and cell necrosis in pancreatitis. However, the underlying mechanisms are unclear. We recently reported that inhibition of protein kinase D (PKD) alleviated NF-κB activation and severity of experimental pancreatitis. Here we investigated whether PKD signaling mediated the modulatory effects of alcohol abuse on pathological responses in alcoholic pancreatitis.MethodsAlcoholic pancreatitis was provoked in two rodent models with pair-feeding control and ethanol-containing Lieber-DeCarli diets for up to 8 weeks followed by up to 7 hourly intraperitoneal injections of cerulein at 1 μg/kg (rats) or 3 μg/kg (mice). Effects of PKD inhibition by PKD inhibitors or genetic deletion of pancreatic PKD isoform (PKD3Δpanc mice) on alcoholic pancreatitis parameters were determined.ResultsEthanol administration amplified PKD signaling by promoting expression and activation of pancreatic PKD, resulted in augmented/promoted pancreatitis responses. Pharmacological inhibition of PKD or with PKD3Δpanc mice prevented the augmenting/sensitizing effect of ethanol on NF-κB activation and inflammatory responses, cell necrotic death and the severity of disease in alcoholic pancreatitis. PKD inhibition prevented alcohol-enhanced trypsinogen activation, mRNA expression of multiple inflammatory molecules, the receptor-interacting protein kinase activation, ATP depletion, and downregulation of pro-survival Bcl-2 protein in alcoholic pancreatitis. Furthermore, PKD inhibitor CID755673 or CRT0066101, administrated after the induction of pancreatitis in mouse and rat alcoholic pancreatitis models, significantly mitigated the severity of pancreatitis.ConclusionPKD mediates effect of alcohol abuse on pathological process of pancreatitis and constitutes a novel therapeutic target to treat this disease.     

Cerebral haemodynamics during motor imagery of self-feeding with chopsticks: differences between dominant and non-dominant hand

Abstract

Purpose: Motor imagery is defined as a dynamic state during which a subject mentally simulates a given action without overt movements. Our aim was to use near-infrared spectroscopy to investigate differences in cerebral haemodynamics during motor imagery of self-feeding with chopsticks using the dominant or non-dominant hand.

Materials and methods: Twenty healthy right-handed people participated in this study. The motor imagery task involved eating sliced cucumber pickles using chopsticks with the dominant (right) or non-dominant (left) hand. Activation of regions of interest (pre-supplementary motor area, supplementary motor area, pre-motor area, pre-frontal cortex, and sensorimotor cortex was assessed.

Results: Motor imagery vividness of the dominant hand tended to be significantly higher than that of the non-dominant hand. The time of peak oxygenated haemoglobin was significantly earlier in the right pre-frontal cortex than in the supplementary motor area and left pre-motor area. Haemodynamic correlations were detected in more regions of interest during dominant-hand motor imagery than during non-dominant-hand motor imagery.

Conclusions: Haemodynamics might be affected by differences in motor imagery vividness caused by variations in motor manipulation.     

Does interhemispheric communication relate to the bilateral function of muscles? A study of scapulothoracic muscles using transcranial magnetic stimulation

Interhemispheric connections have been demonstrated between the motor cortex controlling muscle pairs. However, these investigations have tended to concentrate upon hand muscles. We have extended these investigations to proximal muscles that control the scapula upon the trunk and help to move and stabilise the shoulder. Using a paired pulse transcranial magnetic stimulation protocol, the interhemispheric interactions between different shoulder girdle muscle pairs, serratus anterior, upper trapezius and lower trapezius were investigated. Test motor evoked potentials were conditioned using conditioning pulse intensities of 80% and 120% of active motor threshold at three different condition-test intervals, during three different tasks. Interhemispheric inhibition was observed in upper trapezius using a conditioning intensity of 120% and condition-test interval of 8 ms (17 ± 18%, p < 0.007). A trend towards inhibition was observed in lower trapezius and serratus anterior using a conditioning intensity of 120% and a condition-test interval of 8 ms (13 ± 22%; p < 0.07 and 10 ± 19% respectively; p < 0.07). No interhemispheric facilitation was evoked. The study demonstrates that a low level of interhemispheric inhibition rather than interhemispheric facilitation could be evoked between these muscle pairs.     

Changes in resting motor threshold of the tongue with normal aging and stroke

Aim of study: To examine the resting motor threshold of the tongue in healthy adults and stroke survivors.

Methods: Thirty-five healthy adults were classified into three groups: Group 1 (19–38?years; n?=?11), Group 2 (50–64?years; n?=?12) and Group 3 (66–78?years; n?=?12). Six chronic stroke survivors (mean age =59?years, SD?=?9.1?years) were recruited (Group 4). The resting motor thresholds (RMTs) of the tongue were measured and compared (i) among the four groups and (ii) between stroke survivors and age-matched healthy adults.

Results: Group 3 showed significantly higher RMTs than Group 1 (p?=?.001) and 2 (p =?0.007). Group 4 showed significantly higher RMTs than Group 1 (p =?.003) and 2 (p?=?.001). The RMTs of Group 3 and 4 were not significantly different (p =?.385). The RMT was positively correlated with age (r?=?0.534; p =?.001). Group 4 showed significantly higher RMTs than the age-matched controls (U?= 2.5, p?=?.009, r?=?0.77).

Conclusions: The resting motor threshold of the tongue is significantly increased in adults aged above 65 and in stroke survivors when compared with healthy adults. The findings suggested that the cortical excitability of the tongue deteriorates in the elderly and the stroke population.     

Recovery function of somatosensory evoked potentials in juvenile myoclonic epilepsy*

Abstract

Objective: We analysed the recovery function of somatosensory evoked potentials (SEPs) in juvenile myoclonic epilepsy (JME) patients. We hypothesized that there may be disinhibition in the recovery of SEPs at 20–100?ms intervals in JME patients.

Methods: We recorded SEPs and SEP recovery in 19 consecutive patients with JME admitted for a routine follow-up examination, and in a control group composed of 13 healthy subjects who were similar to the patient group regarding age and sex. The recovery function of SEPs was examined using paired stimuli at 30, 40, 60, and 100?ms intervals.

Results: The amplitudes of N20-P25 and P25-N33 components were higher in patients with JME. Ten patients had high-amplitude SEPs. By paired stimulation, there was inhibition of SEPs in both groups. The mean recovery percentages of N20-P25 and P25-N33 components at 30, 40, 60, and 100?ms were not different between healthy subjects and patients with JME.

Conclusions: The recovery function of SEP is normal in JME even in the presence of high-amplitude SEPs.     

Effects of low-frequency repetitive transcranial magnetic stimulation on upper extremity motor recovery and functional outcomes in chronic stroke patients: A randomized controlled trial

Background: Repetitive transcranial magnetic stimulation (rTMS) was suggested as a preconditioning method that would increase brain plasticity and that it would be optimal to combine rTMS with intensive rehabilitation.

Objective: To assess the efficacy of inhibitory rTMS on upper extremity motor recovery and functional outcomes in chronic ischemic stroke patients.

Methods: In this randomized controlled trial, experimental group received low-frequency (LF) rTMS to the primary motor cortex of the unaffected side?+?physical therapy (PT), and control group received PT.

Results: No statistically significant difference was found in baseline demographical and clinical characteristics of the subjects including stroke severity or severity of paralysis prior to intervention. There were statistically significant improvements in all clinical outcome measures except for the Brunnstrom Recovery Stages. Fugl–Meyer Assessment, Box and Block test, motor and total scores of Functional Independence Measurement (FIM), and Functional Ambulation Scale (FAS) scores were significantly increased in both groups, however, these changes were significantly greater in the rTMS group except for FAS score. FIM cognitive scores and standardized mini-mental test scores were significantly increased and distal and hand Modified Ashworth Scale scores were significantly decreased only in the rTMS group (p?Conclusions: LF-rTMS can safely facilitate upper extremity motor recovery in patients with chronic ischemic stroke. TMS seems to be a promising treatment for motor, functional, and cognitive deficits in chronic stroke. Further studies with a larger number of patients with longer follow-up periods are needed to establish its effectiveness in stroke rehabilitation.     

Effects of fatiguing unilateral plantar flexions on corticospinal and transcallosal inhibition in the primary motor hand area

Background

Corticospinal excitability of the primary motor cortex (M1) representing the hand muscle is depressed by bilateral lower limb muscle fatigue. The effects of fatiguing unilateral lower limb contraction on corticospinal excitability and transcallosal inhibition in the M1 hand areas remain unclear. The purpose of this study was to determine the effects of fatiguing unilateral plantar flexions on corticospinal excitability in the M1 hand areas and transcallosal inhibition originated from the M1 hand area contralateral to the fatigued ankle.

Methods

Ten healthy volunteers (26.2 ± 3.8 years) participated in the study. Using transcranial magnetic stimulation, we examined motor evoked potentials (MEPs) and interhemispheric inhibition (IHI) recorded from resting first dorsal interosseous (FDI) muscles before, immediately after, and 10 min after fatiguing unilateral lower limb muscle contraction, which was consisted of 40 unilateral maximal isometric plantar flexions intermittently with a 2-s contraction followed by 1 s of rest.

Results

We demonstrated no significant changes in MEPs in the FDI muscle ipsilateral to the fatigued ankle and decrease in IHI from the M1 hand area contralateral to the fatigued ankle to the ipsilateral M1 hand area after the fatiguing contraction. MEPs in the FDI muscle contralateral to the fatigued ankle were increased after the fatiguing contraction.

Conclusions

These results suggest that fatiguing unilateral lower limb muscle contraction differently influences corticospinal excitability of the contralateral M1 hand area and IHI from the contralateral M1 hand area to the ipsilateral M1 hand area. Although fatiguing unilateral lower limb muscle contraction increases corticospinal excitability of the ipsilateral M1 hand area, the increased corticospinal excitability is not associated with the decreased IHI.     

Phenotypes and <Emphasis Type="Italic">PRRT2</Emphasis> mutations in Chinese families with benign familial infantile epilepsy and infantile convulsions with paroxysmal choreoathetosis

Background

Mutations in the PRRT2 gene have been identified as the major cause of benign familial infantile epilepsy (BFIE), paroxysmal kinesigenic dyskinesia (PKD) and infantile convulsions with paroxysmal choreoathetosis/dyskinesias (ICCA). Here, we analyzed the phenotypes and PRRT2 mutations in Chinese families with BFIE and ICCA.

Methods

Clinical data were collected from 22 families with BFIE and eight families with ICCA. PRRT2 mutations were screened using PCR and direct sequencing.

Results

Ninety-five family members were clinically affected in the 22 BFIE families. During follow-up, two probands had one seizure induced by diarrhea at the age of two years. Thirty-one family members were affected in the eight ICCA families, including 11 individuals with benign infantile epilepsy, nine with PKD, and 11 with benign infantile epilepsy followed by PKD. Two individuals in one ICCA family had PKD or ICCA co-existing with migraine. One affected member in another ICCA family had experienced a fever-induced seizure at 7 years old. PRRT2 mutations were detected in 13 of the 22 BFIE families. The mutation c.649_650insC (p.R217PfsX8) was found in nine families. The mutations c.649delC (p.R217EfsX12) and c.904_905insG (p.D302GfsX39) were identified in three families and one family, respectively. PRRT2 mutations were identified in all eight ICCA families, including c.649_650insC (p.R217PfsX8), c.649delC (p.R217EfsX12), c.514_517delTCTG (p.S172RfsX3) and c.1023A?>?T (X341C). c.1023A?>?T is a novel mutation predicted to elongate the C-terminus of the protein by 28 residues.

Conclusions

Our data demonstrated that PRRT2 is the major causative gene of BFIE and ICCA in Chinese families. Site c.649 is a mutation hotspot: c.649_650insC is the most common mutation, and c.649delC is the second most common mutation in Chinese families with BFIE and ICCA. As far as we know, c.1023A?>?T is the first reported mutation in exon 4 of PRRT2. c.649delC was previously reported in PKD, ICCA and hemiplegic migraine families, but we further detected it in BFIE-only families. c.904_905insG was reported in an ICCA family, but we identified it in a BFIE family. c.514_517delTCTG was previously reported in a PKD family, but we identified it in an ICCA family. Migraine and febrile seizures plus could co-exist in ICCA families.

     

Inhibition of acetylcholinesterase by two arylderivatives: 3a-Acetoxy-5H-pyrrolo(1,2-a) (3,1)benzoxazin-1,5-(3aH)-dione and cis-N-p-Acetoxy-phenylisomaleimide

Two arylderivatives, 3a-Acetoxy-5H-pyrrolo(1,2-a) (3,1)benzoxazin-1,5-(3aH)-dione 3 and cis-N-p-Acetoxy-phenylisomaleimide 4, were synthesized from anthranilic acid and para-aminophenol, respectively. The inhibitory effects of these compounds on acetylcholinesterase (AChE) activity were evaluated in vitro as well as by docking simulations. Both compounds showed inhibition of AChE activity (K_i = 4.72 ± 2.3 μM for 3 and 3.6 ± 1.8 μM for 4) in in vitro studies. Moreover, they behaved as irreversible inhibitors and made π–π interaction with W84 and hydrogen bonded with S200 and Y337 according to experimental data and docking calculations. The docking calculations showed ΔG bind (kcal/mol) of ? 9.22 for 3 and ? 8.58 for 4. These two compounds that can be use as leads for a new family of anti-Alzheimer disease drugs.     

Variations in corticomotor excitability in response to distal focal thermal stimulation

Abstract

Purpose: This study investigated the effects of thermal stimulation on corticomotor excitability with transcranial magnetic stimulation (TMS).

Material and methods: Participants consisted of healthy young adults (n?=?20) and seniors (n?=?15). Each experimental session consisted of a baseline (BL) assessment, followed by a warming and a cooling protocol. At BL, recordings of motor evoked potentials (MEPs) and skin temperature were performed with the index finger covered with a ‘neutral’ gel pack (24?°C). For warming, the same measurements were performed, but with the index covered with a warmed gel pack (45?°C). The gel pack was kept for 5?min, and the measurements were performed at 1?min during warming and 5 and 10?min post. After a break, participants were tested with the cooling protocol (gel pack 10?°C) by repeating the same sequence as in the warming.

Results: The two thermal protocols induced the desired range of skin temperatures (warming?=?35–45°; cooling?=?13–24°). For MEP modulation, the primary analysis revealed no main effects or interactions, owing to the variability of responses to either warming or cooling stimulation. Further analysis of individual responses revealed that modulation, when present, was short-lasting and was characterized by a depression in about half of the participants. Facilitation was also observed, but only in smaller clusters, especially with cooling (13/35). Modulation in MEP amplitude did not correlate with changes in skin temperature.

Conclusion: These results are consistent with previous reports regarding variability in response to sensory stimulation protocols. In the case of thermal stimulation, such variability likely reflects individual differences in the influences exerted by thermal afferents centrally.     

Association between gestational diabetes and biomarkers: a role in diagnosis

Background: We investigated the association between markers of insulin resistance, chronic inflammation, and adipokines and GDM.

Methods: In our case-cohort study in Johannesburg we included women with GDM and controls. We tested the ability of biomarkers to identify women at high risk of GDM.

Results: Of the 262 pregnant women, 83 (31.7%) had GDM. Women with GDM were heavier (p?=?0.04) and had more clinical risk factors (p?=?0.008). We found a significant difference in fasting insulin (p?p?=?0.046), HOMA (p?p?Conclusions: Insulin sensitivity markers are promising tools to identify women at high risk of GDM.