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The study investigated the cortical activity changes and time production task performance induced by changes in motion speed of a non-immersive 3D virtual stimulus.Twenty-one individuals were participated in the crossover study with the visual-time reproduction task under three-speed conditions: original, slow and fast virtual stimulus. In addition, the electroencephalographic analysis of the theta band power in the dorsolateral prefrontal cortex was done simultaneously with time production task execution.The results demonstrated that in the slow speed condition, there is an increase in the error in the time production task after virtual reality (We propose that the modulations of speed of virtual stimulus may underlie the accumulation of temporal pulses, which could be responsible for changes in the performance of the production task of the time intervals and a substantial increase in right dorsolateral prefrontal cortex activity related to attention and memory, acting in cognitive domains of supraseconds.

This study investigated whether time-estimation task exposure influences the severity of Attention Deficit Hyperactivity Disorder (ADHD), as well as theta band activity in the dorsolateral prefrontal cortex and ventrolateral prefrontal cortex.Twenty-two patients with ADHD participated in a crossover experiment with a visual time-estimation task under control conditions (without exposure to time estimation tasks) and experimental (thirty days exposure to time-estimation tasks) in association with electroencephalographic analysis of theta band.ADHD patients with thirty days of time-estimation task exposure presented a worse performance of the time-estimation task, as revealed by the measurements of the absolute error and relative error (We propose that the decrease in EEG theta power may indicate an efficient accumulation of temporal pulses, which could be responsible for the improvement in the patient cognitive aspects as demonstrated by the current study. Time-estimation task improves ADHD cognitive symptoms, with a substantial increase in cortical areas activity related to attention and memory, suggesting its use as a tool for cognitive timing function management and non-invasive therapeutic aid in ADHD.

The voluntary movement demands integration between cognitive and motor functions. During the initial stages of motor learning until mastery of a new motor task, and during a demanding task that is not automatic, cognitive and motor functions can be perceived as independent from each other. Areas used for actually performing motor tasks are essentially the same used by Motor Imagery (MI). The main objective of this study was to investigate inhibition effects on cognitive functions of motor skills induced by low-frequency (1 Hz) Repetitive Transcranial Magnetic Stimulation (rTMS) at the sensory-motor integration site (Cz). In particular, the goal was to examine absolute alpha and beta power changes on frontal regions during Execution, Action observation, and Motor Imagery of finger movement tasks. Eleven healthy, right-handed volunteers of both sexes (5 males, 6 females; mean age 28 ± 5 years), with no history of psychiatric or neurological disorders, participated in the experiment. The execution task consisted of the subject flexing and extending the index finger. The action observation task involved watching a video of the same movement. The motor imagery task was imagining the flexion and extension of the index finger movement. After performing the tasks randomly, subjects were submitted to 15 min of low-frequency rTMS and performed the tasks again. All tasks were executed simultaneously with EEG signals recording. Our results demonstrated a significant interaction between rTMS and the three tasks in almost all analyzed regions showing that rTMS can affect the frontal region regarding Execution, Action observation, and Motor Imagery tasks.

Temporal structure of cognitive and sensory processing holds the key to understanding complex neural mechanisms involved in higher order brain functions like perception of time. A hypothesis of embodied cognition posits that cognitive processes are deeply rooted in the interactions with the external world (Wilson et al., 2002; Anderson et al., 2012). These interactions of the brain with the external world depend on the accurate representation of the time-dimension in neural circuits (Gupta, 2014). For example, one cannot catch a flying ball unless the timing of the movements matches the speed of the ball. Many real world situations depend on the mapping between the neural and physical representation of time, which is maintained at different hierarchical levels. Hierarchical processing, consistent with multiple time scales, is manifested during goal-driven tasks, such as interval timing, duration judgement, and movement coordination. Contributions to this Research Topic elucidate how key aspects of the time-dimension such as the temporal binding of neural events play important roles in various cognitive processes, which include perception, mental time travel, and speech production. Additionally, the multi-scale representation of such processes from the micro to meso scales—from single neurons to a population of neurons to field potentials and macroscopic scales of EEG - is, discussed.

Methylphenidate produces its effects via actions on cortical areas involved with attention and working memory, which have a direct role in time estimation judgment tasks. In particular, the prefrontal and parietal cortex has been the target of several studies to understand the effect of methylphenidate on executive functions and time interval perception. However, it has not yet been studied whether acute administration of methylphenidate influences performance in time estimation task and the changes in alpha band absolute power in the prefrontal and parietal cortex. The current study investigates the influence of the acute use of methylphenidate in both performance and judgment in the time estimation interpretation through the alpha band absolute power activity in the prefrontal and parietal cortex. This is a double-blind, crossover study with a sample of 32 subjects under control (placebo) and experimental (methylphenidate) conditions with absolute alpha band power analysis during a time estimation task. We observed that methylphenidate does not influence task performance (p > 0.05), but it increases the time interval underestimation by over 7 s (p

AIM OF THE STUDY Previous studies have shown that several cortical regions are involved in temporal tasks in multiple timescales. However, the hemispheric predominance of the dorsolateral prefrontal cortex (DLPFC) during time reproduction after repetitive low-frequency transcranial magnetic stimulation (rTMS) is relatively unexplored. Here, we study the effects of 1 Hz rTMS and sham stimulation applied medially over the superior parietal cortex (SPC) on the DLPFC alpha and beta band asymmetry and on time reproduction. MATERIALS AND METHODS For this purpose, we have combined rTMS with electroencephalography in 20 healthy subjects who performed the time reproduction task in two conditions (sham and 1 Hz). RESULTS The worst performance was observed in sham and 1Hz conditions for longer time intervals (p

Parkinson disease causes several changes in gait, such as postural stability, which consequently induces fall risk factors and loss of quality of life. Alternative forms of treatment through rhythmic and dance stimuli have been used to minimize the Parkinson disease effects, which have been shown to be effective in improving gait and providing social well-being and quality of life in the patient. Aim: This review aims to demonstrate the efficiency of music and dance for gait improvement and symptom alleviation in Parkinson disease. Methodology: Studies that analyzed sound stimuli and dance in gait improvement in Parkinson disease were searched through PubMed, Scopus, Doaj, MEDLINE, and ScienceDirect databases from November 2017 to April 2018 and repeated in September 2018. Results and Discussion: Forty-five studies met the inclusion criteria to synthesize the findings on dance and music performance as a treatment for classical symptoms of Parkinson disease. Five reviews and 40 experimental papers have shown that rhythmic stimulation and dance provide the motor, cognitive, and quality of life benefits for participants with Parkinson disease. Thus, sound stimuli and dance offer satisfactory effects for gait, improving cognitive abilities such as motor control and adjustment and spatial memory. In addition, these new treatment modalities stimulate the elderly population to practice physical exercise, generating well-being and helping self-esteem. Conclusion: Dance and music therapy interventions are noninvasive, simple treatment options, which promote gait and cognition.

Background Parkinson’s disease is described as resulting from dopaminergic cells progressive degeneration, specifically in the substantia nigra pars compacta that influence the voluntary movements control, decision making and time perception. Aim This review had a goal to update the relation between time perception and Parkinson’s Disease. Methodology We used the PRISMA methodology for this investigation built guided for subjects dopaminergic dysfunction in the time judgment, pharmacological models with levodopa and new studies on the time perception in Parkinson’s Disease. We researched on databases Scielo, Pubmed / Medline and ISI Web of Knowledge on August 2017 and repeated in September 2017 and February 2018 using terms and associations relevant for obtaining articles in English about the aspects neurobiology incorporated in time perception. No publication status or restriction of publication date was imposed, but we used as exclusion criteria: dissertations, book reviews, conferences or editorial work. Results/Discussion We have demonstrated that the time cognitive processes are underlying to performance in cognitive tasks and that many are the brain areas and functions involved and the modulators in the time perception performance. Conclusions The influence of dopaminergic on Parkinson’s Disease is an important research tool in Neuroscience while allowing for the search for clarifications regarding behavioral phenotypes of Parkinson’s disease patients and to study the areas of the brain that are involved in the dopaminergic circuit and their integration with the time perception mechanisms.

Bromazepam emulates the inhibitory effect of the neurotransmitter gamma-aminobutyric acid (GABA) and can lead to impaired visuomotor performance. However, few studies have evaluated its effects on cortical coupling in target shooting activities. The present study aimed to analyze the acute effects of bromazepam administration in a target shooting task and the EEG theta rhythm coherence between frontal, temporal, and motor cortical areas in four shooting preparation periods. Thus, a double blind, crossover study was conducted with 30 subjects under two conditions: bromazepam (6mg) and placebo, with electroencephalographic analysis to simultaneously study the theta rhythm coherence in frontal, temporal, and motor cortex in a target shooting task; and the possible interferences of bromazepam administration. Subjects in the bromazepam group showed lower performance on the task compared to placebo (p=0.001). In addition, our analysis showed decreased coherence between regions in the same hemisphere, increased theta rhythm coherence in interhemispheric regions in frontal, temporal and motor cortex at different intervals in the preparation preceding the shooting (p=0.001). The use of bromazepam may influence task execution, possibly due to neurochemical modulation, during decision making, developing shooting preparation strategies, as well as interfering with the flow of information at the level of attention during task execution. El bromazepam imita el efecto inhibidor del neurotransmisor ácido gamma-aminobutírico (GABA) y puede provocar un deterioro del rendimiento visuomotor. Sin embargo, pocos estudios han evaluado sus efectos sobre el acoplamiento cortical en las actividades de tiro al blanco. El presente estudio tuvo como objetivo analizar los efectos agudos de la administración de bromazepam en una tarea de tiro al blanco y la coherencia del ritmo theta del EEG entre las áreas corticales frontales, temporales y motoras en cuatro períodos de preparación de tiro. Así, se realizó un estudio cruzado y a doble ciego con 30 sujetos en dos condiciones: bromazepam (6 mg) y placebo, con análisis electroencefalográfico para estudiar simultáneamente la coherencia del ritmo theta en la corteza frontal, temporal y motora en una tarea de tiro al blanco; y las posibles interferencias de la administración de bromazepam. Los sujetos del grupo de bromazepam mostraron un menor rendimiento en la tarea en comparación con el placebo (p=0,001). Además, nuestro análisis mostró una disminución de la coherencia entre regiones del mismo hemisferio y un aumento de la coherencia del ritmo theta en regiones interhemisféricas de la corteza frontal, temporal y motora a diferentes intervalos en la preparación que precede al disparo (p=0,001). El uso de bromazepam puede influir en la ejecución de la tarea, posiblemente debido a la modulación neuroquímica, durante la toma de decisiones, el desarrollo de estrategias para preparar el tiro, así como la interferencia en el flujo de información a nivel de la atención durante la ejecución de la tarea. O bromazepam imita o efeito inibidor do neurotransmissor ácido gama-aminobutírico (GABA) e podem levar ao prejuízo do desempenho visuomotor. No entanto, poucos estudos avaliaram seus efeitos no acoplamento cortical em atividades de tiro ao alvo. O presente estudo objetivou analisar os efeitos agudo da administração de bromazepam numa tarefa de tiro ao alvo e a coerência do ritmo teta do EEG entre as áreas da cortical frontal, temporal, e motora em quatro períodos preparatórios de tiro. Desse modo, foi realizado um estudo crossover e duplo cego, com 30 sujeitos sob duas condições: bromazepam (6mg) e placebo, com análise eletroencefalográfica para estudar simultaneamente a coerência do ritmo teta no córtex frontal, temporal e motor, numa tarefa de tiro ao alvo; e as possíveis interferências da administração do bromazepam. Os sujeitos do grupo bromazepam apresentaram um desempenho inferior na tarefa em comparação com o placebo (p=0,001). Além disso, a nossa análise mostrou uma diminuição da coerência entre regiões no mesmo hemisfério, um aumento da coerência do ritmo teta nas regiões interhemisféricas no córtex frontal, temporal e motor em diferentes intervalos na preparação que antecedeu o tiroteio (p=0,001). O uso de bromazepam pode influenciar a execução da tarefa, possivelmente devido à modulação neuroquímica, durante a tomada de decisões, desenvolvendo estratégias de preparação do tiro, além de interferir com o fluxo de informação ao nível da atenção durante a execução da tarefa.

Transcranial direct current stimulation (tDCS) has been used as a non-invasive method for enhanced motor and cognitive abilities. However, no previous study has investigated if the tDCS application in unskilled shooters on cortical sites, selected based on the cortical activity of skilled shooters, improves the accuracy and shot grouping. Sixty participants were selected, which included 10 skilled shooters and 50 unskilled shooters. After we identified the right dorsolateral prefrontal cortex (DLPFC) as the area with the highest activity in skilled shooters, we applied anodal tDCS over the right DLPFC in the unskilled shooters under two conditions: sham-tDCS (placebo) and real-tDCS (anodal tDCS). We also analyzed electroencephalography. Our results indicated that anodal tDCS application enhanced the shot accuracy (p = 0.001). Furthermore, the beta power in the EEG recording was higher in the left DLPFC, left and right parietal cortex (p = 0,001) after applying anodal tDCS, while the low-gamma power was higher in the right DLPFC in sham-tDCS (p = 0.001) and right parietal cortex after anodal-tDCS (p = 0.001). Our findings indicate that anodal tDCS can improve accuracy and shot grouping when applied over the unskilled shooters' right DLPFC. Furthermore, beta and low-gamma bands are influenced by anodal tDCS over the right DLPFC, which may be predictive of skill improvement.

Background and objectives Several studies indicate that subjects with Parkinson’s disease present motor impaired, timing and many interventions used to improve their motor behavior, but so far no training protocols that use time-estimation tasks. In this preliminary study, we aimed to report the effects of the time-estimation task training on motor behaviour and the electroencephalographic activity of the dorsolateral prefrontal cortex and motor cortex. Methods We analysed motor-exploration behaviour in 5 Parkinson’s patients using the Unified Parkinson’s Disease Rating Scale, in addition to the alpha band absolute power activity of the electroencephalogram. Results Our results show the motor-exploration behaviour improvement in Parkinson patients after the training (p

The low-frequency repetitive transcranial magnetic stimulation (rTMS) application has been associated with changes in cognitive processes embedded during time perception tasks. Although several studies have investigated the influence of neuromodulation on time perception, the effect of the 1-Hz rTMS application on the superior parietal cortex is not clearly understood. This study analyzes the effect of the low-frequency rTMS on time estimation when applied in the parietal medial longitudinal fissure. For the proposed study, 20 subjects were randomly selected for a crossover study with two conditions (sham and 1 Hz). Our findings reveal that participant underestimate 1-s time interval and overestimate 4-s and 9-s time intervals after 1-Hz rTMS (p ≤ 0.05). We conclude that the 1-Hz rTMS in the parietal medial longitudinal fissure delays short interval and speed up long time intervals. This could be due to the effect of parietal inhibition on the attentional level and working memory functions during time estimation.

We review the role of oscillations in the brain and in the auditory system showing that the ability of humans to distinguish changes in pitch can be explained as a precise analysis of temporal information in auditory signals by neural oscillations. The connections between auditory brain stem chopper neurons construct neural oscillators, which discharge spikes at various constant intervals that are integer multiples of 0.4 ms, contributing to the temporal processing of auditory cochlear output. This is subsequently spatially mapped in the inferior colliculus. Electrophysiological measurements of auditory chopper neurons in different species show oscillations with periods which are integer multiples of 0.4 ms. The constant intervals of 0.4 ms can be attributed to the smallest synaptic delay between interconnected simulated chopper neurons. We also note the patterns of similarities between microcircuits in the brain stem and other parts of the brain (e.g., the pallidum, reticular formation, locus coeruleus, oculomotor nuclei, limbic system, amygdala, hippocampus, basal ganglia and substantia nigra), dedicated to the processing of temporal information. Similarities in microcircuits across the brain reflect the importance of one of the key mechanisms in the information processing in the brain, namely the temporal coupling of different neural events via coincidence detection.

The development of lung tumors after transplacental N-ethyl-N-nitrosourea (ENU) exposure has been demonstrated in Swiss and Balb/c mice F1 mice. We also suggest the molecular changes that could be affecting the susceptibility to chemical carcinogens during tumor development in the fetus. In this study, ENU administered on the 17th day of gestation resulted in the formation of lung tumors in Balb/c F1 mice, while only lymphocytic infiltration was observed in Swiss F1 mice, at the end of three months. Molecular changes were observed in both strains, but the degree of alteration in some genes was greater in Balb/c F1 mice than in Swiss F1 mice. Administration of 2% inositol hexaphosphate (IP6) to F1 mice attenuated proliferation, inflammation and upregulated the apoptotic machinery, in terms of the expression of cyclin D1, NF-κβ p50, COX-2, mut p53, Bax, Bcl-2, and Bcl-XL including caspase enzyme activities and DNA damage. These could be important pathways involved in lung tumor development in offspring of the carcinogen-predisposed mothers; IP6 attenuated lymphocytic infiltration and tumor development by modulating these events. Analysis of the molecular changes and the chemopreventive potential of IP6 during ENU-induced transplacental lung tumorigenesis suggests that the susceptibility to the induction of lung tumors in Balb/c F1 mice could possibly be due to greater over-expression in Balb/c F1 mice than Swiss F1 mice, of genes involved in proliferation and inflammation in transplacental lung tumor development.

Spatial working memory has been extensively investigated with different tasks, treatments, and analysis tools. Several studies suggest that low frequency of the repetitive transcranial magnetic stimulation (rTMS) applied to the parietal cortex may influence spatial working memory (SWM). However, it is not yet known if after low-frequency rTMS applied to the superior parietal cortex, according to Pz electroencephalography (EEG) electrode, would change the orientation interpretation about the vertical and horizontal axes coordinates in an SWM task. The current study aims at filling this gap and obtains a better understanding of the low-frequency rTMS effect in SWM. In this crossover study, we select 20 healthy subjects in two conditions (control and 1-Hz rTMS). The subjects performed an SWM task with two random coordinates. Our results presented that low-frequency rTMS applied over the superior parietal cortex may influence the SWM to lead to a larger distance of axes interception point (p

In the present study, we showed the correlation of EZH2, SUV39H1 or G9a expression and histone modifications with the urethane induced mouse lung tumorigenesis in the presence or absence of antitumor agent, inositol hexaphosphate (IP6). Tumorigenesis and the molecular events involved therein were studied at 1, 4, 12 or 36 weeks after the exposure. There were no tumors at 1 or 4 weeks but tumors started appearing at 12 weeks and grew further till 36 weeks after urethane exposure. Among the molecular events, upregulation of EZH2 and SUV39H1 expressions appeared to be time dependent, but G9a expression was altered significantly only at later stages of 12 or 36 weeks. Alteration in miR-138 expression supports the upregulation of its target, EZH2. H3K9me2, H3K27me3 or H4K20me3 was found to be altered at 12 or 36 weeks. However, ChIP analysis of p16 and MLH1 promoters showed their binding with H3K9me2 and H3K27me3 which was maximum at 36 weeks. Thus, histone modification and their interactions with gene promoter resulted in the reduced expression of p16 and MLH1. IP6 prevented the incidence and the size of urethane induced lung tumors. IP6 also prevented the urethane induced alterations in EZH2, SUV39H1, G9a expressions and histone modifications. Our results suggest that the alterations in the histone modification pathways involving EZH2 and SUV39H1 expressions are among the early events in urethane induced mouse lung tumorigenesis and could be exploited for cancer control.

A number of thiazolidin-4-one and thiazinan-4-one derivatives were prepared by three component condensation in one pot reaction method. These compounds were evaluated for anti-hyperglycemic activity by in vitro and in vivo assay systems. The compounds with thiazolidin-4-one and thiazinan-4-one moieties exhibited significant anti-hyperglycemic activity. A few compounds (3a, 3b, 4a and 4b) have exhibited both anti-hyperglycemic and anti-dyslipidemic activities. Among them the thiazinan-4-one derivative 4a showed maximal (45%) improvement in oral glucose tolerance test in db/db mice at 30 mg/kg oral dose.

Tobacco chewing is a widespread habit which leads to DNA damage. We are reporting a case of a tobacco chewer in which chromosomal aberrations, DNA breakage, buccal micronuclei and urinary thioether excretion level were studied. The study was carried out on a 28 year old male subject who is polio affected since his childhood. He has been chewing tobacco since the last 17 yrs @ 4 g, 08 times per day. The medical report of the subject indicates no abnormalities except post-polio paralysis in both lower limbs. He has no family history of any genetic disorder. He is not occupationally exposed to tobacco. The findings of the present investigation indicate increased incidence of chromosomal aberration % and micronuclei in buccal epithelial cells than the control values obtained from a subject of similar age and socioeconomic condition but not addicted to tobacco chewing. However, the urinary thioether values of the subject were lower than control values indicating a depression of the detoxification pathway.

Complications of spinal cord injury in males include losing brainstem control of pudendal nerve–innervated perineal muscles involved in erection and ejaculation. We previously described, in adult male rats, a bulbospinal pathway originating in a discrete area within the medullary gigantocellularis (GiA/Gi), and lateral paragigantocellularis (LPGi) nuclei, which when electrically microstimulated unilaterally, produces a bilateral inhibition of pudendal motoneuron reflex circuitry after crossing to the contralateral spinal cord below T8. Microstimulation following a long-term lateral hemisection, however, revealed reflex inhibition from both sides of the medulla, suggesting the development or unmasking of an injury-induced bulbospinal pathway crossing the midline cranial to the spinal lesion. In the present study, we investigated this pathway anatomically using the transsynaptic neuronal tracer pseudorabies virus (PRV) injected unilaterally into the bulbospongiosus muscle in uninjured controls, and ipsilateral to a chronic (1–2 months) unilateral lesion of the lateral funiculus. At 4.75 days post-injection, PRV-labeled cells were found bilaterally in the GiA/Gi/LPGi with equal side-to-side labeling in uninjured controls, and with significantly greater labeling contralateral to the lesion/injection in lesioned animals. The finding of PRV-labeled neurons on both sides of the medulla after removing the mid-thoracic spinal pathway on one side provides anatomical evidence for the bilaterality in both the brainstem origin and the lumbosacral pudendal circuit termination of the spared lateral funicular bulbospinal pathway. This also suggests that this bilaterality may contribute to the quick functional recovery of bladder and sexual functions observed in animals and humans with lateral hemisection injury.

Pharmacological and behavioral studies suggest that spinal delta- and kappa-opioid antinociceptive systems are functionally associated with ovarian sex steroids. These interactions can be demonstrated specifically during pregnancy or hormone-simulated pregnancy (HSP). The analgesia associated with both conditions can be abolished by blockade of either spinal kappa-opioid receptors or delta-opioid receptors (DOR). Furthermore, both dynorphin (DYN) release (J Pharmacol Exp Ther 298:1213-1220, 2001) and the processing of the DYN precursor (J Neurochem 65:1374-1380, 1995) are significantly increased in the spinal cord during HSP. We undertook the current study to determine whether DYN, DOR, and estrogen receptor alpha (ERalpha) share anatomical relationships that permit their direct interaction. Coexpression of DOR or ERalpha by DYN neurons was assessed using fluorescence immunohistochemistry and a synaptosomal release assay. Findings show that ERalpha and DYN are coexpressed. Moreover, in the spinal cord of HSP animals, there were significant increases in the number of DYN-immunoreactive (DYN-ir) cells, ERalpha-ir cells, cells double-labeled for DYN-ir and ERalpha-ir and the proportion of DYN-ir cells coexpressing ERalpha. Some varicose fibers in the spinal cord dorsal horn and intermediate gray matter that expressed DYN-ir also expressed DOR-ir. Activation of DORs located on DYN terminals was sufficient to inhibit K(+)-evoked DYN release. These data define, at least in part, the anatomical substrates that may be relevant to the antinociception of gestation and its hormonal simulation. Furthermore, they provide a framework for understanding sex-based nociception and antinociception and suggest novel strategies for treating pain.

Inactivation of dystrophin gene is the primary cause of Duchenne muscular dystrophy (DMD) in humans and mdx mice. However, the underpinning mechanisms, which govern the pathogenesis of dystrophin-deficient skeletal muscle, remain poorly understood. We have previously reported activation of mitogen-activated protein kinases (MAPK), nuclear factor-kappa B (NF-kappaB), and phosphatidyl-inositol 3-kinase/Akt (PI3K/Akt) signaling pathways in diaphragm muscle of mdx mice. In this study, using a protein-DNA array-based approach, we have investigated the activation of 345 transcription factors in diaphragm muscle of 6-week old normal and dystrophin-deficient mdx mice. Our data demonstrate increased activation of a number nuclear transcription factors including AP1, HFH-3, PPARalpha, c.myb BP, ETF, Fra-1/JUN, kBF-A, N-rasBP, lactoferrin BP, Myb(2), EBP40_45, EKLF(1), p53(2), TFEB, Myc-Max; c-Rel; E2, ISRE; NF-kB; Stat1 p84/p91, Antioxidant RE, EVI-1, Stat3, AP3, p53, Stat4, AP4, HFH-1, FAST-1, Pax-5, and Beta-RE in the diaphragm muscle of mdx mice compared to corresponding normal mice. The level of activation for p53 was highest among all the transcription factors studied. Furthermore, higher activation of p53 in diaphragm muscle of mdx mice was associated with its increased phosphorylation and nuclear translocation. Collectively, our data suggest that the primary deficiency of dystrophin leads to the aberrant activation of nuclear transcription factors which might further contribute to muscle pathogenesis in mdx mice.

Mu-opioid receptor (MOR) agonists have been shown to be more potent analgesics in male than female rodents. Regulation of spinal MOR-coupled antinociception by 17beta-estradiol (estrogen, E2) and progesterone (P) is also sexually dimorphic; pregnancy levels of E2/P activate MOR-coupled analgesic pathways in male but not female rats. We hypothesized that the sexual dimorphic characteristics of MOR-coupled antinociception reflects sexual dimorphism in the regulation of the release from spinal cord of the endogenous MOR agonist, endomorphin 2 (EM2). Parameters of spinal EM2 release manifesting sexual dimorphism include its 1) magnitude: in vitro basal and K+-evoked release of EM2 from spinal tissue of male rats is approximately 50% greater than that observed from spinal cord of females; 2) modulation by ovarian sex steroids: E2/P treatment significantly enhanced K+-evoked EM2 release from spinal tissue of males, but not females; and 3) enhancement by opioid receptor blockade: naloxone enhanced stimulated EM2 release from spinal tissue of both males and females, but it augmented basal release from spinal tissue of only males. Enhancement of EM2 release by naloxone reflects negative coupling of MOR to EM2 release and hence its modulation by negative feedback since only activation of MOR, not kappa-or delta-opioid receptors, was able to inhibit evoked EM2 release. These data reveal that the EM2-MOR spinal analgesic system is more robust and "higher gain" in male versus female rodents. These findings could provide a mechanistic rubric for understanding the male female dichotomy in prevalence and intensity of chronic pain syndromes.

Several recent studies have found changes in the expression of genes functionally related to myelination and oligodendrocyte homeostasis in schizophrenia. These studies utilized microarrays and quantitative PCR (QPCR), methodologies which do not permit direct, unamplified examination of mRNA expression. In addition, these studies generally only examined transcript expression in homogenates of gray matter. In the present study, we examined the expression of myelination-related genes previously implicated in schizophrenia by microarray or QPCR. Using in situ hybridization, we measured transcript expression of 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNP), myelin-associated glycoprotein (MAG), transferrin (TF), quaking (QKI), gelsolin, myelin oligodendrocyte glycoprotein, v-erb-b2 erythroblastic leukemia viral oncogene homolog 3, erbb2 interacting protein, motility-related protein-1, SRY-box containing gene 10, oligodendrocyte transcription factor 2, peripheral myelin protein 22, and claudin-11 in both gray and white matter of the anterior cingulate cortex (ACC) in subjects with schizophrenia (n = 41) and a comparison group (n = 34). We found decreased expression of MAG, QKI, TF, and CNP transcripts in white matter. We did not find any differences in expression of these transcripts between medicated (n = 31) and unmedicated (n = 10) schizophrenics, suggesting that these changes are not secondary to treatment with antipsychotics. Finally, we found significant positive correlations between QKI and MAG or CNP mRNA expression, suggesting that the transcription factor QKI regulates MAG and CNP expression. Our results support the hypothesis that myelination and oligodendrocyte function are impaired in schizophrenia.

The concomitant activation of spinal kappa- and delta-opioid systems is a prerequisite for the antinociception of gestation and its hormonal simulation [via 17 beta-estradiol and progesterone administration; hormone-simulated pregnancy (HSP)]. However, it is not known whether the release of kappa- and delta-opioids is also concomitantly regulated. This study investigates whether the release of methionine-enkephalin and modulation thereof is altered during HSP, as has been reported for dynorphin. K+-stimulated release of spinal methionine-enkephalin from lumbar spinal tissue obtained from control animals is negatively modulated by nociceptin (orphanin FQ; N/OFQ) in a dose-dependent manner, but not by opioids. Conversely, selective blockade of spinal N/OFQ, but not opioid receptors, augments the K+-induced increase in methionine-enkephalin release, indicating that endogenous N/OFQ also functions as a negative modulator of methionine-enkephalin release. The magnitude of K+-evoked methionine-enkephalin release from spinal tissue obtained from ovarian steroid-treated animals remains unchanged, consistent with the insensitivity of its modulation by N/OFQ to the ovarian sex steroid milieu. These characteristics of methionine-enkephalin release stand in sharp contrast to those previously reported for the evoked release of spinal dynorphin. Dynorphin release is subject to negative modulation by opioid (predominantly delta) as well as N/OFQ, both of which are offset during HSP, resulting in an approximately 2-fold increase in the magnitude of its release. These observations reveal that regulation of spinal dynorphin/kappa- and methionine-enkephalin/delta-spinal opioid antinociceptive systems is independent, divergent, and not symmetrical and support the formulation that spinal methionine-enkephalin/delta-opioid tone acts in a permissive/facilitative capacity to accentuate spinal dynorphin/kappa-activity.

The processing of time intervals in the sub- to supra-second range by the brain is critical for the interaction of primates with their surroundings in activities, such as foraging and hunting. For an accurate processing of time intervals by the brain, representation of physical time within neuronal circuits is necessary. I propose that time dimension of the physical surrounding is represented in the brain by different types of neuronal oscillators, generating spikes or spike bursts at regular intervals. The proposed oscillators include the pacemaker neurons, tonic inputs, and synchronized excitation and inhibition of inter-connected neurons. Oscillators, which are built inside various circuits of brain, help to form modular clocks, processing time intervals or other temporal characteristics specific to functions of a circuit. Relative or absolute duration is represented within neuronal oscillators by “neural temporal unit,” defined as the interval between regularly occurring spikes or spike bursts. Oscillator output is processed to produce changes in activities of neurons, named frequency modulator neuron, wired within a separate module, represented by the rate of change in frequency, and frequency of activities, proposed to encode time intervals. Inbuilt oscillators are calibrated by (a) feedback processes, (b) input of time intervals resulting from rhythmic external sensory stimulation, and (c) synchronous effects of feedback processes and evoked sensory activity. A single active clock is proposed per circuit, which is calibrated by one or more mechanisms. Multiple calibration mechanisms, inbuilt oscillators, and the presence of modular connections prevent a complete loss of interval timing functions of the brain.

Despite common comorbidity of sexual and urinary dysfunctions, the interrelationships between the neural control of these functions are poorly understood. The medullary reticular formation (MRF) contributes to both mating/arousal functions and micturition, making it a good site to test circuitry interactions. Urethane-anesthetized adult Wistar rats were used to examine the impact of electrically stimulating different nerve targets [dorsal nerve of the penis (DNP) or clitoris (DNC); L6/S1 trunk] on responses of individual extracellularly recorded MRF neurons. The effect of bladder filling on MRF neurons was also examined, as was stimulation of DNP on bladder reflexes via cystometry. In total, 236 MRF neurons responded to neurostimulation: 102 to DNP stimulation (12 males), 64 to DNC stimulation (12 females), and 70 to L6/S1 trunk stimulation (12 males). Amplitude thresholds were significantly different at DNP (15.0 ± 0.6 μA), DNC (10.5 ± 0.7 μA), and L6/S1 trunk (54.2 ± 4.6 μA), whereas similar frequency responses were found (max responses near 30–40 Hz). In five males, filling/voiding cycles were lengthened with DNP stimulation (11.0 ± 0.9 μA), with a maximal effective frequency plateau beginning at 30 Hz. Bladder effects lasted ∼2 min after DNP stimulus offset. Many MRF neurons receiving DNP/DNC input responded to bladder filling (35.0% and 68.3%, respectively), either just before (43%) or simultaneously with (57%) the voiding reflex. Taken together, MRF-evoked responses with neurostimulation of multiple nerve targets along with different responses to bladder infusion have implications for the role of MRF in multiple aspects of urogenital functions.

Administration of the ovarian steroid estradiol in male and female animals has been shown to have neuromodulatory and neuroprotective effects in a variety of experimental models. In the present study, spinal tissues from dermatomes just above (T5-7, at level) a severe chronic spinal cord injury (SCI) at T8 were analyzed for expression levels of prodynorphin (PRDN) and phospho-(serine 369) К-opioid receptor (KOR-P) in 17 β estradiol (EB)- and placebo-treated adult male rats. Dynorphin was targeted since 1) it has previously been shown to be elevated post-SCI, 2) intrathecal injection of dynorphin produces several of the same adverse effects seen with a SCI, and 3) its increased expression is known to occur in a variety of different experimental models of central neuropathic pain. A significant elevation of extracellular levels of both PRDN and KOR-P in the placebo-treated SCI group relative to uninjured surgical sham controls was found in spinal tissues above the injury level, indicating increased dynorphin levels. Importantly, the EB-treated SCI group did not show elevations of PRDN levels at 6 weeks post-injury. Immunohistochemical analysis of at level tissues revealed that EB treatment significantly prevented a post-SCI increase in expression of PRDN puncta co-labeling synapsin I, a nerve terminal marker. The dynorphin containing terminals co-labeled vesicular glutamate receptor-2 (a marker of glutamatergic terminals), a finding consistent with a non-opioid basis for the adverse effects of dynorphin. These results support a beneficial role for EB treatment post-SCI through a reduction in excessive spinal cord levels of dynorphin. Current studies manipulating the timing of the EB treatment post-injury along with specific functional assessments will address whether the beneficial effects are due to EB’s potential neuromodulatory or neuroprotective action.

Various phenolic C-glycosides were evaluated for their in vitro and in vivo antihyperglycemic activity employing glucose uptake by rat muscle cell lines (L-6) and low dosed-streptozotocin-induced diabetic rats, respectively. Some of phenolic C-glycosides were isolated from Pterocarpus marsupium and Ulmus wallichiana and other were synthesized by unprotected sugar and phloroacetophenone using Sc(OTf)(3) in aqueous ethanol. Eight among tested compounds showed significant lowering of blood glucose level on low dosed-streptozotocin-induced diabetic rats. The compound 24 lowered the blood glucose levels by 34.9% and 33.6% during 0-5h and 0-24h, respectively, at the dose of 25mg/kg body weight which is comparable to standard antidiabetic drug metformin.

The development of central neuropathic pain varies among patients with spinal cord injury (SCI). The factors contributing to the development and perpetuation of segmental pain (at-level allodynia) has been the focus of ongoing experiments in our laboratory. One such factor is hormonal status. We have shown previously, using a male rat model of SCI, that a severe contusion injury is necessary for the development of allodynia in trunk regions at and just above the level of a T8 injury. In this study, we examined at-level sensitivity for SCI ovariectomized (ovx) and cycling female rats as well as for SCI males implanted with either a placebo pellet or one that slowly releases 17beta-estradiol. The proportion of ovx SCI female rats and placebo-treated SCI males displaying pain-like behaviors to touch/pressure of at-level dermatomes up to 6 weeks post-injury (67% and 75%, respectively) was similar to our previous studies on SCI males (69%). In contrast, significantly fewer cycling SCI female rats and 17beta-estradiol treated SCI male rats showed sensitivity to touch at-level (26% and 30%, respectively). These results implicate 17beta-estradiol as a potential target that can readily be modulated to prevent segmental pain following SCI.

Approximately 70% of male rats receiving severe T8 spinal contusions develop allodynia in T5-7 dermatomes (at-level) beginning 2 weeks after injury. In contrast, rats having either complete transections or dorsal hemisections do not develop allodynia at-level after chronic spinal cord injury (SCI). In the present study, incomplete laceration and contusion injuries were made to test for neuroanatomical correlates between areas of white matter damage/sparing at the lesion epicenter and the presence/absence of allodynia. After incomplete laceration lesions and 6 weeks of behavioral testing, histological reconstruction and analysis of the lesion epicenters revealed a significant difference (P.001) in the amount of ventrolateral funiculus (VLF) asymmetry between rats showing pain-like responses evoked by touch (74.5% +/- 8.4% side-to-side difference in VLF damage) versus those not responding to touch (11.3% +/- 4.4% side-to-side difference in VLF damage). A 5-week mean allodynia score for each rat that incorporates a full range of forces that are all innocuous in intact controls revealed that the degree of hypersensitivity at level is related to the extent of VLF asymmetry after SCI. No other damaged spinal white matter or gray matter area was correlated with sensitivity to touch. Similar findings were obtained for rats receiving T8 contusions, a more clinically relevant injury. These data suggest that different extents of damage/sparing between the 2 sides of VLF probably are a requisite for the development of allodynia after SCI.A side-to-side lesion asymmetry after chronic SCI in a rodent model was found to be highly correlated with the presence and degree of allodynia. Greater insight of key factors contributing to the development and maintenance of chronic neuropathic pain is important for improving quality of life.

Destruction of skeletal muscle extracellular matrix is an important pathological consequence of many diseases involving muscle wasting. However, the underlying mechanisms leading to extracellular matrix breakdown in skeletal muscle tissues remain unknown. Using a microarray approach, we investigated the effect of tumor necrosis factor-related weak inducer of apoptosis (TWEAK), a recently identified muscle-wasting cytokine, on the expression of extracellular proteases in skeletal muscle. Among several other matrix metalloproteinases (MMPs), we found that the expression of MMP-9, a type IV collagenase, was drastically increased in myotubes in response to TWEAK. The level of MMP-9 was also higher in myofibers of TWEAK transgenic mice. TWEAK increased the activation of both classical and alternative nuclear factor-kappaB (NF-kappaB) signaling pathways. Inhibition of NF-kappaB activity blocked the TWEAK-induced production of MMP-9 in myotubes. TWEAK also increased the activation of AP-1, and its inhibition attenuated the TWEAK-induced MMP-9 production. Overexpression of a kinase-dead mutant of NF-kappaB-inducing kinase or IkappaB kinase-beta but not IkappaB kinase-alpha significantly inhibited the TWEAK-induced activation of MMP-9 promoter. The activation of MMP-9 also involved upstream recruitment of TRAF2 and cIAP2 proteins. TWEAK increased the activity of ERK1/2, JNK1, and p38 MAPK. However, the inhibition of only p38 MAPK blocked the TWEAK-induced expression of MMP-9 in myotubes. Furthermore the loss of body and skeletal muscle weights, inflammation, fiber necrosis, and degradation of basement membrane around muscle fibers were significantly attenuated in Mmp9 knock-out mice on chronic administration of TWEAK protein. The study unveils a novel mechanism of skeletal muscle tissue destruction in pathological conditions.

Glutamate cycling is critically important for neurotransmission, and may be altered in schizophrenia. The excitatory amino acid transporters (EAATs) facilitate the reuptake of glutamate from the synaptic cleft and have a key role in glutamate cycling. We hypothesized that expression of the EAATs and the EAAT regulating proteins ARHGEF11, JWA, G-protein suppressor pathway 1 (GPS1), and KIAA0302 are altered in the brain in schizophrenia. To test this, we measured expression of EAAT1, EAAT2, EAAT3, and EAAT interacting proteins in postmortem tissue from the dorsolateral prefrontal and anterior cingulate cortex of patients with schizophrenia and a comparison group using in situ hybridization and Western blot analysis. We found increased EAAT1 transcripts and decreased protein expression, increased EAAT3 transcripts and protein, and elevated protein expression of both GPS1 and KIAA0302 protein. We did not find any changes in expression of EAAT2. These data indicate that proteins involved in glutamate reuptake and cycling are altered in the cortex in schizophrenia, and may provide potential targets for future treatment strategies.

This laboratory has previously reported that the maternal opioid analgesia associated with pregnancy and parturition is mediated, at least in part, by a maternal spinal cord dynorphin/kappa opioid system. This analgesia is accompanied by an increase in dynorphin peptides (1-17 and 1-8) in the lumbar spinal cord. Levels of trypsin-generated arginine6-leucine-enkephalin (Leu-Enk-Arg)-immunoreactive determinants were also determined and used to reflect the content of dynorphin precursor intermediates. In spinal tissue, the amount of dynorphin A (1-17) contained in the form of precursor is, at a minimum, 10-fold higher than the content of mature dynorphin A (1-17) or dynorphin (1-8). During gestational day 22, the content of dynorphin precursor is reduced significantly (approximately 50%). The decline in the magnitude of dynorphin precursor intermediates in the spinal cord of pregnant rats vastly exceeds the magnitude of increase in the content of dynorphin peptides (1-17 and 1-8). This difference can best be explained by postulating a corresponding increase in the rate of release of spinal cord dynorphin (1-17). It is suggested that enhanced processing of dynorphin precursor intermediates represents the initial biochemical level of adaptation of spinal dynorphin neurons to increased demands of pregnancy.

Purpose In recent decades, the medical and surgical treatment of limbal stem cell deficiency (LSCD) has evolved significantly through the incorporation of innovative pharmacological strategies, surgical techniques, bioengineering, and cell therapy. With such a wide variety of options, there is a need to establish a global consensus on the preferred approaches for the medical and surgical treatment of LSCD. Methods An international LSCD Working Group was established by the Cornea Society in 2012 and divided into subcommittees. Four face-to-face meetings, frequent email discussions, and teleconferences were conducted since then to reach agreement on a strategic plan and methods after a comprehensive literature search. A writing group drafted the current study. Results A consensus in the medical and surgical management of LSCD was reached by the Working Group. Optimization of the ocular surface by eyelid and conjunctival reconstruction, antiinflammatory therapy, dry eye and meibomian gland dysfunction treatment, minimization of ocular surface toxicity from medications, topical medications that promote epithelialization, and use of a scleral lens is considered essential before surgical treatment of LSCD. Depending on the laterality, cause, and stage of LSCD, surgical strategies including conjunctival epitheliectomy, amniotic membrane transplantation, transplantation of limbal stem cells using different techniques and sources (allogeneic vs. autologous vs. ex vivo-cultivated), transplantation of oral mucosal epithelium, and keratoprosthesis can be performed as treatment. A stepwise flowchart for use in treatment decision-making was established. Conclusions This global consensus provides an up-to-date and comprehensive framework for the management of LSCD.

Background— The nitroxyl (HNO) donor, Angeli’s salt, exerts positive inotropic, lusitropic, and vasodilator effects in vivo that are cAMP independent. Its clinical usefulness is limited by chemical instability and cogeneration of nitrite which itself has vascular effects. Here, we report on effects of a novel, stable, pure HNO donor (CXL-1020) in isolated myoctyes and intact hearts in experimental models and in patients with heart failure (HF). Methods and Results— CXL-1020 converts solely to HNO and inactive CXL-1051 with a t 1/2 of 2 minutes. In adult mouse ventricular myocytes, it dose dependently increased sarcomere shortening by 75% to 210% (50–500 μmol/L), with a ≈30% rise in the peak Ca 2+ transient only at higher doses. Neither inhibition of protein kinase A nor soluble guanylate cyclase altered this contractile response. Unlike isoproterenol, CXL-1020 was equally effective in myocytes from normal or failing hearts. In anesthetized dogs with coronary microembolization-induced HF, CXL-1020 reduced left ventricular end-diastolic pressure and myocardial oxygen consumption while increasing ejection fraction from 27% to 40% and maximal ventricular power index by 42% (both P Conclusions— These data show the functional efficacy of a novel pure HNO donor to enhance myocardial function and present first-in-man evidence for its potential usefulness in HF. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifiers: NCT01096043, NCT01092325.