Infraslow (<0.1 Hz) oscillations in thalamic relay nuclei basic mechanisms and significance to health and disease states

In the absence of external stimuli, the mammalian brain continues to display a rich variety of spontaneous activity. Such activity is often highly stereotypical, is invariably rhythmic, and can occur with periodicities ranging from a few milliseconds to several minutes. Recently, there has been a particular resurgence of interest in fluctuations in brain activity occurring at <0.1 Hz, commonly referred to as very slow or infraslow oscillations (ISOs). Whilst this is primarily due to the emergence of functional magnetic resonance imaging (fMRI) as a technique which has revolutionized the study of human brain dynamics, it is also a consequence of the application of full band electroencephalography (fbEEG). Despite these technical advances, the precise mechanisms which lead to ISOs in the brain remain unclear. In a host of animal studies, one brain region that consistently shows oscillations at <0.1 Hz is the thalamus. Importantly, similar oscillations can also be observed in slices of isolated thalamic relay nuclei maintained in vitro. Here, we discuss the nature and mechanisms of these oscillations, paying particular attention to a potential role for astrocytes in their genesis. We also highlight the relationship between this activity and ongoing local network oscillations in the alpha (a; ~8-13 Hz) band, drawing clear parallels with observations made in vivo. Last, we consider the relevance of these thalamic ISOs to the pathological activity that occurs in certain types of epilepsy.

Hand somatosensory subcortical and cortical sources assessed by functional source separation:an EEG study

We propose a novel electroencephalographic application of a recently developed cerebral source extraction method (Functional Source Separation, FSS), which starts from extracranial signals and adds a functional constraint to the cost function of a basic independent component analysis model without requiring solutions to be independent. Five ad-hoc functional constraints were used to extract the activity reflecting the temporal sequence of sensory information processing along the somatosensory pathway in response to the separate left and right median nerve galvanic stimulation. Constraints required only the maximization of the responsiveness at specific latencies following sensory stimulation, without taking into account that any frequency or spatial information. After source extraction, the reliability of identified FS was assessed based on the position of single dipoles fitted on its retroprojected signals and on a discrepancy measure. The FS positions were consistent with previously reported data (two early subcortical sources localized in the brain stem and thalamus, the three later sources in cortical areas), leaving negligible residual activity at the corresponding latencies. The high-frequency component of the oscillatory activity (HFO) of the extracted component was analyzed. The integrity of the low amplitude HFOs was preserved for each FS. On the basis of our data, we suggest that FSS can be an effective tool to investigate the HFO behavior of the different neuronal pools, recruited at successive times after median nerve galvanic stimulation. As FSs are reconstructed along the entire experimental session, directional and dynamic HFO synchronization phenomena can be studied.

Sustained insulin secretory response in human islets co-cultured with pancreatic duct-derived epithelial cells within a rotational cell culture system

Aims/hypothesis - Loss of the trophic support provided by surrounding non-endocrine pancreatic cell populations underlies the decline in beta cell mass and insulin secretory function observed in human islets following isolation and culture. This study sought to determine whether restoration of regulatory influences mediated by ductal epithelial cells promotes sustained beta cell function in vitro. Methods - Human islets were isolated according to existing protocols. Ductal epithelial cells were harvested from the exocrine tissue remaining after islet isolation, expanded in monolayer culture and characterised using fluorescence immunocytochemistry. The two cell types were co-cultured under conventional static culture conditions or within a rotational cell culture system. The effect of co-culture on islet structural integrity, beta cell mass and insulin secretory capacity was observed for 10 days following isolation. Results - Human islets maintained under conventional culture conditions exhibited a characteristic loss in structural integrity and functional viability as indicated by a diminution of glucose responsiveness. By contrast, co-culture of islets with ductal epithelial cells led to preserved islet morphology and sustained beta cell function, most evident in co-cultures held within the rotational cell culture system, which showed a significantly (p<0.05) greater insulin secretory response to elevated glucose compared with control islets. Similarly, insulin/protein ratio data suggested that the presence of ductal epithelial cells is beneficial for the maintenance of beta cell mass. Conclusions/interpretation - The data indicate a supportive role for ductal epithelial cells in islet viability. Further characterisation of the regulatory influences may lead to novel strategies to improve long-term beta cell function both in vitro and following islet transplantation.

Ocular biometric correlates of ciliary muscle thickness in human myopia

Purpose - Anterior segment optical coherent tomography (AS-OCT) is used to further examine previous reports that ciliary muscle thickness (CMT) is increased in myopic eyes. With reference to temporal and nasal CMT, interrelationships between biometric and morphological characteristics of anterior and posterior segments are analysed for British-White and British-South-Asian adults with and without myopia. Methods - Data are presented for the right eyes of 62 subjects (British-White n = 39, British-South-Asian n = 23, aged 18–40 years) with a range of refractive error (mean spherical error (MSE (D)) -1.74 ± 3.26; range -10.06 to +4.38) and separated into myopes (MSE (D) <-0.50, range -10.06 to -0.56; n = 30) and non-myopes (MSE (D) =-0.50, -0.50 to +4.38; n = 32). Temporal and nasal ciliary muscle cross-sections were imaged using a Visante AS-OCT. Using Visante software, manual measures of nasal and temporal CMT (NCMT and TCMT respectively) were taken in successive posterior 1 mm steps from the scleral spur over a 3 mm distance (designated NCMT1, TCMT1 et seq). Measures of axial length and anterior chamber depth were taken with an IOLMaster biometer. MSE and corneal curvature (CC) measurements were taken with a Shin-Nippon auto-refractor. Magnetic resonance imaging was used to determine total ocular volume (OV) for 31 of the original subject group. Statistical comparisons and analyses were made using mixed repeated measures anovas, Pearson's correlation coefficient and stepwise forward multiple linear regression. Results - MSE was significantly associated with CMT, with thicker CMT2 and CMT3 being found in the myopic eyes (p = 0.002). In non-myopic eyes TCMT1, TCMT2, NCMT1 and NCMT2 correlated significantly with MSE, AL and OV (p < 0.05). In contrast, myopic eyes failed generally to exhibit a significant correlation between CMT, MSE and axial length but notably retained a significant correlation between OV, TCMT2, TCMT3, NCMT2 and NCMT3 (p < 0.05). OV was found to be a significantly better predictor of TCMT2 and TCMT3 than AL by approximately a factor of two (p < 0.001). Anterior chamber depth was significantly associated with both temporal and nasal CMT2 and CMT3; TCMT1 correlated positively with CC. Ethnicity had no significant effect on differences in CMT. Conclusions - Increased CMT is associated with myopia. We speculate that the lack of correlation in myopic subjects between CMT and axial length, but not between CMT and OV, is evidence that disrupted feedback between the fovea and ciliary apparatus occurs in myopia development.

Psychophysiological responses to pain identify reproducible human clusters

Pain is a ubiquitous yet highly variable experience. The psychophysiological and genetic factors responsible for this variability remain unresolved. We hypothesised the existence of distinct human pain clusters (PCs) composed of distinct psychophysiological and genetic profiles coupled with differences in the perception and the brain processing of pain. We studied 120 healthy subjects in whom the baseline personality and anxiety traits and the serotonin transporter-linked polymorphic region (5-HTTLPR) genotype were measured. Real-time autonomic nervous system parameters and serum cortisol were measured at baseline and after standardised visceral and somatic pain stimuli. Brain processing reactions to visceral pain were studied in 29 subjects using functional magnetic resonance imaging (fMRI). The reproducibility of the psychophysiological responses to pain was assessed at 1 year. In group analysis, visceral and somatic pain caused an expected increase in sympathetic and cortisol responses and activated the pain matrix according to fMRI studies. However, using cluster analysis, we found 2 reproducible PCs: at baseline, PC1 had higher neuroticism/anxiety scores (P ≤ 0.01); greater sympathetic tone (P < 0.05); and higher cortisol levels (P ≤ 0.001). During pain, less stimulus was tolerated (P ≤ 0.01), and there was an increase in parasympathetic tone (P ≤ 0.05). The 5-HTTLPR short allele was over-represented (P ≤ 0.005). PC2 had the converse profile at baseline and during pain. Brain activity differed (P ≤ 0.001); greater activity occurred in the left frontal cortex in PC1, whereas PC2 showed greater activity in the right medial/frontal cortex and right anterior insula. In health, 2 distinct reproducible PCs exist in humans. In the future, PC characterization may help to identify subjects at risk for developing chronic pain and may reduce variability in brain imaging studies. © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Do left and right asymmetries of hemispheric preference interact with attention to predict local and global performance in applied tasks?

Many cognitive neuroscience studies show that the ability to attend to and identify global or local information is lateralised between the two hemispheres in the human brain; the left hemisphere is biased towards the local level, whereas the right hemisphere is biased towards the global level. Results of two studies show attention-focused people with a right ear preference (biased towards the left hemisphere) are better at local tasks, whereas people with a left ear preference (biased towards the right hemisphere) are better at more global tasks. In a third study we determined if right hemisphere-biased followers who attend to global stimuli are likely to have a stronger relationship between attention and globally based supervisor ratings of performance. Results provide evidence in support of this hypothesis. Our research supports our model and suggests that the interaction between attention and lateral preference is an important and novel predictor of work-related outcomes. © 2012 Copyright Psychology Press Ltd.

Does rebound tonometry probe misalignment modify intraocular pressure measurements in human eyes?

Purpose. To examine the influence of positional misalignments on intraocular pressure (IOP) measurement with a rebound tonometer. Methods. Using the iCare rebound tonometer, IOP readings were taken from the right eye of 36 healthy subjects at the central corneal apex (CC) and compared to IOP measures using the Goldmann applanation tonometer (GAT). Using a bespoke rig, iCare IOP readings were also taken 2 mm laterally from CC, both nasally and temporally, along with angular deviations of 5 and 10 degrees, both nasally and temporally to the visual axis. Results. Mean IOP ± SD, as measured by GAT, was 14.7±2.5 mmHg versus iCare tonometer readings of 17.4±3.6 mmHg at CC, representing an iCare IOP overestimation of 2.7±2.8 mmHg (P<0.001), which increased at higher average IOPs. IOP at CC using the iCare tonometer was not significantly different to values at lateral displacements. IOP was marginally underestimated with angular deviation of the probe but only reaching significance at 10 degrees nasally. Conclusions. As shown previously, the iCare tonometer overestimates IOP compared to GAT. However, IOP measurement in normal, healthy subjects using the iCare rebound tonometer appears insensitive to misalignments. An IOP underestimation of <1 mmHg with the probe deviated 10 degrees nasally reached statistical but not clinical significance levels. © 2013 Ian G. Beasley et al.

Right hemisphere contributions to imitation tasks

Humans imitate biological movements faster than non-biological movements. The faster response has been attributed to an activation of the human mirror neuron system, which is thought to match observation and execution of actions. However, it is unclear which cortical areas are responsible for this behavioural advantage. Also, little is known about the timing of activations. Using whole-head magnetoencephalography we recorded neuronal responses to single biological finger movements and non-biological dot movements while the subjects were required to perform an imitation task or an observation task, respectively. Previous imaging studies on the human mirror neurone system suggested that activation in response to biological movements would be stronger in ventral premotor, parietal and superior temporal regions. In accordance with previous studies, reaction times to biological movements were faster than those to dot movements in all subjects. The analysis of evoked magnetic fields revealed that the reaction time benefit was paralleled by stronger and earlier activation of the left temporo-occipital cortex, right superior temporal area and right ventral motor/premotor area. The activity patterns suggest that the latter areas mediate the observed behavioural advantage of biological movements and indicate a predominant contribution of the right temporo-frontal hemisphere to action observation–execution matching processes in intransitive movements, which has not been reported previously.

Development of a neurotoxicity test-system, using human post-mitotic, astrocytic and neuronal cell lines in co-culture

Astrocytes are essential for neuronal function and survival, so both cell types were included in a human neurotoxicity test-system to assess the protective effects of astrocytes on neurons, compared with a culture of neurons alone. The human NT2.D1 cell line was differentiated to form either a co-culture of post-mitotic NT2.N neuronal (TUJ1, NF68 and NSE positive) and NT2.A astrocytic (GFAP positive) cells (∼2:1 NT2.A:NT2.N), or an NT2.N mono-culture. Cultures were exposed to human toxins, for 4 h at sub-cytotoxic concentrations, in order to compare levels of compromised cell function and thus evidence of an astrocytic protective effect. Functional endpoints examined included assays for cellular energy (ATP) and glutathione (GSH) levels, generation of hydrogen peroxide (H2O2) and caspase-3 activation. Generally, the NT2.N/A co-culture was more resistant to toxicity, maintaining superior ATP and GSH levels and sustaining smaller significant increases in H2O2 levels compared with neurons alone. However, the pure neuronal culture showed a significantly lower level of caspase activation. These data suggest that besides their support for neurons through maintenance of ATP and GSH and control of H2O2 levels, following exposure to some substances, astrocytes may promote an apoptotic mode of cell death. Thus, it appears the use of astrocytes in an in vitro predictive neurotoxicity test-system may be more relevant to human CNS structure and function than neuronal cells alone. © 2007 Elsevier Ltd. All rights reserved.

A comparison of the apoptotic and cytotoxic effects of hexanedione derivatives on human non-neuronal lines and the neuroblastoma line SH-SY5Y

The effects of the alpha-diketone derivatives 2,3- and 3,4-hexanediones were investigated in three non-neuronal cell lines (MCF7, HepG2 and CaCo-2) as well as in the neuroblastoma line, SH-SY5Y. The MTT reduction assay was employed to determine the necrotic effects of the alpha-diketones and the neurotoxin 2,5-hexanedione over 4, 24 and 48 hr exposures. Flow cytometry was also used to study the effects of the three isomers on the cell cycle of the SH-SY5Y line only. With 2,5-hexanedione, the mean MTT IC50 decreased more than 10-fold from 4 to 48 hr. The toxicities of both alpha-diketones were similar, with a more than 18-fold increase in sensitivity of the SH-SY5Y at 24 hr compared to that of 4 hr. With flow cytometry at 48 hr, SH-SY5Y apoptosis with 2,5-hexanedione rose throughout the concentration range evaluated (0-30 mM) while 2,3- and 3,4-hexanediones showed apoptosis over the concentration range 1-1.6 mM, with 3,4-hexanedione being the more potent compared to the 2,3-isomer. At 1.6 mM nearly all the cells had entered apoptosis in the presence of the 3,4-isomer, (94.9 ± 1.4%) but only 57.5 ±4.1% of the 2,3-isomer-treated cells had reached that stage. The 2,3-and 3,4-isomers in diets alone may not pose a serious threat to human health. Further studies may be necessary to evaluate the effects of other dietary components on their toxicity. These alpha-diketones also display a degree of toxic selectivity towards neuroblastoma cells, which may have therapeutic implications.

Effects of lipoic acid and dihydrolipoic acid on total erythrocytic thiols under conditions of restricted glucose in vitro

The effects of lipoic acid and dihydrolipoic acid were explored on total thiol maintenance in diabetic and non-diabetic human erythrocytes in vitro over 22 hr in a 37°C incubation system with no added glucose. Over 18-22.5 hr after treatment in both non-diabetic and diabetic cells, lipoic acid (1 mM) was associated with greater loss of cellular thiols than dihydrolipoic acid (1 mM), compared to respective control values. At 0.1 mM, in non-diabetic cells, although lipoic acid-treated cells' thiol levels were significantly lower than control, there was no significant difference between dihydrolipoic acid-treated cells and control cells regarding thiol levels. In addition, at 0.1 mM, dihydrolipoic acid-treated diabetic cells showed a reduction in thiol levels compared to control. At 0.01 mM, lipoic acid-treated cells had significantly lower measured thiol levels compared with diabetic cells exposed to dihydrolipoic acid, whereas in non-diabetic cells, dihydrolipoic acid-treated erythrocytic thiol levels were significantly greater than those treated with lipoic acid, although there were no other significant differences between the groups. At 22.5 hr, control values of methaemoglobin rose to 6.4 ± 1.1% in diabetic cells and 3.6 ± 2.1% in non-diabetic cells. Lipoic acid (1 mM) showed greater methaemoglobin formation in diabetic rather than non-diabetic cells (13.6 ± 1.5% versus 11.6 ± 1.5%), whereas dihydrolipoic acid-treated diabetic and non-diabetic cells were less potent in methaemoglobin generation (8.5 ± 2.4% and 8.4 ± 1.4%, respectively). These studies suggest that in certain circumstances such as hypoglycaemia, lipoic acid administration may actually be detrimental to cellular oxidant protection status. © 2006 The Authors.

Leontief Model Analysis with Fuzzy Parameters by Basic Matrixes Method

The basic matrixes method is suggested for the Leontief model analysis (LM) with some of its components indistinctly given. LM can be construed as a forecast task of product’s expenses-output on the basis of the known statistic information at indistinctly given several elements’ meanings of technological matrix, restriction vector and variables’ limits. Elements of technological matrix, right parts of restriction vector LM can occur as functions of some arguments. In this case the task’s dynamic analog occurs. LM essential complication lies in inclusion of variables restriction and criterion function in it.

Dimensioning of Telecommunication Network Based on Quality of Services Demand and Detailed Behaviour of Users

The aim of this paper is to be determined the network capacity (number of necessary internal switching lines) based on detailed users’ behaviour and demanded quality of service parameters in an overall telecommunication system. We consider detailed conceptual and its corresponded analytical traffic model of telecommunication system with (virtual) circuit switching, in stationary state with generalized input flow, repeated calls, limited number of homogeneous terminals and losses due to abandoned and interrupted dialing, blocked and interrupted switching, not available intent terminal, blocked and abandoned ringing (absent called user) and abandoned conversation. We propose an analytical - numerical solution for finding the number of internal switching lines and values of the some basic traffic parameters as a function of telecommunication system state. These parameters are requisite for maintenance demand level of network quality of service (QoS). Dependencies, based on the numericalanalytical results are shown graphically. For proposed conceptual and its corresponding analytical model a network dimensioning task (NDT) is formulated, solvability of the NDT and the necessary conditions for analytical solution are researched as well. It is proposed a rule (algorithm) and computer program for calculation of the corresponded number of the internal switching lines, as well as corresponded values of traffic parameters, making the management of QoS easily.

Receptor for activated C Kinase 1 protein binds to and activates the human estrogen receptor α

The classical concept of estrogen receptor (ER) activation is that steroid passes the cell membrane, binds to its specific protein receptor in the cell's cytoplasm and the steroid-receptor complex travels to the nucleus where it activates responsive genes. This basic idea has been challenged by results of experiments demonstrating insulin-like growth factor 1 (IGF-1) activation of the ER in the complete absence of estrogen suggesting at least one other mechanism of ER activation not involving steroid. One explanation is that activation of the cell surface IGF-1 receptor leads to synthesis of an intracellular protein(s) able to bind to and stimulate the ER. Based on results using the two-hybrid system, coimmunoprecipitation and transfection-luciferase assays, we herein show that one of these proteins could well be receptor for activated C kinase 1 (RACK-1). Using the human ER type α (ER-α) as bait, a cloned complementary deoxyribonucleic acid (cDNA) library from IGF-1 treated human breast cancer MCF-7 cells was screened for ER-α - protein interactions. Many positive clones were obtained which contained the RACK-1 cDNA sequence. Coimmunoprecipitation of in-vitro translation products of the ER-α and RACK-1 confirmed the interaction between the two proteins. Transfection studies using the estrogen response element spliced to a luciferase reporter gene revealed that constitutive RACK-1 expression was able to powerfully stimulate ER-α activity under estrogen-free conditions. This effect could be enhanced by 17β-estradiol (E2) and blocked by tamoxifen, an E2 antagonist. These results show that RACK-1 is able to activate the ER-α in the absence of E2, although together with the latter, enhanced effects occur. Since RACK-1 gene expression is stimulated by IGF-1, it is distinctly possible that RACK-1 is the mediator of the stimulatory effects of IGF-1 on ER-α. © 2014 JMS.

The effects of the fungicides fenhexamid and myclobutanil on SH-SY5Y and U-251 MG human cell lines

Mixtures of pesticides in foodstuffs and the environment are ubiquitous in the developed world and although agents are usually exhaustively tested individually, the toxicological implications of pesticide mixtures are underreported. In this study, the effects of two fungicides, fenhexamid and myclobutanil were investigated individually and in combination on two human cell lines, SH-SY5Y neuronal cells and U-251 MG glial cells. After 48. h of incubation with increasing concentrations of pesticides ranging from 1 to 1000. μM, gene expression profiles were studied in addition to toxicity end points, including cell viability, mitochondrial depolarisation as well as cellular glutathione maintenance. There were no significant differences between the susceptibility of the two cell lines in terms of cell viability assessment or mitochondrial membrane potential, when agents were administered either individually or in combination. By contrast, in the presence of the fungicides, the SH-SY5Y cells showed significantly greater susceptibility to oxidative stress in terms of total thiol depletion in comparison with the astrocytic cells. Treatment with the two pesticides led to significant changes in the cell lines' expression of several genes which regulate cell cycle control and growth (RB1, TIMP1) as well as responses to DNA attrition (ATM and CDA25A) and control of apoptosis (FAS). There was no evidence in this study that the combination of fenhexamid and myclobutanil was significantly more toxic than individual exposure, although gene expression changes suggested there may be differences in the sub-lethal response of both cell lines to both individual and combined exposure.