Studying the effects of thalamic interneurons in a thalamocortical neural mass model

Neural mass models of the thalamocortical circuitry are often used to mimic brain activity during sleep and wakefulness as observed in scalp electroencephalogram (EEG) signals [1]. It is understood that alpha rhythms (8-13 Hz) dominate the EEG power-spectra in the resting-state [2] as well as the period immediately before sleep [3]. Literature review shows that the thalamic interneurons (IN) are often ignored in thalamocortical population models; the emphasis is on the connections between the thalamo cortical relay (TCR) and the thalamic reticular nucleus (TRN). In this work, we look into the effects of the IN cell population on the behaviour of an existing thalamocortical model containing the TCR and TRN cell populations [4]. A schematic of the extended model used in this work is shown in Fig.1. The model equations are solved in Matlab using the Runge-Kutta method of the 4th/5th order. The model shows high sensitivity to the forward and reverse rates of reactions during synaptic transmission as well as on the membrane conductance of the cell populations. The input to the model is a white noise signal simulating conditions of resting state with eyes closed, a condition well known to be associated with dominant alpha band oscillations in EEG e.g. [5]. Thus, the model parameters are calibrated to obtain a set of basal parameter values when the model oscillates with a dominant frequency within the alpha band. The time series plots and the power spectra of the model output are compared with those when the IN cell population is disconnected from the circuit (by setting the inhibitory connectivity parameter from the IN to the TCR to zero). We observe (Fig. 2 inset) a significant difference in time series output of the TRN cell population with and without the IN cell population in the model; this in spite of the IN having no direct connectivity to and from the TRN cell population (Fig. 1). A comparison of the power spectra behaviour of the model output within the delta (1-3.5Hz), theta (3.75-7.5Hz), alpha (7.75-13.5Hz) and beta (13.75-30.5Hz) bands is shown in Fig. 2. Disconnecting the IN cell population shows a significant drop in the alpha band power and the dominant frequency of oscillation now lies within the theta band. An overall ‘slowing’ (left-side shift) of the power spectra is observed with an increase within the delta and theta bands and a decrease in the alpha and beta bands. Such a slowing of EEG is a signature of slow wave sleep in healthy individuals, and this suggests that the IN cell population may be centrally involved in the phase transition to slow wave sleep [6]. It is also characteristic of the waking EEG in Alzheimer’s disease, and may help us to understand the role of the IN cell population in modulating TCR and TRN cell behaviour in pathological brain conditions

Sodium in the dermis colocates to glycosaminoglycan scaffold, with diminishment in type 2 diabetes mellitus

BACKGROUND. Dietary sodium intake mismatches urinary sodium excretion over prolonged periods. Our aims were to localize and quantify electrostatically bound sodium within human skin using triple-quantum–filtered (TQF) protocols for MRI and magnetic resonance spectroscopy (MRS) and to explore dermal sodium in type 2 diabetes mellitus (T2D). METHODS. We recruited adult participants with T2D (n = 9) and euglycemic participants with no history of diabetes mellitus (n = 8). All had undergone lower limb amputations or abdominal skin reduction surgery for clinical purposes. We used 20 μm in-plane resolution 1H MRI to visualize anatomical skin regions ex vivo from skin biopsies taken intraoperatively, 23Na TQF MRI/MRS to explore distribution and quantification of freely dissolved and bound sodium, and inductively coupled plasma mass spectrometry to quantify sodium in selected skin samples. RESULTS. Human dermis has a preponderance (>90%) of bound sodium that colocalizes with the glycosaminoglycan (GAG) scaffold. Bound and free sodium have similar anatomical locations. T2D associates with a severely reduced dermal bound sodium capacity. CONCLUSION. We provide the first evidence to our knowledge for high levels of bound sodium within human dermis, colocating to the GAG scaffold, consistent with a dermal “third space repository” for sodium. T2D associates with diminished dermal electrostatic binding capacity for sodium

Development of an acute ovine model of polycystic ovaries to assess the effect of ovarian denervation

Introduction: Polycystic ovary syndrome (PCOS) seems to be associated with increased ovarian sympathetic nerve activity and in rodent models of PCOS reducing the sympathetic drive to the ovary, through denervation or neuromodulation, improves ovulation rate. We hypothesised that sympathetic nerves work with gonadotropins to promote development and survival of small antral follicles to develop a polycystic ovary phenotype.Methods: Using a clinically realistic ovine model we showed a rich sympathetic innervation to the normal ovary and reinnervation after ovarian transplantation. Using needlepoint diathermy to the nerve plexus in the ovarian vascular pedicle we were able to denervate the ovary resulting in reduced intraovarian noradrenaline and tyrosine hydroxylase immunostained sympathetic nerves. We developed an acute polycystic ovary (PCO) model using gonadotrophin releasing hormone (GnRH) agonist followed infusion of follicle stimulating hormone (FSH) with increased pulsatile luteinising hormone (LH). This resulted in increased numbers of smaller antral follicles in the ovary when compared to FSH infusion suggesting a polycystic ovary.Results: Denervation had no effect of the survival or numbers of follicles in the acute PCO model and did not impact on ovulation, follicular and luteal hormone profiles in a normal cycle.Discussion: Although the ovary is richly inervated we did not find evidence for a role of sympathetic nerves in ovarian function or small follicle growth and surviva

Pediatric pan-central nervous system tumor analysis of immune-cell infiltration identifies correlates of antitumor immunity

Here, using methylCIBERSORT, the authors characterize the tumour-immune microenvironment of paediatric central nervous system (CNS) tumours and its association with tumour type and prognosis. These findings suggest that immuno-methylomic profiling may inform immunotherapy approaches in paediatric patients with CNS tumour

How a Diverse Research Ecosystem Has Generated New Rehabilitation Technologies: Review of NIDILRR’s Rehabilitation Engineering Research Centers

Over 50 million United States citizens (1 in 6 people in the US) have a developmental, acquired, or degenerative disability. The average US citizen can expect to live 20% of his or her life with a disability. Rehabilitation technologies play a major role in improving the quality of life for people with a disability, yet widespread and highly challenging needs remain. Within the US, a major effort aimed at the creation and evaluation of rehabilitation technology has been the Rehabilitation Engineering Research Centers (RERCs) sponsored by the National Institute on Disability, Independent Living, and Rehabilitation Research. As envisioned at their conception by a panel of the National Academy of Science in 1970, these centers were intended to take a “total approach to rehabilitation”, combining medicine, engineering, and related science, to improve the quality of life of individuals with a disability. Here, we review the scope, achievements, and ongoing projects of an unbiased sample of 19 currently active or recently terminated RERCs. Specifically, for each center, we briefly explain the needs it targets, summarize key historical advances, identify emerging innovations, and consider future directions. Our assessment from this review is that the RERC program indeed involves a multidisciplinary approach, with 36 professional fields involved, although 70% of research and development staff are in engineering fields, 23% in clinical fields, and only 7% in basic science fields; significantly, 11% of the professional staff have a disability related to their research. We observe that the RERC program has substantially diversified the scope of its work since the 1970’s, addressing more types of disabilities using more technologies, and, in particular, often now focusing on information technologies. RERC work also now often views users as integrated into an interdependent society through technologies that both people with and without disabilities co-use (such as the internet, wireless communication, and architecture). In addition, RERC research has evolved to view users as able at improving outcomes through learning, exercise, and plasticity (rather than being static), which can be optimally timed. We provide examples of rehabilitation technology innovation produced by the RERCs that illustrate this increasingly diversifying scope and evolving perspective. We conclude by discussing growth opportunities and possible future directions of the RERC program

Genetic variation exists for telomeric array organization within and among the genomes of normal, immortalized, and transformed chicken systems

This study investigated telomeric array organization of diverse chicken genotypes utilizing in vivo and in vitro cells having phenotypes with different proliferation potencies. Our experimental objective was to characterize the extent and nature of array variation present to explore the hypothesis that mega-telomeres are a universal and fixed feature of chicken genotypes. Four different genotypes were studied including normal (UCD 001, USDA-ADOL Line 0), immortalized (DF-1), and transformed (DT40) cells. Both cytogenetic and molecular approaches were utilized to develop an integrated view of telomeric array organization. It was determined that significant variation exists within and among chicken genotypes for chromosome-specific telomeric array organization and total genomic-telomeric sequence content. Although there was variation for mega-telomere number and distribution, two mega-telomere loci were in common among chicken genetic lines (GGA 9 and GGA W). The DF-1 cell line was discovered to maintain a complex derivative karyotype involving chromosome fusions in the homozygous and heterozygous condition. Also, the DF-1 cell line was found to contain the greatest amount of telomeric sequence per genome (17%) as compared to UCD 001 (5%) and DT40 (1.2%). The chicken is an excellent model for studying unique and universal features of vertebrate telomere biology, and characterization of the telomere length variation among genotypes will be useful in the exploration of mechanisms controlling telomere length maintenance in different cell types having unique phenotypes

Sustained proliferation in cancer: mechanisms and novel therapeutic targets

Proliferation is an important part of cancer development and progression. This is manifest by altered expression and/or activity of cell cycle related proteins. Constitutive activation of many signal transduction pathways also stimulates cell growth. Early steps in tumor development are associated with a fibrogenic response and the development of a hypoxic environment which favors the survival and proliferation of cancer stem cells. Part of the survival strategy of cancer stem cells may manifested by alterations in cell metabolism. Once tumors appear, growth and metastasis may be supported by overproduction of appropriate hormones (in hormonally dependent cancers), by promoting angiogenesis, by undergoing epithelial to mesenchymal transition, by triggering autophagy, and by taking cues from surrounding stromal cells. A number of natural compounds (e.g., curcumin, resveratrol, indole-3-carbinol, brassinin, sulforaphane, epigallocatechin-3-gallate, genistein, ellagitannins, lycopene and quercetin) have been found to inhibit one or more pathways that contribute to proliferation (e.g., hypoxia inducible factor 1, nuclear factor kappa B, phosphoinositide 3 kinase/Akt, insulin-like growth factor receptor 1, Wnt, cell cycle associated proteins, as well as androgen and estrogen receptor signaling). These data, in combination with bioinformatics analyses, will be very important for identifying signaling pathways and molecular targets that may provide early diagnostic markers and/or critical targets for the development of new drugs or drug combinations that block tumor formation and progression

Survival among older adults with kidney failure is better in the first three years with chronic dialysis treatment than not

Comparisons of survival between dialysis and nondialysis care for older adults with kidney failure have been limited to those managed by nephrologists, and are vulnerable to lead and immortal time biases. So we compared time to all-cause mortality among older adults with kidney failure treated vs. not treated with chronic dialysis. Our retrospective cohort study used linked administrative and laboratory data to identify adults aged 65 or more years of age in Alberta, Canada, with kidney failure (2002-2012), defined by two or more consecutive outpatient estimated glomerular filtration rates less than 10 mL/min/1.73m2, spanning 90 or more days. We used marginal structural Cox models to assess the association between receipt of dialysis and all-cause mortality by allowing control for both time-varying and baseline confounders. Overall, 838 patients met inclusion criteria (mean age 79.1; 48.6% male; mean estimated glomerular filtration rate 7.8 mL/min/1.73m2). Dialysis treatment (vs. no dialysis) was associated with a significantly lower risk of death for the first three years of follow-up (hazard ratio 0.59 [95% confidence interval 0.46-0.77]), but not thereafter (1.22 [0.69-2.17]). However, dialysis was associated with a significantly higher risk of hospitalization (1.40 [1.16-1.69]). Thus, among older adults with kidney failure, treatment with dialysis was associated with longer survival up to three years after reaching kidney failure, though with a higher risk of hospital admissions. These findings may assist shared decision-making about treatment of kidney failure

CATALISE: A multinational and multidisciplinary Delphi consensus study. Identifying language impairments in children

Delayed or impaired language development is a common developmental concern, yet thereis little agreement about the criteria used to identify and classify language impairments inchildren. Children's language difficulties are at the interface between education, medicineand the allied professions, who may all adopt different approaches to conceptualising them.Our goal in this study was to use an online Delphi technique to see whether it was possibleto achieve consensus among professionals on appropriate criteria for identifying childrenwho might benefit from specialist services. We recruited a panel of 59 experts representingten disciplines (including education, psychology, speech-language therapy/pathology, paediatricsand child psychiatry) from English-speaking countries (Australia, Canada, Ireland,New Zealand, United Kingdom and USA). The starting point for round 1 was a set of 46statements based on articles and commentaries in a special issue of a journal focusing onthis topic. Panel members rated each statement for both relevance and validity on a sevenpointscale, and added free text comments. These responses were synthesised by the firsttwo authors, who then removed, combined or modified items with a view to improving consensus.The resulting set of statements was returned to the panel for a second evaluation(round 2). Consensus (percentage reporting 'agree' or 'strongly agree') was at least 80 percentfor 24 of 27 round 2 statements, though many respondents qualified their responsewith written comments. These were again synthesised by the first two authors. The resultingconsensus statement is reported here, with additional summary of relevant evidence, and aconcluding commentary on residual disagreements and gaps in the evidence base.</p