Granger causality analysis of steady-state electroencephalographic signals during propofol-induced anaesthesia

Changes in conscious level have been associated with changes in dynamical integration and segregation among distributed brain regions. Recent theoretical developments emphasize changes in directed functional (i.e., causal) connectivity as reflected in quantities such as 'integrated information' and 'causal density'. Here we develop and illustrate a rigorous methodology for assessing causal connectivity from electroencephalographic (EEG) signals using Granger causality (GC). Our method addresses the challenges of non-stationarity and bias by dividing data into short segments and applying permutation analysis. We apply the method to EEG data obtained from subjects undergoing propofol-induced anaesthesia, with signals source-localized to the anterior and posterior cingulate cortices. We found significant increases in bidirectional GC in most subjects during loss-of-consciousness, especially in the beta and gamma frequency ranges. Corroborating a previous analysis we also found increases in synchrony in these ranges; importantly, the Granger causality analysis showed higher inter-subject consistency than the synchrony analysis. Finally, we validate our method using simulated data generated from a model for which GC values can be analytically derived. In summary, our findings advance the methodology of Granger causality analysis of EEG data and carry implications for integrated information and causal density theories of consciousness.     

Accuracy of rapid tests for malaria and treatment outcomes for malaria and non-malaria cases among under-five children in rural Ghana

Background

WHO now recommends test-based management of malaria across all transmission settings. The accuracy of rapid diagnostic test (RDT) and the outcome of treatment based on the result of tests will influence acceptability of and adherence to the new guidelines.

Method

We conducted a study at the Kintampo hospital in rural Ghana to evaluate the performance of CareStart, a HRP-2 based RDT, using microscopy as reference. We applied IMCI treatment guidelines, restricted ACT to RDT-positive children and followed-up both RDT-positive (malaria) and RDT-negative (non-malaria) cases over 28 days.

Results

436 children were enrolled in the RDT evaluation and 391 (children with haemoglobin >8.0 gm/dl) were followed-up to assess treatment outcomes. Mean age was 25.4 months (s.d. 14.6). Sensitivity and specificity of the RDT were 100.0% and 73.0% respectively. Over the follow-up period, 32 (18.5%) RDT-negative children converted to positive, with 7 (4.0%) of them presenting with fever. More children in the non-malaria group made unscheduled visits than children in the malaria group (13.3% versus 7.7%) On all scheduled follow-up visits, proportion of children having a temperature higher than that recorded on day 0 was higher in the non-malaria group compared to the malaria group. Reports of unfavourable treatment outcomes by caregivers were higher among the non-malaria group than the malaria group.

Conclusions

The RDT had good sensitivity and specificity. However a minority of children who will not receive ACT based on RDT results may develop clinical malaria within a short period in high transmission settings. This could undermine caregivers'' and health workers'' confidence in the new guidelines. Improving the quality of management of non-malarial febrile illnesses should be a priority in the era of test-based management of malaria.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00832754","term_id":"NCT00832754"}}NCT00832754     

Comparative Study of Human and Mouse Postsynaptic Proteomes Finds High Compositional Conservation and Abundance Differences for Key Synaptic Proteins

Direct comparison of protein components from human and mouse excitatory synapses is important for determining the suitability of mice as models of human brain disease and to understand the evolution of the mammalian brain. The postsynaptic density is a highly complex set of proteins organized into molecular networks that play a central role in behavior and disease. We report the first direct comparison of the proteome of triplicate isolates of mouse and human cortical postsynaptic densities. The mouse postsynaptic density comprised 1556 proteins and the human one 1461. A large compositional overlap was observed; more than 70% of human postsynaptic density proteins were also observed in the mouse postsynaptic density. Quantitative analysis of postsynaptic density components in both species indicates a broadly similar profile of abundance but also shows that there is higher abundance variation between species than within species. Well known components of this synaptic structure are generally more abundant in the mouse postsynaptic density. Significant inter-species abundance differences exist in some families of key postsynaptic density proteins including glutamatergic neurotransmitter receptors and adaptor proteins. Furthermore, we have identified a closely interacting set of molecules enriched in the human postsynaptic density that could be involved in dendrite and spine structural plasticity. Understanding synapse proteome diversity within and between species will be important to further our understanding of brain complexity and disease.     

2-Color calcium pump reveals closure of the cytoplasmic headpiece with calcium binding

The sarco(endo)plasmic reticulum calcium ATPase (SERCA) undergoes conformational changes while transporting calcium, but the details of the domain motions are still unclear. The objective of the present study was to measure distances between the cytoplasmic domains of SERCA2a in order to reveal the magnitude and direction of conformational changes. Using fluorescence microscopy of live cells, we measured intramolecular fluorescence resonance energy transfer (FRET) from a donor fluorescent protein fused to the SERCA N-terminus to an acceptor fluorescent protein fused to either the N-, P-, or transmembrane domain. The "2-color" SERCA constructs were catalytically active as indicated by ATPase activity in vitro and Ca uptake in live cells. All constructs exhibited dynamic FRET changes in response to the pump ligands calcium and thapsigargin (Tg). These FRET changes were quantified as an index of SERCA conformational changes. Intramolecular FRET decreased with Tg for the two N-domain fusion sites (at residue 509 or 576), while the P- (residue 661) and TM-domain (C-terminus) fusions showed increased FRET with Tg. The magnitude of the Tg-dependent conformational change was not decreased by coexpression of phospholamban (PLB), nor did PLB slow the kinetics of Tg binding. FRET in ionophore-permeabilized cells was lower in EGTA than in saturating calcium for all constructs, indicating a decrease in domain separation distance with the structural transition from E2 (Ca-free) to E1 (Ca-bound). The data suggest closure of the cytoplasmic headpiece with Ca-binding. The present results provide insight into the structural dynamics of the Ca-ATPase. In addition, the 2-color SERCA constructs developed for this study may be useful for evaluating candidate small molecule regulators of Ca uptake activity.     

Effects of habitat fragmentation and black-tailed prairie dogs on urban avian diversity

Urbanization and habitat fragmentation have the potential to influence bird communities. In addition, these phenomena, as well as ongoing lethal control measures, have also greatly reduced the range of the black-tailed prairie dog (Cynomys ludovicianus) since the beginning of the 20th century. Although prairie dogs are highly interactive species that can influence avian communities, few studies have investigated whether these interactions persist in urban settings. Our goal was to investigate the relative impacts of habitat fragmentation and prairie dogs on bird communities within an urban matrix. We performed bird surveys on 20 habitat fragments (10 colonized by prairie dogs, 10 uncolonized by prairie dogs) distributed throughout the Denver metropolitan area, and calculated Shannon–Weiner diversity and richness of all birds and native species, as well as total counts of grassland birds and raptors. Diversity, richness, and counts of many species increased with increasing fragment connectivity, and decreased on fragments isolated for longer periods of time. Avian diversity and richness did not differ between fragments with and without prairie dogs, suggesting that this element of the ecological role of prairie dogs is not fully retained in urban habitat. Future studies of the role of prairie dogs as keystone species in urban systems should include other taxa as well as consider the influence of the urban matrix surrounding prairie dog habitat. Our results emphasize that conservation of urban avian diversity should focus on landscape connectivity as well as local habitat features.     

Cell Polarity: Overdosing on PCPs

Several spatial cues combine to influence cell polarity within the plane of?the?Drosophila wing epithelium, orienting two separable mechanisms of?short-range intercellular communication, one utilizing the 'core' polarity proteins, and another utilizing the protocadherins Dachsous and Fat, and the atypical myosin Dachs.     

Factors affecting hatch success of hawksbill sea turtles on Long Island, Antigua, West Indies

Current understanding of the factors influencing hawksbill sea turtle (Eretmochelys imbricata) hatch success is disparate and based on relatively short-term studies or limited sample sizes. Because global populations of hawksbills are heavily depleted, evaluating the parameters that impact hatch success is important to their conservation and recovery. Here, we use data collected by the Jumby Bay Hawksbill Project (JBHP) to investigate hatch success. The JBHP implements saturation tagging protocols to study a hawksbill rookery in Antigua, West Indies. Habitat data, which reflect the varied nesting beaches, are collected at egg deposition, and nest contents are exhumed and categorized post-emergence. We analyzed hatch success using mixed-model analyses with explanatory and predictive datasets. We incorporated a random effect for turtle identity and evaluated environmental, temporal and individual-based reproductive variables. Hatch success averaged 78.6% (SD: 21.2%) during the study period. Highly supported models included multiple covariates, including distance to vegetation, deposition date, individual intra-seasonal nest number, clutch size, organic content, and sand grain size. Nests located in open sand were predicted to produce 10.4 more viable hatchlings per clutch than nests located >1.5 m into vegetation. For an individual first nesting in early July, the fourth nest of the season yielded 13.2 more viable hatchlings than the initial clutch. Generalized beach section and inter-annual variation were also supported in our explanatory dataset, suggesting that gaps remain in our understanding of hatch success. Our findings illustrate that evaluating hatch success is a complex process, involving multiple environmental and individual variables. Although distance to vegetation and hatch success were inversely related, vegetation is an important component of hawksbill nesting habitat, and a more complete assessment of the impacts of specific vegetation types on hatch success and hatchling sex ratios is needed. Future research should explore the roles of sand structure, nest moisture, and local weather conditions.     

Oscillation in cycle length induces transient discordant and steady-state concordant alternans in the heart

Alternans is a beat-to-beat alternation of the cardiac action potential duration (APD) or intracellular calcium (Ca(i)) transient. In cardiac tissue, alternans can be spatially concordant or discordant, of which the latter has been shown to increase dispersion of repolarization and promote a substrate for initiation of ventricular fibrillation. Alternans has been studied almost exclusively under constant cycle length pacing conditions. However, heart rate varies greatly on a beat-by-beat basis in normal and pathological conditions. The purpose of this study was to determine if applying a repetitive but non-constant pacing pattern, specifically cycle length oscillation (CLO), promotes or suppresses a proarrhythmic substrate. We performed computational simulations and optical mapping experiments to investigate the potential consequences of CLO. In a single cell computational model, CLO induced APD and Ca(i) alternans, which became "phase-matched" with the applied oscillation. As a consequence of the phase-matching, in one-dimensional cable simulations, neonatal rat ventricular myocyte monolayers, and isolated adult guinea pig hearts CLO could transiently induce spatial and electromechanical discordant alternans followed by a steady-state of concordance. Our results demonstrated that under certain conditions, CLO can initiate ventricular fibrillation in the isolated hearts. On the other hand, CLO can also exert an antiarrhythmic effect by converting an existing state of discordant alternans to concordant alternans.     

Haematological and biochemical reference values for healthy adults in the middle belt of Ghana

Background

Reference values are very important in clinical management of patients, screening participants for enrolment into clinical trials and for monitoring the onset of adverse events during these trials. The aim of this was to establish gender-specific haematological and biochemical reference values for healthy adults in the central part of Ghana.

Methods

A total of 691 adults between 18 and 59 years resident in the Kintampo North Municipality and South District in the central part of Ghana were randomly selected using the Kintampo Health and Demographic Surveillance System and enrolled in this cross-sectional survey. Out of these, 625 adults made up of 316 males and 309 females were assessed by a clinician to be healthy. Median values and nonparametric 95% reference values for 16 haematology and 22 biochemistry parameters were determined for this population based on the Clinical Laboratory and Standards Institute guidelines. Values established in this study were compared with the Caucasian values being used currently by our laboratory as reference values and also with data from other African and western countries.

Results

Reference values established include: haemoglobin 113–164 g/L for males and 88–144 g/L for females; total white blood cell count 3.4–9.2×10⁹/L; platelet count 88–352×10⁹/L for males and 89–403×10⁹/L for females; alanine aminotransferase 8–54 U/L for males and 6–51 U/L for females; creatinine 56–119 µmol/L for males and 53–106 µmol/L for females. Using the haematological reference values based on the package inserts would have screened out up to 53% of potential trial participants and up to 25% of the population using the biochemical parameters.

Conclusion

We have established a panel of locally relevant reference parameters for commonly used haematological and biochemical tests. This is important as it will help in the interpretation of laboratory results both for clinical management of patients and safety monitoring during a trial.     

The Spectrum of Podoplanin Expression in Encapsulating Peritoneal Sclerosis

Encapsulating peritoneal sclerosis (EPS) is a life threatening complication of peritoneal dialysis (PD). Podoplanin is a glycoprotein expressed by mesothelial cells, lymphatic endothelial cells, and myofibroblasts in peritoneal biopsies from patients with EPS. To evaluate podoplanin as a marker of EPS we measured podoplanin mRNA and described the morphological patterns of podoplanin-positive cells in EPS. Included were 20 peritoneal biopsies from patients with the diagnosis of EPS (n = 5), patients on PD without signs of EPS (n = 5), and control patients (uremic patients not on PD, n = 5, non-uremic patients n = 5). EPS patient biopsies revealed significantly elevated levels of podoplanin mRNA (p<0.05). In 24 peritoneal biopsies from patients with EPS, podoplanin and smooth muscle actin (SMA) were localized by immunohistochemistry. Four patterns of podoplanin distribution were distinguishable. The most common pattern (8 of 24) consisted of organized, longitudinal layers of podoplanin-positive cells and vessels in the fibrotic zone (“organized” pattern). 7 of 24 biopsies demonstrated a diffuse distribution of podoplanin-positive cells, accompanied by occasional, dense clusters of podoplanin-positive cells. Five biopsies exhibited a mixed pattern, with some diffuse areas and some organized areas ("mixed"). These contained cuboidal podoplanin-positive cells within SMA-negative epithelial structures embedded in extracellular matrix. Less frequently observed was the complete absence of, or only focal accumulations of podoplanin-positive fibroblasts outside of lymphatic vessels (podoplanin “low”, 4 of 24 biopsies). Patients in this group exhibited a lower index of systemic inflammation and a longer symptomatic period than in EPS patients with biopsies of the "mixed" type (p<0.05). In summary we confirm the increased expression of podoplanin in EPS, and distinguish EPS biopsies according to different podoplanin expression patterns which are associated with clinical parameters. Podoplanin might serve as a useful adjunct to the morphological workup of peritoneal biopsies.