Diazepam induced sleep spindle increase correlates with cognitive recovery in a child with epileptic encephalopathy.

BACKGROUND: Continuous spike and wave of sleep with encephalopathy (CSWS) is a rare and severe developmental electroclinical epileptic encephalopathy characterized by seizures, abundant sleep activated interictal epileptiform discharges, and cognitive regression or deceleration of expected cognitive growth. The cause of the cognitive symptoms is unknown, and efforts to link epileptiform activity to cognitive function have been unrevealing. Converging lines of evidence implicate thalamocortical circuits in these disorders. Sleep spindles are generated and propagated by the same thalamocortical circuits that can generate spikes and, in healthy sleep, support memory consolidation. As such, sleep spindle deficits may provide a physiologically relevant mechanistic biomarker for cognitive dysfunction in epileptic encephalopathies. CASE PRESENTATION: We describe the longitudinal course of a child with CSWS with initial cognitive regression followed by dramatic cognitive improvement after treatment. Using validated automated detection algorithms, we analyzed electroencephalograms for epileptiform discharges and sleep spindles alongside contemporaneous neuropsychological evaluations over the course of the patient's disease. We found that sleep spindles increased dramatically with high-dose diazepam treatment, corresponding with marked improvements in cognitive performance. We also found that the sleep spindle rate was anticorrelated to spike rate, consistent with a competitively shared underlying thalamocortical circuitry. CONCLUSIONS: Epileptic encephalopathies are challenging electroclinical syndromes characterized by combined seizures and a deceleration or regression in cognitive skills over childhood. This report identifies thalamocortical circuit dysfunction in a case of epileptic encephalopathy and motivates future investigations of sleep spindles as a biomarker of cognitive function and a potential therapeutic target in this challenging disease.

EEG functional connectivity is partially predicted by underlying white matter connectivity.

Over the past decade, networks have become a leading model to illustrate both the anatomical relationships (structural networks) and the coupling of dynamic physiology (functional networks) linking separate brain regions. The relationship between these two levels of description remains incompletely understood and an area of intense research interest. In particular, it is unclear how cortical currents relate to underlying brain structural architecture. In addition, although theory suggests that brain communication is highly frequency dependent, how structural connections influence overlying functional connectivity in different frequency bands has not been previously explored. Here we relate functional networks inferred from statistical associations between source imaging of EEG activity and underlying cortico-cortical structural brain connectivity determined by probabilistic white matter tractography. We evaluate spontaneous fluctuating cortical brain activity over a long time scale (minutes) and relate inferred functional networks to underlying structural connectivity for broadband signals, as well as in seven distinct frequency bands. We find that cortical networks derived from source EEG estimates partially reflect both direct and indirect underlying white matter connectivity in all frequency bands evaluated. In addition, we find that when structural support is absent, functional connectivity is significantly reduced for high frequency bands compared to low frequency bands. The association between cortical currents and underlying white matter connectivity highlights the obligatory interdependence of functional and structural networks in the human brain. The increased dependence on structural support for the coupling of higher frequency brain rhythms provides new evidence for how underlying anatomy directly shapes emergent brain dynamics at fast time scales.

Spike height improves prediction of future seizure risk.

OBJECTIVE: We evaluated whether interictal epileptiform discharge (IED) rate and morphological characteristics predict seizure risk. METHODS: We evaluated 10 features from automatically detectable IEDs in a stereotyped population with self-limited epilepsy with centrotemporal spikes (SeLECTS). We tested whether the average value or the most extreme values from each feature predicted future seizure risk in cross-sectional and longitudinal models. RESULTS: 10,748 individual centrotemporal IEDs were analyzed from 59 subjects at 81 timepoints. In cross-sectional models, increases in average spike height, spike duration, slow wave rising slope, slow wave falling slope, and the most extreme values of slow wave rising slope each improved prediction of an increased risk of a future seizure compared to a model with age alone (p < 0.05, each). In longitudinal model, spike rising height improved prediction of future seizure risk compared to a model with age alone (p = 0.04) CONCLUSIONS: Spike height improves prediction of future seizure risk in SeLECTS. Several other morphological features may also improve prediction and should be explored in larger studies. SIGNIFICANCE: Discovery of a relationship between novel IED features and seizure risk may improve clinical prognostication, visual and automated IED detection strategies, and provide insights into the underlying neuronal mechanisms that contribute to IED pathology.

Association of the G-protein and α2-adrenergic receptor gene and plasma norepinephrine level with clonidine improvement of the effects of diuretics in patients with cirrhosis with refractory ascites: a randomised clinical trial.

OBJECTIVE: Clonidine is an α(2)-adrenoceptor agonist which, by coupling with G-protein, has been proposed as an alternative treatment for refractory ascites of patients with cirrhosis for several years. Genetic polymorphisms of ß-adrenoceptor and angiotensin II type 1 receptor blockers have been reported to affect drug response in patients with cirrhosis. This study evaluated the clonidine-diuretic response rate, favourable predictors and genetic components of the clonidine-diuretic response in patients with cirrhosis with refractory ascites. METHODS: 270 patients with cirrhosis with refractory ascites were randomised equally into two treatment groups to receive diuretics alone or the clonidine-diuretics association. The primary end point was clonidine-diuretic response rate. Secondary end points were mean daily dose of diuretics, times of paracentesis, ascites-related readmission and 1-year survival rate. RESULTS: Good clonidine responders had better natriuresis and diuresis as well as a significant decrease in abdominal circumference, plasma renin, aldosterone and norepinephrine levels. The overall clonidine-diuretics response rate was 55-60%. In patients with cirrhosis, the prevalence of ARDA(2)C WD/DD and GNB3 CT/TT genotypes was 71% and 77%, respectively. Among the responders, 71% of patients with cirrhosis had the ARDA(2)C WD/DD genotype and 67% has the GNB3 CT/TT genotype. Besides higher baseline norepinephrine levels, the presence of both ARDA(2)C WD/DD and GNB3 CT/TT genotypes showed a positive predictive value of 82% and a negative predictive value of 79% for good clonidine response. CONCLUSIONS: These results suggest that neurohormonal and genetic testing may be used as predictive factors for the additive effects of clonidine on the diuresis and natriuresis effects of diuretics in patients with cirrhosis with refractory ascites.

Yields from blood cultures of patients with suspected paratyphoid fever A.

The yield and speed of detection of Salmonella enterica serotype Paratyphi A from the blood of patients with suspected paratyphoid fever A in 13 500 paired aerobic and anaerobic bottles (AEB, ANB) that were each filled with 5 ml of blood by the BacT/ALERT 3D system were compared, and the blood bacterial counts of 1 000 probable patients were estimated by pour plate method. A total of 4 060 isolates were recovered, of these, 3 149 were recovered from both AEB and ANB, 461 from the AEB only, and 450 from the ANB only. The estimating median bacterial count in blood from 400 patients was 0.5 CFU/ml. The research findings demonstrate that the blood volume drawn is an important factor determining the yields from blood cultures. Growth of significantly more isolates was detected earlier in AEB.

Robust dynamic community detection with applications to human brain functional networks.

While current technology permits inference of dynamic brain networks over long time periods at high temporal resolution, the detailed structure of dynamic network communities during human seizures remains poorly understood. We introduce a new methodology that addresses critical aspects unique to the analysis of dynamic functional networks inferred from noisy data. We propose a dynamic plex percolation method (DPPM) that is robust to edge noise, and yields well-defined spatiotemporal communities that span forward and backwards in time. We show in simulation that DPPM outperforms existing methods in accurately capturing certain stereotypical dynamic community behaviors in noisy situations. We then illustrate the ability of this method to track dynamic community organization during human seizures, using invasive brain voltage recordings at seizure onset. We conjecture that application of this method will yield new targets for surgical treatment of epilepsy, and more generally could provide new insights in other network neuroscience applications.

A procedure to increase the power of Granger-causal analysis through temporal smoothing.

BACKGROUND: How the human brain coordinates network activity to support cognition and behavior remains poorly understood. New high-resolution recording modalities facilitate a more detailed understanding of the human brain network. Several approaches have been proposed to infer functional networks, indicating the transient coordination of activity between brain regions, from neural time series. One category of approach is based on statistical modeling of time series recorded from multiple sensors (e.g., multivariate Granger causality). However, fitting such models remains computationally challenging as the history structure may be long in neural activity, requiring many model parameters to fully capture the dynamics. NEW METHOD: We develop a method based on Granger causality that makes the assumption that the history dependence varies smoothly. We fit multivariate autoregressive models such that the coefficients of the lagged history terms are smooth functions. We do so by modelling the history terms with a lower dimensional spline basis, which requires many fewer parameters than the standard approach and increases the statistical power of the model. RESULTS: We show that this procedure allows accurate estimation of brain dynamics and functional networks in simulations and examples of brain voltage activity recorded from a patient with pharmacoresistant epilepsy. COMPARISON WITH EXISTING METHOD: The proposed method has more statistical power than the Granger method for networks of signals that exhibit extended and smooth history dependencies. CONCLUSIONS: The proposed tool permits conditional inference of functional networks from many brain regions with extended history dependence, furthering the applicability of Granger causality to brain network science.

Application of OCT-angiography to characterise the evolution of chorioretinal lesions in acute posterior multifocal placoid pigment epitheliopathy.

PurposeThe aim of this study was to determine a sequence of structural changes in acute posterior multifocal placoid pigment epitheliopathy (APMPPE) using optical coherence tomography-angiography (OCT-A) and comparing with other imaging modalities.Patients and methodsPatients with a new diagnosis of acute-onset APMPPE referred to a regional specialist centre from October 2015 to October 2016 were included. Multimodal imaging employed on all patients from diagnosis included the following: fundus fluorescein angiography, indocyanine green angiography, fundus autofluorescence, spectral domain-OCT (SD-OCT), and OCT-A. All non-invasive imaging processes were repeated during follow-up.ResultsTen eyes of five patients were included in the study, three males and two females, with a mean age of 26.2 years (range: 21-32) and a mean follow-up of 6.4 months (range: 2.6-13.3). All patients presented with bilateral disease and macular involving lesions. OCT-A imaging of the choriocapillaris was supportive of hypoperfusion at the site of APMPPE lesions during the acute phase of this condition with normalisation of choroidal vasculature during follow-up. Multimodal imaging consistently highlighted four sequential phases from presentation to resolution of active disease.ConclusionsMultimodal imaging in patients with APMPPE in acute and long-term follow-up demonstrates a reversible choroidal hypoperfusion supporting the primary inciting pathology as a choriocapillaritis. The evolution shows resolution of the ischaemia through a defined sequence that results in persistent changes at the level of the retinal pigment epithelium and outer retina. OCT-A was able to detect preclinical changes and chart resolution at the level of the choriocapillaris.

Increased serum interleukin-6, not minimal hepatic encephalopathy, predicts poor sleep quality in nonalcoholic cirrhotic patients.

BACKGROUND: Sleep-wake disturbances are common in patients with cirrhosis and have a considerable effect on health-related quality of life; however, the underlying mechanism behind the phenomenon is unclear. Cytokines are involved in the mediation of signalling pathways regulating fibrogenesis, leading to cirrhosis. In addition, increased cytokines could contribute to sleep disturbances. AIM: To determine the relationship between pro-inflammatory cytokines and sleep disturbance in cirrhotic patients. METHODS: Ninety-eight nonalcoholic cirrhotic patients without overt hepatic encephalopathy were enrolled in this cross-sectional study. The Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep quality. The Psychometric Hepatic Encephalopathy Score (PHES) was used to examine cognitive performance and define minimal hepatic encephalopathy (MHE). The Hospital Anxiety and Depression Scale (HADS) was used to evaluate the mood status of the patients. Pro-inflammatory cytokines that include interleukin 6 (IL-6) and tumour necrosis factor-α, as well as HBV-DNA or HCV-RNA levels were determined in patients. RESULTS: A total of 56 (57%) cirrhotic patients were identified as 'poor' sleepers (PSQI > 5). After multivariate analysis, IL-6 (P = 0.001) and HADS scores (P = 0.002) were found to be independent predictive factors of poor sleep quality. No significant relationships were observed between the sleep indices and the presence of MHE. HCV-RNA, but not HBV-DNA, viraemia was associated with sleep disturbance in cirrhotic patients. CONCLUSIONS: Sleep disturbance is found commonly in cirrhotic patients and a high serum IL-6 level is predictive of poor sleep quality. Minimal hepatic encephalopathy by itself may not contribute to sleep dysfunction in cirrhotic patients.

Motor skills training enhances lesion-induced structural plasticity in the motor cortex of adult rats.

To assess behavioral experience effects on synaptic plasticity after brain damage, the present study examined the effects of complex motor skills training (the acrobatic task) on synaptic changes in layer V of the motor cortex opposite unilateral damage to the forelimb sensorimotor cortex (FLsmc). Adult male rats were given lesions or sham operations followed by 28 d of training on the acrobatic task [acrobat condition (AC)]. As a motor activity control [motor control (MC)], lesion and sham animals were given simple repetitive exercise. Previously, FLsmc lesions and acrobatic training have independently been found to result in increases in synapse to neuron ratios in the intact motor cortex relative to controls, and both of these effects were replicated in the present study. In addition, acrobat training after lesions significantly increased layer V synapses per neuron relative to sham-AC and lesion-MC rats. Thus, the combination of acrobatic training and lesions resulted in an enhanced synaptogenic response. Synapse subtypes were also differentially affected by the conditions. Lesion-MC and sham-AC primarily had increases in the number of synapses per neuron formed by multiple synaptic boutons in comparison to sham-MC. In contrast, lesion-AC had increases in both multiple and single synapses. Multiple synaptic spines and perforated synapses were also differentially affected by training versus lesions. On tests of coordinated forelimb use, lesion-AC rats performed better than lesion-MC rats. In addition to supporting a link between behavioral experience and structural plasticity after brain damage, these findings suggest that adaptive neural plasticity may be enhanced using behavioral manipulations as "therapy."

Molecular analysis of mucosa-associated lymphoid tissue (MALT) lymphoma of ocular adnexa.

Lymphomas of mucosa-associated lymphoid tissue (MALT) are a distinct subgroup of extranodal B-cell non-Hodgkin's lymphomas. Most studies have failed to demonstrate the clonal rearrangement of BCL-1, BCL-2 or c-MYC genes for MALT lymphomas. Further, alteration of the p53 gene is rarely demonstrated in low-grade MALT lymphomas, but can be detected in high-grade disease. Lymphomas of the ocular adnexa represent approximately eight percent of all extranodal lymphomas, most of which are MALT lymphomas, but few studies had explored the alterations of BCL-1, BCL-2, c-MYC and p53 genes specifically for ocular MALT lymphomas. We investigated the changes to BCL-1, BCL-2, c-MYC and p53 genes in these lymphomas for Taiwanese patients. Clonal rearrangement for immunoglobulin heavy-chain (IgH), BCL-1, BCL-2, c-MYC and p53 genes was examined for 16 cases of ocular MALT lymphoma. Restriction-length polymorphism and polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) of the DNA, corresponding to exons 5 through 9, followed by DNA sequencing, were utilized to analyze the possible mutations of the p53 gene for these tumors. Thirteen of the cases revealed rearranged IgH genes using Southern blotting or PCR. No rearrangement of BCL-1, BCL-2, c-MYC or p53 genes was discovered, with point mutation of the p53 gene in one case. As for other types of MALT lymphomas, BCL-1, BCL-2 and c-MYC genes are not implicated in the pathogenesis of the ocular sub-group. Although alteration of the p53 gene is rare for low-grade ocular MALT lymphoma, its role in disease progression merits further research.

The maturation of cortical sleep rhythms and networks over early development.

OBJECTIVE: Although neuronal activity drives all aspects of cortical development, how human brain rhythms spontaneously mature remains an active area of research. We sought to systematically evaluate the emergence of human brain rhythms and functional cortical networks over early development. METHODS: We examined cortical rhythms and coupling patterns from birth through adolescence in a large cohort of healthy children (n=384) using scalp electroencephalogram (EEG) in the sleep state. RESULTS: We found that the emergence of brain rhythms follows a stereotyped sequence over early development. In general, higher frequencies increase in prominence with striking regional specificity throughout development. The coordination of these rhythmic activities across brain regions follows a general pattern of maturation in which broadly distributed networks of low-frequency oscillations increase in density while networks of high frequency oscillations become sparser and more highly clustered. CONCLUSION: Our results indicate that a predictable program directs the development of key rhythmic components and physiological brain networks over early development. SIGNIFICANCE: This work expands our knowledge of normal cortical development. The stereotyped neurophysiological processes observed at the level of rhythms and networks may provide a scaffolding to support critical periods of cognitive growth. Furthermore, these conserved patterns could provide a sensitive biomarker for cortical health across development.

Gene therapy for noninfectious uveitis.

Noninfectious intraocular inflammatory disease remains a significant cause of visual loss, even with current systemic immunosuppression. Alternative novel treatments are thus required, particularly for severe forms of posterior uveitis. Encouraging results from several phase I/II clinical trials of gene therapy for monogenic retinal disorders have paved the way for the development of this approach for other ocular conditions. Gene therapy for uveitis offers the possibility of potent, self-regulating, long-term disease control following a single treatment and without systemic side effects. To date, gene therapy approaches using interleukin-10, interleukin-1 receptor antagonist, interferon-alpha, soluble TNF-alpha receptors, and alpha-MSH gene transfer have been used successfully to attenuate experimental animal models of uveitis. This review evaluates these preclinical studies, considers the route to clinical application, and explores future targets and approaches.

Assessing facilitative responses to a nurse shrub at the community level: the example of Potentilla fruticosa in a sub-alpine grassland of northwest China.

Biotic interaction studies have revealed a large discrepancy among experiments in target responses to the effects of neighbours, which may in part be due to both high species-specificity of plant responses and low number of target species used in experiments. Our aim was to assess facilitative responses at the community level and the role of both functional groups and ecological attributes of target species. In a sub-alpine grassland on the eastern Tibet plateau, we assessed growth responses of all species in the community to removal of a dominant shrub. We also measured changes in the main environmental variables. Species responses were analysed by functional group and in relation to their mean regional altitudinal distribution. All significant interactions were positive and affected one-third of the total species richness of the community. All functional groups were facilitated but forbs were less strongly facilitated than in the two other groups. High-alpine species were less strongly facilitated than low-sub-alpine species, but the strength of this relationship was weaker than that reported in previous work. There was evidence of a decrease in extreme temperatures below the canopy of the shrub but no variations in soil moisture. We conclude that the highly stressful conditions induced by the dry continental climate of the eastern Tibet plateau are a main driver of the exclusive dominance of positive interactions. Assessing interactive responses at the community level is likely to provide a useful tool to better understand the role of biotic interactions in community responses to environmental changes.

Insulin resistance is a major determinant of sustained virological response in genotype 1 chronic hepatitis C patients receiving peginterferon alpha-2b plus ribavirin.

BACKGROUND: Cross-sectional studies suggest insulin resistance is strongly associated with hepatic steatosis and fibrosis in patients with chronic hepatitis C (CHC), which might affect the efficacy of antiviral therapy. Aim To investigate retrospectively the impact of insulin resistance on treatment response in Chinese genotype 1 CHC patients receiving a 24-week course therapy with peginterferon alpha-2b/ribavirin. METHODS: A total of 133 biopsy-proven CHC patients were enrolled for analyses. Insulin resistance was evaluated by homeostasis model assessment of insulin resistance (HOMA-IR). Hepatic fibrosis was graded by the METAVIR scoring system. RESULTS: Mean HOMA-IR progressively elevated along with the severity of hepatic fibrosis (F1-F2 fibrosis: 2.55 +/- 0.16 vs. F3-F4 fibrosis: 3.61 +/- 0.20, P < 0.001). Compared with patients with sustained virological response (SVR), patients without SVR had significantly higher percentages of F3-F4 fibrosis (62.2% vs. 21.6%, P < 0.001) and baseline high viral load (>or=600,000 IU/mL; 64.4% vs. 35.6%, P = 0.038). In addition, patients without SVR had significantly higher plasma levels of insulin (15.03 +/- 0.89 vs. 10.19 +/- 0.55 microU/mL, P < 0.001) and HOMA-IR values (3.76 +/- 0.23 vs. 2.50 +/- 0.15, P < 0.001). Multivariate analyses showed that F1-F2 fibrosis (odds ratio: 4.49, P = 0.001), HOMA-IR < 2 (odds ratio: 7.15, P = 0.005) and pre-treatment hepatitis C virus RNA < 600,000 IU/mL (odds ratio: 3.26, P = 0.012) were the independent factors associated with SVR. CONCLUSIONS: Insulin resistance is a major determinant of SVR in genotype 1 CHC patients receiving peginterferon alpha-2b/ribavirin. Strategies to modify insulin resistance may be effective in enhancing SVR before or during anti-viral therapy.