Viral Load, Clinical Disease Severity and Cellular Immune Responses in Primary Varicella Zoster Virus Infection in Sri Lanka

BACKGROUND: In Sri Lanka, varicella zoster virus (VZV) is typically acquired during adulthood with significant associated disease morbidity and mortality. T cells are believed to be important in the control of VZV replication and in the prevention of reactivation. The relationship between viral load, disease severity and cellular immune responses in primary VZV infection has not been well studied. METHODOLOGY: We used IFNgamma ELISpot assays and MHC class II tetramers based on VZV gE and IE63 epitopes, together with quantitative real time PCR assays to compare the frequency and phenotype of specific T cells with virological and clinical outcomes in 34 adult Sri Lankan individuals with primary VZV infection. PRINCIPAL FINDINGS: Viral loads were found to be significantly higher in patients with moderate to severe infection compared to those with mild infection (p<0.001) and were significantly higher in those over 25 years of age (P<0.01). A significant inverse correlation was seen between the viral loads and the ex vivo IFNgamma ELISpot responses of patients (P<0.001, r = -0.85). VZV-specific CD4+ T cells expressed markers of intermediate differentiation and activation. CONCLUSIONS: Overall, these data show that increased clinical severity in Sri Lankan adults with primary VZV infection associates with higher viral load and reduced viral specific T cell responses

The non-coding landscape of head and neck squamous cell carcinoma

published_or_final_versio

Targeting BTK for the treatment of FLT3-ITD mutated acute myeloid leukemia

Approximately 20% of patients with acute myeloid leukaemia (AML) have a mutation in FMS-like-tyrosine-kinase-3 (FLT3). FLT3 is a trans-membrane receptor with a tyrosine kinase domain which, when activated, initiates a cascade of phosphorylated proteins including the SRC family of kinases. Recently our group and others have shown that pharmacologic inhibition and genetic knockdown of Bruton's tyrosine kinase (BTK) blocks AML blast proliferation, leukaemic cell adhesion to bone marrow stromal cells as well as migration of AML blasts. The anti-proliferative effects of BTK inhibition in human AML are mediated via inhibition of downstream NF-κB pro-survival signalling however the upstream drivers of BTK activation in human AML have yet to be fully characterised. Here we place the FLT3-ITD upstream of BTK in AML and show that the BTK inhibitor ibrutinib inhibits the survival and proliferation of FLT3-ITD primary AML blasts and AML cell lines. Furthermore ibrutinib inhibits the activation of downstream kinases including MAPK, AKT and STAT5. In addition we show that BTK RNAi inhibits proliferation of FLT3-ITD AML cells. Finally we report that ibrutinib reverses the cyto-protective role of BMSC on FLT3-ITD AML survival. These results argue for the evaluation of ibrutinib in patients with FLT3-ITD mutated AML

Interocular yoking in human saccades examined by mutual information analysis

International audienceABSTRACT : BACKGROUND : Saccadic eye movements align the two eyes precisely to foveate a target. Trial-by-trial variance of eye movement is always observed within an identical experimental condition. This has often been treated as experimental error without addressing its significance. The present study examined statistical linkages between the two eyes' movements, namely interocular yoking, for the variance of eye position and velocity. METHODS : Horizontal saccadic movements were recorded from twelve right-eye-dominant subjects while they decided on saccade direction in Go-Only sessions and on both saccade execution and direction in Go/NoGo sessions. We used infrared corneal reflection to record simultaneously and independently the movement of each eye. Quantitative measures of yoking were provided by mutual information analysis of eye position or velocity, which is sensitive to both linear and non-linear relationships between the eyes' movements. Our mutual information analysis relied on the variance of the eyes movements in each experimental condition. The range of movements for each eye varies for different conditions so yoking was further studied by comparing GO-Only vs. Go/NoGo sessions, leftward vs. rightward saccades. RESULTS : Mutual information analysis showed that velocity yoking preceded positional yoking. Cognitive load increased trial variances of velocity with no increase in velocity yoking, suggesting that cognitive load may alter neural processes in areas to which oculomotor control is not tightly linked. The comparison between experimental conditions showed that interocular linkage in velocity variance of the right eye lagged that of the left eye during saccades. CONCLUSIONS : We conclude quantitative measure of interocular yoking based on trial-to-trial variance within a condition, as well as variance between conditions, provides a powerful tool for studying the binocular movement mechanism

The impact of SARS on hospital performance

© 2008 Chu et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Improving a Natural CaMKII Inhibitor by Random and Rational Design

CaM-KIIN has evolved to inhibit stimulated and autonomous activity of the Ca(2+)/calmodulin (CaM)-dependent protein kinase II (CaMKII) efficiently, selectively, and potently (IC50 ∼100 nM). The CN class of peptides, derived from the inhibitory region of CaM-KIIN, provides powerful new tools to study CaMKII functions. The goal of this study was to identify the residues required for CaMKII inhibition, and to assess if artificial mutations could further improve the potency achieved during evolution.First, the minimal region with full inhibitory potency was identified (CN19) by determining the effect of truncated peptides on CaMKII activity in biochemical assays. Then, individual residues of CN19 were mutated. Most individual Ala substitutions decreased potency of CaMKII inhibition, however, P3A, K13A, and R14A increased potency. Importantly, this initial Ala scan suggested a specific interaction of the region around R11 with the CaMKII substrate binding site, which was exploited for further rational mutagenesis to generate an optimized pseudo-substrate sequence. Indeed, the potency of the optimized peptide CN19o was >250fold improved (IC50 <0.4 nM), and CN19o has characteristics of a tight-binding inhibitor. The selectivity for CaMKII versus CaMKI was similarly improved (to almost 100,000fold for CN19o). A phospho-mimetic S12D mutation decreased potency, indicating potential for regulation by cellular signaling. Consistent with importance of this residue in inhibition, most other S12 mutations also significantly decreased potency, however, mutation to V or Q did not.These results provide improved research tools for studying CaMKII function, and indicate that evolution fine-tuned CaM-KIIN not for maximal potency of CaMKII inhibition, but for lower potency that may be optimal for dynamic regulation of signal transduction

Global and regional brain metabolic scaling and its functional consequences

Background: Information processing in the brain requires large amounts of metabolic energy, the spatial distribution of which is highly heterogeneous reflecting complex activity patterns in the mammalian brain. Results: Here, it is found based on empirical data that, despite this heterogeneity, the volume-specific cerebral glucose metabolic rate of many different brain structures scales with brain volume with almost the same exponent around -0.15. The exception is white matter, the metabolism of which seems to scale with a standard specific exponent -1/4. The scaling exponents for the total oxygen and glucose consumptions in the brain in relation to its volume are identical and equal to $0.86\pm 0.03$, which is significantly larger than the exponents 3/4 and 2/3 suggested for whole body basal metabolism on body mass. Conclusions: These findings show explicitly that in mammals (i) volume-specific scaling exponents of the cerebral energy expenditure in different brain parts are approximately constant (except brain stem structures), and (ii) the total cerebral metabolic exponent against brain volume is greater than the much-cited Kleiber's 3/4 exponent. The neurophysiological factors that might account for the regional uniformity of the exponents and for the excessive scaling of the total brain metabolism are discussed, along with the relationship between brain metabolic scaling and computation.Comment: Brain metabolism scales with its mass well above 3/4 exponen

The clinical features of the piriformis syndrome: a systematic review

Piriformis syndrome, sciatica caused by compression of the sciatic nerve by the piriformis muscle, has been described for over 70 years; yet, it remains controversial. The literature consists mainly of case series and narrative reviews. The objectives of the study were: first, to make the best use of existing evidence to estimate the frequencies of clinical features in patients reported to have PS; second, to identify future research questions. A systematic review was conducted of any study type that reported extractable data relevant to diagnosis. The search included all studies up to 1 March 2008 in four databases: AMED, CINAHL, Embase and Medline. Screening, data extraction and analysis were all performed independently by two reviewers. A total of 55 studies were included: 51 individual and 3 aggregated data studies, and 1 combined study. The most common features found were: buttock pain, external tenderness over the greater sciatic notch, aggravation of the pain through sitting and augmentation of the pain with manoeuvres that increase piriformis muscle tension. Future research could start with comparing the frequencies of these features in sciatica patients with and without disc herniation or spinal stenosis

On the Resolution of Critical Flow Regions in Inviscid Linear And Nonlinear Instability Calculations

Numerical methods for tackling the inviscid instability problem are discussed. Convergence is demon- strated to be a necessary, but not a sufficient condition for accuracy. Inviscid flow physics set requirements regarding grid-point distribution in order for physically accurate results to be obtained. These requirements are relevant to the viscous problem also and are shown to be related to the resolution of the critical layers. In this respect, high-resolution nonlinear calculations based on the inviscid initial-boundary-value problem are presented for a model shear-layer flow, aiming at identification of the regions that require attention in the course of high-Reynolds-number viscous calculations. The results bear a remarkable resemblance with those pertinent to viscous flow, with a cascade of high-shear regions being shed towards the vortex-core centre as time progresses. In parallel, numerical instability related to the finite-time singularity of the nonlinear equations solved globally contaminates and eventually destroys the simulations, irrespective of resolution