Quantifying T2 relaxation time changes within lesions defined by apparent diffusion coefficient in grey and white matter in acute stroke patients

The apparent diffusion coefficient (ADC) of cerebral water, as measured by diffusion MRI, rapidly decreases in ischaemia, highlighting a lesion in acute stroke patients. The MRI T 2 relaxation time changes in ischaemic brain such that T 2 in ADC lesions may be informative of the extent of tissue damage, potentially aiding in stratification for treatment. We have developed a novel user-unbiased method of determining the changes in T 2 in ADC lesions as a function of clinical symptom duration based on voxel-wise referencing to a contralateral brain volume. The spherical reference method calculates the most probable pre-ischaemic T 2 on a voxel-wise basis, making use of features of the contralateral hemisphere presumed to be largely unaffected. We studied whether T 2 changes in the two main cerebral tissue types, i.e. in grey matter (GM) and white matter (WM), would differ in stroke. Thirty-eight acute stroke patients were accrued within 9 h of symptom onset and scanned at 3 T for 3D T 1-weighted, multi b-value diffusion and multi-echo spin echo MRI for tissue type segmentation, quantitative ADC and absolute T 2 images, respectively. T 2 changes measured by the spherical reference method were 1.94  ±  0.61, 1.50  ±  0.52 and 1.40  ±  0.54 ms h−1 in the whole, GM, and WM lesions, respectively. Thus, T 2 time courses were comparable between GM and WM independent of brain tissue type involved. We demonstrate that T 2 changes in ADC-delineated lesions can be quantified in the clinical setting in a user unbiased manner and that T 2 change correlated with symptom onset time, opening the possibility of using the approach as a tool to assess severity of tissue damage in the clinical setting

Comprehensive Biotransformation Analysis of Phenylalanine-Tyrosine Metabolism Reveals Alternative Routes of Metabolite Clearance in Nitisinone-Treated Alkaptonuria

Metabolomic analyses in alkaptonuria (AKU) have recently revealed alternative pathways in phenylalanine-tyrosine (phe-tyr) metabolism from biotransformation of homogentisic acid (HGA), the active molecule in this disease. The aim of this research was to study the phe-tyr metabolic pathway and whether the metabolites upstream of HGA, increased in nitisinone-treated patients, also undergo phase 1 and 2 biotransformation reactions. Metabolomic analyses were performed on serum and urine from patients partaking in the SONIA 2 phase 3 international randomised-controlled trial of nitisinone in AKU (EudraCT no. 2013-001633-41). Serum and urine samples were taken from the same patients at baseline (pre-nitisinone) then at 24 and 48 months on nitisinone treatment (patients N = 47 serum; 53 urine) or no treatment (patients N = 45 serum; 50 urine). Targeted feature extraction was performed to specifically mine data for the entire complement of theoretically predicted phase 1 and 2 biotransformation products derived from phenylalanine, tyrosine, 4-hydroxyphenylpyruvic acid and 4-hydroxyphenyllactic acid, in addition to phenylalanine-derived metabolites with known increases in phenylketonuria. In total, we observed 13 phase 1 and 2 biotransformation products from phenylalanine through to HGA. Each of these products were observed in urine and two were detected in serum. The derivatives of the metabolites upstream of HGA were markedly increased in urine of nitisinone-treated patients (fold change 1.2–16.2) and increases in 12 of these compounds were directly proportional to the degree of nitisinone-induced hypertyrosinaemia (correlation coefficient with serum tyrosine = 0.2–0.7). Increases in the urinary phenylalanine metabolites were also observed across consecutive visits in the treated group. Nitisinone treatment results in marked increases in a wider network of phe-tyr metabolites than shown before. This network comprises alternative biotransformation products from the major metabolites of this pathway, produced by reactions including hydration (phase 1) and bioconjugation (phase 2) of acetyl, methyl, acetylcysteine, glucuronide, glycine and sulfate groups. We propose that these alternative routes of phe-tyr metabolism, predominantly in urine, minimise tyrosinaemia as well as phenylalanaemia

Determining T2 relaxation time and stroke onset relationship in ischaemic stroke within apparent diffusion coefficient-defined lesions. A user-independent method for quantifying the impact of stroke in the human brain

Background and objective:In hyperacute ischaemic stroke, T2 of cerebral water increases with time. Quantifying this change may be informative of the extent of tissue damage and onset time. Our objective was to develop a user-unbiased method to measure the effect of cerebral ischaemia on T2 to study stroke onset time-dependency in human acute stroke lesions. Methods:Six rats were subjected to permanent middle cerebral occlusion to induce focal ischaemia, and a consecutive cohort of acute stroke patients (n=38) were recruited within 9 hours from symptom onset. T1-weighted structural, T2 relaxometry, and diffusion MRI for apparent diffusion coefficient (ADC) were acquired. Ischaemic lesions were defined as regions of lowered ADC. The median T2 difference (ΔT2) between lesion and contralateral non-ischaemic control region was determined by the newly-developed spherical reference method, and data compared to that obtained by the mirror reference method. Linear regressions and receiver operating characteristics (ROC) were compared between the two methods. Results:ΔT2 increases linearly in rat brain ischaemia by 1.9 ± 0.8 ms/h during the first 6 hours, as determined by the spherical reference method. In patients, ΔT2 linearly increases by 1.6 ± 1.4 and 1.9 ± 0.9 ms/h in the lesion, as determined by the mirror reference and spherical reference method, respectively. ROC analyses produced areas under the curve of 0.83 and 0.71 for the spherical and mirror reference methods, respectively. Conclusions:Data from the spherical reference method showed that the median T2 increase in the ischaemic lesion is correlated with stroke onset time in a rat as well as in a human patient cohort, opening the possibility of using the approach as a timing tool in clinics.</p

The use of thaumatin and bovine serum albumin as proteins in model wine solutions in bentonite fining

This study examined the viability of using thaumatin and bovine serum albumin (BSA) as proteins in model wine solutions for bentonite fining studies and compared them with unfined New Zealand sauvignon blanc (SB) wine. Bentonite fining trials were performed on model wine solutions and unfined SB wines (pH range 3.5 to 4.3). Thaumatin was more readily adsorbed onto bentonites of all types than BSA and its adsorption onto bentonite was less affected by the pH of the solution. Specifically, the amount of BSA adsorbed onto bentonite decreased significantly as the pH of the solution approached the isoelectric point (pI) of BSA while thaumatin was adsorbed at that pH due to its higher pI. Changing pH affected protein adsorption of real wine less noticeably than of BSA and thaumatin, and decreasing pH increased protein adsorption in contrast to the model solutions. Neither of the model solutions can fully represent the response of real wine to bentonite fining but they are simple and cost effective to prepare and reacted to changes in bentonite concentration similar to real wine. Thaumatin is potentially a better protein to use in simple model solutions for wine stabilisation studies like filtration where molecular weights are important consideration

Transcriptomic profiling of host-parasite interactions in the microsporidian <i>Trachipleistophora hominis</i>

BACKGROUND: Trachipleistophora hominis was isolated from an HIV/AIDS patient and is a member of a highly successful group of obligate intracellular parasites. METHODS: Here we have investigated the evolution of the parasite and the interplay between host and parasite gene expression using transcriptomics of T. hominis-infected rabbit kidney cells. RESULTS: T. hominis has about 30 % more genes than small-genome microsporidians. Highly expressed genes include those involved in growth, replication, defence against oxidative stress, and a large fraction of uncharacterised genes. Chaperones are also highly expressed and may buffer the deleterious effects of the large number of non-synonymous mutations observed in essential T. hominis genes. Host expression suggests a general cellular shutdown upon infection, but ATP, amino sugar and nucleotide sugar production appear enhanced, potentially providing the parasite with substrates it cannot make itself. Expression divergence of duplicated genes, including transporters used to acquire host metabolites, demonstrates ongoing functional diversification during microsporidian evolution. We identified overlapping transcription at more than 100 loci in the sparse T. hominis genome, demonstrating that this feature is not caused by genome compaction. The detection of additional transposons of insect origin strongly suggests that the natural host for T. hominis is an insect. CONCLUSIONS: Our results reveal that the evolution of contemporary microsporidian genomes is highly dynamic and innovative. Moreover, highly expressed T. hominis genes of unknown function include a cohort that are shared among all microsporidians, indicating that some strongly conserved features of the biology of these enormously successful parasites remain uncharacterised. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12864-015-1989-z) contains supplementary material, which is available to authorized users

The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy

Background: The ability to accurately predict operative duration has the potential to optimise theatre efficiency and utilisation, thus reducing costs and increasing staff and patient satisfaction. With laparoscopic cholecystectomy being one of the most commonly performed procedures worldwide, a tool to predict operative duration could be extremely beneficial to healthcare organisations. Methods: Data collected from the CholeS study on patients undergoing cholecystectomy in UK and Irish hospitals between 04/2014 and 05/2014 were used to study operative duration. A multivariable binary logistic regression model was produced in order to identify significant independent predictors of long (> 90 min) operations. The resulting model was converted to a risk score, which was subsequently validated on second cohort of patients using ROC curves. Results: After exclusions, data were available for 7227 patients in the derivation (CholeS) cohort. The median operative duration was 60 min (interquartile range 45–85), with 17.7% of operations lasting longer than 90 min. Ten factors were found to be significant independent predictors of operative durations > 90 min, including ASA, age, previous surgical admissions, BMI, gallbladder wall thickness and CBD diameter. A risk score was then produced from these factors, and applied to a cohort of 2405 patients from a tertiary centre for external validation. This returned an area under the ROC curve of 0.708 (SE = 0.013, p  90 min increasing more than eightfold from 5.1 to 41.8% in the extremes of the score. Conclusion: The scoring tool produced in this study was found to be significantly predictive of long operative durations on validation in an external cohort. As such, the tool may have the potential to enable organisations to better organise theatre lists and deliver greater efficiencies in care

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure