A composite measure to explore visual disability in primary progressive multiple sclerosis

Background: Optical coherence tomography (OCT) and magnetic resonance imaging (MRI) can provide complementary information on visual system damage in multiple sclerosis (MS). Objectives: The objective of this paper is to determine whether a composite OCT/MRI score, reflecting cumulative damage along the entire visual pathway, can predict visual deficits in primary progressive multiple sclerosis (PPMS). Methods: Twenty-five PPMS patients and 20 age-matched controls underwent neuro-ophthalmologic evaluation, spectral-domain OCT, and 3T brain MRI. Differences between groups were assessed by univariate general linear model and principal component analysis (PCA) grouped instrumental variables into main components. Linear regression analysis was used to assess the relationship between low-contrast visual acuity (LCVA), OCT/MRI-derived metrics and PCA-derived composite scores. Results: PCA identified four main components explaining 80.69% of data variance. Considering each variable independently, LCVA 1.25% was significantly predicted by ganglion cell-inner plexiform layer (GCIPL) thickness, thalamic volume and optic radiation (OR) lesion volume (adjusted R2 0.328, p = 0.00004; adjusted R2 0.187, p = 0.002 and adjusted R2 0.180, p = 0.002). The PCA composite score of global visual pathway damage independently predicted both LCVA 1.25% (adjusted R2 value 0.361, p = 0.00001) and LCVA 2.50% (adjusted R2 value 0.323, p = 0.00003). Conclusion: A multiparametric score represents a more comprehensive and effective tool to explain visual disability than a single instrumental metric in PPMS

An automated pipeline for extracting histological stain area fraction for voxelwise quantitative MRI-histology comparisons

The acquisition of MRI and histology in the same post-mortem tissue sample enables direct correlation between MRI and histologically-derived parameters. However, there still lacks a standardised automated pipeline to process histology data, with most studies relying on manual intervention. Here, we introduce an automated pipeline to extract a quantitative histological measure for staining density (stain area fraction, SAF) from multiple immunohistochemical (IHC) stains. The pipeline is designed to directly address key IHC artefacts related to tissue staining and slide digitisation. Here, the pipeline was applied to post-mortem human brain data from multiple subjects, relating MRI parameters (FA, MD, RD, AD, R2*, R1) to IHC slides stained for myelin, neurofilaments, microglia and activated microglia. Utilising high-quality MRI-histology co-registrations, we then performed whole-slide voxelwise comparisons (simple correlations, partial correlations and multiple regression analyses) between multimodal MRI- and IHC-derived parameters. The pipeline was found to be reproducible, robust to artefacts and generalisable across multiple IHC stains. Our partial correlation results suggest that some simple MRI-SAF correlations should be interpreted with caution, due to the co-localisation of other tissue features (e.g., myelin and neurofilaments). Further, we find activated microglia—a generic biomarker of inflammation—to consistently be the strongest predictor of high DTI FA and low RD, which may suggest sensitivity of diffusion MRI to aspects of neuroinflammation related to microglial activation, even after accounting for other microstructural changes (demyelination, axonal loss and general microglia infiltration). Together, these results show the utility of this approach in carefully curating IHC data and performing multimodal analyses to better understand microstructural relationships with MRI

An open resource combining multi-contrast MRI and microscopy in the macaque brain

Understanding brain structure and function often requires combining data across different modalities and scales to link microscale cellular structures to macroscale features of whole brain organisation. Here we introduce the BigMac dataset, a resource combining in vivo MRI, extensive postmortem MRI and multi-contrast microscopy for multimodal characterisation of a single whole macaque brain. The data spans modalities (MRI and microscopy), tissue states (in vivo and postmortem), and four orders of spatial magnitude, from microscopy images with micrometre or sub-micrometre resolution, to MRI signals on the order of millimetres. Crucially, the MRI and microscopy images are carefully co-registered together to facilitate quantitative multimodal analyses. Here we detail the acquisition, curation, and first release of the data, that together make BigMac a unique, openly-disseminated resource available to researchers worldwide. Further, we demonstrate example analyses and opportunities afforded by the data, including improvement of connectivity estimates from ultra-high angular resolution diffusion MRI, neuroanatomical insight provided by polarised light imaging and myelin-stained histology, and the joint analysis of MRI and microscopy data for reconstruction of the microscopy-inspired connectome. All data and code are made openly available

The internal thoracic artery skeletonization study: A paired, within-patient comparison [NCT00265499]

BACKGROUND: Traditional harvesting of the internal thoracic artery (ITA) for use as a conduit in coronary bypass surgery involves the dissection of a rim of tissue surrounding the artery on either side. Recent studies, primarily observational, have suggested that skeletonization of the ITA can improve conduit flow, increase length, and reduce the risk of deep sternal infection in high risk patients. Furthermore, skeletonization of the ITA can potentially preserve intercostal nerves and reduce post-operative pain and dysesthesias associated with ITA harvesting. In order to assess the effects of ITA skeletonization, we report a prospective, randomized, within-patient study design that shares many features of a cross-over study. METHODS: Patients undergoing bilateral internal thoracic artery harvest will be randomized to having one side skeletonized and the other harvested in a non-skeletonized manner. Outcome measures include ITA flow and length measured intra-operatively, post-operative pain and dysesthesia, evaluated at discharge, four weeks, and three months post-operatively, and sternal perfusion assessed using single photon emission computed tomography. Harvest times as well as safety endpoints of ITA injury will be recorded. DISCUSSION: This study design, using within-patient comparisons and paired analyses, minimizes the variability of the outcome measures, which is seldom possible in the evaluation of surgical techniques, with minimal chance of carryover effects that can hamper the interpretation of traditional cross-over studies. This study will provide a valid evaluation of clinically relevant effects of internal thoracic artery skeletonization in improving outcomes following coronary artery bypass surgery

Distinguishing Asthma Phenotypes Using Machine Learning Approaches.

Asthma is not a single disease, but an umbrella term for a number of distinct diseases, each of which are caused by a distinct underlying pathophysiological mechanism. These discrete disease entities are often labelled as asthma endotypes. The discovery of different asthma subtypes has moved from subjective approaches in which putative phenotypes are assigned by experts to data-driven ones which incorporate machine learning. This review focuses on the methodological developments of one such machine learning technique-latent class analysis-and how it has contributed to distinguishing asthma and wheezing subtypes in childhood. It also gives a clinical perspective, presenting the findings of studies from the past 5 years that used this approach. The identification of true asthma endotypes may be a crucial step towards understanding their distinct pathophysiological mechanisms, which could ultimately lead to more precise prevention strategies, identification of novel therapeutic targets and the development of effective personalized therapies

Hidden SUSY at the LHC: the light higgsino-world scenario and the role of a lepton collider

While the SUSY flavor, CP and gravitino problems seem to favor a very heavy spectrum of matter scalars, fine-tuning in the electroweak sector prefers low values of superpotential mass \mu. In the limit of low \mu, the two lightest neutralinos and light chargino are higgsino-like. The light charginos and neutralinos may have large production cross sections at LHC, but since they are nearly mass degenerate, there is only small energy release in three-body sparticle decays. Possible dilepton and trilepton signatures are difficult to observe after mild cuts due to the very soft p_T spectrum of the final state isolated leptons. Thus, the higgsino-world scenario can easily elude standard SUSY searches at the LHC. It should motivate experimental searches to focus on dimuon and trimuon production at the very lowest p_T(\mu) values possible. If the neutralino relic abundance is enhanced via non-standard cosmological dark matter production, then there exist excellent prospects for direct or indirect detection of higgsino-like WIMPs. While the higgsino-world scenario may easily hide from LHC SUSY searches, a linear e^+e^- collider or a muon collider operating in the \sqrt{s}\sim 0.5-1 TeV range would be able to easily access the chargino and neutralino pair production reactions.Comment: 20 pages including 12 .eps figure

Neutralino versus axion/axino cold dark matter in the 19 parameter SUGRA model

We calculate the relic abundance of thermally produced neutralino cold dark matter in the general 19 parameter supergravity (SUGRA-19) model. A scan over GUT scale parameters reveals that models with a bino-like neutralino typically give rise to a dark matter density \Omega_{\tz_1}h^2\sim 1-1000, i.e. between 1 and 4 orders of magnitude higher than the measured value. Models with higgsino or wino cold dark matter can yield the correct relic density, but mainly for neutralino masses around 700-1300 GeV. Models with mixed bino-wino or bino-higgsino CDM, or models with dominant co-annihilation or A-resonance annihilation can yield the correct abundance, but such cases are extremely hard to generate using a general scan over GUT scale parameters; this is indicative of high fine-tuning of the relic abundance in these cases. Requiring that m_{\tz_1}\alt 500 GeV (as a rough naturalness requirement) gives rise to a minimal probably dip in parameter space at the measured CDM abundance. For comparison, we also scan over mSUGRA space with four free parameters. Finally, we investigate the Peccei-Quinn augmented MSSM with mixed axion/axino cold dark matter. In this case, the relic abundance agrees more naturally with the measured value. In light of our cumulative results, we conclude that future axion searches should probe much more broadly in axion mass, and deeper into the axion coupling.Comment: 23 pages including 17 .eps figure

A new family of giardial cysteine-rich non-VSP protein genes and a novel cyst protein

© 2006 Davids et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The definitive version was published in PLoS ONE 1 (2006): e44, doi:10.1371/journal.pone.0000044.Since the Giardia lamblia cyst wall is necessary for survival in the environment and host infection, we tested the hypothesis that it contains proteins other than the three known cyst wall proteins. Serial analysis of gene expression during growth and encystation revealed a gene, “HCNCp” (High Cysteine Non-variant Cyst protein), that was upregulated late in encystation, and that resembled the classic Giardia variable surface proteins (VSPs) that cover the trophozoite plasmalemma. HCNCp is 13.9% cysteine, with many “CxxC” tetrapeptide motifs and a transmembrane sequence near the C-terminus. However, HCNCp has multiple “CxC” motifs rarely found in VSPs, and does not localize to the trophozoite plasmalemma. Moreover, the HCNCp C-terminus differed from the canonical VSP signature. Full-length epitope-tagged HCNCp expressed under its own promoter was upregulated during encystation with highest expression in cysts, including 42 and 21 kDa C-terminal fragments. Tagged HCNCp targeted to the nuclear envelope in trophozoites, and co-localized with cyst proteins to encystation-specific secretory vesicles during encystation. HCNCp defined a novel trafficking pathway as it localized to the wall and body of cysts, while the cyst proteins were exclusively in the wall. Unlike VSPs, HCNCp is expressed in at least five giardial strains and four WB subclones expressing different VSPs. Bioinformatics identified 60 additional large high cysteine membrane proteins (HCMp) containing ≥20 CxxC/CxC's lacking the VSP-specific C-terminal CRGKA. HCMp were absent or rare in other model or parasite genomes, except for Tetrahymena thermophila with 30. MEME analysis classified the 61 gHCMp genes into nine groups with similar internal motifs. Our data suggest that HCNCp is a novel invariant cyst protein belonging to a new HCMp family that is abundant in the Giardia genome. HCNCp and the other HCMp provide a rich source for developing parasite-specific diagnostic reagents, vaccine candidates, and subjects for further research into Giardia biology

First experience with a new negative pressure incision management system on surgical incisions after cardiac surgery in high risk patients

<p>Abstract</p> <p>Background</p> <p>Sternal wound infection remains a serious potential complication after cardiac surgery. A recent development for preventing wound complications after surgery is the adjunctive treatment of closed incisions with negative pressure wound therapy. Suggested mechanisms of preventive action are improving the local blood flow, removing fluids and components in these fluids, helping keep the incision edges together, protecting the wound from external contamination and promoting incision healing. This work reports on our initial evaluation and clinical experience with the Prevena™Incision Management System, a recently introduced new negative pressure wound therapy system specifically developed for treating closed surgical incisions and helping prevent potential complications. We evaluated the new treatment on sternal surgical incisions in patients with multiple co-morbidities and consequently a high risk for wound complications.</p> <p>Methods</p> <p>The Prevena™incision management system was used in 10 patients with a mean Fowler risk score of 15.1 [Range 8-30]. The negative pressure dressing was applied immediately after surgery and left in place for 5 days with a continuous application of -125 mmHg negative pressure. Wounds and surrounding skin were inspected immediately after removal of the Prevena™ incision management system and at day 30 after surgery.</p> <p>Results</p> <p>Wounds and surrounding skin showed complete wound healing with the absence of skin lesions due to the negative pressure after removal of the Prevena™ dressing. No device-related complications were observed. No wound complications occurred in this high risk group of patients until at least 30 days after surgery.</p> <p>Conclusions</p> <p>The Prevena™system appears to be safe, easy to use and may help achieve uncomplicated wound healing in patients at risk of developing wound complications after cardiothoracic surgery.</p