The effect of fluid resuscitation on the effective circulating volume in patients undergoing liver surgery: a post-hoc analysis of a randomized controlled trial

To assess the significance of an analogue of the mean systemic filling pressure (Pmsa) and its derived variables, in providing a physiology based discrimination between responders and non-responders to fluid resuscitation during liver surgery. A post-hoc analysis of data from 30 patients undergoing major hepatic surgery was performed. Patients received 15 ml kg(-1) fluid in 30 min. Fluid responsiveness (FR) was defined as an increase of 20% or greater in cardiac index, measured by FloTrac-Vigileo((R)). Dynamic preload variables (pulse pressure variation and stroke volume variation: PPV, SVV) were recorded additionally. Pvr, the driving pressure for venous return (=Pmsa-central venous pressure) and heart performance (EH; Pvr/Pmsa) were calculated according to standard formula. Pmsa increased following fluid administration in responders (n = 18; from 13 +/- 3 to 17 +/- 4 mmHg, p < 0.01) and in non-responders (n = 12; from 14 +/- 4 to 17 +/- 4 mmHg, p < 0.01). Pvr, which was lower in responders before fluid administration (6 +/- 1 vs. 7 +/- 1 mmHg; p = 0.02), increased after fluid administration only in responders (from 6 +/- 1 to 8 +/- 1 mmHg; p < 0.01). EH only decreased in non-responders (from 0.56 +/- 0.17 to 0.45 +/- 0.12; p < 0.05). The area under the receiver operating characteristics curve of Pvr, PPV and SVV for predicting FR was 0.75, 0.73 and 0.72, respectively. Changes in Pmsa, Pvr and EH reflect changes in effective circulating volume and heart performance following fluid resuscitation, providing a physiologic discrimination between responders and non-responders. Also, Pvr predicts FR equivalently compared to PPV and SVV, and might therefore aid in predicting FR in case dynamic preload variables cannot be used

Hierarchical Cluster Analysis to Aid Diagnostic Image Data Visualization of MS and Other Medical Imaging Modalities

Perceiving abnormal regions in the images of different medical modalities plays a crucial role in diagnosis and subsequent treatment planning. In medical images to visually perceive abnormalities’ extent and boundaries requires substantial experience. Consequently, manually drawn region of interest (ROI) to outline boundaries of abnormalities suffers from limitations of human perception leading to inter-observer variability. As an alternative to human drawn ROI, it is proposed the use of a computer-based segmenta- tion algorithm to segment digital medical image data. Hierarchical Clustering-based Segmentation (HCS) process is a generic unsupervised segmentation process that can be used to segment dissimilar regions in digital images. HCS process generates a hierarchy of segmented images by partitioning an image into its constituent regions at hierarchical levels of allowable dissimilarity between its different regions. The hierarchy represents the continuous merging of similar, spatially adjacent, and/or disjoint regions as the allowable threshold value of dissimilarity between regions, for merging, is gradually increased. This chapter discusses in detail first the implementation of the HCS process, second the implementa- tion details of how the HCS process is used for the presentation of multi-modal imaging data (MALDI and MRI) of a biological sample, third the implementation details of how the process is used as a perception aid for X-ray mammogram readers, and finally the implementation details of how it is used as an interpreta- tion aid for the interpretation of Multi-parametric Magnetic Resonance Imaging (mpMRI) of the Prostate

Modeling BCR-ABL and MLL-AF9 leukemia in a human bone marrow-like scaffold based xenograft model

While NOD-SCID IL2Rγ(-/-) (NSG) xenograft mice are currently the most frequently used model to study human leukemia in vivo, the absence of a human niche severely hampers faithful recapitulation of the disease. We used NSG mice in which ceramic scaffolds seeded with human mesenchymal stromal cells were implanted to generate a human bone marrow (huBM-sc)-like niche. We observed that, in contrast to the murine bone marrow (mBM) niche, expression of BCR-ABL or MLL-AF9 was sufficient to induce both primary AML and ALL. Stemness was preserved within the human niches as demonstrated by serial transplantation assays. Efficient engraftment of AML MLL-AF9 and blast-crisis CML patient cells was also observed, whereby the immature blast-like phenotype was maintained in the huBM-sc niche, but to a much lesser extent in mBM niches. We compared transcriptomes of leukemias derived from mBM niches versus leukemias from huBM-like scaffold-based niches, which revealed striking differences in expression of genes associated with hypoxia, mitochondria and metabolism. Finally, we utilized the huBM-sc MLL-AF9 B-ALL model to evaluate the efficacy of the I-BET151 inhibitor in vivo. In conclusion, we have established human niche models in which the myeloid and lymphoid features of BCR-ABL(+) and MLL-AF9(+) leukemias can be studied in detail. Accepted article preview online 29 April 2016; Advance online publication 17 May 2016This work was supported by grants from the Dutch Cancer Society (2009-4411; VU2011-5127) and by the EU (ITN EuroCSC). I-BET151 was kindly provided by Nicholas Smithers (GSK R&D, UK)

A generic model for the assessment of disease epidemiology: the computational basis of DisMod II

Epidemiology as an empirical science has developed sophisticated methods to measure the causes and patterns of disease in populations. Nevertheless, for many diseases in many countries only partial data are available. When the partial data are insufficient, but data collection is not an option, it is possible to supplement the data by exploiting the causal relations between the various variables that describe a disease process. We present a simple generic disease model with incidence, one prevalent state, and case fatality and remission. We derive a set of equations that describes this disease process and allows calculation of the complete epidemiology of a disease given a minimum of three input variables. We give the example of asthma with age-specific prevalence, remission, and mortality as inputs. Outputs are incidence and case fatality, among others. The set of equations is embedded in a software package called 'DisMod II', which is made available to the public domain by the World Health Organization

Optical Scattering Measurements of Laser Induced Damage in the Intraocular Lens

This study optically determines whether the amount of light scatter due to laser-induced damage to the intraocular lens (IOL) is significant in relation to normal straylight values in the human eye. Two IOLs with laser-induced damage were extracted from two donor eyes. Each IOL had 15 pits and/or cracks. The surface area of each pit was measured using a microscope. For 6 pits per intraocular lens the point spread function (PSF) in terms of straylight was measured and the total straylight for all 15 pits was estimated. The damage in the IOLs was scored as mild/moderate. The total damaged surface areas, for a 3.5 mm pupil, in the two IOLs were 0.13% (0.0127 mm2) and 0.66% (0.064 mm2), respectively. The angular dependence of the straylight caused by the damage was similar to that of the normal PSF. The total average contribution to straylight was log(s) = −0.82 and −0.42, much less than the straylight value of the normal eye

The Structural Architecture of an Infectious Mammalian Prion Using Electron Cryomicroscopy

The structure of the infectious prion protein (PrPSc), which is responsible for Creutzfeldt-Jakob disease in humans and bovine spongiform encephalopathy, has escaped all attempts at elucidation due to its insolubility and propensity to aggregate. PrPSc replicates by converting the non-infectious, cellular prion protein (PrPC) into the misfolded, infectious conformer through an unknown mechanism. PrPSc and its N-terminally truncated variant, PrP 27-30, aggregate into amorphous aggregates, 2D crystals, and amyloid fibrils. The structure of these infectious conformers is essential to understanding prion replication and the development of structure-based therapeutic interventions. Here we used the repetitive organization inherent to GPI-anchorless PrP 27-30 amyloid fibrils to analyze their structure via electron cryomicroscopy. Fourier-transform analyses of averaged fibril segments indicate a repeating unit of 19.1 Å. 3D reconstructions of these fibrils revealed two distinct protofilaments, and, together with a molecular volume of 18,990 Å3, predicted the height of each PrP 27-30 molecule as ~17.7 Å. Together, the data indicate a four-rung β-solenoid structure as a key feature for the architecture of infectious mammalian prions. Furthermore, they allow to formulate a molecular mechanism for the replication of prions. Knowledge of the prion structure will provide important insights into the self-propagation mechanisms of protein misfolding

STK295900, a Dual Inhibitor of Topoisomerase 1 and 2, Induces G<inf>2</inf> Arrest in the Absence of DNA Damage

STK295900, a small synthetic molecule belonging to a class of symmetric bibenzimidazoles, exhibits antiproliferative activity against various human cancer cell lines from different origins. Examining the effect of STK295900 in HeLa cells indicates that it induces G2 phase arrest without invoking DNA damage. Further analysis shows that STK295900 inhibits DNA relaxation that is mediated by topoisomerase 1 (Top 1) and topoisomerase 2 (Top 2) in vitro. In addition, STK295900 also exhibits protective effect against DNA damage induced by camptothecin. However, STK295900 does not affect etoposide-induced DNA damage. Moreover, STK295900 preferentially exerts cytotoxic effect on cancer cell lines while camptothecin, etoposide, and Hoechst 33342 affected both cancer and normal cells. Therefore, STK295900 has a potential to be developed as an anticancer chemotherapeutic agent. © 2013 Kim et al

Complementary structural and functional abnormalities to localise epileptogenic tissue

\ua9 2023 The Authors. Background: When investigating suitability for epilepsy surgery, people with drug-refractory focal epilepsy may have intracranial EEG (iEEG) electrodes implanted to localise seizure onset. Diffusion-weighted magnetic resonance imaging (dMRI) may be acquired to identify key white matter tracts for surgical avoidance. Here, we investigate whether structural connectivity abnormalities, inferred from dMRI, may be used in conjunction with functional iEEG abnormalities to aid localisation of the epileptogenic zone (EZ), improving surgical outcomes in epilepsy. Methods: We retrospectively investigated data from 43 patients (42% female) with epilepsy who had surgery following iEEG. Twenty-five patients (58%) were free from disabling seizures (ILAE 1 or 2) at one year. Interictal iEEG functional, and dMRI structural connectivity abnormalities were quantified by comparison to a normative map and healthy controls. We explored whether the resection of maximal abnormalities related to improved surgical outcomes, in both modalities individually and concurrently. Additionally, we suggest how connectivity abnormalities may inform the placement of iEEG electrodes pre-surgically using a patient case study. Findings: Seizure freedom was 15 times more likely in patients with resection of maximal connectivity and iEEG abnormalities (p = 0.008). Both modalities separately distinguished patient surgical outcome groups and when used simultaneously, a decision tree correctly separated 36 of 43 (84%) patients. Interpretation: Our results suggest that both connectivity and iEEG abnormalities may localise epileptogenic tissue, and that these two modalities may provide complementary information in pre-surgical evaluations. Funding: This research was funded by UKRI, CDT in Cloud Computing for Big Data, NIH, MRC, Wellcome Trust and Epilepsy Research UK

The effect of cigarette smoke exposure on the development of inflammation in lungs, gut and joints of TNFΔARE mice

The inflammatory cytokine TNF-alpha is a central mediator in many immune-mediated diseases, such as Crohn's disease (CD), spondyloarthritis (SpA) and chronic obstructive pulmonary disease (COPD). Epidemiologic studies have shown that cigarette smoking (CS) is a prominent common risk factor in these TNF-dependent diseases. We exposed TNF Delta ARE mice; in which a systemic TNF-alpha overexpression leads to the development of inflammation; to 2 or 4 weeks of air or CS. We investigated the effect of deregulated TNF expression on CS-induced pulmonary inflammation and the effect of CS exposure on the initiation and progression of gut and joint inflammation. Upon 2 weeks of CS exposure, inflammation in lungs of TNF Delta ARE mice was significantly aggravated. However, upon 4 weeks of CS-exposure, this aggravation was no longer observed. TNF Delta ARE mice have no increases in CD4+ and CD8+ T cells and a diminished neutrophil response in the lungs after 4 weeks of CS exposure. In the gut and joints of TNF Delta ARE mice, 2 or 4 weeks of CS exposure did not modulate the development of inflammation. In conclusion, CS exposure does not modulate gut and joint inflammation in TNF Delta ARE mice. The lung responses towards CS in TNF Delta ARE mice however depend on the duration of CS exposure