Regional Symmetry of the Pelvis

Understanding the left-right symmetry of the pelvis can assist with the virtual reconstruction of fractured pelvises in the future. Further specifying the different regions can give more information regarding the anatomy of the bone. CT scans of intact pelvises are turned into 3D models using a computer program called Mimics. The femurs and spine are removed manually to isolate the bone. The model can then be analyzed and the regions defined. The pelvis is split into three pieces using the program Geomagic, the iliac, acetabular, and pubic rami regions. The two cuts are made based around the highest and lowest points of the acetabular cup. From here each cut piece can be mirrored and aligned with the opposing side of the pelvis. Colour deviation maps can then be generated to visualize the asymmetry, as well as the RMS value and the percentage of points within a 2 mm deviation threshold. The average RMS values are below 2 mm and the percentage of points within 2 mm is high. My research reflects that the pelvis is symmetrical and may be used to assist in the surgical planning process of pelvic fractures

3D Models of Fractured Pelvic Bones for Analysis of Symmetry and Deviation

Pelvic fractures are a fairly common result of falls, automobile collisions, or other direct impact incidents. Most fractures are relatively mild and not life-threatening, but severe damage may have debilitating effects on the victim's health and quality of life. Pelvic breakage often requires surgery to alleviate, but procedures may be difficult given the complex anatomical structure of the area and the specific location of the fractures. This project aimed to make the planning stage easier for surgeons by analyzing left-right symmetry of the pelvis and using this property to create, in cases where one side is fractured and the other remains intact, 3D models of reconstructed pelvic fractures. Pelvic bone has been proven to be highly symmetrical. This method would provide surgeons with a clearer idea of how to best reassemble and otherwise correct fractures in the pelvis. First, various one-sided pelvic fractures from a batch of anonymized subjects obtained from the University of Alberta Hospital were digitized in medical imaging software. Data from six subjects in total was used in the collection of results. The digitized pelvises were then used to construct 3D models. The fractured pieces were aligned in best-fit with a mirrored intact side. Colour deviation maps, which differentiated between areas of high and low symmetry by measuring the degree of point deviance against a scale, were then generated. Deviance was generally more prevalent along the fracture lines. The predefined threshold considered a maximum of 2 mm of deviation as highly symmetrical. The average RMS value was found to be 1.65 mm and the average percentage of points within 2 mm of difference was 85.1%, indicating that the pelvic bones studied possessed a reasonably high degree of left-right symmetry. The results from this study suggest that this virtual reconstruction method is reliable for use in surgical planning for one-sided pelvic fractures

FL118, a novel camptothecin derivative, is insensitive to ABCG2 expression and shows improved efficacy in comparison with irinotecan in colon and lung cancer models with ABCG2-induced resistance

International audienceAbstractBackgroundIrinotecan is a camptothecin analogue currently used in clinical practice to treat advanced colorectal cancer. However, acquired resistance mediated by the drug efflux pump ABCG2 is a recognized problem. We reported on a novel camptothecin analogue, FL118, which shows anticancer activity superior to irinotecan. In this study, we sought to investigate the potency of FL118 versus irinotecan or its active metabolite, SN-38, in both in vitro and in vivo models of human cancer with high ABCG2 activity. We also sought to assess the potency and ABCG2 affinity of several FL118 analogues with B-ring substitutions.MethodsColon and lung cancer cells with and without ABCG2 overexpression were treated with FL118 in the presence and absence of Ko143, an ABCG2-selective inhibitor, or alternatively by genetically modulating ABCG2 expression. Using two distinct in vivo human tumor animal models, we further assessed whether FL118 could extend time to progression in comparison with irinotecan. Lastly, we investigated a series of FL118 analogues with B-ring substitutions for ABCG2 sensitivity.ResultsBoth pharmacological inhibition and genetic modulation of ABCG2 demonstrated that, in contrast to SN-38, FL118 was able to bypass ABCG2-mediated drug resistance. FL118 also extended time to progression in both in vivo models by more than 50% compared with irinotecan. Lastly, we observed that FL118 analogues with polar substitutions had higher affinity for ABCG2, suggesting that the nonpolar nature of FL118 plays a role in bypassing ABCG2-mediated resistance.ConclusionsOur results suggest that in contrast to SN-38 and topotecan, FL118 is a poor substrate for ABCG2 and can effectively overcome ABCG2-mediated drug resistance. Our findings expand the uniqueness of FL118 and support continued development of FL118 as an attractive therapeutic option for patients with drug-refractory cancers resulting from high expression of ABCG2

Development of a wearable bioartificial kidney using the Bioartificial Renal Epithelial Cell System (BRECS)

Cell therapy for the treatment of renal failure in the acute setting has proved successful, with therapeutic impact, yet development of a sustainable, portable bioartificial kidney for treatment of chronic renal failure has yet to be realized. Challenges in maintaining an anticoagulated blood circuit, the typical platform for solute clearance and support of the biological components, have posed a major hurdle in advancement of this technology. This group has developed a Bioartificial Renal Epithelial Cell System (BRECS) capable of differentiated renal cell function while sustained by body fluids other than blood. To evaluate this device for potential use in endâ stage renal disease, a large animal model was established that exploits peritoneal dialysis fluid for support of the biological device and delivery of cell therapy while providing uraemic control. Anephric sheep received a continuous flow peritoneal dialysis (CFPD) circuit that included a BRECS. Sheep were treated with BRECS containing 1 à  108 renal epithelial cells or acellular sham devices for up to 7 days. The BRECS cell viability and activity were maintained with extracorporeal peritoneal fluid circulation. A systemic immunological effect of BRECS therapy was observed as cellâ treated sheep retained neutrophil oxidative activity better than shamâ treated animals. This model demonstrates that use of the BRECS within a CFPD circuit embodies a feasible approach to a sustainable and effective wearable bioartificial kidney. Copyright © 2016 John Wiley & Sons, Ltd.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140038/1/term2206.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/140038/2/term2206_am.pd

Translation of immunomodulatory therapy to treat chronic heart failure: Preclinical studies to first in human

BACKGROUND: Inflammation has been associated with progression and complications of chronic heart failure (HF) but no effective therapy has yet been identified to treat this dysregulated immunologic state. The selective cytopheretic device (SCD) provides extracorporeal autologous cell processing to lessen the burden of inflammatory activity of circulating leukocytes of the innate immunologic system. AIM: The objective of this study was to evaluate the effects of the SCD as an extracorporeal immunomodulatory device on the immune dysregulated state of HF. HF. METHODS AND RESULTS: SCD treatment in a canine model of systolic HF or HF with reduced ejection fraction (HFrEF) diminished leukocyte inflammatory activity and enhanced cardiac performance as measured by left ventricular (LV) ejection fraction and stroke volume (SV) up to 4 weeks after treatment initiation. Translation of these observations in first in human, proof of concept clinical study was evaluated in a patient with severe HFrEFHFrEF ineligible for cardiac transplantation or LV LV assist device (LVAD) due to renal insufficiency and right ventricular dysfunction. Six hour SCD treatments over 6 consecutive days resulted in selective removal of inflammatory neutrophils and monocytes and reduction in key plasma cytokines, including tumor necrosis factor-alpha (TNF-α),), interleukin (IL)-6, IL-8, and monocyte chemoattractant protein (MCP)-1. These immunologic changes were associated with significant improvements in cardiac power output, right ventricular stroke work index, cardiac index and LVSV index…. Stabilization of renal function with progressive volume removal permitted successful LVAD implantation. CONCLUSION: This translational research study demonstrates a promising immunomodulatory approach to improve cardiac performance in HFrEFHFrEF and supports the important role of inflammation in the progression of HFHF

Automated tracking of level of consciousness and delirium in critical illness using deep learning

Over- and under-sedation are common in the ICU, and contribute to poor ICU outcomes including delirium. Behavioral assessments, such as Richmond Agitation-Sedation Scale (RASS) for monitoring levels of sedation and Confusion Assessment Method for the ICU (CAM-ICU) for detecting signs of delirium, are often used. As an alternative, brain monitoring with electroencephalography (EEG) has been proposed in the operating room, but is challenging to implement in ICU due to the differences between critical illness and elective surgery, as well as the duration of sedation. Here we present a deep learning model based on a combination of convolutional and recurrent neural networks that automatically tracks both the level of consciousness and delirium using frontal EEG signals in the ICU. For level of consciousness, the system achieves a median accuracy of 70% when allowing prediction to be within one RASS level difference across all patients, which is comparable or higher than the median technician-nurse agreement at 59%. For delirium, the system achieves an AUC of 0.80 with 69% sensitivity and 83% specificity at the optimal operating point. The results show it is feasible to continuously track level of consciousness and delirium in the ICU

The broad-spectrum antiviral favipiravir protects guinea pigs from lethal Lassa virus infection post-disease onset

With up to 500,000 infections annually, Lassa virus (LASV), the cause of Lassa fever, is one of the most prevalent etiological agents of viral hemorrhagic fever (VHF) in humans. LASV is endemic in several West African countries with sporadic cases and prolonged outbreaks observed most commonly in Sierra Leone, Liberia, Guinea and Nigeria. Additionally several cases of Lassa fever have been imported into North America, Europe and Asia making LASV a global threat to public health. Despite this, currently no approved therapeutic or vaccine exists to treat or prevent LASV infections. Here, using a passaged strain of LASV that is uniformly lethal in Hartley guinea pigs, we demonstrate that favipiravir, a broad-spectrum antiviral agent and leading treatment option for influenza, has potent activity against LASV infection. In this model, once daily treatment with favipiravir significantly reduced viral titers in tissue samples and reduced mortality rates when compared with animals receiving vehicle-only or ribavirin, the current standard of care for Lassa fever. Favipiravir remained highly effective against lethal LASV infection when treatments were initiated nine days post-infection, a time when animals were demonstrating advanced signs of disease. These results support the further preclinical evaluation of favipiravir for Lassa fever and other VHFs

A Biomimetic Membrane Device That Modulates the Excessive Inflammatory Response to Sepsis

OBJECTIVE: Septic shock has a clinical mortality rate approaching fifty percent. The major clinical manifestations of sepsis are due to the dysregulation of the host's response to infection rather than the direct consequences of the invading pathogen. Central to this initial immunologic response is the activation of leukocytes and microvascular endothelium resulting in cardiovascular instability, lung injury and renal dysfunction. Due to the primary role of leukocyte activation in the sepsis syndrome, a synthetic biomimetic membrane, called a selective cytopheretic device (SCD), was developed to bind activated leukocytes. The incorporation of the SCD along an extracorporeal blood circuit coupled with regional anticoagulation with citrate to lower blood ionized calcium was devised to modulate leukocyte activation in sepsis. DESIGN: Laboratory investigation. SETTING: University of Michigan Medical School. SUBJECTS: Pigs weighing 30-35 kg. INTERVENTIONS: To assess the effect of the SCD in septic shock, pigs were administered 30×10(10) bacteria/kg body weight of Escherichia coli into the peritoneal cavity and within 1 hr were immediately placed in an extracorporeal circuit containing SCD. MEASUREMENTS AND MAIN RESULTS: In this animal model, the SCD with citrate compared to control groups without the SCD or with heparin anticoagulation ameliorated the cardiovascular instability and lung sequestration of activated leukocytes, reduced renal dysfunction and improved survival time compared to various control groups. This effect was associated with minimal elevations of systemic circulating neutrophil activation. CONCLUSIONS: These preclinical studies along with two favorable exploratory clinical trials form the basis of an FDA-approved investigational device exemption for a pivotal multicenter, randomized control trial currently underway

Common Genetic Variants Found in HLA and KIR Immune Genes in Autism Spectrum Disorder

The “common variant—common disease” hypothesis was proposed to explain diseases with strong inheritance. This model suggests that a genetic disease is the result of the combination of several common genetic variants. Common genetic variants are described as a 5% frequency differential between diseased vs. matched control populations. This theory was recently supported by an epidemiology paper stating that about 50% of genetic risk for autism resides in common variants. However, rare variants, rather than common variants, have been found in numerous genome wide genetic studies and many have concluded that the “common variant—common disease” hypothesis is incorrect. One interpretation is that rare variants are major contributors to genetic diseases and autism involves the interaction of many rare variants, especially in the brain. It is obvious there is much yet to be learned about autism genetics. Evidence has been mounting over the years indicating immune involvement in autism, particularly the HLA genes on chromosome 6 and KIR genes on chromosome 19. These two large multigene complexes have important immune functions and have been shown to interact to eliminate unwanted virally infected and malignant cells. HLA proteins have important functions in antigen presentation in adaptive immunity and specific epitopes on HLA class I proteins act as cognate ligands for KIR receptors in innate immunity. Data suggests that HLA alleles and KIR activating genes/haplotypes are common variants in different autism populations. For example, class I allele (HLA-A2 and HLA-G 14 bp-indel) frequencies are significantly increased by more than 5% over control populations (Table 2). The HLA-DR4 Class II and shared epitope frequencies are significantly above the control populations (Table 2). Three activating KIR genes: 3DS1, 2DS1, and 2DS2 have increased frequencies of 15, 22, and 14% in autism populations, respectively. There is a 6% increase in total activating KIR genes in autism over control subjects. And, more importantly there is a 12% increase in activating KIR genes and their cognate HLA alleles over control populations (Torres et al., 2012a). These data suggest the interaction of HLA ligand/KIR receptor pairs encoded on two different chromosomes is more significant as a ligand/receptor complex than separately in autism

Characterization of a Novel STAT 2 Knock Out Hamster Model of Crimean Congo Hemorrhagic Fever Virus Pathogenesis

Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne pathogen causing a febrile illness in humans, which can progress to hemorrhagic manifestations, multi-organ failure, and death. Current mouse models of CCHFV infection reliably succumb to virus challenge but vary in their ability to reflect signs of disease similar to humans. In this study, we established a signal transducer and activator of transcription 2 (STAT2) knockout hamster model to expand the repertoire of animal models of CCHFV pathogenesis that can be used for therapeutic development. These hamsters demonstrated a systemic and lethal disease in response to infection. Hallmarks of human disease were observed including petechial rash, blood coagulation dysfunction, and various biochemistry and blood cell count abnormalities. Furthermore, we also demonstrated the utility of this model for anti-CCHFV therapeutic evaluation. The STAT2 knock-out hamster model of CCHFV infection may provide some further insights into clinical disease, viral pathogenesis, and pave the way for testing of potential drug and vaccine candidates