A prospective comparison of a noninvasive cardiac output monitor versus esophageal doppler monitor for goal-directed fluid therapy in colorectal surgery patients

Copyright © 2014 International Anesthesia Research Society.BACKGROUND: Goal-directed fluid therapy (GDFT) is associated with improved outcomes after surgery. The esophageal Doppler monitor (EDM) is widely used, but has several limitations. The NICOM, a completely noninvasive cardiac output monitor (Cheetah Medical), may be appropriate for guiding GDFT. No prospective studies have compared the NICOM and the EDM. We hypothesized that the NICOM is not significantly different from the EDM for monitoring during GDFT. METHODS: One hundred adult patients undergoing elective colorectal surgery participated in this study. Patients in phase I (n = 50) had intraoperative GDFT guided by the EDM while the NICOM was connected, and patients in phase II (n = 50) had intraoperative GDFT guided by the NICOM while the EDM was connected. Each patient's stroke volume was optimized using 250- mL colloid boluses. Agreement between the monitors was assessed, and patient outcomes (postoperative pain, nausea, and return of bowel function), complications (renal, pulmonary, infectious, and wound complications), and length of hospital stay (LOS) were compared. RESULTS: Using a 10% increase in stroke volume after fluid challenge, agreement between monitors was 60% at 5 minutes, 61% at 10 minutes, and 66% at 15 minutes, with no significant systematic disagreement (McNemar P > 0.05) at any time point. The EDM had significantly more missing data than the NICOM. No clinically significant differences were found in total LOS or other outcomes. The mean LOS was 6.56 ± 4.32 days in phase I and 6.07 ± 2.85 days in phase II, and 95% confidence limits for the difference were -0.96 to +1.95 days (P = 0.5016). CONCLUSIONS: The NICOM performs similarly to the EDM in guiding GDFT, with no clinically significant differences in outcomes, and offers increased ease of use as well as fewer missing data points. The NICOM may be a viable alternative monitor to guide GDFT.

An identity-based motivational model of the effects of perceived discrimination on health-related behaviors

Perceived discrimination is associated with increased engagement in unhealthy behaviors. We propose an identity-based pathway to explain this link. Drawing on an identity-based motivation model of health behaviors (Oyserman, Fryberg, & Yoder, 2007), we propose that erceptions of discrimination lead individuals to engage in ingroup-prototypical behaviors in the service of validating their identity and creating a sense of ingroup belonging. To the extent that people perceive unhealthy behaviors as ingroup-prototypical, perceived discrimination may thus increase motivation to engage in unhealthy behaviors. We describe our theoretical model and two studies that demonstrate initial support for some paths in this model. In Study 1, African American participants who reflected on racial discrimination were more likely to endorse unhealthy ingroup-prototypical behavior as self-characteristic than those who reflected on a neutral event. In Study 2, among African American participants who perceived unhealthy behaviors to be ingroup-prototypical, discrimination predicted greater endorsement of unhealthy behaviors as self-characteristic as compared to a control condition. These effects held both with and without controlling for body mass index (BMI) and income. Broader implications of this model for how discrimination adversely affects health-related decisions are discussed.

The effects of aging on the BTBR mouse model of autism spectrum disorder.

Autism spectrum disorder (ASD) is a complex heterogeneous neurodevelopmental disorder characterized by alterations in social functioning, communicative abilities, and engagement in repetitive or restrictive behaviors. The process of aging in individuals with autism and related neurodevelopmental disorders is not well understood, despite the fact that the number of individuals with ASD aged 65 and older is projected to increase by over half a million individuals in the next 20 years. To elucidate the effects of aging in the context of a modified central nervous system, we investigated the effects of age on the BTBR T + tf/j mouse, a well characterized and widely used mouse model that displays an ASD-like phenotype. We found that a reduction in social behavior persists into old age in male BTBR T + tf/j mice. We employed quantitative proteomics to discover potential alterations in signaling systems that could regulate aging in the BTBR mice. Unbiased proteomic analysis of hippocampal and cortical tissue of BTBR mice compared to age-matched wild-type controls revealed a significant decrease in brain derived neurotrophic factor and significant increases in multiple synaptic markers (spinophilin, Synapsin I, PSD 95, NeuN), as well as distinct changes in functional pathways related to these proteins, including "Neural synaptic plasticity regulation" and "Neurotransmitter secretion regulation." Taken together, these results contribute to our understanding of the effects of aging on an ASD-like mouse model in regards to both behavior and protein alterations, though additional studies are needed to fully understand the complex interplay underlying aging in mouse models displaying an ASD-like phenotype.

Hippocampal Transcriptomic and Proteomic Alterations in the BTBR Mouse Model of Autism Spectrum Disorder.

Autism spectrum disorders (ASD) are complex heterogeneous neurodevelopmental disorders of an unclear etiology, and no cure currently exists. Prior studies have demonstrated that the black and tan, brachyury (BTBR) T+ Itpr3tf/J mouse strain displays a behavioral phenotype with ASD-like features. BTBR T+ Itpr3tf/J mice (referred to simply as BTBR) display deficits in social functioning, lack of communication ability, and engagement in stereotyped behavior. Despite extensive behavioral phenotypic characterization, little is known about the genes and proteins responsible for the presentation of the ASD-like phenotype in the BTBR mouse model. In this study, we employed bioinformatics techniques to gain a wide-scale understanding of the transcriptomic and proteomic changes associated with the ASD-like phenotype in BTBR mice. We found a number of genes and proteins to be significantly altered in BTBR mice compared to C57BL/6J (B6) control mice controls such as BDNF, Shank3, and ERK1, which are highly relevant to prior investigations of ASD. Furthermore, we identified distinct functional pathways altered in BTBR mice compared to B6 controls that have been previously shown to be altered in both mouse models of ASD, some human clinical populations, and have been suggested as a possible etiological mechanism of ASD, including "axon guidance" and "regulation of actin cytoskeleton." In addition, our wide-scale bioinformatics approach also discovered several previously unidentified genes and proteins associated with the ASD phenotype in BTBR mice, such as Caskin1, suggesting that bioinformatics could be an avenue by which novel therapeutic targets for ASD are uncovered. As a result, we believe that informed use of synergistic bioinformatics applications represents an invaluable tool for elucidating the etiology of complex disorders like ASD.

Fluid management and goal-directed therapy as an adjunct to Enhanced Recovery After Surgery (ERAS)

© 2014, Canadian Anesthesiologists' Society.Optimal perioperative fluid management is an important component of Enhanced Recovery After Surgery (ERAS) pathways. Fluid management within ERAS should be viewed as a continuum through the preoperative, intraoperative, and postoperative phases. Each phase is important for improving patient outcomes, and suboptimal care in one phase can undermine best practice within the rest of the ERAS pathway. The goal of preoperative fluid management is for the patient to arrive in the operating room in a hydrated and euvolemic state. To achieve this, prolonged fasting is not recommended, and routine mechanical bowel preparation should be avoided. Patients should be encouraged to ingest a clear carbohydrate drink two to three hours before surgery. The goals of intraoperative fluid management are to maintain central euvolemia and to avoid excess salt and water. To achieve this, patients undergoing surgery within an enhanced recovery protocol should have an individualized fluid management plan. As part of this plan, excess crystalloid should be avoided in all patients. For low-risk patients undergoing low-risk surgery, a “zero-balance” approach might be sufficient. In addition, for most patients undergoing major surgery, individualized goal-directed fluid therapy (GDFT) is recommended. Ultimately, however, the additional benefit of GDFT should be determined based on surgical and patient risk factors. Postoperatively, once fluid intake is established, intravenous fluid administration can be discontinued and restarted only if clinically indicated. In the absence of other concerns, detrimental postoperative fluid overload is not justified and “permissive oliguria” could be tolerated.

A Model of Lung Tumor Angiogenesis in a Biomimetic Poly(ethylene glycol)-based Hydrogel System

Tumor angiogenesis is critical to tumor growth and metastasis, yet much is unknown about the role vascular cells play in the tumor microenvironment. A major outstanding challenge associated with studying tumor angiogenesis is that existing preclinical models are limited in their recapitulation of in vivo cellular organization in 3D. This disparity highlights the need for better approaches to study the dynamic interplay of relevant cells and signaling molecules as they are organized in the tumor microenvironment. In this thesis, we combined 3D culture of lung adenocarcinoma cells with adjacent 3D microvascular cell culture in 2-layer cell-adhesive, proteolytically-degradable poly(ethylene glycol) (PEG)-based hydrogels to study tumor angiogenesis and the impacts of neovascularization on tumor cell behavior.

In initial studies, 344SQ cells, a highly metastatic, murine lung adenocarcinoma cell line, were characterized alone in 3D in PEG hydrogels. 344SQ cells formed spheroids in 3D culture and secreted proangiogenic growth factors into the conditioned media that significantly increased with exposure to transforming growth factor beta 1 (TGF-β1), a potent tumor progression-promoting factor. Vascular cells alone in hydrogels formed tubule networks with localized activated TGF-β1. To study cancer cell-vascular cell interactions, the engineered 2-layer tumor angiogenesis model with 344SQ and vascular cell layers was employed. Large, invasive 344SQ clusters developed at the interface between the layers, and were not evident further from the interface or in control hydrogels without vascular cells. A modified model with spatially restricted 344SQ and vascular cell layers confirmed that observed 344SQ cluster morphological changes required close proximity to vascular cells. Additionally, TGF-β1 inhibition blocked endothelial cell-driven 344SQ migration.

Two other lung adenocarcinoma cell lines were also explored in the tumor angiogenesis model: primary tumor-derived metastasis-incompetent, murine 393P cells and primary tumor-derived metastasis-capable human A549 cells. These lung cancer cells also formed spheroids in 3D culture and secreted proangiogenic growth factors into the conditioned media. Epithelial morphogenesis varied for the primary tumor-derived cell lines compared to 344SQ cells, with far less epithelial organization present in A549 spheroids. Additionally, 344SQ cells secreted the highest concentration of two of the three angiogenic growth factors assessed. This finding correlated to 344SQ exhibiting the most pronounced morphological response in the tumor angiogenesis model compared to the 393P and A549 cell lines.

Overall, this dissertation demonstrates the development of a novel 3D tumor angiogenesis model that was used to study vascular cell-cancer cell interactions in lung adenocarcinoma cell lines with varying metastatic capacities. Findings in this thesis have helped to elucidate the role of vascular cells in tumor progression and have identified differences in cancer cell behavior in vitro that correlate to metastatic capacity, thus highlighting the usefulness of this model platform for future discovery of novel tumor angiogenesis and tumor progression-promoting targets.