Crystalloids versus colloids for goal-directed fluid therapy in major surgery

INTRODUCTION: Perioperative hypovolemia arises frequently and contributes to intestinal hypoperfusion and subsequent postoperative complications. Goal-directed fluid therapy might reduce these complications. The aim of this study was to compare the effects of goal-directed administration of crystalloids and colloids on the distribution of systemic, hepatosplanchnic, and microcirculatory (small intestine) blood flow after major abdominal surgery in a clinically relevant pig model. METHODS: Twenty-seven pigs were anesthetized and mechanically ventilated and underwent open laparotomy. They were randomly assigned to one of three treatment groups: the restricted Ringer lactate (R-RL) group (n = 9) received 3 mL/kg per hour of RL, the goal-directed RL (GD-RL) group (n = 9) received 3 mL/kg per hour of RL and intermittent boluses of 250 mL of RL, and the goal-directed colloid (GD-C) group (n = 9) received 3 mL/kg per hour of RL and boluses of 250 mL of 6% hydroxyethyl starch (130/0.4). The latter two groups received a bolus infusion when mixed venous oxygen saturation was below 60% ('lockout' time of 30 minutes). Regional blood flow was measured in the superior mesenteric artery and the celiac trunk. In the small bowel, microcirculatory blood flow was measured using laser Doppler flowmetry. Intestinal tissue oxygen tension was measured with intramural Clark-type electrodes. RESULTS: After 4 hours of treatment, arterial blood pressure, cardiac output, mesenteric artery flow, and mixed oxygen saturation were significantly higher in the GD-C and GD-RL groups than in the R-RL group. Microcirculatory flow in the intestinal mucosa increased by 50% in the GD-C group but remained unchanged in the other two groups. Likewise, tissue oxygen tension in the intestine increased by 30% in the GD-C group but remained unchanged in the GD-RL group and decreased by 18% in the R-RL group. Mesenteric venous glucose concentrations were higher and lactate levels were lower in the GD-C group compared with the two crystalloid groups. CONCLUSIONS: Goal-directed colloid administration markedly increased microcirculatory blood flow in the small intestine and intestinal tissue oxygen tension after abdominal surgery. In contrast, goal-directed crystalloid and restricted crystalloid administrations had no such effects. Additionally, mesenteric venous glucose and lactate concentrations suggest that intestinal cellular substrate levels were higher in the colloid-treated than in the crystalloid-treated animals. These results support the notion that perioperative goal-directed therapy with colloids might be beneficial during major abdominal surgery.

Goal-directed colloid administration improves the microcirculation of healthy and perianastomotic colon

BACKGROUND: The aim of this study was to compare the effects of goal-directed colloid fluid therapy with goal-directed crystalloid and restricted crystalloid fluid therapy on healthy and perianastomotic colon tissue in a pig model of colon anastomosis surgery. METHODS: Pigs (n = 27, 9 per group) were anesthetized and mechanically ventilated. A hand-sewn colon anastomosis was performed. The animals were subsequently randomized to one of the following treatments: R-RL group, 3 ml x kg(-1) x h(-1) Ringer lactate (RL); GD-RL group, 3 ml x kg(-1) x h(-1) RL + bolus 250 ml of RL; GD-C group, 3 ml x kg(-1) x h(-1) RL + bolus 250 ml of hydroxyethyl starch (HES 6%, 130/0.4). A fluid bolus was administered when mixed venous oxygen saturation dropped below 60%. Intestinal tissue oxygen tension and microcirculatory blood flow were measured continuously. RESULTS: After 4 h of treatment, tissue oxygen tension in healthy colon increased to 150 +/- 31% in group GD-C versus 123 +/- 40% in group GD-RL versus 94 +/- 23% in group R-RL (percent of postoperative baseline values, mean +/- SD; P < 0.01). Similarly perianastomotic tissue oxygen tension increased to 245 +/- 93% in the GD-C group versus 147 +/- 58% in the GD-RL group and 116 +/- 22% in the R-RL group (P < 0.01). Microcirculatory flow was higher in group GD-C in healthy colon. CONCLUSIONS: Goal-directed colloid fluid therapy significantly increased microcirculatory blood flow and tissue oxygen tension in healthy and injured colon compared to goal-directed or restricted crystalloid fluid therapy.

Cyclic automorphic graph decompositions

Chapter 1 introduces the tools and mechanics necessary for this report. Basic definitions and topics of graph theory which pertain to the report and discussion of automorphic decompositions will be covered in brief detail. An automorphic decomposition D of a graph H by a graph G is a G-decomposition of H such that the intersection of graph (D) @H. H is called the automorhpic host, and G is the automorphic divisor. We seek to find classes of graphs that are automorphic divisors, specifically ones generated cyclically. Chapter 2 discusses the previous work done mainly by Beeler. It also discusses and gives in more detail examples of automorphic decompositions of graphs. Chapter 2 also discusses labelings and their direct relation to cyclic automorphic decompositions. We show basic classes of graphs, such as cycles, that are known to have certain labelings, and show that they also are automorphic divisors. In Chapter 3, we are concerned with 2-regular graphs, in particular rCm, r copies of the m-cycle. We seek to show that rCm has a ρ-labeling, and thus is an automorphic divisor for all r and m. we discuss methods including Skolem type difference sets to create cycle systems and their correlation to automorphic decompositions. In the Appendix, we give classes of graphs known to be graceful and our java code to generate ρ-labelings on rCm.

ANALYSIS AND VISUALIZATION OF FLOW FIELDS USING INFORMATION-THEORETIC TECHNIQUES AND GRAPH-BASED REPRESENTATIONS

Three-dimensional flow visualization plays an essential role in many areas of science and engineering, such as aero- and hydro-dynamical systems which dominate various physical and natural phenomena. For popular methods such as the streamline visualization to be effective, they should capture the underlying flow features while facilitating user observation and understanding of the flow field in a clear manner. My research mainly focuses on the analysis and visualization of flow fields using various techniques, e.g. information-theoretic techniques and graph-based representations. Since the streamline visualization is a popular technique in flow field visualization, how to select good streamlines to capture flow patterns and how to pick good viewpoints to observe flow fields become critical. We treat streamline selection and viewpoint selection as symmetric problems and solve them simultaneously using the dual information channel [81]. To the best of my knowledge, this is the first attempt in flow visualization to combine these two selection problems in a unified approach. This work selects streamline in a view-independent manner and the selected streamlines will not change for all viewpoints. My another work [56] uses an information-theoretic approach to evaluate the importance of each streamline under various sample viewpoints and presents a solution for view-dependent streamline selection that guarantees coherent streamline update when the view changes gradually. When projecting 3D streamlines to 2D images for viewing, occlusion and clutter become inevitable. To address this challenge, we design FlowGraph [57, 58], a novel compound graph representation that organizes field line clusters and spatiotemporal regions hierarchically for occlusion-free and controllable visual exploration. We enable observation and exploration of the relationships among field line clusters, spatiotemporal regions and their interconnection in the transformed space. Most viewpoint selection methods only consider the external viewpoints outside of the flow field. This will not convey a clear observation when the flow field is clutter on the boundary side. Therefore, we propose a new way to explore flow fields by selecting several internal viewpoints around the flow features inside of the flow field and then generating a B-Spline curve path traversing these viewpoints to provide users with closeup views of the flow field for detailed observation of hidden or occluded internal flow features [54]. This work is also extended to deal with unsteady flow fields. Besides flow field visualization, some other topics relevant to visualization also attract my attention. In iGraph [31], we leverage a distributed system along with a tiled display wall to provide users with high-resolution visual analytics of big image and text collections in real time. Developing pedagogical visualization tools forms my other research focus. Since most cryptography algorithms use sophisticated mathematics, it is difficult for beginners to understand both what the algorithm does and how the algorithm does that. Therefore, we develop a set of visualization tools to provide users with an intuitive way to learn and understand these algorithms.

DESIGN AND SYNTHESIS OF MULTIFUNCTIONAL POLYMERIC MICELLES FOR GENE-DIRECTED ENZYME PRODRUG THERAPY

Gene-directed enzyme prodrug therapy is a form of cancer therapy in which delivery of a gene that encodes an enzyme is able to convert a prodrug, a pharmacologically inactive molecule, into a potent cytotoxin. Currently delivery of gene and prodrug is a two-step process. Here, we propose a one-step method using polymer nanocarriers to deliver prodrug, gene and cytotoxic drug simultaneously to malignant cells. Prodrugs acyclovir, ganciclovir and 5-doxifluridine were used to directly to initiate ring-opening polymerization of epsilon-caprolactone, forming a hydrophobic prodrug-tagged poly(epsilon-caprolactone) which was further grafted with hydrophilic polymers (methoxy poly(ethylene glycol), chitosan or polyethylenemine) to form amphiphilic copolymers for micelle formation. Successful synthesis of copolymers and micelle formation was confirmed by standard analytical means. Conversion of prodrugs to their cytotoxic forms was analyzed by both two-step and one-step means i.e. by first delivering gene plasmid into cell line HT29 and then challenging the cells with the prodrug-tagged micelle carriers and secondly by complexing gene plasmid onto micelle nanocarriers and delivery gene and prodrug simultaneously to parental HT29 cells. Anticancer effectiveness of prodrug-tagged micelles was further enhanced by encapsulating chemotherapy drugs doxorubicin or SN-38. Viability of colon cancer cell line HT29 was significantly reduced. Furthermore, in an effort to develop a stealth and targeted carrier, CD47-streptavidin fusion protein was attached onto the micelle surface utilizing biotin-streptavidin affinity. CD47, a marker of self on the red blood cell surface, was used for its antiphagocytic efficacy, results showed that micelles bound with CD47 showed antiphagocytic efficacy when exposed to J774A.1 macrophages. Since CD47 is not only an antiphagocytic ligand but also an integrin associated protein, it was used to target integrin alpha(v)beta(3), which is overexpressed on tumor-activated neovascular endothelial cells. Results showed that CD47-tagged micelles had enhanced uptake when treated to PC3 cells which have high expression of alpha(v)beta(3). The synthesized multifunctional polymeric micelle carriers developed could offer a new platform for an innovative cancer therapy regime.

Multivariate modelling of responses to conditional items: New possibilities for latent class analysis

Questionnaire data may contain missing values because certain questions do not apply to all respondents. For instance, questions addressing particular attributes of a symptom, such as frequency, triggers or seasonality, are only applicable to those who have experienced the symptom, while for those who have not, responses to these items will be missing. This missing information does not fall into the category 'missing by design', rather the features of interest do not exist and cannot be measured regardless of survey design. Analysis of responses to such conditional items is therefore typically restricted to the subpopulation in which they apply. This article is concerned with joint multivariate modelling of responses to both unconditional and conditional items without restricting the analysis to this subpopulation. Such an approach is of interest when the distributions of both types of responses are thought to be determined by common parameters affecting the whole population. By integrating the conditional item structure into the model, inference can be based both on unconditional data from the entire population and on conditional data from subjects for whom they exist. This approach opens new possibilities for multivariate analysis of such data. We apply this approach to latent class modelling and provide an example using data on respiratory symptoms (wheeze and cough) in children. Conditional data structures such as that considered here are common in medical research settings and, although our focus is on latent class models, the approach can be applied to other multivariate models.

VH1-69 germline encoded antibodies directed towards ADAMTS13 in patients with acquired thrombotic thrombocytopenic purpura

BACKGROUND: Autoantibodies directed towards ADAMTS13 are present in the majority of patients with acquired thrombotic thrombocytopenic purpura (TTP). Analysis of a set of antibodies derived from two patients with acquired TTP revealed frequent use of the VH1-69 heavy chain gene segment for the assembly of anti-ADAMTS13 antibodies. OBJECTIVE: We explored the ability of two VH1-69 germline gene-encoded antibodies to inhibit the von Willebrand factor (VWF)-processing activity of ADAMTS13 under different experimental conditions. Furthermore, the presence of VH1-69 encoded anti-ADAMTS13 antibodies in 40 patients with acquired TTP was monitored using monoclonal antibody G8, which specifically reacts with an idiotype expressed on VH1-69 encoded antibodies. METHODS AND RESULTS: Binding of the two VH1-69 encoded monoclonal antibodies was dependent on the presence of the spacer domain. Both antibodies inhibited ADAMTS13 activity under static conditions, as measured by cleavage of FRETS-VWF73 substrate and cleavage of VWF multimers. The recombinant antibodies were also capable of inhibiting the processing of UL-VWF strings on the surface of endothelial cells. G8-reactive antibodies directed towards ADAMTS13 were present in plasma of all patients containing anti ADAMTS13 antibodies. CONCLUSIONS: These results suggest that VH1-69 derived antibodies directed towards ADAMTS13 develop in the majority of patients with acquired TTP.

Autoantibodies directed against bactericidal/permeability-increasing protein in patients with cystic fibrosis: association with microbial respiratory tract colonization

BACKGROUND: Cystic fibrosis (CF) is associated with the appearance of serum autoantibodies directed against bactericidal/permeability-increasing protein (BPI). OBJECTIVES: To determine the age-specific seroprevalence rates of anti-BPI-IgG and IgA in a population of patients with CF and to correlate anti-BPI antibody concentrations with microbial respiratory tract colonization and pulmonary function variables at the time of serum sampling and 6 years thereafter. METHODS: Determination of BPI antibodies of the IgG and IgA isotypes using a commercial enzyme-linked immunosorbent assay in sera of a CF serum bank of 1992; correlation of anti-BPI antibody concentrations with age, clinical score, pulmonary function variables in 1992 and 1998, total serum immunoglobulin isotype concentrations and respiratory tract colonization with Pseudomonas aeruginosa and Aspergillus spp. RESULTS: Seventy-one patients (age in 1992, 14.1 +/- 7.5 years) were studied. Reactivities for anti-BPI-IgG and IgA were found in 28 (39%) and 26 (37%) patients, respectively. The seroprevalence of anti-BPI-IgA, but not IgG, increased significantly with age. P. aeruginosa colonization was associated with elevated concentrations of anti-BPI-IgG (P = 0.003) and IgA (P = 0.037). There were significant negative correlations between pulmonary function variables (vital capacity, forced expiratory volume in 1 s) in 1992 and 1998, respectively, and concentrations of anti-BPI-IgG or IgA in a multiple regression analysis. Anti-BPI-IgG, but not IgA, remained significantly associated with P. aeruginosa colonization (P = 0.006) and with reduced vital capacity (P = 0.01) in 1998 after correction for total serum isotype concentration. CONCLUSIONS: Anti-BPI-IgG are strongly associated with concurrent P. aeruginosa colonization and with long term restrictive pulmonary function abnormalities.