A model of late long-term potentiation simulates aspects of memory maintenance.

Late long-term potentiation (L-LTP) denotes long-lasting strengthening of synapses between neurons. L-LTP appears essential for the formation of long-term memory, with memories at least partly encoded by patterns of strengthened synapses. How memories are preserved for months or years, despite molecular turnover, is not well understood. Ongoing recurrent neuronal activity, during memory recall or during sleep, has been hypothesized to preferentially potentiate strong synapses, preserving memories. This hypothesis has not been evaluated in the context of a mathematical model representing ongoing activity and biochemical pathways important for L-LTP. In this study, ongoing activity was incorporated into two such models - a reduced model that represents some of the essential biochemical processes, and a more detailed published model. The reduced model represents synaptic tagging and gene induction simply and intuitively, and the detailed model adds activation of essential kinases by Ca(2+). Ongoing activity was modeled as continual brief elevations of Ca(2+). In each model, two stable states of synaptic strength/weight resulted. Positive feedback between synaptic weight and the amplitude of ongoing Ca(2+) transients underlies this bistability. A tetanic or theta-burst stimulus switches a model synapse from a low basal weight to a high weight that is stabilized by ongoing activity. Bistability was robust to parameter variations in both models. Simulations illustrated that prolonged periods of decreased activity reset synaptic strengths to low values, suggesting a plausible forgetting mechanism. However, episodic activity with shorter inactive intervals maintained strong synapses. Both models support experimental predictions. Tests of these predictions are expected to further understanding of how neuronal activity is coupled to maintenance of synaptic strength. Further investigations that examine the dynamics of activity and synaptic maintenance can be expected to help in understanding how memories are preserved for up to a lifetime in animals including humans.

Ontogeny and regulation of interleukin-7 expressing thymic epithelial cells

T cell development is a multistage process of differentiation that depends on proper thymocyte-thymic epithelial cell (TEC) interactions. Epithelial cells in the thymus are organized in a three-dimensional network that provides support and signals for thymocyte maturation. Concurrently, proper TEC differentiation in the adult thymus relies on thymocyte-derived signals. TECs produce interleukin-7 (IL-7), a non-redundant cytokine that promotes the survival, differentiation, and proliferation of thymocytes. We have identified IL-7 expressing TECs throughout ontogeny and in the adult thymus by in situ hybridization analysis. IL-7 expression is initiated in the thymic fated domain of the thymic primordium by embryonic day 11.5, in a Foxn1 independent pathway. Marked changes occur in the localization and regulation of IL-7 expressing TECs during development. Whereas IL-7 expressing TECs are present throughout the early thymic rudiment, the majority of IL-7 producing TECs are concentrated in the adult thymic medulla. By analyzing mouse strains that sustain blocks at different stages of thymocyte development, we show that IL-7 expression is initiated independently of hematopoietic-derived signals during thymic organogenesis. However, thymocyte-derived signals play an essential role in regulating IL-7 expression in the adult TEC compartment. Furthermore, distinct thymocyte subsets regulate the expression of IL-7 and keratin 5 in adult cortical epithelium. Intraperitoneal injection of Recombination Activating Gene deficient mice (RAG-2−/−) with anti-CD3ϵ monoclonal antibody (mAb) induces CD4− 8− double negative thymocytes to undergo β-selection and differentiate into CD4+8+ cells. Analysis of the thymic stromal compartment reveals that progression through β-selection renders thymocytes competent to alter the pattern of IL-7 expression in the cortical TEC compartment. RAG-2−/− mice do not generate mature T cells and therefore the RAG-2−/− thymus is devoid of organized medullary regions. Histological examination of RAG-2−/− thymus following anti-CD3ϵ stimulation reveals the emergence of mature thymic medullary regions, as assessed by H & E staining and expression of thymic stromal medullary markers. Stromal medullary reorganization occurs in the absence of T cell receptor αβ expression, suggesting that activation of RAG-2−/− thymocytes by CD3ϵ ligation generates thymocyte-derived signals that induce thymic epithelial reorganization, generating a mature medullary compartment. This model provides a tool to assess the mechanisms underlying thymic medullary development. ^

ASSESSMENT OF SKELETAL MUSCLE BLOOD FLOW AND GLUCOSE METABOLISM WITH POSITRON EMITTING RADIONUCLIDES

In order to evaluate factors regulating substrate metabolism in vivo positron emitting radionuclides were used for the assessment of skeletal muscle blood flow and glucose utilization. The potassium analog, Rb-82 was used to measure skeletal muscle blood flow and the glucose analog, 18-F-2-deoxy-2-fluoro-D-glucose (FDG) was used to examine the kinetics of skeletal muscle transport and phosphorylation.^ New Zealand white rabbits' blood flow ranged from 1.0-70 ml/min/100g with the lowest flows occurring under baseline conditions and the highest flows were measured immediately after exercise. Elevated plasma glucose had no effect on increasing blood flow, whereas high physiologic to pharmacologic levels of insulin doubled flow as measured by the radiolabeled microspheres, but a proportionate increase was not detected by Rb-82. The data suggest that skeletal muscle blood flow can be measured using the positron emitting K+ analog Rb-82 under low flow and high flow conditions but not when insulin levels in the plasma are elevated. This may be due to the fact that insulin induces an increase in the Na+/K+-ATPase activity of the cell indirectly through a direct increase in the Na+/H+pump activity. This suggests that the increased cation pump activity counteracts the normal decrease in extraction seen at higher flows resulting in an underestimation of flow as measured by rubidium-82.^ Glucose uptake as measured by FDG employed a three compartment mathematical model describing the rates of transport, countertransport and phosphorylation of hexose. The absolute values for the metabolic rate of FDG were found to be an order of magnitude higher than those reported by other investigators. Changes noted in the rate constant for transport (k1) were found to disagree with the a priori information on the effects of insulin on skeletal muscle hexose transport. Glucose metabolism was however, found to increase above control levels with administration of insulin and electrical stimulation. The data indicate that valid measurements of skeletal muscle glucose transport and phosphorylation using the positron emitting glucose analog FDG requires further model application and biochemical validation. (Abstract shortened with permission of author.) ^

CHARACTERIZING, ASSESSING AND IMPROVING HEALTHCARE REFERRAL COMMUNICATION

Similar to other health care processes, referrals are susceptible to breakdowns. These breakdowns in the referral process can lead to poor continuity of care, slow diagnostic processes, delays and repetition of tests, patient and provider dissatisfaction, and can lead to a loss of confidence in providers. These facts and the necessity for a deeper understanding of referrals in healthcare served as the motivation to conduct a comprehensive study of referrals. The research began with the real problem and need to understand referral communication as a mean to improve patient care. Despite previous efforts to explain referrals and the dynamics and interrelations of the variables that influence referrals there is not a common, contemporary, and accepted definition of what a referral is in the health care context. The research agenda was guided by the need to explore referrals as an abstract concept by: 1) developing a conceptual definition of referrals, and 2) developing a model of referrals, to finally propose a 3) comprehensive research framework. This dissertation has resulted in a standard conceptual definition of referrals and a model of referrals. In addition a mixed-method framework to evaluate referrals was proposed, and finally a data driven model was developed to predict whether a referral would be approved or denied by a specialty service. The three manuscripts included in this dissertation present the basis for studying and assessing referrals using a common framework that should allow an easier comparative research agenda to improve referrals taking into account the context where referrals occur.

Effect of VEGF treatment on the blood-spinal cord barrier permeability in experimental spinal cord injury: dynamic contrast-enhanced magnetic resonance imaging.

Compromised blood-spinal cord barrier (BSCB) is a factor in the outcome following traumatic spinal cord injury (SCI). Vascular endothelial growth factor (VEGF) is a potent stimulator of angiogenesis and vascular permeability. The role of VEGF in SCI is controversial. Relatively little is known about the spatial and temporal changes in the BSCB permeability following administration of VEGF in experimental SCI. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) studies were performed to noninvasively follow spatial and temporal changes in the BSCB permeability following acute administration of VEGF in experimental SCI over a post-injury period of 56 days. The DCE-MRI data was analyzed using a two-compartment pharmacokinetic model. Animals were assessed for open field locomotion using the Basso-Beattie-Bresnahan score. These studies demonstrate that the BSCB permeability was greater at all time points in the VEGF-treated animals compared to saline controls, most significantly in the epicenter region of injury. Although a significant temporal reduction in the BSCB permeability was observed in the VEGF-treated animals, BSCB permeability remained elevated even during the chronic phase. VEGF treatment resulted in earlier improvement in locomotor ability during the chronic phase of SCI. This study suggests a beneficial role of acutely administered VEGF in hastening neurobehavioral recovery after SCI.

Prediction of sepsis in the burn intensive care unit patient

Sepsis is a significant cause for multiple organ failure and death in the burn patient, yet identification in this population is confounded by chronic hypermetabolism and impaired immune function. The purpose of this study was twofold: 1) determine the ability of the systemic inflammatory response syndrome (SIRS) and American Burn Association (ABA) criteria to predict sepsis in the burn patient; and 2) develop a model representing the best combination of clinical predictors associated with sepsis in the same population. A retrospective, case-controlled, within-patient comparison of burn patients admitted to a single intensive care unit (ICU) was conducted for the period January 2005 to September 2010. Blood culture results were paired with clinical condition: "positive-sick"; "negative-sick", and "screening-not sick". Data were collected for the 72 hours prior to each blood culture. The most significant predictors were evaluated using logistic regression, Generalized Estimating Equations (GEE) and ROC area under the curve (AUC) analyses to assess model predictive ability. Bootstrapping methods were employed to evaluate potential model over-fitting. Fifty-nine subjects were included, representing 177 culture periods. SIRS criteria were not found to be associated with culture type, with an average of 98% of subjects meeting criteria in the 3 days prior. ABA sepsis criteria were significantly different among culture type only on the day prior (p = 0.004). The variables identified for the model included: heart rate>130 beats/min, mean blood pressure<60 mmHg, base deficit<-6 mEq/L, temperature>36°C, use of vasoactive medications, and glucose>150 mg/d1. The model was significant in predicting "positive culture-sick" and sepsis state, with AUC of 0.775 (p < 0.001) and 0.714 (p < .001), respectively; comparatively, the ABA criteria AUC was 0.619 (p = 0.028) and 0.597 (p = .035), respectively. SIRS criteria are not appropriate for identifying sepsis in the burn population. The ABA criteria perform better, but only for the day prior to positive blood culture results. The time period useful to diagnose sepsis using clinical criteria may be limited to 24 hours. A combination of predictors is superior to individual variable trends, yet algorithms or computer support will be necessary for the clinician to find such models useful. ^

Quality of care for uninsured type 2 diabetic patients in a financial assistance medical home model

The medically uninsured population in the United States is 16% or 42 million people and consists of a significant number of Type 2 diabetic patients which is the predominant form of diabetes with 798,000 new cases diagnosed each year. There is limited health services research on uninsured populations concerning health system measures or specific disease conditions. ^ The purpose of this investigation was to determine the impact a newly implemented health care program had on the quality of care provided to patients with Type 2 diabetes. The primary study objective was to compare the quality of care while controlling for utilization, and health status of patients in the new program to their status during the previous financial assistance program. The research design was a retrospective matched-pairs design. The study population consisted of 225 patients who received medical care during 1996 and 1997 at the University Health System in San Antonio, Texas. ^ Six quality of care measures individually failed to demonstrate a statistically significant difference when compared between the two periods. However, an index measure reflecting the number of patients who received all six of the quality of care measures demonstrated a statistically significant increase in 1997 (p-value < 0.05). In 1996, 8 patients (2.6%) received all six medical management components. In 1997, 38 patients (16.8%) received all six medical management components. Four regression models were analyzed; two out of the four models demonstrated inconsistent results based on the program membership variable. ^ It is concluded that there has been a small effect of the Carelink program demonstrated by an increase from 8 to 38 patients receiving all quality of care components for Type 2 diabetics at the UHS. It is recommended that additional research be conducted in order to evaluate the quality of care provided to Type 2 diabetic patients. ^

Concomitant Mycobacterium tuberculosis infection and type 2 diabetes: A descriptive model with global health implications

The type 2 diabetes (diabetes) pandemic is recognized as a threat to tuberculosis (TB) control worldwide. This secondary data analysis project estimated the contribution of diabetes to TB in a binational community on the Texas-Mexico border where both diseases occur. Newly-diagnosed TB patients > 20 years of age were prospectively enrolled at Texas-Mexico border clinics between January 2006 and November 2008. Upon enrollment, information regarding social, demographic, and medical risks for TB was collected at interview, including self-reported diabetes. In addition, self-reported diabetes was supported by blood-confirmation according to guidelines published by the American Diabetes Association (ADA). For this project, data was compared to existing statistics for TB incidence and diabetes prevalence from the corresponding general populations of each study site to estimate the relative and attributable risks of diabetes to TB. In concordance with historical sociodemographic data provided for TB patients with self-reported diabetes, our TB patients with diabetes also lacked the risk factors traditionally associated with TB (alcohol abuse, drug abuse, history of incarceration, and HIV infection); instead, the majority of our TB patients with diabetes were characterized by overweight/obesity, chronic hyperglycemia, and older median age. In addition, diabetes prevalence among our TB patients was significantly higher than in the corresponding general populations. Findings of this study will help accurately characterize TB patients with diabetes, thus aiding in the timely recognition and diagnosis of TB in a population not traditionally viewed as at-risk. We provide epidemiological and biological evidence that diabetes continues to be an increasingly important risk factor for TB.^