Cardiac antibody production to self-antigens in children and adolescents during and following the correction of severe diabetic ketoacidosis.

Diabetic cardiomyopathy (DC) is an independent phenotype of diabetic cardiovascular disease. The understanding of the pathogenesis of DC in young patients with type 1 diabetes (T1D) is limited. The cardiac insults of diabetic ketoacidosis (DKA) and progression of DC could include development of antibodies (Abs) to cardiac self-antigens (SAgs) such as: myosin (M), vimentin (V) and k-alpha 1 tubulin (Kα1T). The goal of this study is to determine if the insults of severe DKA and its inflammatory cascade are associated with immune responses to SAgs. Development of Abs to the SAgs were determined by an ELISA using sera collected at three time points in relation to severe DKA (pH < 7.2). Results demonstrate significant differences between the development of Abs to VIM and a previously reported diastolic abnormality (DA) during DKA and its treatment and a NDA group at 2-3 months post DKA (p = 0.0452). A significant association is present between T1D duration (<3 years) and Abs to Kα1T (p = 0.0134). Further, Abs to MYO and VIM are associated with inflammatory cytokines. We propose that severe DKA initiates the synthesis of Abs to cardiac SAgs that are involved in the early immunopathogenesis of DC in young patients with T1D.

Increased systemic Th17 cytokines are associated with diastolic dysfunction in children and adolescents with diabetic ketoacidosis.

Diastolic dysfunction suggestive of diabetic cardiomyopathy is established in children with T1DM, but its pathogenesis is not well understood. We studied the relationships of systemic inflammatory cytokines/chemokines and cardiac function in 17 children with T1DM during and after correction of diabetic ketoacidosis (DKA). Twenty seven of the 39 measured cytokines/chemokines were elevated at 6-12 hours into treatment of DKA compared to values after DKA resolution. Eight patients displayed at least one parameter of diastolic abnormality (DA) during acute DKA. Significant associations were present between nine of the cytokine/chemokine levels and the DA over time. Interestingly, four of these nine interactive cytokines (GM-CSF, G-CSF, IL-12p40, IL-17) are associated with a Th17 mediated cell response. Both the DA and CCL7 and IL-12p40, had independent associations with African American patients. Thus, we report occurrence of a systemic inflammatory response and the presence of cardiac diastolic dysfunction in a subset of young T1DM patients during acute DKA.

Empirical evidence of the effectiveness of concept mapping as a learning intervention for nuclear medicine technology students in a distance learning radiation protection and biology course.

UNLABELLED: Metacognitive learning strategies are based on instructional learning theory, which promotes deep, meaningful learning. Educators in a baccalaureate-level nuclear medicine technology program demonstrated that students enrolled in an online, distance learning section of an introductory radiation protection and radiobiology course performed better when traditional instruction was supplemented with nontraditional metacognitive learning strategies. METHODS: The metacognitive learning strategy that was used is best known as concept mapping. The concept map, in addition to the standard homework problem assignment and opportunity for question-answer sessions, became the template for misconception identification and remediation interactions between the instructor and the student. The control group relied on traditional homework problems and question-answer sessions alone. Because students in both the "treatment" groups (i.e., students who used concept mapping) and the control group were distance learning students, all personal communications were conducted via e-mail or telephone. The final examination of the course was used to facilitate a quantitative comparison of the performance of students who used concept mapping and the performance of students who did not use concept mapping. RESULTS: The results demonstrated a significantly higher median final examination score for the concept mapping group than for the non-concept mapping group (z = -2.0381, P = 0.0415), with an appropriately large effect size (2.65). CONCLUSION: Concept mapping is a cognitive learning intervention that effectively enables meaningful learning and is suitable for use in the independent learner-oriented distance learning environments used by some nuclear medicine technology programs.

Development of a concept map to convey understanding of patient and family-centered care.

Even though the expression "Patient and Family-Centered Care (PFCC)" is widely used, there remains a lack of clarity regarding how the fundamental tenets of PFCC fit with our current model of healthcare. The purpose of this manuscript was to describe the first step in developing an organizational understanding of the operational construct for PFCC utilizing a concept map and the fundamental concept mapping learning theories. The overall goals were to build a more robust organization-wide understanding of the basic PFCC tenets guided by the philosophy of concept mapping. The long-range aspirations of this process are to improve safety and quality of life by incorporating the PFCC philosophy in the career development path of our students and healthcare professionals.

Insulin and IGF-1 receptors, nitrotyrosin and cerebral neuronal deficits in two young patients with diabetic ketoacidosis and fatal brain edema.

Gray and white matter structural deficits may accompany type 1 diabetes. Earlier experimental studies have demonstrated neuronal deficits associated with impaired neurotrophic support, inflammation and oxidative stress. In this study we demonstrate in two patients with histories of poorly controlled type 1 diabetes and fatal brain edema of ketoacidosis neuronal deficits associated with a decreased presence of insulin and IGF-1 receptors and accumulation of nitrotyrosin in neurons of affected areas and the choroid plexus. The findings add support to the suggested genesis of T1DM encephalopathy due to compromised neurotrophic protection, oxidative stress, inflammation and neuronal deficits, as demonstrated in T1DM encephalopathy in the BB/Wor-rat.

Receptor for advanced glycation end products and neuronal deficit in the fatal brain edema of diabetic ketoacidosis.

Radiologic and neuropsychologic studies suggest that diabetes mellitus causes structural changes in the brain and adversely effects cognitive development. Experimental animal models of type 1 diabetes mellitus (T1DM) have advanced these findings by demonstrating duration-related neuronal and cognitive deficits in T1DM BB/Wor rats. We studied the expression of receptor for advanced glycation end products (RAGE) and neuronal densities in the brains of two patients who died as the result of clinical brain edema(BE)that developed during the treatment of severe diabetic ketoacidosis (DKA). RAGE was markedly and diffusely expressed in blood vessels, neurons, and the choroid plexus and co-localized with glial fibrillary acidic protein (GFAP) in astrocytes. Significant neuronal loss was seen in the hippocampus and frontal cortex. Astrocytosis was present and white matter was atrophied in both cases when compared to age-matched controls. Our data supports that a neuroinflammatory response occurs in the BE associated with DKA, and that even after a relatively short duration of poorly controlled T1DM, the pathogenesis of primary diabetic encephalopathy can be initiated.

Diabetic ketoacidosis increases extracellular levels of the major inducible 70-kDa heat shock protein.

OBJECTIVES: Diabetic ketoacidosis (DKA) represents a metabolic stress whose treatment induces a systemic proinflammatory cytokine profile and accentuates life-threatening acute complications. The present study determined whether serum levels of the major inducible 70-kDa heat shock protein (Hsp72), a modulator of cytokine expression, were influenced by DKA and its treatment. DESIGN AND METHODS: Serum levels of Hsp72 and glucose were measured in five adolescents with type 1 diabetes mellitus (T1DM) prior to, during and following correction of severe DKA. Samples from nine relatively euglycemic T1DM patients served as controls. RESULTS: DKA pre-treatment samples showed significant elevation in Hsp72 (40.8 +/- 6.9 ng/ml) relative to euglycemic T1DM controls (33.6 +/- 3.2 ng/ml) (P < 0.05). Treatment resulted in a decline in Hsp72 to control levels within 24 h, with Hsp72 and glucose levels being tightly correlated (r = 0.9258). CONCLUSION: Extracellular Hsp72 is increased by DKA, paralleling changes in serum glucose levels.

Retinal vascular integrity following correction of diabetic ketoacidosis in children and adolescents.

OBJECTIVE: Increased permeability of the cerebral microvasculature occurs during the treatment of diabetic ketoacidosis (DKA). Microvascular changes consistent with diabetic retinopathy have been reported prior to and after the treatment of DKA. This study evaluated the structural and functional aspects of the retina immediately following the correction of DKA. METHODS: Seven young patients had comprehensive ophthalmologic examinations, including fluorescein angiography, within 24 h after the correction of severe DKA (pH <7.2). RESULTS: None of the patients had clinical, photographic, or angiographic evidence of a retinal abnormality. CONCLUSION: The blood-retinal barrier (BRB) does not experience the same degree of perturbation as the blood-brain barrier (BBB) does and may be a protected site during the insult of DKA and its treatment. The greater stability of the retinal microvasculature may be due to the increased number of pericytes in the BRB in comparison with the BBB.

Complement activation in diabetic ketoacidosis and its treatment.

Recent studies support the presence of an inflammatory response during the treatment of diabetic ketoacidosis (DKA). The objectives of this study were to monitor the complement activation products C3a, C4a, Bb, and C5b-9 prior to, during, and after correction of DKA. All patients had increased levels of C3a at 6-8 h and 24 h (P<0.05). C4a was increased in only one patient. Bb showed an upward trend at 6-8 h, and was significantly elevated at 24 h (P<0.05); sC5b-9 was elevated in all patients prior to treatment or in the first 6-8 h of treatment. Results indicate that the alternative pathway may be the primary pathway of activation. These results extend the observation that both DKA and its treatment produce varying degrees of immunologic stress during the time when acute complications are most likely to occur.

Study of subclinical cerebral edema in diabetic ketoacidosis by magnetic resonance imaging T2 relaxometry and apparent diffusion coefficient maps.

Cerebral edema is the most significant complication in children with diabetic ketoacidosis (DKA). Our goal was to study whether subclinical cerebral edema was preferentially vasogenic or cytotoxic. Magnetic resonance imaging (MRI)--diffusion-weighted imaging (DWI) and T2 relaxometry (T2R)--were obtained in pediatric patients presenting with severe diabetic ketoacidosis (DKA) 6-12 hours after initial DKA treatment and stabilization and 96 hours after correction of DKA. T2 relaxometry was significantly increased during treatment in both white and gray matter, in comparison to the absolute T2R values 96 hours after correction of DKA (p = .034). Classic intracellular cytotoxic edema could not be detected, based on the lack of a statistically significant decrease in ADC values. ADC values were instead elevated, implying a large component of cell membrane water diffusion, correlating with the elevated white and gray matter T2R We discuss the findings in relation to cerebral blood volume, cerebral vasoregulatory dysfunction, and cerebral hyperemia.

Plasma C-reactive protein levels in severe diabetic ketoacidosis.

Elevated plasma levels of C-reactive protein (CRP) and IL-6 have been reported to be sensitive indicators of infection in adults with diabetic ketoacidosis (DKA). However, both CRP and the pro-inflammatory cytokines, which regulate CRP, can be elevated without infection. Our hypothesis was that CRP is increased in young patients with severe DKA, even in the absence of an infection, and may serve as a marker for systemic inflammatory response syndrome (SIRS). In 7 patients with severe DKA without infection, we measured plasma CRP, IL-6, IL-1beta and TNF-alpha levels prior to, during, and following correction of DKA. CRP was significantly but transiently elevated in 4 of the patients prior to or during treatment of DKA, compared to their baseline values (96 hr after correction of DKA). There were significant positive relationships between CRP and both IL-6 and IL-1beta prior to treatment (p <0.05); between CRP and IL-6, IL-1beta, and TNF-alpha at 6 hr (p <0.05); and between CRP and IL-1beta at 24 hr (p <0.05). The results support the hypothesis that CRP is increased in some patients by severe DKA and its treatment, and that DKA can be associated with a non-infectious form of SIRS.

Diabetic ketoacidosis and its treatment increase plasma 3-deoxyglucosone.

OBJECTIVES: Highly reactive dicarbonyl compounds are known to be increased by hyperglycemia, ketone bodies and lipid peroxidation. This study was carried out to investigate the effect of diabetic ketoacidosis (DKA) and its treatment on the plasma concentration of 3 deoxyglucosone (3-DG) one of the dicarbonyl compounds. DESIGN AND METHODS: 3-DG was measured in 7 children before, during and following correction of severe DKA. 3-DG was elevated before treatment (610 nmol/L +or/- 70) in comparison to baseline (120 h) (200 nmol/L+/or- 17) (p < 0.05). At 6 to 24 h into treatment 3-DG was further elevated (1080 nmol/L +or/- 80) in comparison to both pretreatment (p < 0.05) and baseline (p < 0.05). CONCLUSION: 3-DG is significantly elevated before the treatment of DKA and increases further during the treatment of DKA. The time course of the increase of 3-DG coincides with the time of progression of subclinical brain edema, which occurs in DKA.

Diabetic ketoacidosis promotes a prothrombotic state.

Cerebrovascular accidents are one of the life-threatening complications of diabetic ketoacidosis (DKA) in children and adolescents. Our objective was to evaluate the effect of DKA and its treatment on factors known to affect thrombotic activity (protein C; protein S; von Willebrand factor, fibrinogen; homocysteine; and folate) by comparing seven adolescents with DKA prior to treatment and at 6, 24, and 120 hours after initiation of treatment. We found that protein C activity was significantly decreased by DKA, but normalized slowly following treatment. Free protein S was low throughout the study. Protein C antigen and protein S antigen showed varying degrees ofchange within the first 24 hours, but remained in the normal range, with the exception of the initial value of protein C antigen, which was elevated. von Willebrand factor (vWF) antigen and vWF activity were both significantly increased prior to treatment, but decreased with treatment. However, vWF activity remained elevated at 120 hours. Fibrinogen concentrations showed no significant changes throughout the study. Homocysteine was significantly decreased prior to treatment and increased with the initiation of treatment Folate was significantly increased prior to treatment, and decreased to high normal levels. The increased vWF and the decreased levels of protein C activity and of free protein S support the hypothesis that DKA and its treatment results in a prothrombotic state and activation of the vascular endothelium, which, in turn, predispose to cerebrovascular accidents.

Acetoacetate increases expression of intercellular adhesion molecule-1 (ICAM-1) in human brain microvascular endothelial cells.

It has been hypothesized that ketone bodies cause activation of brain endothelial cells and that this is a factor in the intracerebral crises of diabetic ketoacidosis (DKA). In this study we used cultured human brain microvascular endothelial cells (HBMEC) to investigate the effect of beta hydroxybutyrate (BOHB) and acetoacetate (AcAc) on the expression of the adhesion molecule, intercellular adhesion molecule-1 (ICAM-1). Increasing concentrations of AcAc, but not BOHB, caused a significant upregulation of ICAM-1 in comparison to unstimulated cells. Glucose concentrations of 10 and 30 mM, but not 50 mM, also resulted in increased expression of ICAM-1. These results support the hypothesis that activation of HBMEC is involved in the acute complications of DKA, and that ketone bodies and hyperglycemia are factors in the perturbed membrane function.