Browsing by Subject "Physiopathology"

Now showing 1 - 10 of 22
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    Abnormal Amygdala Functional Connectivity Associated With Emotional Lability in Children With Attention-Deficit/Hyperactivity Disorder
    (Elsevier, 2014-03) Hulvershorn, Leslie A.; Mennes, Maarten; Castellanos, F. Xavier; Di Martino, Adriana; Milham, Michael P.; Hummer, Tom A.; Roy, Amy Krain; Department of Psychiatry, IU School of Medicine
    Objective A substantial proportion of children with attention-deficit/hyperactivity disorder (ADHD) also display emotion regulation deficits manifesting as chronic irritability, severe temper outbursts, and aggression. The amygdala is implicated in emotion regulation, but its connectivity and relation to emotion regulation in ADHD has yet to be explored. The purpose of this study was to examine the relationship between intrinsic functional connectivity (iFC) of amygdala circuits and emotion regulation deficits in youth with ADHD. Method Bilateral amygdala iFC was examined using functional magnetic resonance imaging in 63 children with ADHD, aged 6 to 13 years. First, we examined the relationship between amygdala IFC and parent ratings of emotional lability (EL) in children with ADHD. Second, we compared amygdala iFC across subgroups of children with ADHD and high EL (n = 18), ADHD and low EL (n = 20), and typically developing children (TDC), all with low EL (n = 19). Results Higher EL ratings were associated with greater positive iFC between the amygdala and rostral anterior cingulate cortex in youth with ADHD. EL scores were also negatively associated with iFC between bilateral amygdala and posterior insula/superior temporal gyrus. Patterns of amygdala-cortical iFC in ADHD participants with low EL were not different from the comparison group, and the effect sizes for these comparisons were smaller than those for the trend-level differences observed between the high-EL and TDC groups. Conclusions In children with ADHD and a range of EL, deficits in emotion regulation were associated with altered amygdala–cortical iFC. When comparing groups that differed on ADHD status but not EL, differences in amygdala iFC were small and nonsignificant, highlighting the specificity of this finding to emotional deficits, independent of other ADHD symptoms.
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    Alterations in the rate of binge ethanol consumption: implications for preclinical studies in mice
    (Wiley Blackwell (Blackwell Publishing), 2014-09) Linsenbardt, David N.; Boehm, Stephen L.; Department of Psychology, IU School of Science
    The rate at which alcohol (ethanol) is consumed has direct impact on its behavioral and subjective effects. For this reason, alterations in the pattern of ethanol consumption as a function of drinking history might be critical to the development and maintenance of alcoholism. Furthermore, because pharmacological interventions aimed at disrupting the motivation to consume ethanol are dependent on the brain/plasma concentrations present when an individual is most likely to engage in consumption of this substance, characterizing temporal drinking patterns might be useful to determine the timing of such treatments. The primary goal of the present study was to evaluate alterations in the timecourse of daily binge (drinking-in-the-dark; DID) ethanol consumption. We gave 14 daily 2 hour DID ethanol or water access sessions to male C57BL/6J (B6) mice using a state of the art volumetric drinking monitoring device. We then, primarily as a proof-of-principle, used the GABAB allosteric modulator GS39783 (GS) to determine how this compound influenced the timecourse of binge-like ethanol intake. The rate of ethanol consumption increased dramatically over sessions with the majority occurring in the first few minutes of the final session. Additionally, ethanol consumption occurring immediately following access was almost completely abolished in mice pre-treated with GS; an effect which was ethanol-specific only at this early time interval. These data characterize progressive alterations in the rate of ethanol intake using the DID model and suggest that careful consideration of prior ethanol history and timing of drug administration are warranted when interpreting results of pre-clinical drug administration studies.
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    Autophagy dysregulation in cell culture and animals models of Spinal Muscular Atrophy
    (Elsevier, 2014-07) Custer, Sara K.; Androphy, Elliot J.; Department of Dermatology, IU School of Medicine
    Abnormal autophagy has become a central thread linking neurodegenerative diseases, particularly of the motor neuron. One such disease is spinal muscular atrophy (SMA), a genetic neuromuscular disorder caused by mutations in the SMN1 gene resulting in low levels of Survival Motor Neuron (SMN) protein. Despite knowing the causal protein, the exact intracellular processes that are involved in the selective loss of motor neurons remains unclear. Autophagy induction can be helpful or harmful depending on the situation, and we sought to understand the state of the autophagic response in SMA. We show that cell culture and animal models demonstrate induction of autophagy accompanied by attenuated autophagic flux, resulting in the accumulation of autophagosomes and their associated cargo. Expression of the SMN-binding protein a-COP, a known modulator of autophagic flux, can ameliorate this autophagic traffic jam.
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    B-type natriuretic peptide is not a volume marker among patients on hemodialysis
    (Oxford University Press, 2013-12) Agarwal, Rajiv; Department of Medicine, IU School of Medicine
    Background Although the cardiac biomarker B-type natriuretic peptide (BNP) is strongly related to mortality in end-stage renal disease (ESRD), whether it is a predictor of weight change or blood pressure (BP) response upon probing dry weight among hypertensive hemodialysis patients remains unknown. The purpose of this study was to examine among people with hypertension on hemodialysis whether BNP is a biomarker of excess volume. Methods Hypertensive hemodialysis patients (n = 150) were randomized to a control group (n = 50) or an ultrafiltration group (n = 100) and followed up for 30 dialysis treatments. After a baseline run-in of six treatments, those assigned to the ultrafiltration group had dry weight probed over 8 weeks. Forty-four-hour interdialytic ambulatory BP and predialysis BNP were measured at the end of run-in period, at 4 weeks and at 8 weeks. Results The median BNP concentration was 93 pg/mL (interquartile range 31–257 pg/mL). The magnitude of decline in the BNP depended on the baseline concentration of BNP, but did not require probing dry weight or weight loss. No relationship existed between decline in postdialysis weight upon probing dry weight and baseline BNP. Furthermore, reduction in the BNP was not required for decline in postdialysis weight. Predialysis log BNP modestly predicted ambulatory systolic and pulse pressure independently of other risk factors. No relationship was found between decline in BP upon probing dry weight and baseline BNP. Upon probing dry weight, reduction in BNP was not required for decline in systolic ambulatory BP. Conclusion Taken together, these data suggest that among hypertensive patients on hemodialysis BNP is not a volume marker.
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    Cancer impacts microRNA expression, release and function in cardiac and skeletal muscle
    (American Association for Cancer Research, 2014-08-15) Chen, Daohong; Goswami, Chirayu P; Burnett, Riesa M; Anjanappa, Manjushree; Bhat-Nakshatri, Poornima; Muller, William; Nakshatri, Harikrishna; Department of Surgery, IU School of Medicine
    Circulating microRNAs are emerging as important biomarkers of various diseases including cancer. Intriguingly, circulating levels of several microRNAs are lower in cancer patients compared with healthy individuals. In this study, we tested the hypothesis that a circulating microRNA might serve as a surrogate of the effects of cancer on microRNA expression or release in distant organs. Here we report that circulating levels of the muscle-enriched miR-486 is lower in breast cancer patients compared with healthy individuals, and that this difference is replicated faithfully in MMTV-PyMT and MMTV-Her2 transgenic mouse models of breast cancer. In tumor-bearing mice, levels of miR-486 were relatively reduced in muscle, where there was elevated expression of the miR-486 target genes PTEN and FOXO1A and dampened signaling through the PI3K/AKT pathway. Skeletal muscle expressed lower levels of the transcription factor MyoD which controls miR-486 expression. Conditioned media (CM) obtained from MMTV-PyMT and MMTV-Her2/Neu tumor cells cultured in vitro was sufficient to elicit reduced levels of miR-486 and increased PTEN and FOXO1A expression in C2C12 murine myoblasts. Cytokine analysis implicated TNFα and four additional cytokines as mediators of miR-486 expression in CM-treated cells. Since miR-486 is a potent modulator of PI3K/AKT signaling and the muscle-enriched transcription factor network in cardiac/skeletal muscle, our findings implicated TNFα-dependent miRNA circuitry in muscle differentiation and survival pathways in cancer.
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    Comparison of isoflurane and α-chloralose in an anesthetized swine model of acute pulmonary embolism producing right ventricular dysfunction
    (American Association for Laboratory Animal Science, 2015-02) Beam, Daren M.; Neto-Neves, Evandro M.; Stubblefield, William B.; Alves, Nathan J.; Tune, Johnathan D.; Kline, Jeffrey A.; Department of Emergency Medicine, IU School of Medicine
    Pulmonary embolism (PE) is a leading cause of sudden cardiac death, and a model is needed for testing potential treatments. In developing a model, we compared the hemodynamic effects of isoflurane and α-chloralose in an acute swine model of PE because the choice of anesthesia will likely affect the cardiovascular responses of an animal to PE. At baseline, swine that received α-chloralose (n = 6) had a lower heart rate and cardiac output and higher SpO2, end-tidal CO2, and mean arterial pressure than did those given isoflurane (n = 9). After PE induction, swine given α-chloralose compared with isoflurane exhibited a lower heart rate (63 ± 10 compared with 116 ± 15 bpm) and peripheral arterial pressure (52 ± 12 compared with 61 ± 12 mm Hg); higher SpO2 (98% ± 3% compared with 95% ± 1%), end-tidal CO2 (35 ± 4 compared with 32 ± 5), and systolic blood pressure (121 ± 8 compared with 104 ± 20 mm Hg); and equivalent right ventricular:left ventricular ratios (1.32 ± 0.50 compared with 1.23 ± 0.19) and troponin I mean values (0.09 ± 0.07 ng/mL compared with 0.09 ± 0.06 ng/mL). Isoflurane was associated with widely variable fibrinogen and activated partial thromboplastin time. Intraexperiment mortality was 0 of 6 animals for α-chloralose and 2 of 9 swine for isoflurane. All swine anesthetized with α-chloralose survived with sustained pulmonary hypertension, RV-dilation-associated cardiac injury without the confounding vasodilatory or coagulatory effects of isoflurane. These data demonstrate the physiologic advantages of α-chloralose over isoflurane for anesthesia in a swine model of severe submassive PE.
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    Coupling Interval Variability Differentiates Ventricular Ectopic Complexes Arising in the Aortic Sinus of Valsalva and Great Cardiac Vein From Other Sources
    (Elsevier, 2014-05-27) Bradfield, Jason S.; Homsi, Mohamed; Shivkumar, Kalyanam; Miller, John M.; Department of Medicine, IU School of Medicine
    Objectives The objective of this study was to determine whether premature ventricular contractions (PVCs) arising from the aortic sinuses of Valsalva (SOV) and great cardiac vein (GCV) have coupling interval (CI) characteristics that differentiate them from other ectopic foci. Background PVCs occur at relatively fixed CI from the preceding normal QRS complex in most patients. However, we observed patients with PVCs originating in unusual areas (SOV and GCV) in whom the PVC CI was highly variable. We hypothesized that PVCs from these areas occur seemingly randomly because of the lack of electrotonic effects of the surrounding myocardium. Methods Seventy-three consecutive patients referred for PVC ablation were assessed. Twelve consecutive PVC CIs were recorded. The ΔCI (maximum – minimum CI) was measured. Results We studied 73 patients (age 50 ± 16 years, 47% male). The PVC origin was right ventricular (RV) in 29 (40%), left ventricular (LV) in 17 (23%), SOV in 21 (29%), and GCV in 6 (8%). There was a significant difference between the mean ΔCI of RV/LV PVCs compared with SOV/GCV PVCs (33 ± 15 ms vs. 116 ± 52 ms, p < 0.0001). A ΔCI of >60 ms demonstrated a sensitivity of 89%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 94%. Cardiac events were more common in the SOV/GCV group versus the RV/LV group (7 of 27 [26%] vs. 2 of 46 [4%], p < 0.02). Conclusions ΔCI is more pronounced in PVCs originating from the SOV or GCV. A ΔCI of 60 ms helps discriminate the origin of PVCs before diagnostic electrophysiological study and may be associated with increased frequency of cardiac events.
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    Fragmented ECG as a risk marker in cardiovascular diseases
    (Bentham Science, 2014-08) Jain, Rahul; Singh, Robin; Yamini, Sundermurthy; Das, Mithilesh K.; Department of Medicine, IU School of Medicine
    Various noninvasive tests for risk stratification of sudden cardiac death (SCD) were studied, mostly in the context of structural heart disease such as coronary artery disease (CAD), cardiomyopathy and heart failure but have low positive predictive value for SCD. Fragmented QRS complexes (fQRS) on a 12-lead ECG is a marker of depolarization abnormality. fQRS include presence of various morphologies of the QRS wave with or without a Q wave and includes the presence of an additional R wave (R') or notching in the nadir of the R' (fragmentation) in two contiguous leads, corresponding to a major coronary artery territory. fQRS represents conduction delay from inhomogeneous activation of the ventricles due to myocardial scar. It has a high predictive value for myocardial scar and mortality in patients CAD. fQRS also predicts arrhythmic events and mortality in patients with implantable cardioverter defibrillator. It also signifies poor prognosis in patients with nonischemic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy and Brugada syndrome. However, fQRS is a nonspecific finding and its diagnostic prognostic should only be interpreted in the presence of pertinent clinical evidence and type of myocardial involvement (structural vs. structurally normal heart).
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    Hypokalemia Promotes Late Phase 3 Early Afterdepolarization and Recurrent Ventricular Fibrillation During Isoproterenol Infusion in Langendorff Perfused Rabbit Ventricles
    (Elsevier, 2014-04) Maruyama, Mitsunori; Ai, Tomohiko; Chua, Su-Kiat; Park, Hyung-Wook; Lee, Young-Soo; Shen, Mark J.; Chang, Po-Cheng; Lin, Shien-Fong; Chen, Peng-Sheng; Department of Medicine, IU School of Medicine
    BACKGROUND Hypokalemia and sympathetic activation are commonly associated with electrical storm (ES) in normal and diseased hearts. The mechanisms remain unclear. OBJECTIVE To test the hypothesis that late phase 3 early afterdepolarization (EAD) induced by IKATP activation underlies the mechanisms of ES during isoproterenol infusion and hypokalemia. METHODS Intracellular calcium (Cai) and membrane voltage were optically mapped in 32 Langendorff-perfused normal rabbit hearts. RESULTS Repeated episodes of electrically-induced VF at baseline did not result in spontaneous VF (SVF). During isoproterenol infusion, SVF occurred in 1 of 15 hearts (7%) studied in normal extracellular potassium ([K+]o) (4.5 mmol/L), 3 of 8 hearts (38%) in 2.0 mmol/L [K+]o, 9 of 10 hearts (90%) in 1.5 mmol/L [K+]o, and 7 of 7 hearts (100%) in 1.0 mmol/L [K+]o (P<0.001). Optical mapping showed isoproterenol and hypokalemia enhanced Cai transient duration (CaiTD) and heterogeneously shortened action potential duration (APD) after defibrillation, leading to late phase 3 EAD and SVF. IKATP blocker (glibenclamide, 5 μmol/L) reversed the post-defibrillation APD shortening and suppressed recurrent SVF in all hearts studied despite no evidence of ischemia. Nifedipine reliably prevented recurrent VF when given before, but not after, the development of VF. IKr blocker (E-4031) and small conductance calcium activated potassium channel blocker (apamin) failed to prevent recurrent SVF. CONCLUSION Beta-adrenergic stimulation and concomitant hypokalemia could cause non-ischemic activation of IKATP, heterogeneous APD shortening and prolongation of CaiTD to provoke late phase 3 EAD, triggered activity and recurrent SVF. IKATP inhibition may be useful in managing ES during resistant hypokalemia.
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    Identifying the neuroanatomical basis of cognitive impairment in Alzheimer's disease by correlation- and nonlinearity-aware sparse Bayesian learning
    (Institute of Electrical and Electronics Engineers, 2014-07) Wan, Jing; Zhang, Zhilin; Rao, Bhaskar D.; Fang, Shiaofen; Yan, Jingwen; Saykin, Andrew J.; Shen, Li; Department of Medicine, IU School of Medicine
    Predicting cognitive performance of subjects from their magnetic resonance imaging (MRI) measures and identifying relevant imaging biomarkers are important research topics in the study of Alzheimer's disease. Traditionally, this task is performed by formulating a linear regression problem. Recently, it is found that using a linear sparse regression model can achieve better prediction accuracy. However, most existing studies only focus on the exploitation of sparsity of regression coefficients, ignoring useful structure information in regression coefficients. Also, these linear sparse models may not capture more complicated and possibly nonlinear relationships between cognitive performance and MRI measures. Motivated by these observations, in this work we build a sparse multivariate regression model for this task and propose an empirical sparse Bayesian learning algorithm. Different from existing sparse algorithms, the proposed algorithm models the response as a nonlinear function of the predictors by extending the predictor matrix with block structures. Further, it exploits not only inter-vector correlation among regression coefficient vectors, but also intra-block correlation in each regression coefficient vector. Experiments on the Alzheimer's Disease Neuroimaging Initiative database showed that the proposed algorithm not only achieved better prediction performance than state-of-the-art competitive methods, but also effectively identified biologically meaningful patterns.