Association between neural reactivity and startle reactivity to uncertain threat in two independent samples

Prior studies indicate that anxiety disorders are associated with heightened sensitivity to uncertain threat (U threat). Individual differences in reactivity to U threat have been measured in the laboratory with two methodologies—startle eyeblink potentiation and fMRI. While startle and fMRI are purported to relate to each other, very little research exists on whether individual differences in one measure are associated with individual differences in another and, thus, whether startle and fMRI capture shared mechanisms. Therefore, the current study was designed to investigate if and where in the brain measures of startle potentiation and fMRI BOLD signal correlate during response to U threat across two independent samples. Participants in both studies completed two threat anticipation tasks—once during collection of startle potentiation and once during fMRI. In Study 1 (n = 43), the startle and fMRI tasks both used electric shock as the threat. As an extension, in Study 2 (n = 38), the startle task used electric shock but the fMRI task used aversive images. Despite these methodological differences, greater startle potentiation to U threat was associated with greater dorsal anterior cingulate, caudate, and orbitofrontal cortex reactivity to U threat in both samples. The findings suggest that startle and fMRI measures of responding to U threat overlap, and points toward an integrated brain‐behavior profile of aberrant U threat responding.     

Quantification of left and right ventricular function and myocardial mass: comparison of low-radiation dose 2nd generation dual-source CT and cardiac MRI

Objective

To prospectively evaluate the accuracy of left and right ventricular function and myocardial mass measurements based on a dual-step, low radiation dose protocol with prospectively ECG-triggered 2nd generation dual-source CT (DSCT), using cardiac MRI (cMRI) as the reference standard.

Materials and methods

Twenty patients underwent 1.5 T cMRI and prospectively ECG-triggered dual-step pulsing cardiac DSCT. This image acquisition mode performs low-radiation (20% tube current) imaging over the majority of the cardiac cycle and applies full radiation only during a single adjustable phase. Full-radiation-phase images were used to assess cardiac morphology, while low-radiation-phase images were used to measure left and right ventricular function and mass. Quantitative CT measurements based on contiguous multiphase short-axis reconstructions from the axial CT data were compared with short-axis SSFP cardiac cine MRI. Contours were manually traced around the ventricular borders for calculation of left and right ventricular end-diastolic volume, end-systolic volume, stroke volume, ejection fraction and myocardial mass for both modalities. Statistical methods included independent t-tests, the Mann–Whitney U test, Pearson correlation statistics, and Bland–Altman analysis.

Results

All CT measurements of left and right ventricular function and mass correlated well with those from cMRI: for left/right end-diastolic volume r = 0.885/0.801, left/right end-systolic volume r = 0.947/0.879, left/right stroke volume r = 0.620/0.697, left/right ejection fraction r = 0.869/0.751, and left/right myocardial mass r = 0.959/0.702. Mean radiation dose was 6.2 ± 1.8 mSv.

Conclusions

Prospectively ECG-triggered, dual-step pulsing cardiac DSCT accurately quantifies left and right ventricular function and myocardial mass in comparison with cMRI with substantially lower radiation exposure than reported for traditional retrospective ECG-gating.     

Quantification of Coronary Artery Calcium on the Basis of Dual-Energy Coronary CT Angiography

Purpose: To evaluate the feasibility of using virtual noncontrast material-enhanced (VNC) computed tomographic (CT) series derived from dual-energy CT imaging studies for coronary artery calcium quantification. Materials and Methods: This HIPAA-compliant study was institutional review board approved; all patients provided written informed consent. Thirty-six patients prospectively underwent noncontrast-enhanced CT calcium scoring followed by coronary CT angiography performed in dual-energy mode. By using different reconstruction algorithms, three VNC series were generated and evaluated for noise and efficiency of virtual iodine removal. Two readers independently quantified calcium on VNC images and true noncontrast-enhanced conventional calcium scoring series. A leave-one-out cross validation was used to assess the accuracy of calcium score prediction from VNC series by means of linear regression. Results: CT value histograms of the VNC series closely resembled the profile in the true noncontrast-enhanced series. There was excellent correlation between calcium volumes on the VNC series and true noncontrast-enhanced series on a per-patient (r = 0.94, P < .001, n = 36) and per-vessel (r = 0.94, 0.91, and 0.92 for the three coronary arteries, all P < .001, n = 36 each) level. The ability of a linear regression model to predict actual calcium scores from calcium volumes on VNC series was excellent (r = 0.82). Multiethnic Study of Atherosclerosis rankings that were derived from the predicted calcium scores also showed excellent agreement (intraclass correlation coefficient = 0.909). Conclusion: Coronary artery calcium identification and quantification based on dual-energy coronary CT angiographic studies may obviate the need for dedicated CT calcium scoring studies. ? RSNA, 2012 Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12112455/-/DC1.     

Relative to Quinine and Quinidine,Their 9-Epimers Exhibit Decreased Cytostatic Activity and Altered Heme Binding but Similar Cytocidal Activity versus Plasmodium falciparum

The 9-epimers of quinine (QN) and quinidine (QD) are known to exhibit poor cytostatic potency against P. falciparum (Karle JM, Karle IL, Gerena L, Milhous WK, Antimicrob. Agents Chemother. 36:1538–1544, 1992). We synthesized 9-epi-QN (eQN) and 9-epi-QD (eQD) via Mitsunobu esterification-saponification and evaluated both cytostatic and cytocidal antimalarial activities. Relative to the cytostatic activity of QN and QD, we observed a large decrease in cytostatic activity (higher 50% inhibitory concentration [IC₅₀s]) against QN-sensitive strain HB3, QN-resistant strain Dd2, and QN-hypersensitive strain K76I, consistent with previous work. However, we observed relatively small changes in cytocidal activity (the 50% lethal dose), similar to observations with chloroquine (CQ) analogues with a wide range of IC₅₀s (see the accompanying paper [A. P. Gorka, J. N. Alumasa, K. S. Sherlach, L. M. Jacobs, K. B. Nickley, J. P. Brower, A. C. de Dios, and P. D. Roepe, Antimicrob. Agents Chemother. 57:356–364, 2013]). Compared to QN and QD, the 9-epimers had significantly reduced hemozoin inhibition efficiency and did not affect pH-dependent aggregation of ferriprotoporphyrin IX (FPIX) heme. Magnetic susceptibility measurements showed that the 9-epimers perturb FPIX monomer-dimer equilibrium in favor of monomer, and UV-visible (VIS) titrations showed that eQN and eQD bind monomer with similar affinity relative to QN and QD. However, unique ring proton shifts in the presence of zinc(II) protoporphyrin IX (ZnPIX) indicate that binding of the 9-epimers to monomeric heme is via a distinct geometry. We isolated eQN- and eQD-FPIX complexes formed under aqueous conditions and analyzed them by mass, fluorescence, and UV-VIS spectroscopies. The 9-epimers produced low-fluorescent adducts with a 2:1 stoichiometry (drug to FPIX) which did not survive electrospray ionization, in contrast to QN and QD complexes. The data offer important insight into the relevance of heme interactions as a drug target for cytostatic versus cytocidal dosages of quinoline antimalarial drugs and further elucidate a surprising structural diversity of quinoline antimalarial drug-heme complexes.     

An integral approach to the etiopathogenesis of human neurodegenerative diseases (HNDDs) and cancer. Possible therapeutic consequences within the frame of the trophic factor withdrawal syndrome (TFWS)

A novel and integral approach to the understanding of human neurodegenerative diseases (HNDDs) and cancer based upon the disruption of the intracellular dynamics of the hydrogen ion (H⁺) and its physiopathology, is advanced. From an etiopathological perspective, the activity and/or deficiency of different growth factors (GFs) in these pathologies are studied, and their relationships to intracellular acid-base homeostasis reviewed. Growth and trophic factor withdrawal in HNDDs indicate the need to further investigate the potential utilization of certain GFs in the treatment of Alzheimer disease and other neurodegenerative diseases. Platelet abnormalities and the therapeutic potential of platelet-derived growth factors in these pathologies, either through platelet transfusions or other clinical methods, are considered. Finally, the etiopathogenic mechanisms of apoptosis and antiapoptosis in HNDDs and cancer are viewed as opposite biochemical and biological disorders of cellular acid-base balance and their secondary effects on intracellular signaling pathways and aberrant cell metabolism are considered in the light of the both the seminal and most recent data available. The “trophic factor withdrawal syndrome” is described for the first time in English-speaking medical literature, as well as a Darwinian-like interpretation of cellular behavior related to specific and nonspecific aspects of cell biology.     

Phagocytic NADPH oxidase overactivity underlies oxidative stress in metabolic syndrome

Oxidative stress plays a critical role in the pathogenesis of atherosclerosis in patients with metabolic syndrome. This study aimed to investigate whether a relationship exists between phagocytic NADPH oxidase activity and oxidative stress and atherosclerosis in metabolic syndrome patients. The study was performed in 56 metabolic syndrome patients (metabolic syndrome group), 99 patients with one or two cardiovascular risk factors (cardiovascular risk factor group), and 28 healthy subjects (control group). NADPH oxidase expression and activity was augmented (P < 0.05) in metabolic syndrome compared with cardiovascular risk factor and control groups. Insulin was enhanced (P < 0.05) in metabolic syndrome patients compared with cardiovascular risk factor and control groups and correlated with NADPH oxidase activity in the overall population. Insulin stimulated NADPH oxidase activity; this effect was abolished by a specific protein kinase C inhibitor. Oxidized LDL and nitrotyrosine levels and carotid intima-media thickness were increased (P < 0.05) in the metabolic syndrome group compared with cardiovascular risk factor and control groups and correlated with NADPH oxidase activity in the overall population. These findings suggest that phagocytic NADPH oxidase overactivity is involved in oxidative stress and atherosclerosis in metabolic syndrome patients. Our findings also suggest that hyperinsulinemia may contribute to oxidative stress in metabolic syndrome patients through activation of NADPH oxidase.     

Design and synthesis of a series of melamine-based nitroheterocycles with activity against Trypanosomatid parasites

The parasites that give rise to human African trypanosomiasis (HAT) are auxotrophs for various nutrients from the human host, including purines. They have specialist nucleoside transporters to import these metabolites. In addition to uptake of purine nucleobases and purine nucleosides, one of these transporters, the P2 transporter, can carry melamine derivatives; these derivatives are not substrates for the corresponding mammalian transporters. In this paper, we report the coupling of the melamine moiety to selected nitro heterocycles with the aim of selectively delivering these compounds to the parasites. Some compounds prepared have similar in vitro trypanocidal activities as melarsoprol, the principal drug used against late-stage HAT, with 50% growth inhibitory concentrations in the submicromolar range. Selected compounds were also evaluated in vivo in rodent models infected with Trypanosoma brucei brucei and T. brucei rhodesiense and showed pronounced activity and in two cases were curative without overt signs of toxicity. Compounds were also tested against other trypanosomatid pathogens, Leishmania donovani and Trypanosoma cruzi, and significant activity in vitro was noted for T. cruzi against which various nitro heterocycles are already registered for use.     

The C242T CYBA polymorphism of NADPH oxidase is associated with essential hypertension

OBJECTIVE: Oxidative stress is implicated in hypertension. The reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidases are the main source of superoxide in phagocytic and vascular cells. The C242T polymorphism of CYBA, the human gene that encodes p22phox, has been found to be functionally associated with vascular NADPH oxidase activity in atherosclerotic patients. We investigated the association of the C242T polymorphism with hypertension and its potential impact on NADPH oxidase activity. We also analysed the interaction of C242T polymorphism with the -930A/G CYBA variant. DESIGN: Case-control study in a random sample of 623 subjects (326 hypertensive patients and 297 normotensive controls) from the general population. METHODS: CYBA polymorphisms were determined by restriction fragment length polymorphism (RFLP) or allelic discrimination. NADPH oxidase activity and p22phox expression were quantified in phagocytic cells by chemiluminescence and by northern and western blots, respectively. RESULTS: The prevalence of the CC genotype and the C allele frequency were significantly higher (P < 0.05) in hypertensives than in normotensives. CC genotype remained associated with hypertension after adjusting for potential confounders in a logistic regression analysis. Increased phagocytic NADPH oxidase activity was observed in CC hypertensives compared with CT and TT hypertensives (P < 0.05). Enhanced plasma levels of von Willebrand factor were found in CC hypertensives compared with TT hypertensives (P < 0.05). The C242T polymorphism was not in linkage disequilibrium with the -930A/G CYBA promoter variation, which also associates with hypertension. CONCLUSION: The C242T CYBA polymorphism is associated with essential hypertension. Furthermore, hypertensives carrying the CC genotype of this polymorphism exhibit features of NADPH oxidase-mediated oxidative stress and endothelial damage.