Hypervigilance for fear after basolateral amygdala damage in humans

Recent rodent research has shown that the basolateral amygdala (BLA) inhibits unconditioned, or innate, fear. It is, however, unknown whether the BLA acts in similar ways in humans. In a group of five subjects with a rare genetic syndrome, that is, Urbach–Wiethe disease (UWD), we used a combination of structural and functional neuroimaging, and established focal, bilateral BLA damage, while other amygdala sub-regions are functionally intact. We tested the translational hypothesis that these BLA-damaged UWD-subjects are hypervigilant to facial expressions of fear, which are prototypical innate threat cues in humans. Our data indeed repeatedly confirm fear hypervigilance in these UWD subjects. They show hypervigilant responses to unconsciously presented fearful faces in a modified Stroop task. They attend longer to the eyes of dynamically displayed fearful faces in an eye-tracked emotion recognition task, and in that task recognize facial fear significantly better than control subjects. These findings provide the first direct evidence in humans in support of an inhibitory function of the BLA on the brain's threat vigilance system, which has important implications for the understanding of the amygdala's role in the disorders of fear and anxiety

Suppression of the Nrf2-Dependent Antioxidant Response by Glucocorticoids and 11β-HSD1-Mediated Glucocorticoid Activation in Hepatic Cells

Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a key transcription factor regulating a plethora of detoxifying enzymes and antioxidant genes involved in drug metabolism and defence against oxidative stress. The glucocorticoid receptor (GR) is a ligand-induced transcription factor involved in the regulation of energy supply for metabolic needs to cope with various stressors. GR activity is controlled by glucocorticoids, which are synthesized in the adrenal glands and regenerated mainly in the liver from inactive cortisone by 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1).; Using transfected HEK-293 cells and hepatic H4IIE cells we show that glucocorticoids, activated by 11β-HSD1 and acting through GR, suppress the Nrf2-dependent antioxidant response. The expression of the marker genes NQO1, HMOX1 and GST2A was suppressed upon treatment of 11β-HSD1 expressing cells with cortisone, an effect that was reversed by 11β-HSD1 inhibitors. Furthermore, our results demonstrate that elevated glucocorticoids lowered the ability of cells to detoxify H(2)O(2). Moreover, a comparison of gene expression in male and female rats revealed an opposite sexual dimorphism with an inverse relationship between 11β-HSD1 and Nrf2 target gene expression.; The results demonstrate a suppression of the cellular antioxidant defence capacity by glucocorticoids and suggest that elevated 11β-HSD1 activity may lead to impaired Nrf2-dependent antioxidant response. The gender-specific differences in hepatic expression levels of 11β-HSD1 and Nrf2 target genes and the impact of pharmacological inhibition of 11β-HSD1 on improving cellular capacity to cope with oxidative stress warrants further studies in vivo

GMOs in animal agriculture: time to consider both costs and benefits in regulatory evaluations

In 2012, genetically engineered (GE) crops were grown by 17.3 million farmers on over 170 million hectares. Over 70% of harvested GE biomass is fed to food producing animals, making them the major consumers of GE crops for the past 15 plus years. Prior to commercialization, GE crops go through an extensive regulatory evaluation. Over one hundred regulatory submissions have shown compositional equivalence, and comparable levels of safety, between GE crops and their conventional counterparts. One component of regulatory compliance is whole GE food/feed animal feeding studies. Both regulatory studies and independent peer-reviewed studies have shown that GE crops can be safely used in animal feed, and rDNA fragments have never been detected in products (e.g. milk, meat, eggs) derived from animals that consumed GE feed. Despite the fact that the scientific weight of evidence from these hundreds of studies have not revealed unique risks associated with GE feed, some groups are calling for more animal feeding studies, including long-term rodent studies and studies in target livestock species for the approval of GE crops. It is an opportune time to review the results of such studies as have been done to date to evaluate the value of the additional information obtained. Requiring long-term and target animal feeding studies would sharply increase regulatory compliance costs and prolong the regulatory process associated with the commercialization of GE crops. Such costs may impede the development of feed crops with enhanced nutritional characteristics and durability, particularly in the local varieties in small and poor developing countries. More generally it is time for regulatory evaluations to more explicitly consider both the reasonable and unique risks and benefits associated with the use of both GE plants and animals in agricultural systems, and weigh them against those associated with existing systems, and those of regulatory inaction. This would represent a shift away from a GE evaluation process that currently focuses only on risk assessment and identifying ever diminishing marginal hazards, to a regulatory approach that more objectively evaluates and communicates the likely impact of approving a new GE plant or animal on agricultural production systems

Evidence of reversible axonal dysfunction in systemic lupus erythematosus: a proton MRS study

Our objective was to investigate axonal dysfunction in patients with systemic lupus erythematosus (SLE) using proton magnetic resonance spectroscopy ((1)H-MRS).We studied prospectively 90 SLE patients (mean age of 32.5 years) and 23 normal volunteers (mean age of 33.8 years). We performed single voxel proton MRS using point resolved spectroscopy sequence over the superior-posterior region of the corpus callosum. We measured signals from N-acetyl compounds [N-acetylaspartate (NAA)] at 2.01 p.p.m., choline-based compounds (Cho) at 3.2 p.p.m. and creatine and phosphocreatine containing compounds (Cr) at 3.0 p.p.m. and determined NAA/Cr ratios. After 12 months, MRI and MRS were repeated in 50 patients and 9 volunteers. Patients were divided according to disease activity (measured by SLE disease activity index) during initial and follow-up MRS. We performed paired t-test and ANOVA with Tukey's post hoc comparisons to evaluate group differences. At study entry, 29 patients had active SLE with involvement of central nervous system (CNS) and 28 patients had active SLE without CNS manifestations. A total of 14 patients had inactive SLE with past CNS presentation, and 19 had inactive SLE without history of CNS involvement. NAA/Cr ratios were significant lower in patients with active SLE, independently of CNS involvement, when compared with patients with inactive SLE (P = 0.005) and controls (P = 0.01). We observed a significant increase in NAA/Cr ratio in 15 patients who had active SLE at initial MRS and inactive SLE at follow-up (P = 0.04). In 10 patients with active SLE both at initial and at follow-up MRS we observed a reduction in NAA/Cr ratio (P = 0.02). By contrast, there was a significant reduction of NAA/Cr ratio in 15 patients who had inactive SLE at initial MRS and active SLE at follow-up (P = 0.001). In 10 patients with inactive SLE both at initial and at follow-up MRS NAA/Cr ratio did not change (P = 0.2). This study shows evidence of axonal dysfunction in patients with active SLE, independently of CNS manifestations that may be reversible, at least in part, during periods of inactivity of disease.128122933294

Neurometabolic changes in normal white matter may predict appearance of hyperintense lesions in systemic lupus erythematosus

To determine if neurometabolic changes in the white matter (WM) of systemic lupus erythematosus (SLE) patients may predict the appearance of small hyperintense lesions on T2-weighted magnetic resonance imaging (MRI) inside the magnetic resonance spectroscopy (MRS) region of interest (ROI). We included 30 SLE patients and 23 controls. We performed single voxel proton MRS over the superior-posterior region of the corpus callosum. We measured signals from N-acetyl-compounds (NAA), choline (Cho) and creatine-phosphocreatin (Cr) and determined NAA/Cr and Cho/Cr ratios. After a minimum of 12 months, MRI and MRS were repeated in all patients and nine volunteers. Twenty patients had normal MRI and 10 patients had MRI hyperintense lesions in the MRS ROI at baseline. All patients had hyperintense lesions in the MRS ROI in follow-up MRIs. All SLE patients had increased Cho/Cr values at both MRS when compared with normal controls (P = 0.001). In addition, there was an increase in Cho/Cr values when patients' baseline and follow-up MRS were compared (P = 0.001). We observed a correlation between Cho/Cr ratios and number of WM lesions (r = 0.69; P = 0.001). Increased Cho/Cr in normal appearing WM may be indicative of future appearance of hyperintense T2-weighted MRI lesions in SLE patients.161296397

Cerebral and corpus callosum atrophy in systemic lupus erythematosus

Objective. To determine cerebral and corpus callosum volumes in patients with systemic lupus erythematosus (SLE), using semiautomatic magnetic resonance imaging (MRI) volumetric measurements, and to determine possible relationships between a reduction in cerebral volume and disease duration, total corticosteroid dose, neuropsychiatric manifestations, and the presence of antiphospholipid antibodies. Methods. We studied 115 consecutive patients with SLE and 44 healthy volunteers. A complete clinical, laboratory, and neurologic evaluation was performed. MRI scans were obtained through a standardized protocol. Sagittal T1-weighted images were used for semiautomatic volumetric measurements. We compared SLE patients with controls using the 2-sample t-test. Analysis of variance was used to test for differences between groups, followed by Tukey ' s post hoc test for pairwise comparisons, when necessary. Linear regression was used to analyze the association between cerebral atrophy and disease duration and total corticosteroid dose. Results. Cerebral and corpus callosum volumes were significantly smaller in patients with SLE compared with healthy volunteers (P < 0.001). Reduced cerebral and corpus callosum volumes were related to disease duration (P < 0.001). Patients with a history of central nervous system (CNS) involvement more frequently had a reduction in cerebral and corpus callosum volumes (P < 0.001). Patients with cognitive impairment had significantly reduced corpus callosum and cerebral volumes when compared with SLE patients without cognitive impairment (P = 0.001). Cerebral and corpus callosum volumes were not associated with the total corticosteroid dose or the presence of antiphospholipid antibodies. Conclusion. In patients with SLE, a reduction in cerebral and corpus callosum volumes is associated with disease duration, a history of CNS involvement, and cognitive impairment. The total corticosteroid dose and the presence of antiphospholipid antibodies were not associated with more pronounced atrophy.5292783278

Quantitative Magnetic Resonance Imaging Analyses and Clinical Significance of Hyperintense White Matter Lesions in Systemic Lupus Erythematosus Patients

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Objective: To analyze the clinical significance of hyperintense white matter (WM) lesions in both symptomatic and asymptomatic systemic lupus erythematosus (SLE) patients. Methods: We studied 120 consecutive SLE patients and 44 healthy volunteers. Fluid attenuated inversion recovery and T2-weighted magnetic resonance images (MRI) were used for visual and semiautomatic volumetric measurements. Results: At baseline, 61 MRI were normal and 59 had hyperintense WM lesions. Mean volumes of WM lesions were 96.14 (SD = 85.14) mm(3) in T2 weighted and 197.2 (161.13) mm(3) in FLAIR images. The Volume of WM lesions was associated with age (r = 0.45; p = 0.01), total corticosteroid dose (r = 0.53; p = 0.001), and Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index scores (r = 0.55; p = 0.002). After a median follow-up time of 24 months (SD = 2.3; range = 12-28 months), 20 patients had still normal MRIs, 30 patients had stable MRI findings, and 30 had new WM lesions. Predictors for new or increased WM lesions were past central nervous system manifestations (p = 0.001; OR = 12.2; 95% CI = 3.5-21.2), antiphospholipid antibodies (p = 0.003; OR = 6.9; 95% CI = 2.1-15.3); Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index scores (p = 0.002; OR = 7.2; 95% CI = 1.4-17.8) and higher dose of total corticosteroid dose (p = 0.01; OR = 2.4; 95% CI = 1.4-6.7). Conclusion: Small hyperintense WM lesions in SLE are associated with central nervous system symptoms and antiphospholipid antibodies, and progress over time in patients with more severe SLE. Therefore, in the on context of SLE, these lesions arc likely consequences of central nervous system damage and not mere incidental finding.646635643Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPESP [03/01527-0, 06/50260-5