Fed intervention: managing moral hazard in financial crises

At the end of September 2008, U.S. policymakers had been working for more than a year to contain the shock waves from plunging home prices and the subsequent financial market turmoil. For the Federal Reserve, the crisis has given new meaning to the adage that extraordinary times call for extraordinary measures. The central bank has dusted off Depression-era powers and rewritten old rules to address serious risks to the global financial system.Monetary policy - United States ; Financial crises ; Financial markets ; Federal Reserve System

Effects of mavoglurant on visual attention and pupil reactivity while viewing photographs of faces in Fragile X Syndrome.

BackgroundNumerous preclinical studies have supported the theory that enhanced activation of mGluR5 signaling, due to the absence or reduction of the FMR1 protein, contributes to cognitive and behavioral deficits in patients with fragile X syndrome (FXS). However multiple phase 2 controlled trials in patients with FXS have failed to demonstrate efficacy of compounds that negatively modulate mGluR5, including two phase 2b randomized controlled trials (RCT) of mavoglurant (AFQ056, Novartis Pharma AG), when the primary measures of interest were behavioral ratings. This has cast some doubt onto the translation of the mGluR5 theory from animal models to humans with the disorder.MethodsWe evaluated social gaze behavior-a key phenotypic feature of the disorder-and sympathetic nervous system influence on pupil size using a previously-validated eye tracking paradigm as a biobehavioral probe, in 57 adolescent or adult patients with FXS at baseline and following three months of blinded treatment with one of three doses of mavoglurant or placebo, within the context of the AFQ056 RCTs.ResultsPatients with FXS treated with mavoglurant demonstrated increased total absolute looking time and number of fixations to the eye region while viewing human faces relative to baseline, and compared to those treated with placebo. In addition, patients had greater pupil reactivity to faces relative to baseline following mavoglurant treatment compared to placebo.DiscussionThe study shows that negative modulation of mGluR5 activity improves eye gaze behavior and alters sympathetically-driven reactivity to faces in patients with FXS, providing preliminary evidence of this drug's impact on behavior in humans with the disorder

Common and specific impairments in attention functioning in girls with chromosome 22q11.2 deletion, fragile X or Turner syndromes.

BACKGROUND: Chromosome 22q11.2 deletion syndrome (22q11.2DS), fragile X syndrome (FXS), and Turner syndrome (TS) are complex and variable developmental syndromes caused by different genetic abnormalities; yet, they share similar cognitive impairments in the domains of numbers, space, and time. The atypical development of foundational neural networks that underpin the attentional system is thought to result in further impairments in higher-order cognitive functions. The current study investigates whether children with similar higher-order cognitive impairments but different genetic disorders also show similar impairments in alerting, orienting, and executive control of attention. METHODS: Girls with 22q11.2DS, FXS, or TS and typically developing (TD) girls, aged 7 to 15 years, completed an attention network test, a flanker task with alerting and orienting cues. Exploration of reaction times and accuracy allowed us to test for potential commonalities in attentional functioning in alerting, orienting, and executive control. Linear regression models were used to test whether the predictors of group and chronological age were able to predict differences in attention indices. RESULTS: Girls with 22q11.2DS, FXS, or TS demonstrated unimpaired function of the alerting system and impaired function of the executive control system. Diagnosis-specific impairments were found such that girls with FXS made more errors and had a reduced orienting index, while girls with 22q11.2DS showed specific age-related deficits in the executive control system. CONCLUSIONS: These results suggest that the control but not the implementation of attention is selectively impaired in girls with 22q11.2DS, TS or FXS. Additionally, the age effect on executive control in girls with 22q11.2DS implies a possible altered developmental trajectory

Quantifying the resolution of spatial and temporal representation in children with 22q11.2 deletion syndrome.

ObjectivesOur ability to generate mental representation of magnitude from sensory information affects how we perceive and experience the world. Reduced resolution of the mental representations formed from sensory inputs may generate impairment in the proximal and distal information processes that utilize these representations. Impairment of spatial and temporal information processing likely underpins the non-verbal cognitive impairments observed in 22q11.2 deletion syndrome (22q11DS). The present study builds on prior research by seeking to quantify the resolution of spatial and temporal representation in children with 22q11DS, sex chromosome aneuploidy (SCA), and a typically developing (TD) control group.Participants and methodsChildren (22q11DS = 70, SCA = 49, TD = 46) responded to visual or auditory stimuli with varying difference ratios. The participant's task was to identify which of two sequentially presented stimuli was of larger magnitude in terms of, size, duration, or auditory frequency. Detection threshold was calculated as the minimum difference ratio between the "standard" and the "target" stimuli required to achieve 75% accuracy in detecting that the two stimuli were different.ResultsChildren with 22q11DS required larger magnitude difference between spatial stimuli for accurate identification compared with both the SCA and TD groups (% difference from standard: 22q11DS = 14; SCA = 8; TD: 7; F  = 8.42, p < 0.001). Temporal detection threshold was also higher for the 22q11DS group to both visual (% difference from standard: 22q11DS = 14; SCA = 8; TD = 7; F  = 8.33, p < 0.001) and auditory (% difference from standard: 22q11DS = 23; SCA = 12; TD: 8; F  = 8.99, p < 0.001) stimuli compared with both the SCA and TD groups, while the SCA and TD groups displayed equivalent performance on these measures (p's > 0.05). Pitch detection threshold did not differ among the groups (p's > 0.05).ConclusionsThe observation of higher detection thresholds to spatial and temporal stimuli indicates further evidence for reduced resolution in both spatial and temporal magnitude representation in 22q11DS, that does not extend to frequency magnitude representation (pitch detection), and which is not explained by generalized cognitive impairment alone. These findings generate further support for the hypothesis that spatiotemporal hypergranularity of mental representations contributes to the non-verbal cognitive impairment seen in 22q11DS

A review of sedentary behavior assessment in national surveillance systems

Background: Temporal changes in sedentary behavior patterns reflect the evolving nature of our built and social environments, particularly the expanding availability of electronic media. It is important to understand what types of sedentary behavior are assessed in national surveillance to determine whether, and to what extent, they reflect contemporary patterns. The aims of this review were to describe the characteristics of questionnaires used for national surveillance of sedentary behavior and to identify the types of sedentary behaviors being measured. Method: We reviewed questionnaires from national surveillance systems listed on the Global Observatory for Physical Activity (GoPA!) country cards to locate items on sedentary behavior. Questionnaire characteristics were categorized using the Taxonomy of Self-reported Sedentary Behavior Tools (TASST). The purpose and type of sedentary behaviors captured were classified using the Sedentary Behavior International Taxonomy (SIT). Results: Overall, 346 surveillance systems were screened for eligibility, of which 93 were included in this review. Most questionnaires used a single-item direct measure of sitting time (n = 78, 84%). Work and domestic were the most frequently captured purposes of sedentary behavior, while television viewing and computer use were the most frequently captured types of behaviors. Conclusion: National surveillance systems should be periodically reviewed in response to evidence on contemporary behavior patterns in the population and the release of updated public health guidelines

Acute peripheral immune activation alters cytokine expression and glial activation in the early postnatal rat brain.

BACKGROUND:Neuroinflammation can modulate brain development; however, the influence of an acute peripheral immune challenge on neuroinflammatory responses in the early postnatal brain is not well characterized. To address this gap in knowledge, we evaluated the peripheral and central nervous system (CNS) immune responses to a mixed immune challenge in early postnatal rats of varying strains and sex. METHODS:On postnatal day 10 (P10), male and female Lewis and Brown Norway rats were injected intramuscularly with either a mix of bacterial and viral components in adjuvant, adjuvant-only, or saline. Immune responses were evaluated at 2 and 5 days post-challenge. Cytokine and chemokine levels were evaluated in serum and in multiple brain regions using a Luminex multiplex assay. Multi-factor ANOVAs were used to compare analyte levels across treatment groups within strain, sex, and day of sample collection. Numbers and activation status of astrocytes and microglia were also analyzed in the cortex and hippocampus by quantifying immunoreactivity for GFAP, IBA-1, and CD68 in fixed brain slices. Immunohistochemical data were analyzed using a mixed-model regression analysis. RESULTS:Acute peripheral immune challenge differentially altered cytokine and chemokine levels in the serum versus the brain. Within the brain, the cytokine and chemokine response varied between strains, sexes, and days post-challenge. Main findings included differences in T helper (Th) type cytokine responses in various brain regions, particularly the cortex, with respect to IL-4, IL-10, and IL-17 levels. Additionally, peripheral immune challenge altered GFAP and IBA-1 immunoreactivity in the brain in a strain- and sex-dependent manner. CONCLUSIONS:These findings indicate that genetic background and sex influence the CNS response to an acute peripheral immune challenge during early postnatal development. Additionally, these data reinforce that the developmental time point during which the challenge occurs has a distinct effect on the activation of CNS-resident cells

Children With Chromosome 22q11.2 Deletion Syndrome Exhibit Impaired Spatial Working Memory

Abstract Individuals with chromosome 22q11.2 deletion syndrome (22q11.2DS) have been shown to have impairments in processing spatiotemporal information. The authors examined whether children with 22q11.2DS exhibit impairments in spatial working memory performance due to these weaknesses, even when controlling for maintenance of attention. Children with 22q11.2DS (n 5 47) and typically developing controls (n 5 49) ages 6-15 years saw images within a grid and after a delay, then indicated the positions of the images in the correct temporal order. Children with 22q11.2DS made more spatial and temporal errors than controls. Females with 22q11.2DS made more spatial and temporal errors than males. These results extend findings of impaired spatiotemporal processing into the memory domain in 22q11.2DS by documenting their influence on working memory performance

Machine learning quantification of Amyloid-β deposits in the temporal lobe of 131 brain bank cases.

Accurate and scalable quantification of amyloid-β (Aβ) pathology is crucial for deeper disease phenotyping and furthering research in Alzheimer Disease (AD). This multidisciplinary study addresses the current limitations on neuropathology by leveraging a machine learning (ML) pipeline to perform a granular quantification of Aβ deposits and assess their distribution in the temporal lobe. Utilizing 131 whole-slide-images from consecutive autopsied cases at the University of California Davis Alzheimer Disease Research Center, our objectives were threefold: (1) Validate an automatic workflow for Aβ deposit quantification in white matter (WM) and gray matter (GM); (2) define the distributions of different Aβ deposit types in GM and WM, and (3) investigate correlates of Aβ deposits with dementia status and the presence of mixed pathology. Our methodology highlights the robustness and efficacy of the ML pipeline, demonstrating proficiency akin to experts' evaluations. We provide comprehensive insights into the quantification and distribution of Aβ deposits in the temporal GM and WM revealing a progressive increase in tandem with the severity of established diagnostic criteria (NIA-AA). We also present correlations of Aβ load with clinical diagnosis as well as presence/absence of mixed pathology. This study introduces a reproducible workflow, showcasing the practical use of ML approaches in the field of neuropathology, and use of the output data for correlative analyses. Acknowledging limitations, such as potential biases in the ML model and current ML classifications, we propose avenues for future research to refine and expand the methodology. We hope to contribute to the broader landscape of neuropathology advancements, ML applications, and precision medicine, paving the way for deep phenotyping of AD brain cases and establishing a foundation for further advancements in neuropathological research

The α4 nicotinic acetylcholine receptor is necessary for the initiation of organophosphate-induced neuronal hyperexcitability

Abstract: Acute intoxication with organophosphorus (OP) cholinesterase inhibitors can produce seizures that rapidly progress to life-threateningstatus epilepticus. Significant research effort has been invested investigating the involvement of muscarinic acetylcholine receptors (mAChRs) in OP-induced seizure activity. In contrast, there has been far less effort focused on nicotinic AChRs (nAChRs) in this context. Here, we address this data gap using a combination ofin vitroandin vivomodels. Pharmacological antagonism and genetic deletion of α4, but not α7, nAChR subunits prevented or significantly attenuated OP-induced electrical spike activity in acute hippocampal slices and seizure activity in mice, indicating that α4 nAChR activation is necessary for neuronal hyperexcitability triggered by acute OP exposures. These findings not only suggest that therapeutic strategies for inhibiting the α4 nAChR subunit warrant further investigation as prophylactic and acute treatments for acute OP-induced seizures, but also provide mechanistic insight into the role of the nicotinic cholinergic system in seizure generation

Time- and region-dependent blood-brain barrier impairment in a rat model of organophosphate-induced status epilepticus

Acute organophosphate (OP) intoxication can trigger seizures that progress to status epilepticus (SE), and survivors often develop chronic morbidities, including spontaneous recurrent seizures (SRS). The pathogenic mechanisms underlying OP-induced SRS are unknown, but increased BBB permeability is hypothesized to be involved. Previous studies reported BBB leakage following OP-induced SE, but key information regarding time and regional distribution of BBB impairment during the epileptogenic period is missing. To address this data gap, we characterized the spatiotemporal progression of BBB impairment during the first week post-exposure in a rat model of diisopropylfluorophosphate-induced SE, using MRI and albumin immunohistochemistry. Increased BBB permeability, which was detected at 6 h and persisted up to 7 d post-exposure, was most severe and persistent in the piriform cortex and amygdala, moderate but persistent in the thalamus, and less severe and transient in the hippocampus and somatosensory cortex. The extent of BBB leakage was positively correlated with behavioral seizure severity, with the strongest association identified in the piriform cortex and amygdala. These findings provide evidence of the duration, magnitude and spatial breakdown of the BBB during the epileptogenic period following OP-induced SE and support BBB regulation as a viable therapeutic target for preventing SRS following acute OP intoxication