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To better understand cognitive control impairment in schizophrenia, it is vital to determine the extent of dysfunctional connectivity in the associated fronto-striatal brain network, with a focus on the connections with the anterior cingulate cortex (ACC), prior to the potential confounding effect of medication. It is also essential to determine the effects following antipsychotic medication and the relationship of those effects on psychosis improvement. Twenty-two patients with schizophrenia, initially unmedicated and after a 6-week course of risperidone, and 20 matched healthy controls (HC) performed a fMRI task twice, six weeks apart. We investigated group and longitudinal differences in ACC-related functional connectivity during performance of a Stroop color task as well as connectivity patterns associated with improvement in psychosis symptoms. Unmedicated patients with schizophrenia showed greater functional connectivity between ACC and bilateral caudate and midbrain and lower connectivity with left putamen compared to healthy controls. At baseline, greater functional connectivity between ACC and bilateral putamen predicted subsequent better treatment response. Change in functional connectivity between ACC and left putamen positively correlated with better treatment response. These results suggest that patterns of functional connectivity in fronto-striatal networks can be utilized to predict potential response to antipsychotic medication. Prior to treatment, brain function may be structured with a predisposition that favors or not treatment response. [ABSTRACT FROM AUTHOR]

Abstract: Acquisition of multimodal brain imaging data for the same subject has become more common leading to a growing interest in determining the intermodal relationships between imaging modalities to further elucidate the pathophysiology of schizophrenia. Multimodal data have previously been individually analyzed and subsequently integrated; however, these analysis techniques lack the ability to examine true modality inter‐relationships. The utilization of a multiset canonical correlation and joint independent component analysis (mCCA + jICA) model for data fusion allows shared or distinct abnormalities between modalities to be examined. In this study, first‐episode schizophrenia patients (nSZ=19) and matched controls (nHC=21) completed a resting‐state functional magnetic resonance imaging (fMRI) scan at 7 T. Grey matter (GM), white matter (WM), cerebrospinal fluid (CSF), and amplitude of low frequency fluctuation (ALFF) maps were used as features in a mCCA + jICA model. Results of the mCCA + jICA model indicated three joint group‐discriminating components (GM‐CSF, WM‐ALFF, GM‐ALFF) and two modality‐unique group‐discriminating components (GM, WM). The joint component findings are highlighted by GM basal ganglia, somatosensory, parietal lobe, and thalamus abnormalities associated with ventricular CSF volume; WM occipital and frontal lobe abnormalities associated with temporal lobe function; and GM frontal, temporal, parietal, and occipital lobe abnormalities associated with caudate function. These results support and extend major findings throughout the literature using independent single modality analyses. The multimodal fusion of 7 T data in this study provides a more comprehensive illustration of the relationships between underlying neuronal abnormalities associated with schizophrenia than examination of imaging data independently. [ABSTRACT FROM AUTHOR]

Diffusion tensor imaging (DTI) studies in schizophrenia consistently show global reductions in fractional anisotropy (FA), a putative marker of white matter integrity. The cingulum bundle, which facilitates communication between the anterior cingulate cortex (ACC) and hippocampus, is frequently implicated in schizophrenia. Magnetic resonance spectroscopy (MRS) studies report metabolic abnormalities in the ACC and hippocampus of patients. Combining DTI and MRS offers exploration of the relationship between cortical neuronal biochemistry and the integrity of white matter tracts connecting specific cortical regions; however, few studies have attempted this in schizophrenia. Twenty-nine schizophrenia patients and twenty controls participated in this 3 T imaging study in which we used DTI and tract-based spatial statistics (TBSS) to assess white matter integrity and MRS to quantify metabolites in the ACC and hippocampus. We found FA reductions with overlapping radial diffusivity (RD) elevations in patients in multiple tracts, suggesting white matter abnormalities in schizophrenia are driven by loss of myelin integrity. In controls, we found significant negative correlations between hippocampal N-acetylaspartate/creatine and RD and axial diffusivity (AD) as well as a significant negative correlation between FA and ACC glutamate+glutamine/creatine in the hippocampal part of the cingulum bundle. It is possible that the extent of myelin damage could have resulted in the absence of DTI-MRS correlations in our patient group. In conclusion, we demonstrate the potential utility of a multi-modal neuroimaging approach to help further our understanding of the relationship between white matter microstructure and neurochemistry in distinct cortical regions connected by white matter tracts. [ABSTRACT FROM AUTHOR]

Radiation shielding performance and radiation induced noise levels in ion detection instruments were investigated for a high radiation field. The intensity of primary and secondary radiation behind simple shields of aluminum and tantalum were determined by Monte Carlo computer simulations. Two ion detectors were evaluated: a micro-channel plate and a custom discrete dynode electron multiplier. Europa, an icy moon of Jupiter, was selected because it is one of the most intense radiation environments in our solar system. Based on the combination of computer simulation results and experimental measurements of detector responses to electron and photon radiation, the relative radiation induced background noise was assessed to inform further instrument design considerations and performance optimization, such as anticipated signal-to-noise ratio and minimum detectable concentrations for mass spectroscopy during specific missions. Radiation detection efficiencies between the two detectors were comparable for photons and higher energy electrons, but significant differences were found for electrons with energies less than 0.5 MeV. Higher radiation induced count rates are expected for the micro-channel plate detector owing to its larger cross-sectional area. Superior instrument performance is anticipated for the custom discrete dynode electron multiplier detector in high radiation environments with the same or slightly less shielding. [ABSTRACT FROM PUBLISHER]

Cold pre-conditioning reduces subsequent brain injury in small animals but the underlying mechanisms remain undefined. As hypothermia triggers systemic macrophage tumor necrosis factor alpha (TNF-α) production and other neural pre-conditioning stimuli depend on this cytokine, we reasoned that microglia and TNF-α would be similarly involved with cold preconditioning neuroprotection. Also, as slice cultures closely approximate their in vivo counterpart and include quiescent microglia, we used rat hippocampal slice cultures to confirm this hypothesis. Furthermore, inflammatory cytokine gene screening with subsequent PCR and immunostaining confirmation of targeted mRNA and related protein changes showed that cold pre-conditioning triggered a significant rise in TNF-α that localized to microglia and a significant rise in interleukin (IL)-11 that localized mainly to hippocampal pyramidal neurons and, more rarely, astrocytes. Importantly, costimulation with cold and IL-11, an anti-inflammatory cytokine that inhibits TNF-α expression, abrogated the otherwise evident protection. Instead, cold pre-conditioning coupled with blockade of IL-11 signaling further enhanced neuroprotection from that seen with cold pre-conditioning alone. Thus, physiological activation of brain pro-inflammatory cytokine signaling, and its amplification by inhibition of coincident antiinflammatory cytokine signaling, may be opportune targets for the development of novel therapeutics that can mimic the protection seen in cold pre-conditioning. [ABSTRACT FROM AUTHOR]

Abstract: The molecular epidemiology of Bluetongue virus serotype 11 (BTV11) in an enzootic focus in northern Colorado was investigated. Viruses isolated up to 12 years apart, from both vertebrate and invertebrate hosts, were compared by phylogenetic analysis of nucleotide sequence data from three genome segments: L2, S7, and S10. For each segment, viruses isolated from ruminants in the 1980s were more similar to one another than to viruses isolated from Culicoides spp. insects in the 1990s. Nearly identical BTV11-L2 segments were found in all isolates, but over time they were associated with different S7 and S10 genome segments. Therefore, L2-segment-based serologic identification of BTV isolates underestimates the origin and natural evolution of the viruses. In addition, the use of one or even two genome segments is inadequate to define the molecular epidemiology of the viruses in an enzootic focus. This information could influence import/export regulations based on BTV epidemiology in enzootic areas, as well as our view of the natural biology of the viruses. [Copyright &y& Elsevier]

This report on the first phase of an evaluation and demonstration project to provide high quality mammography services to women in remote and underserved areas appears at a time of considerable controversy regarding the efficacy of screening mammography. The objectives of the first phase were focused on the technical feasibility of utilizing digital mammography in a mobile setting, transmitting the images via satellite for immediate interpretation at centers of excellence, and providing the results to the patient before she left the examination site. The next phase, a field trial on a Native American reservation, will include baseline data and operational measures to address patient participation, compliance with follow-up recommendations, and the costs and benefits of the program.With the support of the Komen Foundation, the project team was able to complete the initial phase of the project to evaluate a new method of providing real-time, expert mammography interpretations to rural and underserved women. In this phase, the project team tested the feasibility of using a mobile breast care center, equipped with a digital mammography unit, and a satellite telecommunication link to medical centers for image interpretation on an electronic review workstation. The satisfactory completion of this first phase supports the recommendation that a field trial using the methods described in this report be conducted with a remote rural population to determine the clinical efficacy and economic viability of this concept in delivering breast cancer detection services. [Copyright &y& Elsevier]

Analyzes the race conscious admission program at the University of Michigan Law School. Appropriate evaluation of admitted students; Roles of patently biased questions, test development specifications and psychological dynamics in creating and maintaining the law school admission test gap; Adoption of standard of fairness.

Background: Cortical thickness (CT) and gyrification are complementary indices that assess different aspects of gray matter structural integrity. Both neurodevelopment insults and acute tissue response to antipsychotic medication could underlie the known heterogeneity of treatment response and are well-suited for interrogation into the relationship between gray matter morphometry and clinical outcomes in schizophrenia (SZ).Methods: Using a prospective design, we enrolled 34 unmedicated patients with SZ and 23 healthy controls. Patients were scanned at baseline and after a 6-week trial with risperidone. CT and local gyrification index (LGI) values were quantified from structural MRI scans using FreeSurfer 5.3.Results: We found reduced CT and LGI in patients compared to controls. Vertex-wise analyses demonstrated that hypogyrification was most prominent in the inferior frontal cortex, temporal cortex, insula, pre/postcentral gyri, temporoparietal junction, and the supramarginal gyrus. Baseline CT was predictive of subsequent response to antipsychotic treatment, and increase in CT after 6 weeks was correlated with greater symptom reductions.Conclusions: In summary, we report evidence of reduced CT and LGI in unmedicated patients compared to controls, suggesting involvement of different aspects of gray matter morphometry in the pathophysiology of SZ. Importantly, we found that lower CT at baseline and greater increase of CT following 6 weeks of treatment with risperidone were associated with better clinical response. Our results suggest that cortical thinning may normalize as a result of a good response to antipsychotic medication, possibly by alleviating potential neurotoxic processes underlying gray matter deterioration. [ABSTRACT FROM AUTHOR]

Highlights • We replicate previously reported findings of elevated choline in the associative striatum in first episode psychosis and extend the literature by showing that decoupling between N -acetyl-aspartate and Glx (glutamate + glutamine) is present in the associative striatum. Decoupling of NAA and Glx could reflect a disruption in neuro-glial energy systems that in turn could affect membrane stability and choline levels. • As with the majority of MRS studies in patients with schizophrenia, we also did not observe any relationships between clinical variables and metabolite levels. Abstract Schizophrenia is a chronic, often progressive, disorder. Understanding the underlying neurobiology present in the early stages of the illness is as a pivotal step in designing targeted interventions aimed at arresting disease progression. The aim of our study was to examine neurometabolic changes in the dopamine rich associative striatum in medication-naïve first episode psychosis (FEP). We quantified neurometabolites in 14 FEP and 18 healthy controls (HC) matched on key demographic characteristics. Spectra from the voxel in the left associative striatum were acquired using a PRESS sequence (TR/TE = 2000/80 ms; 512 averages). MRS data were quantified in the time domain with AMARES in jMRUI. Choline was significantly elevated in FEP compared to HC. No significant alterations in other metabolites were observed. We did not observe correlations between metabolite levels and clinical characteristics in FEP. Here, we demonstrated elevated choline and a disruption of the relationship between N -acetyl-aspartate and Glx (glutamate + glutamine) in medication-naïve FEP patients in the left striatum indicating possible mitochondrial, membrane and glial dysfunction as an underlying pathological phenomenon. In addition, striatal choline shows promise as a biomarker for FEP that may have utility in clinical trials investigating target engagement in experimental regimens. [ABSTRACT FROM AUTHOR]

Pain Coping Skills Training (PCST) is a first-line cognitive-behavioral, non-pharmacological treatment for chronic pain and comorbid symptoms. PCST has been shown to be effective in racially and ethnically diverse cohorts across several chronic medical conditions. However, PCST has not been evaluated in those with end stage kidney disease (ESKD) receiving in-center maintenance hemodialysis. Due to the high rates of morbidity associated with ESKD, and time-intensive treatment, an adaptation of PCST was warranted to address the unique challenges experienced by people living with ESKD. Using current guidelines developed by Card and colleagues for intervention adaptation, PCST was adapted so that it could be implemented among people living with ESKD in a national multisite trial. The objective of this paper was to describe the adaption process outlined by Card and colleagues including how the team selected an effective intervention to adapt, developed a program model, identified mismatches in the original intervention and study population, and then adapted the intervention for those with ESKD treated with in-center maintenance hemodialysis. Finally, we briefly describe future directions for clinical practice and research with the adapted PCST intervention for those with ESKD.Trial registration: ClinicalTrials.gov #NCT04571619. [ABSTRACT FROM AUTHOR]

An abstract of the article "Laryngeal Mask Airway in Outpatient Laparoscopic Surgery," by David M. White is presented.

Proton magnetic resonance spectroscopy (1H-MRS) allows the non-invasive measurement of several metabolites, including N-acetyl-aspartate (NAA), an amino acid exclusively synthesized in the mitochondria of neurons, and glutamate, an amino acid involved in excitatory neurotransmission and metabolism. In view of recent postmortem studies in schizophrenia (SZ) revealing mitochondrial abnormalities as well as perturbed expression of the enzymes regulating the glutamate-glutamine cycle, we hypothesized that a disruption in the homeostasis of NAA and glutamate in SZ is present. Fifty subjects with SZ and 48 matched healthy controls (HC) were enrolled in this 1H-MRS study. Voxels were placed in the anterior cingulate cortex (ACC) and hippocampus; NAA/Cr and glutamate + glutamine (Glx)/Cr ratios were obtained. We did not find any significant differences between the groups in metabolite levels in both the ACC and hippocampus. In the hippocampus we found that NAA/Cr and Glx/Cr ratios were significantly correlated in HC (r=0.40, p<0.01 (corrected p=0.048)) but not in SZ (r=−0.06; p=0.71), a difference that was statistically significant (z=2.22, p=0.02). Although no differences in neurometabolites between SZ and HC were apparent, correlations between NAA/Cr and Glx/Cr in healthy subjects in the hippocampus were found, and this correlation was lost in subjects with SZ. To our knowledge, this is the first study to suggest decoupling of these metabolites, a pathophysiological change that may be unique to SZ. However, these results warrant replication and further exploration before definite conclusions can be drawn. [ABSTRACT FROM AUTHOR]

Abstract: Background: Studies have shown that individuals with schizophrenia suffer from memory impairments. In this study, we combined proton magnetic resonance spectroscopy (1H-MRS) and functional magnetic resonance imaging (fMRI) to clarify the neurobiology of memory deficits in schizophrenia. Methods: We used single-voxel MRS acquired in the left hippocampus and fMRI during performance of a memory task to obtain measures of neurochemistry and functional response in 28 stable, medicated participants with schizophrenia (SZ) and 28 matched healthy controls (HC). Results: The SZ group had significantly decreased blood oxygen level-dependent (BOLD) signal in left inferior frontal gyrus (IFG) during encoding and in the anterior cingulate cortex (ACC) and superior temporal gyrus (STG) during retrieval. We did not find significant differences in N-acetylaspartate/creatine (NAA/Cr) or glutamate+glutamine (Glx/Cr) levels between the groups, but did find a significant positive correlation between NAA/Cr and Glx/Cr in the HC group that was absent in the SZ group. There were no significant correlations between BOLD and MRS measured in the hippocampus. Further analyses revealed a negative correlation between left IFG BOLD and task performance in the SZ group. Finally, in the HC group, the left IFG BOLD was positively correlated with Glx/Cr. Conclusions: We replicated findings of reduced BOLD signal in left IFG and of an altered relationship between IFG BOLD response and task performance in the SZ. The absence of correlation between NAA/Cr and Glx/Cr levels in patients might suggest underlying pathologies of the glutamate–glutamine cycle and/or mitochondria. [Copyright &y& Elsevier]

Background: Neuroimaging and electrophysiologic studies have consistently provided evidence of impairment in anterior cingulate cortex/medial frontal cortex function in people with schizophrenia. In this study, we sought to clarify the nature of this abnormality by combining proton magnetic resonance spectroscopy (1H-MRS) with functional magnetic resonance imaging (fMRI) at 3T. Methods: We used single-voxel MRS acquired in the dorsal anterior cingulate cortex and fMRI during performance of a Stroop color-naming task to investigate the neurochemistry and functional response of the anterior cingulate cortex/medial frontal cortex in 26 stable, medicated subjects with schizophrenia and 23 matched healthy control subjects. Results: In schizophrenia subjects, we found decreased blood oxygen level–dependent signal in the medial frontal wall, with significant clusters restricted to more dorsal regions compared with healthy subjects. In addition, we observed a trend-level decrease in N-acetylaspartate/creatine (NAA/Cr) levels and a significant positive correlation between NAA/Cr level and the blood oxygen level-dependent signal in schizophrenia subjects that did not exist in healthy subjects. Furthermore, in this group of medicated subjects, we did not find evidence of decreased glutamate + glutamine(Glx)/Cr levels, but there was a significant negative correlation between Glx/Cr levels and negative symptoms. Conclusions: Our results suggest that abnormal NAA levels, which may reflect a neuronal dysfunction related to schizophrenia, affect neuronal physiology, as evidenced by reduced blood oxygen level–dependent response. [ABSTRACT FROM AUTHOR]

This study examines college women's intention to receive the Human Papilloma Virus (HPV) vaccine and their perceived barriers to being vaccinated. The study reports findings from an online questionnaire completed by 856 undergraduate women enrolled in a required personal health course at a large (27,000 plus) southeastern university. The majority of the respondents (78.6%) indicated that they would get the vaccine; however, only 60.7% of the respondents who self-identified as not yet sexually active reported that they plan to be vaccinated. Side effects, costs and lack of knowledge about the vaccine were most often indicated as barriers to receiving the vaccine. Education about HPV and the vaccine is needed to address the perceived barriers to vaccination. [ABSTRACT FROM AUTHOR]

Magnetic Resonance Spectroscopy is a popular approach to probe brain chemistry in schizophrenia (SZ), but no consensus exists as to the extent of alterations. This may be attributable to differential effects of populations studied, brain regions examined, or antipsychotic medication effects. Here, we measured neurometabolites in the anterior cingulate cortex (ACC) and hippocampus, two structurally dissimilar brain regions implicated in the SZ pathophysiology. We enrolled 61 SZ with the goal to scan them before and after six weeks of treatment with risperidone. We also scanned 31 matched healthy controls twice, six weeks apart. Using mixed effect repeated measures linear models to examine the effect of group and time on metabolite levels in each voxel, we report an increase in hippocampal glutamate + glutamine (Glx) in SZ compared to controls (p = 0.043), but no effect of antipsychotic medication (p = 0.330). In the ACC, we did not find metabolite alterations or antipsychotic medication related changes after six weeks of treatment with risperidone. The coefficients for the discriminant function (differentiating SZ from HC) in the ACC were greatest for NAA (-0.83), and in the hippocampus for Glx (0.76), the same metabolites were associated with greater treatment response in patients at trend level. Taken together, our data extends the existing literature by demonstrating regionally distinct metabolite alterations in the same patient group and suggests that antipsychotic medications may have limited effects on metabolite levels in these regions. [ABSTRACT FROM AUTHOR]

Background: Impairment in episodic memory is one of the most robust findings in schizophrenia. Disruptions of fronto-temporal functional connectivity that could explain some aspects of these deficits have been reported. Recent work has identified abnormal hippocampal function in unmedicated patients with schizophrenia (SZ), such as increased metabolism and glutamate content that are not always seen in medicated SZ. For these reasons, we hypothesized that altered fronto-temporal connectivity might originate from the hippocampus and might be partially restored by antipsychotic medication. Methods: Granger causality methods were used to evaluate the effective connectivity between frontal and temporal regions in 21 unmedicated SZ and 20 matched healthy controls (HC) during performance of an episodic memory retrieval task. In 16 SZ, effective connectivity between these regions was evaluated before and after 1-week of antipsychotic treatment. Results: In HC, significant effective connectivity originating from the right hippocampus to frontal regions was identified. Compared to HC, unmedicated SZ showed significant altered fronto-temporal effective connectivity, including reduced right hippocampal to right medial frontal connectivity. After 1-week of antipsychotic treatment, connectivity more closely resembled the patterns observed in HC, including increased effective connectivity from the right hippocampus to frontal regions. Conclusions: These results support the notion that memory disruption in schizophrenia might originate from hippocampal dysfunction and that medication restores some aspects of fronto-temporal dysconnectivity. Patterns of fronto-temporal connectivity could provide valuable biomarkers to identify new treatments for the symptoms of schizophrenia, including memory deficits. Hum Brain Mapp 36:1442-1457, 2015. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Medication management in schizophrenia is a lengthy process, as the lack of clinical response can only be confirmed after at least 4 weeks of antipsychotic treatment at a therapeutic dose. Thus, there is a clear need for the discovery of biomarkers that have the potential to accelerate the management of treatment. Using resting-state functional MRI, we examined the functional connectivity of the ventral tegmental area (VTA), the origin of the mesocorticolimbic dopamine projections, in 21 healthy controls and 21 unmedicated patients with schizophrenia at baseline (pre-treatment) and after 1 week of treatment with the antipsychotic drug risperidone (1-week post-treatment). Group-level functional connectivity maps were obtained and group differences in connectivity were assessed on the groups' participant-level functional connectivity maps. We also examined the relationship between pre-treatment/1-week post-treatment functional connectivity and treatment response. Compared with controls, patients exhibited significantly reduced pre-treatment VTA/midbrain connectivity to multiple cortical and subcortical regions, including the dorsal anterior cingulate cortex (dACC) and thalamus. After 1 week of treatment, VTA/midbrain connectivity to bilateral regions of the thalamus was re-established. Pre-treatment VTA/midbrain connectivity strength to dACC was positively correlated with good response to a 6-week course of risperidone, whereas pre-treatment VTA/midbrain connectivity strength to the default mode network was negatively correlated. Our findings suggest that VTA/midbrain resting-state connectivity may be a useful biomarker for the prediction of treatment response. [ABSTRACT FROM AUTHOR]

Abstract: We investigated the relationship between basal ganglia volume and treatment response to the atypical antipsychotic medication risperidone in unmedicated patients with schizophrenia. Basal ganglia volumes included the bilateral caudate, putamen, and pallidum and were measured using the Freesurfer automated segmentation pipeline in 23 subjects. Also, baseline symptom severity, duration of illness, age, gender, time off medication, and exposure to previous antipsychotic were measured. Treatment response was significantly correlated with all three regions of the bilateral basal ganglia (caudate, putamen, and pallidum), baseline symptom severity, duration of illness, and age but not gender, time off antipsychotic medication, or exposure to previous antipsychotic medication. The caudate volume was the basal ganglia region that demonstrated the strongest correlation with treatment response and was significantly negatively correlated with patient age. Caudate volume was not significantly correlated with any other measure. We demonstrated a novel finding that the caudate volume explains a significant amount of the variance in treatment response over the course of 6 weeks of risperidone pharmacotherapy even when controlling for baseline symptom severity and duration of illness. [Copyright &y& Elsevier]

Lassa virus (LASV) is the causative agent of Lassa Fever and is responsible for several hundred thousand infections and thousands of deaths annually in West Africa. LASV and the non-pathogenic Mopeia virus (MOPV) are both rodent-borne African arenaviruses. A live attenuated reassortant of MOPV and LASV, designated ML29, protects rodents and primates from LASV challenge and appears to be more attenuated than MOPV. To gain better insight into LASV-induced pathology and mechanism of attenuation we performed gene expression profiling in human peripheral blood mononuclear cells (PBMC) exposed to LASV and the vaccine candidate ML29. PBMC from healthy human subjects were exposed to either LASV or ML29. Although most PBMC are non-permissive for virus replication, they remain susceptible to signal transduction by virus particles. Total RNA was extracted and global gene expression was evaluated during the first 24 hours using high-density microarrays. Results were validated using RT-PCR, flow cytometry and ELISA. LASV and ML29 elicited differential expression of interferon-stimulated genes (ISG), as well as genes involved in apoptosis, NF-kB signaling and the coagulation pathways. These genes could eventually serve as biomarkers to predict disease outcomes. The remarkable differential expression of thrombomodulin, a key regulator of inflammation and coagulation, suggests its involvement with vascular abnormalities and mortality in Lassa fever disease. Author Summary: The virulent Lassa fever virus (LASV) and the non-pathogenic Mopeia virus (MOPV) infect rodents and, incidentally, people in West Africa. The mechanism of LASV damage in human beings is unclear. There is no licensed Lassa fever vaccine and therapeutic intervention is usually too late. The ML29 vaccine candidate derived from Lassa and Mopeia viruses protects rodents and primates from Lassa fever disease. Peripheral blood mononuclear cells from healthy human subjects were exposed to either LASV or ML29 in order to identify early cellular responses that could be attributed to the difference in virulence between the two viruses. Differential expression of interferon-stimulated genes as well as coagulation-related genes could lead to an explanation for Lassa fever pathogenesis and indicate protective treatments for Lassa fever disease. [ABSTRACT FROM AUTHOR]

Lassa virus (LASV) is the causative agent of Lassa Fever and is responsible for several hundred thousand infections and thousands of deaths annually in West Africa. LASV and the non-pathogenic Mopeia virus (MOPV) are both rodent-borne African arenaviruses. A live attenuated reassortant of MOPV and LASV, designated ML29, protects rodents and primates from LASV challenge and appears to be more attenuated than MOPV. To gain better insight into LASV-induced pathology and mechanism of attenuation we performed gene expression profiling in human peripheral blood mononuclear cells (PBMC) exposed to LASV and the vaccine candidate ML29. PBMC from healthy human subjects were exposed to either LASV or ML29. Although most PBMC are non-permissive for virus replication, they remain susceptible to signal transduction by virus particles. Total RNA was extracted and global gene expression was evaluated during the first 24 hours using high-density microarrays. Results were validated using RT-PCR, flow cytometry and ELISA. LASV and ML29 elicited differential expression of interferon-stimulated genes (ISG), as well as genes involved in apoptosis, NF-kB signaling and the coagulation pathways. These genes could eventually serve as biomarkers to predict disease outcomes. The remarkable differential expression of thrombomodulin, a key regulator of inflammation and coagulation, suggests its involvement with vascular abnormalities and mortality in Lassa fever disease. [ABSTRACT FROM AUTHOR]

Abstract: Background: Converging evidence in schizophrenia points to disruption of the dopamine and glutamate neurotransmitter systems in the pathophysiology of the disorder. Dopamine is produced in the substantia nigra, but few neuroimaging studies have specifically targeted this structure. In fact, no studies of the substantia nigra in schizophrenia have used proton magnetic resonance spectroscopy (MRS). We sought to demonstrate the feasibility of acquiring single-voxel MRS measurements at 3T from the substantia nigra and to determine which metabolites could be reliably quantified in schizophrenia patients and healthy controls. Methods: We used a turbo spin echo sequence with magnetization transfer contrast to visualize the substantia nigra and single-voxel proton MRS to quantify levels of N-acetylaspartate, glutamate and glutamine (Glx), and choline in the left substantia nigra of 35 people with schizophrenia and 22 healthy controls. Results: We obtained spectra from the substantia nigra and quantified neurometabolites in both groups. We found no differences in levels of N-acetylaspartate/creatine, Glx/creatine, or choline/creatine between the groups. We found a significant correlation between Glx/creatine and overall cognitive performance, measured with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), in controls but not patients, a difference that was statistically significant. Conclusions: Our study demonstrates the feasibility of obtaining single-voxel MRS data from the substantia nigra in schizophrenia. Such measurements may prove useful in understanding the biochemistry underlying cellular function in a region implicated in the pathophysiology of schizophrenia. [Copyright &y& Elsevier]

Background: Magnetic resonance imaging (MRI) has multiple contrast mechanisms. Like various staining techniques in histology, each contrast type reveals different information about the structure of the brain. However, it is not always clear how structures visible in MRI correspond to structures previously identified by histology. The purpose of this study was to determine if magnetic transfer contrast (MTC) or T2 contrast MRI was better at delineating the substantia nigra (SN). Methods: MRI scans were acquired in vivo from two nonhuman primates (NHPs). The NHPs were subsequently euthanized, perfused, and their brains sectioned for histologic analyses. Each slice was photographed before sectioning. Each brain was sectioned into approximately 500 sections, 40μm each, encompassing most of the cortex, midbrain, and dorsal parts of the hindbrain. Levels corresponding to anatomic MRI images were selected. From these, adjacent sections were stained using Kluver-Barrera (myelin and cell bodies) or tyrosine hydroxylase (dopaminergic neurons) immunohistochemistry. The resulting images were coregistered to the block-face images using a moving least squares algorithm with similarity transformations. MR images were similarly coregistered to the block-face images, allowing the structures on MRI to be identified with structures on the histologic images. Results: We found that hyperintense (light) areas in MTC images were coextensive with the SN as delineated histologically. The hypointense (dark) areas in T2-weighted images were not coextensive with the SN but extended partially into the SN and partially into the cerebral peduncles. Conclusions: MTC is more accurate than T2-weighting for localizing the SN in vivo. [ABSTRACT FROM AUTHOR]

Environmental enrichment, i.e., increased intellectual, social, and physical activity makes brain more resilient to subsequent neurological disease. The mechanisms for this effect remain incompletely defined, but evidence shows tumor necrosis factor-alpha (TNF-α) is involved. TNF-α, at acutely high levels, possesses the intrinsic capacity to enhance injury associated with neurological disease. Conversely, the effect of TNF-α at low-levels is nutritive over time, consistent with physiological conditioning hormesis. Evidence shows that neural activity triggers low-level pro-inflammatory signaling involving TNF-α. This low-level TNF-α signaling alters gene expression, resulting in an enhanced resilience to disease. Brain-immune signaling may become maladaptive when increased activity is chronic without sufficient periods of reduced activity necessary for nutritive adaptation. Such tonically increased activity may explain, for example, the transformation of episodic to chronic migraine with related increased susceptibility to spreading depression, the most likely underlying cause of this malady. Thus, TNF-α, whose function is to alter gene expression, and its principal cellular source, microglia, seem powerfully positioned to orchestrate hormetic immune signaling that establishes the phenotype of neurological health and disease from brain activity. [ABSTRACT FROM AUTHOR]

Immunoglobulin-like transcripts (ILTs) are immunoregulatory proteins that either activate or inhibit immune responses. ILT3 is inhibitory and is expressed preferentially by antigen-presenting cells. When its extracellular domain binds to an unidentified ligand of activated T cells, the T cell is silenced. Our objective was to study the expression of ILT3 on circulating monocytes in RRMS. Freshly isolated peripheral blood mononuclear cells were analyzed by multicolored flow cytometry. The proportion of ILT3+CD14+ monocytes in blood, and ILT3 levels expressed by them, is lower in untreated multiple sclerosis in relapse than in: (1) untreated multiple sclerosis in remission (p<0.009); (2) stable interferon b-treated relapsing-remitting multiple sclerosis (p<0.001) and; (3) healthy controls (p<0.009). Glatiramer acetate-stimulated CD4+ T cells, co-cultured with freshly isolated monocytes, proliferate significantly better (p=0.0017 for multiple sclerosis; p=0.0015 for controls) when T cell interaction with monocyte-expressed ILT3 is blocked by anti-ILT3 antibody. Interferon β is beneficial in multiple sclerosis; why so remains unclear. Interferon β-1b markedly increases ILT3 expression in vitro by monocytes from multiple sclerosis patients and controls. These findings identify a putative novel mechanism for the therapeutic benefit bestowed by Interferon β and a new target for therapeutic intervention in relapsing-remitting multiple sclerosis. [ABSTRACT FROM AUTHOR]

Fire in the operating theater is a rare but potentially fatal complication. We report igniting an intraperitoneal fire while preforming an exploratory laparotomy for perforated viscus. Fortunately, the patient suffered no injuries as a result. [ABSTRACT FROM AUTHOR]

In brain, monomeric immunoglobin G (IgG) is regarded as quiescent and only poised to initiate potentially injurious inflammatory reactions via immune complex formation associated with phagocytosis and tumor necrosis factor α (TNF-α) production in response to disease. Using rat hippocampal slice and microglial cultures, here we show instead that physiological levels (i.e., 0.2-20 μg/ml) of monomeric IgG unassociated with disease triggered benign low-level proinflammatory signaling that was neuroprotective against CA1 area excitotoxicity and followed a U-shaped or hormetic dose-response. The data indicate that physiological IgG levels activated microglia by enhancing recycling endocytosis plus TNF-α release from these cells to produce the neuroprotection. Minocycline, known for its anti-inflammatory and neuroprotective effects when given after disease onset, abrogated IgG-mediated neuroprotection and related microglial effects when given before injury. In contrast, E-prostanoid receptor subtype 2 (EP2) activation, which served as an exemplary paracrine stimulus like the one expected from neuronal activity, amplified IgG-mediated increased microglial recycling endocytosis and TNF-α production. Furthermore, like monomeric IgG these EP2 related effects took days to be effective, suggesting both were adaptive anabolic effects consistent with those seen from other long-term preconditioning stimuli requiring de novo protein synthesis. The data provide the first evidence that brain monomeric IgG at physiological levels can have signaling function via enhanced recycling endocytosis/TNF-α production from microglia unassociated with disease and that these IgG-mediated changes may be a means by which paracrine signaling from neuronal activity influences microglia to evoke neuroprotection. The data provide further support that low-level proinflammatory neural immune signaling unassociated with disease enhances brain function. [ABSTRACT FROM AUTHOR]

• Post-COVID-19 restrictions, driving days per week decreased 37 % among adolescents. • Vehicle miles driven in past two weeks decreased 35 % among adolescents. • Decrease was lower among ethnic minorities, older and employed adolescents. • Those with greater dire prosocial tendencies showed greater driving decline. Understanding who heeds the driving-related COVID-19 restrictions is critical for assisting public health professionals improve response to this and future pandemic events. The purpose of the current study was to characterize driving behavior changes among adolescents as a function of COVID-19 restrictions. It was hypothesized that adolescent driving would be reduced by COVID-19 restrictions, especially for younger teens, non-minorities, females, non-working teens, and those with higher prosocial tendencies. Participants were licensed drivers in "REACT," a longitudinal study of adolescent driving attention. Upon enrollment in REACT, drivers were required to be age 16 or 18, have been issued a driver's license within the last two weeks, and be fluent in written/spoken English. The current observational cohort study was of drivers reporting driving exposure between February 8 and April 22, 2020. Linear mixed-effects models estimated differences in driving changes between COVID-19 periods. Results indicated a decrease across pre-COVID-19 period (February 8 – March 13, 2020) in days driven per week and vehicle miles driven (VMD) was explained by the change of slope post-COVID-19 restrictions (March 14 – April 22, 2020). Post-COVID-19, driving days per week decreased by 37 % and VMD decreased by 35 %. This decrease was lower in ethnic minorities, older adolescents, and employed adolescents. Those with greater dire prosocial tendencies showed greater post-COVID-19 driving decline. Findings provide early evidence of COVID-19 restriction-related adolescent driving changes suggesting older, employed, minority teens and teens with lower prosocial tendencies are less likely to reduce driving behavior. These observations provide a foundation for more extensive studies of adolescent drivers during various driving and contact restrictions and inform future public health campaigns for social distancing. [ABSTRACT FROM AUTHOR]

The Arenaviridae are a diverse and globally distributed collection of viruses that are maintained primarily by rodent reservoirs. Junin virus (JUNV) and Lassa virus (LASV) can both cause significant outbreaks of severe and often fatal human disease throughout their respective areas of endemicity. In an effort to improve upon the existing live attenuated JUNV Candid1 vaccine, we generated a genetically homogenous stock of this virus from cDNA copies of the virus S and L segments by using a reverse genetics system. Further, these cDNAs were used in combination with LASV cDNAs to successfully generate two recombinant Candid1 JUNV/LASV chimeric viruses (via envelope glycoprotein [GPC] exchange). It was found that while the GPC extravirion domains were readily exchangeable, homologous stable signal peptide (SSP) and G2 transmembrane and cytoplasmic tail domains were essential for correct GPC maturation and production of infectious chimeric viruses. The switching of the JUNV and LASV G1/G2 ectodomains within the Candid1 vaccine background did not alter the attenuated phenotype of the vaccine strain in a lethal mouse model. These recombinant chimeric viruses shed light on the fundamental requirements of arenavirus GPC maturation and may serve as a strategy for the development of bivalent JUNV and LASV vaccine candidates. [ABSTRACT FROM AUTHOR]