Unstable Maternal Environment, Separation Anxiety, and Heightened CO2 Sensitivity Induced by Gene-by-Environment Interplay

Background: In man, many different events implying childhood separation from caregivers/unstable parental environment are associated with heightened risk for panic disorder in adulthood. Twin data show that the occurrence of such events in childhood contributes to explaining the covariation between separation anxiety disorder, panic, and the related psychobiological trait of CO2 hypersensitivity. We hypothesized that early interference with infant-mother interaction could moderate the interspecific trait of response to CO2 through genetic control of sensitivity to the environment. Methodology: Having spent the first 24 hours after birth with their biological mother, outbred NMRI mice were crossfostered to adoptive mothers for the following 4 post-natal days. They were successively compared to normally-reared individuals for: number of ultrasonic vocalizations during isolation, respiratory physiology responses to normal air (20%O2), CO2-enriched air (6% CO2), hypoxic air (10%O2), and avoidance of CO2-enriched environments. Results: Cross-fostered pups showed significantly more ultrasonic vocalizations, more pronounced hyperventilatory responses (larger tidal volume and minute volume increments) to CO2-enriched air and heightened aversion towards CO2- enriched environments, than normally-reared individuals. Enhanced tidal volume increment response to 6%CO2 was present at 16–20, and 75–90 postnatal days, implying the trait’s stability. Quantitative genetic analyses of unrelated individuals, sibs and half-sibs, showed that the genetic variance for tidal volume increment during 6%CO2 breathing was significantly higher (Bartlett x = 8.3, p = 0.004) among the cross-fostered than the normally-reared individuals, yielding heritability of 0.37 and 0.21 respectively. These results support a stress-diathesis model whereby the genetic influences underlying the response to 6%CO2 increase their contribution in the presence of an environmental adversity. Maternal grooming/licking behaviour, and corticosterone basal levels were similar among cross-fostered and normally-reared individuals. Conclusions: A mechanism of gene-by-environment interplay connects this form of early perturbation of infant-mother interaction, heightened CO2 sensitivity and anxiety. Some no

Activation of mGlu3 Receptors Stimulates the Production of GDNF in Striatal Neurons

Metabotropic glutamate (mGlu) receptors have been considered potential targets for the therapy of experimental parkinsonism. One hypothetical advantage associated with the use of mGlu receptor ligands is the lack of the adverse effects typically induced by ionotropic glutamate receptor antagonists, such as sedation, ataxia, and severe learning impairment. Low doses of the mGlu2/3 metabotropic glutamate receptor agonist, LY379268 (0.25–3 mg/kg, i.p.) increased glial cell line-derived neurotrophic factor (GDNF) mRNA and protein levels in the mouse brain, as assessed by in situ hybridization, real-time PCR, immunoblotting, and immunohistochemistry. This increase was prominent in the striatum, but was also observed in the cerebral cortex. GDNF mRNA levels peaked at 3 h and declined afterwards, whereas GDNF protein levels progressively increased from 24 to 72 h following LY379268 injection. The action of LY379268 was abrogated by the mGlu2/3 receptor antagonist, LY341495 (1 mg/kg, i.p.), and was lost in mGlu3 receptor knockout mice, but not in mGlu2 receptor knockout mice. In pure cultures of striatal neurons, the increase in GDNF induced by LY379268 required the activation of the mitogen-activated protein kinase and phosphatidylinositol-3-kinase pathways, as shown by the use of specific inhibitors of the two pathways. Both in vivo and in vitro studies led to the conclusion that neurons were the only source of GDNF in response to mGlu3 receptor activation. Remarkably, acute or repeated injections of LY379268 at doses that enhanced striatal GDNF levels (0.25 or 3 mg/kg, i.p.) were highly protective against nigro-striatal damage induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice, as assessed by stereological counting of tyrosine hydroxylase-positive neurons in the pars compacta of the substantia nigra. We speculate that selective mGlu3 receptor agonists or enhancers are potential candidates as neuroprotective agents in Parkinson's disease, and their use might circumvent the limitations associated with the administration of exogenous GDNF

The STRIP instrument of the Large Scale Polarization Explorer: microwave eyes to map the Galactic polarized foregrounds

In this paper we discuss the latest developments of the STRIP instrument of the "Large Scale Polarization Explorer" (LSPE) experiment. LSPE is a novel project that combines ground-based (STRIP) and balloon-borne (SWIPE) polarization measurements of the microwave sky on large angular scales to attempt a detection of the "B-modes" of the Cosmic Microwave Background polarization. STRIP will observe approximately 25% of the Northern sky from the "Observatorio del Teide" in Tenerife, using an array of forty-nine coherent polarimeters at 43 GHz, coupled to a 1.5 m fully rotating crossed-Dragone telescope. A second frequency channel with six-elements at 95 GHz will be exploited as an atmospheric monitor. At present, most of the hardware of the STRIP instrument has been developed and tested at sub-system level. System-level characterization, starting in July 2018, will lead STRIP to be shipped and installed at the observation site within the end of the year. The on-site verification and calibration of the whole instrument will prepare STRIP for a 2-years campaign for the observation of the CMB polarization.Comment: 17 pages, 15 figures, proceedings of the SPIE Astronomical Telescopes + Instrumentation conference "Millimeter, Submillimeter, and Far-Infrared Detectors and Instrumentation for Astronomy IX", on June 15th, 2018, Austin (TX

Causes of unrest at silicic calderas in the East African Rift: new constraints from InSAR and soil-gas chemistry at Aluto volcano, Ethiopia

This work is a contribution to the Natural Environment Research Council (NERC) funded RiftVolc project (NE/L013932/1, Rift volcanism: past, present, and future). W.H., J.B., T.A.M., and D.M.P. are supported by and contribute to the NERC Centre for the Observation and Modelling of Earthquakes, Volcanoes, and Tectonics (COMET). Envisat data were provided by ESA. ALOS data were provided through ESA third party mission. W.H. funded by NERC studentship, NE/J5000045/1. Additional funding for fieldwork was provided by University College (University of Oxford), the Geological Remote Sensing Group, the Edinburgh Geological Society, and the Leverhulme Trust. Analytical work at the University of New Mexico was supported by the Volcanic and Geothermal Volatiles Lab at the Center for Stable Isotopes and an NSF grant EAR-1113066 to T.P.F.Restless silicic calderas present major geological hazards, and yet many also host significant untapped geothermal resources. In East Africa this poses a major challenge, although the calderas are largely unmonitored their geothermal resources could provide substantial economic benefits to the region. Understanding what causes unrest at these volcanoes is vital for weighing up the opportunities against the potential risks. Here we bring together new field and remote sensing observations to evaluate causes of ground deformation at Aluto, a restless silicic volcano located in the Main Ethiopian Rift (MER). Interferometric Synthetic Aperture Radar (InSAR) data reveal the temporal and spatial characteristics of a ground deformation episode that took place between 2008 and 2010. Deformation time-series reveal pulses of accelerating uplift that transition to gradual long-term subsidence, and analytical models support inflation source depths of ∼5 km. Gases escaping along the major fault zone of Aluto show high CO2 flux, and a clear magmatic carbon signature (CO2–δ13C of −4.2 to −4.5 ‰). This provides compelling evidence that the magmatic and hydrothermal reservoirs of the complex are physically connected. We suggest that a coupled magmatic-hydrothermal system can explain the uplift-subsidence signals. We hypothesize that magmatic fluid injection and/or intrusion in the cap of the magmatic reservoir drives edifice wide inflation while subsequent deflation is related to magmatic degassing and depressurization of the hydrothermal system. These new constraints on the plumbing of Aluto yield important insights into the behaviour of rift volcanic systems and will be crucial for interpreting future patterns of unrest.Publisher PDFPeer reviewe

Data monitoring roadmap. The experience of the Italian Multiple Sclerosis and Related Disorders Register

Introduction Over the years, disease registers have been increasingly considered a source of reliable and valuable population studies. However, the validity and reliability of data from registers may be limited by missing data, selection bias or data quality not adequately evaluated or checked.This study reports the analysis of the consistency and completeness of the data in the Italian Multiple Sclerosis and Related Disorders Register.MethodsThe Register collects, through a standardized Web-based Application, unique patients.Data are exported bimonthly and evaluated to assess the updating and completeness, and to check the quality and consistency. Eight clinical indicators are evaluated.ResultsThe Register counts 77,628 patients registered by 126 centres. The number of centres has increased over time, as their capacity to collect patients.The percentages of updated patients (with at least one visit in the last 24 months) have increased from 33% (enrolment period 2000-2015) to 60% (enrolment period 2016-2022). In the cohort of patients registered after 2016, there were >= 75% updated patients in 30% of the small centres (33), in 9% of the medium centres (11), and in all the large centres (2).Clinical indicators show significant improvement for the active patients, expanded disability status scale every 6 months or once every 12 months, visits every 6 months, first visit within 1 year and MRI every 12 months.ConclusionsData from disease registers provide guidance for evidence-based health policies and research, so methods and strategies ensuring their quality and reliability are crucial and have several potential applications

Hypericum perforatum treatment: effect on behaviour and neurogenesis in a chronic stress model in mice

<p>Abstract</p> <p>Background</p> <p>Extracts of <it>Hypericum perforatum </it>(St. John's wort) have been traditionally recommended for a wide range of medical conditions, in particular mild-to-moderate depression. The present study was designed to investigate the effect of Hypericum perforatum treatment in a mouse model of anxiety/depressive-like behavior, induced by chronic corticosterone administration.</p> <p>Methods</p> <p>CD1 mice were submitted to 7 weeks corticosterone administration and then behavioral tests as Open Field (OF), Novelty-Suppressed Feeding (NSF), Forced Swim Test (FST) were performed. Cell proliferation in hippocampal dentate gyrus (DG) was investigated by both 5-bromo-2'-deoxyuridine (BrdU) and doublecortin (DCX) immunohistochemistry techniques and stereological procedure was used to quantify labeled cells. Golgi-impregnation method was used to evaluate changes in dendritic spines in DG. Hypericum perforatum (30 mg/Kg) has been administered for 3 weeks and then neural development in the adult hippocampus and behavioral changes have been examined.</p> <p>Results</p> <p>The anxiety/depressive-like state due to chronic corticosterone treatment was reversed by exogenous administration of Hypericum perforatum; the proliferation of progenitor cells in mice hippocampus was significantly reduced under chronic corticosterone treatment, whereas a long term treatment with Hypericum perforatum prevented the corticosterone-induced decrease in hippocampal cell proliferation. Corticosterone-treated mice exhibited a reduced spine density that was ameliorated by Hypericum perforatum administration.</p> <p>Conclusion</p> <p>These results provide evidence of morphological adaptations occurring in mature hippocampal neurons that might underlie resilient responses to chronic stress and contribute to the therapeutic effects of chronic Hypericum perforatum treatment.</p

Disease-Modifying Therapies and Coronavirus Disease 2019 Severity in Multiple Sclerosis

Objective: This study was undertaken to assess the impact of immunosuppressive and immunomodulatory therapies on the severity of coronavirus disease 2019 (COVID-19) in people with multiple sclerosis (PwMS). Methods: We retrospectively collected data of PwMS with suspected or confirmed COVID-19. All the patients had complete follow-up to death or recovery. Severe COVID-19 was defined by a 3-level variable: mild disease not requiring hospitalization versus pneumonia or hospitalization versus intensive care unit (ICU) admission or death. We evaluated baseline characteristics and MS therapies associated with severe COVID-19 by multivariate and propensity score (PS)-weighted ordinal logistic models. Sensitivity analyses were run to confirm the results. Results: Of 844 PwMS with suspected (n = 565) or confirmed (n = 279) COVID-19, 13 (1.54%) died; 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty-eight (4.5%) were admitted to an ICU; 99 (11.7%) had radiologically documented pneumonia; 96 (11.4%) were hospitalized. After adjusting for region, age, sex, progressive MS course, Expanded Disability Status Scale, disease duration, body mass index, comorbidities, and recent methylprednisolone use, therapy with an anti-CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio [OR] = 2.37, 95% confidence interval [CI] = 1.18-4.74, p = 0.015) with increased risk of severe COVID-19. Recent use (&lt;1 month) of methylprednisolone was also associated with a worse outcome (OR = 5.24, 95% CI = 2.20-12.53, p = 0.001). Results were confirmed by the PS-weighted analysis and by all the sensitivity analyses. Interpretation: This study showed an acceptable level of safety of therapies with a broad array of mechanisms of action. However, some specific elements of risk emerged. These will need to be considered while the COVID-19 pandemic persists