CADASIL accelerated by acute hypotension: Arterial and venous contribution to leukoaraiosis

Objective: To underline the importance of blood pressure regulation in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and to describe changes that occur in the veins in this condition, specifically venous collagenosis associated with leukoaraiosis. Methods: Case report with neuroimaging and pathologic data. Results: A 61-year-old man with genetically confirmed CADASIL was initially lucid following a motor vehicle accident but subsequently became hypotensive (60/40 mm Hg) due to an open femur fracture and required intubation. Multiple new white matter infarcts appeared on brain imaging. A second hypotensive episode days later was associated with new coin-sized infarcts in the bilateral corona radiata and cerebellar peduncles, and resulted in quadriplegia. No embolic source was found on cardiac or vascular imaging. He died 5 weeks post trauma. Autopsy revealed extensive subcortical and periventricular leukoencephalopathy and multiple cavitations involving deep subcortical gray and white matter. Small arteries had thickened walls, disruption of the muscularis, and intimal periodic acid-Schiff (PAS)-positive material. Both larger periventricular and small caliber veins had thickened walls that were PAS-negative and trichrome-positive, consistent with venous collagenosis. There was no pathologic evidence of global hypoxia or diffuse axonal injury. Conclusions: The findings suggest rapid acceleration of CADASIL pathology from acute hypotension in the setting of impaired vasoreactivity. In addition, collagenosis of veins in the affected white matter regions suggests that the veins may play an important, though largely overlooked, role in maintaining white matter integrity

Activated Bone Marrow-Derived Macrophages Eradicate Alzheimer's-Related Aβ42 Oligomers and Protect Synapses.

Impaired synaptic integrity and function due to accumulation of amyloid β-protein (Aβ42) oligomers is thought to be a major contributor to cognitive decline in Alzheimer's disease (AD). However, the exact role of Aβ42 oligomers in synaptotoxicity and the ability of peripheral innate immune cells to rescue synapses remain poorly understood due to the metastable nature of oligomers. Here, we utilized photo-induced cross-linking to stabilize pure oligomers and study their effects vs. fibrils on synapses and protection by Aβ-phagocytic macrophages. We found that cortical neurons were more susceptible to Aβ42 oligomers than fibrils, triggering additional neuritic arborization retraction, functional alterations (hyperactivity and spike waveform), and loss of VGluT1- and PSD95-excitatory synapses. Co-culturing neurons with bone marrow-derived macrophages protected synapses against Aβ42 fibrils; moreover, immune activation with glatiramer acetate (GA) conferred further protection against oligomers. Mechanisms involved increased Aβ42 removal by macrophages, amplified by GA stimulation: fibrils were largely cleared through intracellular CD36/EEA1+-early endosomal proteolysis, while oligomers were primarily removed via extracellular/MMP-9 enzymatic degradation. In vivo studies in GA-immunized or CD115+-monocyte-grafted APPSWE/PS1ΔE9-transgenic mice followed by pre- and postsynaptic analyses of entorhinal cortex and hippocampal substructures corroborated our in vitro findings of macrophage-mediated synaptic preservation. Together, our data demonstrate that activated macrophages effectively clear Aβ42 oligomers and rescue VGluT1/PSD95 synapses, providing rationale for harnessing macrophages to treat AD

RhoG regulates endothelial apical cup assembly downstream from ICAM1 engagement and is involved in leukocyte trans-endothelial migration

During trans-endothelial migration (TEM), leukocytes use adhesion receptors such as intercellular adhesion molecule-1 (ICAM1) to adhere to the endothelium. In response to this interaction, the endothelium throws up dynamic membrane protrusions, forming a cup that partially surrounds the adherent leukocyte. Little is known about the signaling pathways that regulate cup formation. In this study, we show that RhoG is activated downstream from ICAM1 engagement. This activation requires the intracellular domain of ICAM1. ICAM1 colocalizes with RhoG and binds to the RhoG-specific SH3-containing guanine-nucleotide exchange factor (SGEF). The SH3 domain of SGEF mediates this interaction. Depletion of endothelial RhoG by small interfering RNA does not affect leukocyte adhesion but decreases cup formation and inhibits leukocyte TEM. Silencing SGEF also results in a substantial reduction in RhoG activity, cup formation, and TEM. Together, these results identify a new signaling pathway involving RhoG and its exchange factor SGEF downstream from ICAM1 that is critical for leukocyte TEM

A Mechanistic Analysis of Phase Evolution and Hydrogen Storage Behavior in Nanocrystalline Mg(BH4)2 within Reduced Graphene Oxide.

Magnesium borohydride (Mg(BH4)2, abbreviated here MBH) has received tremendous attention as a promising onboard hydrogen storage medium due to its excellent gravimetric and volumetric hydrogen storage capacities. While the polymorphs of MBH-alpha (α), beta (β), and gamma (γ)-have distinct properties, their synthetic homogeneity can be difficult to control, mainly due to their structural complexity and similar thermodynamic properties. Here, we describe an effective approach for obtaining pure polymorphic phases of MBH nanomaterials within a reduced graphene oxide support (abbreviated MBHg) under mild conditions (60-190 °C under mild vacuum, 2 Torr), starting from two distinct samples initially dried under Ar and vacuum. Specifically, we selectively synthesize the thermodynamically stable α phase and metastable β phase from the γ-phase within the temperature range of 150-180 °C. The relevant underlying phase evolution mechanism is elucidated by theoretical thermodynamics and kinetic nucleation modeling. The resulting MBHg composites exhibit structural stability, resistance to oxidation, and partially reversible formation of diverse [BH4]- species during de- and rehydrogenation processes, rendering them intriguing candidates for further optimization toward hydrogen storage applications

GNOSIS: the first instrument to use fibre Bragg gratings for OH suppression

GNOSIS is a prototype astrophotonic instrument that utilizes OH suppression fibres consisting of fibre Bragg gratings and photonic lanterns to suppress the 103 brightest atmospheric emission doublets between 1.47-1.7 microns. GNOSIS was commissioned at the 3.9-meter Anglo-Australian Telescope with the IRIS2 spectrograph to demonstrate the potential of OH suppression fibres, but may be potentially used with any telescope and spectrograph combination. Unlike previous atmospheric suppression techniques GNOSIS suppresses the lines before dispersion and in a manner that depends purely on wavelength. We present the instrument design and report the results of laboratory and on-sky tests from commissioning. While these tests demonstrated high throughput and excellent suppression of the skylines by the OH suppression fibres, surprisingly GNOSIS produced no significant reduction in the interline background and the sensitivity of GNOSIS and IRIS2 is about the same as IRIS2. It is unclear whether the lack of reduction in the interline background is due to physical sources or systematic errors as the observations are detector noise-dominated. OH suppression fibres could potentially impact ground-based astronomy at the level of adaptive optics or greater. However, until a clear reduction in the interline background and the corresponding increasing in sensitivity is demonstrated optimized OH suppression fibres paired with a fibre-fed spectrograph will at least provide a real benefits at low resolving powers.Comment: 15 pages, 13 figures, accepted to A

Goblet Cell Tumors of the Appendix: Clinical & Molecular Features

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Protocolised non-invasive compared with invasive weaning from mechanical ventilation for adults in intensive care : the Breathe RCT

Background: Invasive mechanical ventilation (IMV) is a life-saving intervention. Following resolution of the condition that necessitated IMV, a spontaneous breathing trial (SBT) is used to determine patient readiness for IMV discontinuation. In patients who fail one or more SBTs, there is uncertainty as to the optimum management strategy. Objective: To evaluate the clinical effectiveness and cost-effectiveness of using non-invasive ventilation (NIV) as an intermediate step in the protocolised weaning of patients from IMV. Design: Pragmatic, open-label, parallel-group randomised controlled trial, with cost-effectiveness analysis. Setting: A total of 51 critical care units across the UK. Participants: Adult intensive care patients who had received IMV for at least 48 hours, who were categorised as ready to wean from ventilation, and who failed a SBT. Interventions: Control group (invasive weaning): patients continued to receive IMV with daily SBTs. A weaning protocol was used to wean pressure support based on the patient’s condition. Intervention group (non-invasive weaning): patients were extubated to NIV. A weaning protocol was used to wean inspiratory positive airway pressure, based on the patient’s condition. Main outcome measures: The primary outcome measure was time to liberation from ventilation. Secondary outcome measures included mortality, duration of IMV, proportion of patients receiving antibiotics for a presumed respiratory infection and health-related quality of life. Results: A total of 364 patients (invasive weaning, n = 182; non-invasive weaning, n = 182) were randomised. Groups were well matched at baseline. There was no difference between the invasive weaning and non-invasive weaning groups in median time to liberation from ventilation {invasive weaning 108 hours [interquartile range (IQR) 57–351 hours] vs. non-invasive weaning 104.3 hours [IQR 34.5–297 hours]; hazard ratio 1.1, 95% confidence interval [CI] 0.89 to 1.39; p = 0.352}. There was also no difference in mortality between groups at any time point. Patients in the non-invasive weaning group had fewer IMV days [invasive weaning 4 days (IQR 2–11 days) vs. non-invasive weaning 1 day (IQR 0–7 days); adjusted mean difference –3.1 days, 95% CI –5.75 to –0.51 days]. In addition, fewer non-invasive weaning patients required antibiotics for a respiratory infection [odds ratio (OR) 0.60, 95% CI 0.41 to 1.00; p = 0.048]. A higher proportion of non-invasive weaning patients required reintubation than those in the invasive weaning group (OR 2.00, 95% CI 1.27 to 3.24). The within-trial economic evaluation showed that NIV was associated with a lower net cost and a higher net effect, and was dominant in health economic terms. The probability that NIV was cost-effective was estimated at 0.58 at a cost-effectiveness threshold of £20,000 per quality-adjusted life-year. Conclusions: A protocolised non-invasive weaning strategy did not reduce time to liberation from ventilation. However, patients who underwent non-invasive weaning had fewer days requiring IMV and required fewer antibiotics for respiratory infections. Future work: In patients who fail a SBT, which factors predict an adverse outcome (reintubation, tracheostomy, death) if extubated and weaned using NIV? Trial registration: Current Controlled Trials ISRCTN15635197. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 48. See the NIHR Journals Library website for further project information

Utility of plasma tumor marker levels in management of patients with appendiceal adenocarcinoma

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On the evolution of an ice shelf melt channel at the base of Filchner Ice Shelf, from observations and viscoelastic modeling

Ice shelves play a key role in the stability of the Antarctic Ice Sheet due to their buttressing effect. A loss of buttressing as a result of increased basal melting or ice shelf disintegration will lead to increased ice discharge. Some ice shelves exhibit channels at the base that are not yet fully understood. In this study, we present in situ melt rates of a channel which is up to 330 m high and located in the southern Filchner Ice Shelf. Maximum observed melt rates are 2 m yr−1. Melt rates inside the channel decrease in the direction of ice flow and turn to freezing ∼55 km downstream of the grounding line. While closer to the grounding line melt rates are higher within the channel than outside, this relationship reverses further downstream. Comparing the modeled evolution of this channel under present-day climate conditions over 250 years with its present geometry reveals a mismatch. Melt rates twice as large as the present-day values are required to fit the observed geometry. In contrast, forcing the model with present-day melt rates results in a closure of the channel, which contradicts observations. The ice shelf experiences strong tidal variability in vertical strain rates at the measured site, and discrete pulses of increased melting occurred throughout the measurement period. The type of melt channel in this study diminishes in height with distance from the grounding line and is hence not a destabilizing factor for ice shelves.</p

Universal Mask Usage for Reduction of Respiratory Viral Infections After Stem Cell Transplant: A Prospective Trial

Background. Respiratory viral infections (RVIs) are frequent complications of hematopoietic stem cell transplant (HSCT). Surgical masks are a simple and inexpensive intervention that may reduce nosocomial spread