TMS-Induced Cortical Potentiation during Wakefulness Locally Increases Slow Wave Activity during Sleep

BACKGROUND: Sleep slow wave activity (SWA) is thought to reflect sleep need, increasing in proportion to the length of prior wakefulness and decreasing during sleep. However, the process responsible for SWA regulation is not known. We showed recently that SWA increases locally after a learning task involving a circumscribed brain region, suggesting that SWA may reflect plastic changes triggered by learning. METHODOLOGY/PRINCIPAL FINDINGS: To test this hypothesis directly, we used transcranial magnetic stimulation (TMS) in conjunction with high-density EEG in humans. We show that 5-Hz TMS applied to motor cortex induces a localized potentiation of TMS-evoked cortical EEG responses. We then show that, in the sleep episode following 5-Hz TMS, SWA increases markedly (+39.1±17.4%, p<0.01, n = 10). Electrode coregistration with magnetic resonance images localized the increase in SWA to the same premotor site as the maximum TMS-induced potentiation during wakefulness. Moreover, the magnitude of potentiation during wakefulness predicts the local increase in SWA during sleep. CONCLUSIONS/SIGNIFICANCE: These results provide direct evidence for a link between plastic changes and the local regulation of sleep need

Congenital syndactyly in cattle: four novel mutations in the low density lipoprotein receptor-related protein 4 gene (LRP4)

BACKGROUND: Isolated syndactyly in cattle, also known as mulefoot, is inherited as an autosomal recessive trait with variable penetrance in different cattle breeds. Recently, two independent mutations in the bovine LRP4 gene have been reported as the primary cause of syndactyly in the Holstein and Angus cattle breeds. RESULTS: We confirmed the previously described LRP4 exon 33 two nucleotide substitution in most of the affected Holstein calves and revealed additional evidence for allelic heterogeneity by the identification of four new LRP4 non-synonymous point mutations co-segregating in Holstein, German Simmental and Simmental-Charolais families. CONCLUSION: We confirmed a significant role of LRP4 mutations in the pathogenesis of congenital syndactyly in cattle. The newly detected missense mutations in the LRP4 gene represent independent mutations affecting different conserved protein domains. However, the four newly described LRP4 mutations do still not explain all analyzed cases of syndactyly

A Fly in the Ointment: Evaluation of Traditional Use of Plants to Repel and Kill Blowfly Larvae in Fermented Fish

Introduction: In rural areas in Laos, fly larvae infestations are common in fermenting fish. Blowflies (Chrysomyamegacephala, Diptera: Calliphoridae) are attracted to oviposit (and/or larviposit) onto fermenting fish which results ininfestations with fly larvae. Knowledge of traditional use of plants to repel larvae during the production of fermented fish iscommon and widespread in Lao PDR. Research Questions: How effective are the most salient species in repelling, and killing fly larvae in fermenting fish? Material and Methods: The three plant species most frequently reported to repel fly larvae during an ethnobotanical surveythroughout Lao PDR were tested for repellence and larvicidal activity of fly larvae infesting fermented fish. The lethality andrepellence of Tadehagi triquetrum (L.) H. Ohashi (Fabaceae), Uraria crinita (L.) Desv. ex DC. (Fabaceae) and Bambusa multiplex(Lour.) Raeusch. ex Schult. &amp; Schult. f. (Poaceae) were tested in an experimental design using fermenting fish in Vientiane,Lao PDR. Results: The repellent effect of fresh material of T. triquetrum and U. crinita, and the larvicidal effect of fresh B. multiplex, issignificantly more effective than that of dried material of the same species, and the total effect (repellence and larvicidaleffect combined) for each of the three species was significantly more effective for fresh than for dry material. Fresh materialof T. triquetrum, U. crinita, or B. multiplex added on top of the fermenting fish repelled 50%, 54%, 37%, and killed 22%, 28%,and 40% of fly larvae. The total effect was not significantly different per species at 72%, 82%, and 77%, respectively. Discussion and Conclusions: The three most salient species are effective in repelling and killing fly larvae in the productionof fermented fish, and may be essential to augment food safety during traditional fermentation in open jars

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns

Measurement of Epstein-Barr virus DNA load using a novel quantification standard containing two EBV DNA targets and SYBR Green I dye

<p>Abstract</p> <p>Background</p> <p>Reactivation of Epstein-Barr virus (EBV) infection may cause serious, life-threatening complications in immunocompromised individuals. EBV DNA is often detected in EBV-associated disease states, with viral load believed to be a reflection of virus activity. Two separate real-time quantitative polymerase chain reaction (QPCR) assays using SYBR Green I dye and a single quantification standard containing two EBV genes, Epstein-Barr nuclear antigen-1 (EBNA-1) and BamHI fragment H rightward open reading frame-1 (BHRF-1), were developed to detect and measure absolute EBV DNA load in patients with various EBV-associated diseases. EBV DNA loads and viral capsid antigen (VCA) IgG antibody titres were also quantified on a population sample.</p> <p>Results</p> <p>EBV DNA was measurable in ethylenediaminetetraacetic acid (EDTA) whole blood, peripheral blood mononuclear cells (PBMCs), plasma and cerebrospinal fluid (CSF) samples. EBV DNA loads were detectable from 8.0 × 10²to 1.3 × 10⁸copies/ml in post-transplant lymphoproliferative disease (n = 5), 1.5 × 10³to 2.0 × 10⁵copies/ml in infectious mononucleosis (n = 7), 7.5 × 10⁴to 1.1 × 10⁵copies/ml in EBV-associated haemophagocytic syndrome (n = 1), 2.0 × 10²to 5.6 × 10³copies/ml in HIV-infected patients (n = 12), and 2.0 × 10²to 9.1 × 10⁴copies/ml in the population sample (n = 218). EBNA-1 and BHRF-1 DNA were detected in 11.0% and 21.6% of the population sample respectively. There was a modest correlation between VCA IgG antibody titre and BHRF-1 DNA load (rho = 0.13, p = 0.05) but not EBNA-1 DNA load (rho = 0.11, p = 0.11).</p> <p>Conclusion</p> <p>Two sensitive and specific real-time PCR assays using SYBR Green I dye and a single quantification standard containing two EBV DNA targets, were developed for the detection and measurement of EBV DNA load in a variety of clinical samples. These assays have application in the investigation of EBV-related illnesses in immunocompromised individuals.</p

Targeting of Natural Killer Cells by Rabbit Antithymocyte Globulin and Campath-1H: Similar Effects Independent of Specificity

T cell depleting strategies are an integral part of immunosuppressive regimens widely used in the hematological and solid organ transplant setting. Although it is known to induce lymphocytopenia, little is known about the effects of the polyclonal rabbit antithymocyte globulin (rATG) or the monoclonal anti-CD52 antibody alemtuzumab on Natural Killer (NK) cells in detail. Here, we demonstrate that induction therapy with rATG following kidney/pancreas transplantation results in a rapid depletion of NK cells. Treatment of NK cells with rATG and alemtuzumab in vitro leads to impairment of cytotoxicity and induction of apoptosis even at a 10-fold lower concentration (0.1 µg/ml) compared with T and B cells. By generating Fc-parts of rATG and alemtuzumab we illustrate that their ligation to FcγRIII (CD16) is sufficient for the significant induction of degranulation, apoptosis and inflammatory cytokine release (FasL, TNFα and IFNγ) exclusively in CD3−CD56dim NK cells whereas application of rATG and alemtuzumab F(ab) fragments abolishes these effects. These findings are of general importance as our data suggest that NK cells are also mediators of the clinically relevant cytokine release syndrome and that their targeting by therapeutic antibodies should be considered as they are functionally relevant for the effective clearance of opportunistic viral infections and anti-tumor activity posttransplantation

Cognitive effects of high-frequency repetitive transcranial magnetic stimulation: a systematic review

Transcranial magnetic stimulation (TMS) was introduced as a non-invasive tool for the investigation of the motor cortex. The repetitive application (rTMS), causing longer lasting effects, was used to study the influence on a variety of cerebral functions. High-frequency (>1 Hz) rTMS is known to depolarize neurons under the stimulating coil and to indirectly affect areas being connected and related to emotion and behavior. Researchers found selective cognitive improvement after high-frequency (HF) stimulation specifically over the left dorsolateral prefrontal cortex (DLPFC). This article provides a systematic review of HF-rTMS studies (1999–2009) stimulating over the prefrontal cortex of patients suffering from psychiatric/neurological diseases or healthy volunteers, where the effects on cognitive functions were measured. The cognitive effect was analyzed with regard to the impact of clinical status (patients/healthy volunteers) and stimulation type (verum/sham). RTMS at 10, 15 or 20 Hz, applied over the left DLPFC, within a range of 10–15 successive sessions and an individual motor threshold of 80–110%, is most likely to cause significant cognitive improvement. In comparison, patients tend to reach a greater improvement than healthy participants. Limitations concern the absence of healthy groups in clinical studies and partly the absence of sham groups. Thus, future investigations are needed to assess cognitive rTMS effects in different psychiatric disorders versus healthy subjects using an extended standardized neuropsychological test battery. Since the pathophysiological and neurobiological basis of cognitive improvement with rTMS remains unclear, additional studies including genetics, experimental neurophysiology and functional brain imaging are necessary to explore stimulation-related functional changes in the brain

Tixagevimab–cilgavimab for treatment of patients hospitalised with COVID-19: a randomised, double-blind, phase 3 trial

Background: Tixagevimab–cilgavimab is a neutralising monoclonal antibody combination hypothesised to improve outcomes for patients hospitalised with COVID-19. We aimed to compare tixagevimab–cilgavimab versus placebo, in patients receiving remdesivir and other standard care. Methods: In a randomised, double-blind, phase 3, placebo-controlled trial, adults with symptoms for up to 12 days and hospitalised for COVID-19 at 81 sites in the USA, Europe, Uganda, and Singapore were randomly assigned in a 1:1 ratio to receive intravenous tixagevimab 300 mg–cilgavimab 300 mg or placebo, in addition to remdesivir and other standard care. Patients were excluded if they had acute organ failure including receipt of invasive mechanical ventilation, extracorporeal membrane oxygenation, vasopressor therapy, mechanical circulatory support, or new renal replacement therapy. The study drug was prepared by an unmasked pharmacist; study participants, site study staff, investigators, and clinical providers were masked to study assignment. The primary outcome was time to sustained recovery up to day 90, defined as 14 consecutive days at home after hospital discharge, with co-primary analyses for the full cohort and for participants who were neutralising antibody-negative at baseline. Efficacy and safety analyses were done in the modified intention-to-treat population, defined as participants who received a complete or partial infusion of tixagevimab–cilgavimab or placebo. This study is registered with ClinicalTrials.gov, NCT04501978 and the participant follow-up is ongoing. Findings: From Feb 10 to Sept 30, 2021, 1455 patients were randomly assigned and 1417 in the primary modified intention-to-treat population were infused with tixagevimab–cilgavimab (n=710) or placebo (n=707). The estimated cumulative incidence of sustained recovery was 89% for tixagevimab–cilgavimab and 86% for placebo group participants at day 90 in the full cohort (recovery rate ratio [RRR] 1·08 [95% CI 0·97–1·20]; p=0·21). Results were similar in the seronegative subgroup (RRR 1·14 [0·97–1·34]; p=0·13). Mortality was lower in the tixagevimab–cilgavimab group (61 [9%]) versus placebo group (86 [12%]; hazard ratio [HR] 0·70 [95% CI 0·50–0·97]; p=0·032). The composite safety outcome occurred in 178 (25%) tixagevimab–cilgavimab and 212 (30%) placebo group participants (HR 0·83 [0·68–1·01]; p=0·059). Serious adverse events occurred in 34 (5%) participants in the tixagevimab–cilgavimab group and 38 (5%) in the placebo group. Interpretation: Among patients hospitalised with COVID-19 receiving remdesivir and other standard care, tixagevimab–cilgavimab did not improve the primary outcome of time to sustained recovery but was safe and mortality was lower. Funding: US National Institutes of Health (NIH) and Operation Warp Speed