Proprioceptive contribution to oculomotor control in humans

This work was supported by an award from the Wellcome Trust Institutional Strategic Support Fund at the University of St Andrews, grant code 204821/Z/16/Z (DB).Stretch receptors in the extraocular muscles (EOMs) inform the central nervous system about the rotation of one's own eyes in the orbits. Whereas fine control of the skeletal muscles hinges critically on proprioceptive feedback, the role of proprioception in oculomotor control remains unclear. Human behavioural studies provide evidence for EOM proprioception in oculomotor control, however, behavioural and electrophysiological studies in the macaque do not. Unlike macaques, humans possess numerous muscle spindles in their EOMs. To find out whether the human oculomotor nuclei respond to proprioceptive feedback we used functional magnetic resonance imaging (fMRI). With their eyes closed, participants placed their right index finger on the eyelid at the outer corner of the right eye. When prompted by a sound, they pushed the eyeball gently and briefly towards the nose. Control conditions separated out motor and tactile task components. The stretch of the right lateral rectus muscle was associated with activation of the left oculomotor nucleus and subthreshold activation of the left abducens nucleus. Because these nuclei control the horizontal movements of the left eye, we hypothesized that proprioceptive stimulation of the right EOM triggered left eye movement. To test this, we followed up with an eye-tracking experiment in complete darkness using the same behavioural task as in the fMRI study. The left eye moved actively in the direction of the passive displacement of the right eye, albeit with a smaller amplitude. Eye tracking corroborated neuroimaging findings to suggest a proprioceptive contribution to ocular alignment.Publisher PDFPeer reviewe

Disease-related factors affecting timely lymphoma diagnosis : a qualitative study exploring patient experiences

Background Expediting cancer diagnosis is widely perceived as one way to improve patient outcomes. Evidence indicates that lymphoma diagnosis is often delayed, yet understanding of issues influencing this is incomplete. Aim To explore patients' and their relatives' perceptions of disease-related factors affecting time to diagnosis of Hodgkin and non-Hodgkin lymphoma. Design and setting Qualitative UK study involving patients with indolent and aggressive lymphomas, and their relatives, from an established population-based cohort in the north of England. Method Semi-structured interviews with 35 patients and 15 of their relatives. Interviews were audiorecorded and transcribed, and qualitative descriptive analysis was undertaken. Results Participant accounts suggest that certain features of lymphoma can impact on patients' and healthcare providers' (HCPs) responses to disease onset. Three characteristics stand out: disease occurrence (rare), manifestation (varied), and investigative options (often inconclusive). Interviewees described how they, and some HCPs, lacked familiarity with lymphoma, seldom considering it a likely explanation for their symptoms. Symptoms reported were highly variable, frequently non-specific, and often initially thought to be associated with various benign, self-limiting causes. Blood tests and other investigations, while frequently able to detect abnormalities, did not reliably indicate malignancy. Interviewees reported the potential for improvements among HCPs in information gathering, communication of uncertainty, and re-presentation advice for non-resolving/ progressive health changes. Conclusion This study demonstrates the complex characteristics of lymphoma, perceived by patients as prolonging time to diagnosis, often despite significant effort by themselves, their relatives, and HCPs to expedite this process. The findings also illustrate why simple solutions to delayed diagnosis of lymphoma are lacking

Design and conduct of 'Xtreme Alps' : a double-blind, randomised controlled study of the effects of dietary nitrate supplementation on acclimatisation to high altitude

The study of healthy human volunteers ascending to high altitude provides a robust model of the complex physiological interplay that emulates human adaptation to hypoxaemia in clinical conditions. Nitric oxide (NO) metabolism may play an important role in both adaptation to high altitude and response to hypoxaemia during critical illness at sea level. Circulating nitrate and nitrite concentrations can be augmented by dietary supplementation and this is associated with improved exercise performance and mitochondrial efficiency. We hypothesised that the administration of a dietary substance (beetroot juice) rich in nitrate would improve oxygen efficiency during exercise at high altitude by enhancing tissue microcirculatory blood flow and oxygenation. Furthermore, nitrate supplementation would lead to measurable increases in NO bioactivity throughout the body. This methodological manuscript describes the design and conduct of the ‘Xtreme Alps’ expedition, a double-blind randomised controlled trial investigating the effects of dietary nitrate supplementation on acclimatisation to hypobaric hypoxia at high altitude in healthy human volunteers. The primary outcome measure was the change in oxygen efficiency during exercise at high altitude between participants allocated to receive nitrate supplementation and those receiving a placebo. A number of secondary measures were recorded, including exercise capacity, peripheral and microcirculatory blood flow and tissue oxygenation. Results from this study will further elucidate the role of NO in adaption to hypoxaemia and guide clinical trials in critically ill patients. Improved understanding of hypoxaemia in critical illness may provide new therapeutic avenues for interventions that will improve survival in critically ill patients

Corrigendum to “No short-term treatment effect of prism adaptation for spatial neglect: An inclusive meta-analysis” [Neuropsychologia 189 (2023) 108566]

The authors regret that there was an error on page 12, Fig. 4, Panel B of our manuscript. Panel B should have had the outlier study, Hreha et al. (2018), excluded. The data point for this study has been excluded, but this exclusion was not reflected in the study labels. Instead, the label for the study by Nys et al. (2008) was mistakenly omitted and the data points were improperly aligned with their labels. We would like to provide Fig. 4. Panel B with the corrected labels below.[Formula presented] The authors would like to apologise for any inconvenience caused. The error has no bearing on the results or conclusions of the study

No short-term treatment effect of prism adaptation for spatial neglect: An inclusive meta-analysis

Despite 25 years of research on the topic, there is still no consensus on whether prism adaptation is an effective therapy for visuospatial neglect. We have addressed this question through a meta-analysis of the most well-controlled studies on the topic. Our main meta-analytic model included studies with a placebo/sham/treatment-as-usual control group from which data from right hemisphere stroke patients and left-sided neglect could be aggregated. The short-term treatment effects on the two commonly used standard tests for neglect, the conventional Behavioural Inattention Test (BIT-C) and cancellation test scores were combined into one random effect model justified by the fact that 89% of the BIT-C score is determined by cancellation tasks. With this approach, we were able to obtain a larger and more homogeneous dataset than previous meta-analyses: sixteen studies including 430 patients. No evidence for beneficial effects of prism adaptation was found. The secondary meta-analysis including data from the Catherine Bergego Scale, a functional measure of activities of daily living, also found no evidence for the therapeutic effects of prism adaptation, although half as many studies were available for this analysis. The results were consistent after the removal of influential outliers, after studies with high risk-of-bias were excluded, and when an alternative measure of effect size was considered. These results do not support the routine use of prism adaptation as a therapy for spatial neglect

The Gp1ba-Cre transgenic mouse::A new model to delineate platelet and leukocyte functions

Conditional knockout (KO) mouse models are invaluable for elucidating the physiological roles of platelets. The Platelet factor 4-Cre recombinase (Pf4-Cre) transgenic mouse is the current model of choice for generating megakaryocyte/platelet-specific KO mice. Platelets and leukocytes work closely together in a wide range of disease settings, yet the specific contribution of platelets to these processes remains unclear. This is partially a result of the Pf4-Cre transgene being expressed in a variety of leukocyte populations. To overcome this issue, we developed a Gp1ba-Cre transgenic mouse strain in which Cre expression is driven by the endogenous Gp1ba locus. By crossing Gp1ba-Cre and Pf4-Cre mice to the mT/mG dual-fluorescence reporter mouse and performing a head-to-head comparison, we demonstrate more stringent megakaryocyte lineage-specific expression of the Gp1ba-Cre transgene. Broader tissue expression was observed with the Pf4-Cre transgene, leading to recombination in many hematopoietic lineages, including monocytes, macrophages, granulocytes, and dendritic and B and T cells. Direct comparison of phenotypes of Csk, Shp1, or CD148 conditional KO mice generated using either the Gp1ba-Cre or Pf4-Cre strains revealed similar platelet phenotypes. However, additional inflammatory and immunological anomalies were observed in Pf4-Cre-generated KO mice as a result of nonspecific deletion in other hematopoietic lineages. By excluding leukocyte contributions to phenotypes, the Gp1ba-Cre mouse will advance our understanding of the role of platelets in inflammation and other pathophysiological processes in which platelet-leukocyte interactions are involved

Folyóirat vagy gyűjteményes kötet? (Csokonai Diétai Magyar Múzsája)

BACKGROUND: The complex interplay between viral replication and host immune response during infection remains poorly understood. While many viruses are known to employ anti-immune strategies to facilitate their replication, highly pathogenic virus infections can also cause an excessive immune response that exacerbates, rather than reduces pathogenicity. To investigate this dichotomy in severe acute respiratory syndrome coronavirus (SARS-CoV), we developed a transcriptional network model of SARS-CoV infection in mice and used the model to prioritize candidate regulatory targets for further investigation. RESULTS: We validated our predictions in 18 different knockout (KO) mouse strains, showing that network topology provides significant predictive power to identify genes that are important for viral infection. We identified a novel player in the immune response to virus infection, Kepi, an inhibitory subunit of the protein phosphatase 1 (PP1) complex, which protects against SARS-CoV pathogenesis. We also found that receptors for the proinflammatory cytokine tumor necrosis factor alpha (TNFα) promote pathogenesis, presumably through excessive inflammation. CONCLUSIONS: The current study provides validation of network modeling approaches for identifying important players in virus infection pathogenesis, and a step forward in understanding the host response to an important infectious disease. The results presented here suggest the role of Kepi in the host response to SARS-CoV, as well as inflammatory activity driving pathogenesis through TNFα signaling in SARS-CoV infections. Though we have reported the utility of this approach in bacterial and cell culture studies previously, this is the first comprehensive study to confirm that network topology can be used to predict phenotypes in mice with experimental validation

A registered re-examination of the effects of leftward prism adaptation on landmark judgements in healthy people

It has long been known that active adaptation to a shift of the visual field, caused by laterally-displacing prisms, induces short-term sensorimotor aftereffects. More recent evidence suggests that prism adaptation may also stimulate higher-level changes in spatial cognition, which can modify the spatial biases of healthy people. The first reported, and most replicated, higher-level aftereffect is a rightward shift in the point of subjective equality (PSE) for a perceptual bisection task (the landmark task), following adaptation to leftward prisms. A recent meta-analysis suggests that this visuospatial aftereffect should be robustly induced by an extended period of adaptation to strong leftward prisms (15°, ∼26.8 prism dioptres). However, we have been unable to replicate this effect, suggesting that the effect size estimated from prior literature might be over-optimistic. This Registered Report compared visuospatial aftereffects on the landmark task for a 15° leftward prism adaptation group (n = 102) against a sham-adaptation control group (n = 102). The effect size for the comparison was Cohen's d = .27, 95% CI [-.01, .55], which did not pass the criterion set for significance. A Bayesian analysis indicated that the data were more than 4.1 times as likely under the null than under an informed experimental hypothesis. Exploratory analyses showed no evidence for a rightward shift of landmark judgements in the prism group considered alone, and no relationship between sensorimotor and visuospatial aftereffects. We further found no support for previous suggestions that visuospatial aftereffects are modulated by a person's baseline bias (leftward or rightward) for the landmark task. Null findings are also presented for a preliminary group of 62 participants adapted to 15° leftward prisms, and an additional group of 29 participants adapted to 10° leftward prisms. We do not rule out the possibility that leftward prisms might induce higher-level visuospatial aftereffects in healthy people, but we should be more sceptical about this claim

Physiological responses during ascent to high altitude and the incidence of acute mountain sickness.

Acute mountain sickness (AMS) occurs when there is failure of acclimatisation to high altitude. The aim of this study was to describe the relationship between physiological variables and the incidence of AMS during ascent to 5300 m. A total of 332 lowland-dwelling volunteers followed an identical ascent profile on staggered treks. Self-reported symptoms of AMS were recorded daily using the Lake Louise score (mild 3-4; moderate-severe ≥5), alongside measurements of physiological variables (heart rate, respiratory rate (RR), peripheral oxygen saturation (SpO2 ) and blood pressure) before and after a standardised Xtreme Everest Step-Test (XEST). The overall occurrence of AMS among participants was 73.5% (23.2% mild, 50.3% moderate-severe). There was no difference in gender, age, previous AMS, weight or body mass index between participants who developed AMS and those who did not. Participants who had not previously ascended >5000 m were more likely to get moderate-to-severe AMS. Participants who suffered moderate-to-severe AMS had a lower resting SpO2 at 3500 m (88.5 vs. 89.6%, p = 0.02), while participants who suffered mild or moderate-to-severe AMS had a lower end-exercise SpO2 at 3500 m (82.2 vs. 83.8%, p = 0.027; 81.5 vs. 83.8%, p 5000 m (OR 2.740, p-value 0.003) predicted the development of moderate-to-severe AMS. The Xtreme Everest Step-Test offers a simple, reproducible field test to help predict AMS, albeit with relatively limited predictive precision

Topological spin memory of antiferromagnetically coupled skyrmion pairs in Co/Gd/Pt multilayers

Antiferromagnetically (AFM) coupled skyrmions offer potential advantages for spintronic devices, including reduced dipolar fields that may enable smaller skyrmion sizes and a reduction of the skyrmion Hall effect. However, the topological stability of AFM-coupled skyrmions subjected to dramatic spin deformation through low-temperature cycling has not been investigated. Here we report the discovery of a topological spin memory effect for AFM-coupled skyrmion pairs in [Co/Gd/Pt]10 multilayered films. Photoemission electron microscopy imaging shows that bubble skyrmions in the multilayer that are stable at room temperature evolve into complex in-plane spin textures as the temperature is lowered and reform completely when the sample is warmed back up. Simulations demonstrate that Dzyaloshinskii-Moriya interactions play a key role in this spin memory effect, and furthermore reveal that the topological charge is preserved throughout the dramatic spin texture rearrangement and recovery. These results highlight a key aspect of topological protection—the preservation of the topological properties under continuous deformation—and also provide a promising avenue for information encryption and recovery