NK1-receptor-expressing paraventricular nucleus neurones modulate daily variation in heart rate and stress-induced changes in heart rate variability

The paraventricular nucleus of the hypothalamus (PVN) is an established centre of cardiovascular control, receiving projections from other nuclei of the hypothalamus such as the dorsomedial hypothalamus and the suprachiasmatic nucleus. The PVN contains a population of “pre-autonomic neurones” which project to the intermediolateralis of the spinal cord and increase sympathetic activity, blood pressure and heart rate. These spinally projecting neurones express a number of membrane receptors including GABA and substance P NK1 receptors. Activation of NK1 expressing neurones increases heart rate, blood pressure and sympathetic activity. However, their role in the pattern of overall of cardiovascular control remains unknown. In this work we use specific saporin lesion of NK1 expressing PVN rat neurones with SSP-SAP and telemetrically measure resting heart rate and heart rate variability (HRV) parameters in response to mild psychological stress. The HRV parameter “low frequency/high frequency ratio” is often used as an indicator of sympathetic activity and is significantly increased with psychological stress in control rats (0.84 ± 0.14 to 2.02 ± 0.15; p0.05; n=3). We also find a shift in daily variation of heart rate rhythm and conclude that NK1 expressing PVN neurones are involved with coupling of the cardiovascular system to daily heart rate variation and the sympathetic response to psychological stress

Supporting active database learning and training through interactive multimedia

The learning objectives of a database course include aspects from conceptual and theoretical knowledge to practical development and implementation skills. We present an interactive educational multimedia system based on the virtual apprenticeship model for the knowledge- and skills-oriented Web-based education of database course students. Combining knowledge learning and skills training in an integrated environment is a central aspect of our system. We show that tool-mediated independent learning and training in an authentic setting is an alternative to traditional classroom-based approaches

Challenges and diagnosis of isolated left ventricular non-compaction: A case series of 4 patients with echocardiographic diagnosis of possible ILVNC

Isolated left ventricular non-compaction (ILVNC) is a rare, congenital, idiopathic cardiomyopathy that may present in adulthood. There is no true gold standard for the diagnosis of ILVNC. Two-dimensional echocardiography with colour Doppler is the modality of choice to diagnose the condition. However, the diagnosis should be confirmed with cardiac magnetic resonance imaging (CMRI), as well as either a positive family history, complications of ILVNC or confirmatory genetic testing.We describe the clinical and echocardiographic features in 4 patients, each with a possible diagnosis of ILVNC, in the setting of potential alternative aetiologies for heart failure. Approval to present these cases was obtained from the institutional ethics committee and the patients also provided consent. Sufficient transthoracic echocardiographic (TTE) evidence of ILVNC according to previously published criteria was found in all the cases, although it was not confirmed with CMRI.This case series highlights the importance of routine echocardiography in all patients who present with heart failure – irrespective of associated risk factors. We caution against over-diagnosis of ILVNC with TTE alone, and recommend the use of CMRI as a second-line diagnostic investigation. Screening of family members and prevention of complications of confirmed cases of ILVNC are important

Leukotrienes provide an NFAT-dependent signal that synergizes with IL-33 to activate ILC2s.

Group 2 innate lymphoid cells (ILC2s) and type 2 helper T cells (Th2 cells) are the primary source of interleukin 5 (IL-5) and IL-13 during type 2 (allergic) inflammation in the lung. In Th2 cells, T cell receptor (TCR) signaling activates the transcription factors nuclear factor of activated T cells (NFAT), nuclear factor κB (NF-κB), and activator protein 1 (AP-1) to induce type 2 cytokines. ILC2s lack a TCR and respond instead to locally produced cytokines such as IL-33. Although IL-33 induces AP-1 and NF-κB, NFAT signaling has not been described in ILC2s. In this study, we report a nonredundant NFAT-dependent role for lipid-derived leukotrienes (LTs) in the activation of lung ILC2s. Using cytokine reporter and LT-deficient mice, we find that complete disruption of LT signaling markedly diminishes ILC2 activation and downstream responses during type 2 inflammation. Type 2 responses are equivalently attenuated in IL-33- and LT-deficient mice, and optimal ILC2 activation reflects potent synergy between these pathways. These findings expand our understanding of ILC2 regulation and may have important implications for the treatment of airways disease

The Impact of Immunocompromise on Outcomes of COVID-19 in Children and Young People - A Systematic Review and Meta-Analysis

Background: Despite children and young people (CYP) having a low risk for severe Coronavirus disease 2019 (COVID-19) outcomes, there is still a degree of uncertainty related to their risk in the context of immunodeficiency or immunosuppression, primarily due to significant reporting bias in most studies, as CYP characteristically experience milder or asymptomatic COVID-19 infection and the severe outcomes tend to be overestimated. Methods: A comprehensive systematic review to identify globally relevant studies in immunosuppressed CYP and CYP in general population (defined as younger than 25 years of age) up to 31st October 2021 (to exclude vaccinated populations), was performed. Studies were included if they reported the two primary outcomes of our study, admission to intensive therapy unit (ITU) and mortality, while data on other outcomes, such as hospitalisation and need for mechanical ventilation were also collected. A meta-analysis estimated the pooled proportion for each severe COVID-19 outcome, using the inverse variance method. Random effects models were used to account for interstudy heterogeneity. Findings: The systematic review identified 30 eligible studies for each of the two populations investigated: immunosuppressed CYP (n=793) and CYP in general population (n=102,022). Our meta-analysis found higher estimated prevalence for hospitalization (46% vs. 16%), ITU admission (12% vs. 2%), mechanical ventilation (8% vs. 1%) and increased mortality due to severe COVID-19 infection (6.5% vs. 0.2%) in immunocompromised CYP compared to CYP in general population. This shows an overall trend for more severe outcomes of COVID-19 infection in immunocompromised CYP, similar to adult studies. Interpretation: This is the only up to date meta-analysis in immunocompromised CYP with high global relevance, which excluded reports from hospitalised cohorts alone and included 35% studies from low- and medium-income countries. Future research is required to characterise individual subgroups of immunocompromised patients, as well as impact of vaccination on severe COVID-19 outcomes. Funding: There was no funding source specifically dedicated for this study. CC is supported by a National Institute of Health Research (NIHR) Biomedical Research Centre (BRC) at University College London Hospital (UCLH). The study was performed within the Centre for Adolescent Rheumatology Versus Arthritis at University College London (UCL), UCL Hospital and Great Ormond Street Hospital (GOSH) supported by grants from Versus Arthritis (21593 and 20164), Great Ormond Street Children’s Charity, and the NIHR-BRC at both GOSH and UCLH

TRPV4 and KCa functionally couple as osmosensors in the PVN

BACKGROUND AND PURPOSE: Transient receptor potential vanilloid type 4 (TRPV4) and calcium-activated potassium channels (KCa ) mediate osmosensing in many tissues. Both TRPV4 and KCa channels are found in the paraventricular nucleus (PVN) of the hypothalamus, an area critical for sympathetic control of cardiovascular and renal function. Here, we have investigated whether TRPV4 channels functionally couple to KCa channels to mediate osmosensing in PVN parvocellular neurones and have characterized, pharmacologically, the subtype of KCa channel involved. EXPERIMENTAL APPROACH: We investigated osmosensing roles for TRPV4 and KCa channels in parvocellular PVN neurones using cell-attached and whole-cell electrophysiology in mouse brain slices and rat isolated PVN neurons. Intracellular Ca(2+) was recorded using Fura-2AM. The system was modelled in the NEURON simulation environment. KEY RESULTS: Hypotonic saline reduced action current frequency in hypothalamic slices; a response mimicked by TRPV4 channel agonists 4αPDD (1 μM) and GSK1016790A (100 nM), and blocked by inhibitors of either TRPV4 channels (RN1734 (5 μM) and HC067047 (300 nM) or the low-conductance calcium-activated potassium (SK) channel (UCL-1684 30 nM); iberiotoxin and TRAM-34 had no effect. Our model was compatible with coupling between TRPV4 and KCa channels, predicting the presence of positive and negative feedback loops. These predictions were verified using isolated PVN neurons. Both hypotonic challenge and 4αPDD increased intracellular Ca(2+) and UCL-1684 reduced the action of hypotonic challenge. CONCLUSIONS AND IMPLICATIONS: There was functional coupling between TRPV4 and SK channels in parvocellular neurones. This mechanism contributes to osmosensing in the PVN and may provide a novel pharmacological target for the cardiovascular or renal systems