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Introduction: The diagnosis of asthma is often based on characteristic patterns of symptoms in the absence of an alternative explanation, resulting in over and under diagnosis. Therefore, diagnostic guidelines usually recommend including confirmation of variable airflow obstruction. Some recommend using a sequence of objective tests; however the tests used, the specific cut-off values and the specified order are yet to be validated. We aimed to determine the optimal cut-off values and series of investigations to diagnose asthma. We also explore the potential for novel tests of small airways function and biomarkers, which could be incorporated into future diagnostic pathways., Methods and Analysis: The Rapid Access Diagnostics for Asthma study is an observational study of 300 symptomatic patients with 'clinician-suspected asthma' and healthy controls (aged ≥3 to <70 years), recruited from primary and secondary care in Greater Manchester, UK. Symptomatic participants will undergo four core visits and one optional visit. Participants will complete two baseline visits and undergo a series of established (spirometry, bronchodilator reversibility, exhaled nitric oxide, home peak flow monitoring and bronchial challenge testing) and novel tests. Following visit 2, participants will receive monitored medium-dose inhaled corticosteroid therapy for 6-8 weeks, after which they will return for repeat testing. Patients will be diagnosed with asthma by 'expert panel' opinion (minimum two respiratory specialists) on review of all data (excluding novel tests) pre and post treatment. Healthy controls will attend two visits to establish reference intervals and calculate repeatability coefficients for novel tests where there is a lack of evidence on what threshold constitutes a 'normal' set of values. The primary end point is to determine the optimum diagnostic pathway for diagnosing asthma., Ethics and Dissemination: The study was approved by Greater Manchester East Research Ethics Committee (18/NW/0777). All participants or parents/guardians are required to provide written informed consent and children to provide written assent. The results will be published in peer-review journals and disseminated widely at conferences and with the help of Asthma and Lung UK (www.asthmaandlung.org.uk)., Trial Registration Number: ISRCTN11676160., Competing Interests: Competing interests: CM has received grants from NIHR, Asthma UK, Innovate UK, Moulton Charitable Foundation, GSK and MRC; travel grants from Sanofi and lecture fees from Novartis, GSK and Sanofi. AngS has received grants from NIHR, Asthma UK, Innovate UK, Moulton Charitable Foundation, GSK and MRC. SF reports personal fees from AstraZeneca, Chiesi, GlaxoSmithKline, Novartis and Teva and grants and personal fees from Boehringer Ingelheim. All other authors declare no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Performing fractional exhaled nitric oxide and bronchodilator reversibility tests in the morning is more likely to lead to a positive test result than when performed in the afternoon. Therefore, time of day should be considered during test interpretation. https://bit.ly/4b79e5J., Competing Interests: Conflict of interest: R. Wang reports support for the present manuscript from Manchester BRC; research grants from the National Institute of Health Research and Moulton Charitable Foundation, outside the submitted work; support for attending meetings and/or travel from ICAN meeting, GSK/AZ/Sanofi, Asthma and Lung UK/BTS, outside the submitted work. Conflict of interest: R. Maidstone reports support for the present manuscript from Asthma and Lung UK Grant WAPG22/100005. Conflict of interest: A. Simpson reports support for the present manuscript from the Medical Research Council, Asthma UK, National Institute of Health Research and GSK. Conflict of interest: C.S. Murray reports support for the present manuscript from the National Institute for Health Research and Asthma UK; grants or contracts from the North West Lung Centre Charity and Moulton Charitable Foundation, outside the submitted work; and lecture fees from Novartis and GSK, outside the submitted work. Conflict of interest: H.J. Durrington reports support for the present manuscript from the Medical Research Council, Asthma and Lung UK, and Mouton Charitable Trust; consulting fees from Chiesi and Healthnet Homecare, outside the submitted work; and is a member of the Drug Safety and Monitoring Board for HEAL-COVID, Deputy Chair of the NIHR Respiratory Translational Research Collaboration for the Manchester BRC and a member of the Lung Research and Innovation Group, UK, outside the submitted work. Conflict of interest: The remaining authors have nothing to disclose., (Copyright ©The authors 2024.)

Background: Allergic diseases impose a significant global disease burden, however, the influence of light at night exposure on these diseases in humans has not been comprehensively assessed. We aimed to summarize available evidence considering the association between light at night exposure and major allergic diseases through a systematic review and meta-analysis., Methods: We completed a search of six databases, two registries, and Google Scholar from inception until December 15, 2023, and included studies that investigated the influence of artificial light at night (ALAN, high vs. low exposure), chronotype (evening vs. morning chronotype), or shift work (night vs. day shift work) on allergic disease outcomes (asthma, allergic rhinitis, and skin allergies). We performed inverse-variance random-effects meta-analyses to examine the association between the exposures (ALAN exposure, chronotype, or shiftwork) and these allergic outcomes. Stratification analyses were conducted by exposure type, disease type, participant age, and geographical location along with sensitivity analyses to assess publication bias., Results: We included 12 publications in our review. We found that exposure to light at night was associated with higher odds of allergic diseases, with the strongest association observed for ALAN exposure (OR: 1.88; 95% CI: 1.04 to 3.39), followed by evening chronotype (OR: 1.35; 95% CI: 0.98 to 1.87) and exposure to night shift work (OR: 1.33; 95% CI: 1.06 to 1.67). When analyses were stratified by disease types, light at night exposure was significantly associated with asthma (OR: 1.62; 95% CI: 1.19 to 2.20), allergic rhinitis (OR: 1.89; 95% CI: 1.60 to 2.24), and skin allergies (OR: 1.11; 95% CI: 1.09 to 1.91). We also found that the association between light at night exposure and allergic diseases was more profound in youth (OR: 1.63; 95% CI: 1.07 to 2.48) than adults (OR: 1.30; 95% CI: 1.03 to 1.63). Additionally, we observed significant geographical variations in the association between light at night exposure and allergic diseases., Conclusions: Light at night exposure was associated with a higher prevalence of allergic diseases, both in youth and adults. More long-term epidemiological and mechanistic research is required to understand the possible interactions between light at night and allergic diseases., (© 2024. The Author(s).)

Rationale: Asthma is a rhythmic inflammatory disease of the airway, regulated by the circadian clock. "Spill-over" of airway inflammation into the systemic circulation occurs in asthma and is reflected in circulating immune cell repertoire. The objective of the present study was to determine how asthma impacts peripheral blood diurnal rhythmicity., Methods: 10 healthy and 10 mild/moderate asthma participants were recruited to an overnight study. Blood was drawn every 6 h for 24 h., Main Results: The molecular clock in blood cells in asthma is altered; PER3 is significantly more rhythmic in asthma compared to healthy controls. Blood immune cell numbers oscillate throughout the day, in health and asthma. Peripheral blood mononucleocytes from asthma patients show significantly enhanced responses to immune stimulation and steroid suppression at 16:00 h, compared to at 04:00 h. Serum ceramides show complex changes in asthma: some losing and others gaining rhythmicity., Conclusions: This is the first report showing that asthma is associated with a gain in peripheral blood molecular clock rhythmicity. Whether the blood clock is responding to rhythmic signals received from the lung or driving rhythmic pathology within the lung itself is not clear. Dynamic changes occur in serum ceramides in asthma, probably reflecting systemic inflammatory action. The enhanced responses of asthma blood immune cells to glucocorticoid at 16:00 h may explain why steroid administration is more effective at this time., Competing Interests: Conflict of interest: R.J. Maidstone reports support for the present manuscript from D.W. Ray's Wellcome Trust Grant (107849/Z/15/Z) and D.W. Ray's Medical Research Council grant (MR/P023576/1). Conflict of interest: A.C. Kendall reports support for the present manuscript from the BBSRC and The Boots Company PLC. Conflict of interest: P. Downton reports support for the present manuscript from MRC Programme Grant MR/P023576/1, awarded to D.W. Ray. Conflict of interest: A. Nicolaou reports support for the present manuscript from the BBSRC (BB/R018952/1 and BB/W006022/1), The Boots Company PLC and Waters; grants or contracts from the BBSRC, The Boots company PLC and Waters, outside the submitted work; honoraria for work at grant evaluation panels received from the BBSRC outside the submitted work; support for travel to conferences from The Eicosanoid Foundation and ISSFAL, outside the submitted work; a Unilever patent filed on a project outside the submitted work; and is an ISSFAL Board member and EuroFedLipid Chair of the Lipidomics Division, outside the submitted work. Conflict of interest: D. Singh reports consulting fees from Aerogen, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipl, CSL Behring, Epiendo, Genentech, GlaxoSmithKline, Glenmark, Gossamerbio, Kinaset, Menarini, Novartis, Pulmatrix, Sanofi, Teva, Theravance and Verona, outside the submitted work. Conflict of interest: A.S.I. Loudon reports grant from Wellcome Trust Investigator Award (grant 107851/Z/15/Z) outside the submitted work. Conflict of interest: D.W. Ray grants or contracts from the Medical Research Council UK and Wellcome Trust UK, outside the submitted work; payment or honoraria for speakers’ bureaus from the European Biological Rhythms Society outside the submitted work; and is Chair of the Bioscientifica Trust outside the submitted work. Conflict of interest: H.J. Durrington reports support for the present manuscript from the MRC, Asthma and Lung UK, and the Moulton Charitable Trust; consulting fees from Chiesi and Healthnet Homecare, outside the submitted work; support for attending meetings and/or travel from ICAN outside the submitted work; is a member of the Drug Safety and Monitoring Board for HEAL-COVID outside the submitted work; and is Deputy Chair of the NIHR Respiratory Translational Research Collaboration (TRC) for the Manchester BRC outside the submitted work. Conflict of interest: The remaining authors have nothing to disclose., (Copyright ©The authors 2023.)

Circadian regulation causes the activity of biological processes to vary over a 24-h cycle. The pathological effects of this variation are predominantly studied using two different approaches: pre-clinical models or observational clinical studies. Both these approaches have provided useful insights into how underlying circadian mechanisms operate and specifically which are regulated by the molecular oscillator, a key time-keeping mechanism in the body. This review compares and contrasts findings from these two approaches in the context of four common respiratory diseases (asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, and respiratory infection). Potential methods used to identify and measure human circadian oscillations are also discussed as these will be useful outcome measures in future interventional human trials that target circadian mechanisms., (© 2023 The Author(s).)

Asthma is the most common chronic respiratory disease in the UK; however, the misdiagnosis rate is substantial. The lack of consistency in national guidelines and the paucity of data on the performance of diagnostic algorithms compound the challenges in asthma diagnosis. Asthma is a highly rhythmic disease, characterised by diurnal variability in clinical symptoms and pathogenesis. Asthma also varies day to day, seasonally and from year to year. As much as it is a hallmark for asthma, this variability also poses significant challenges to asthma diagnosis. Almost all established asthma diagnostic tools demonstrate diurnal variation, yet few are performed with standardised timing of measurements. The dichotomous interpretation of diagnostic outcomes using fixed cut-off values may further limit the accuracy of the tests, particularly when diurnal variability straddles cut-off values within a day, and careful interpretation beyond the 'positive' and 'negative' outcome is needed. The day-to-day and more long-term variations are less predictable and it is unclear whether performing asthma diagnostic tests during asymptomatic periods may influence diagnostic sensitivities. With the evolution of asthma diagnostic tools, home monitoring and digital apps, novel strategies are needed to bridge these gaps in knowledge, and circadian variability should be considered during the standardisation process. This review summarises the biological mechanisms of circadian rhythms in asthma and highlights novel data on the significance of time (the fourth dimension) in asthma diagnosis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Shift work is associated with lung disease and infections. We therefore investigated the impact of shift work on significant COVID-19 illness., Methods: 501 000 UK Biobank participants were linked to secondary care SARS-CoV-2 PCR results from Public Health England. Healthcare worker occupational testing and those without an occupational history were excluded from analysis., Results: Multivariate logistic regression (age, sex, ethnicity and deprivation index) revealed that irregular shift work (OR 2.42, 95% CI 1.92 to 3.05), permanent shift work (OR 2.5, 95% CI 1.95 to 3.19), day shift work (OR 2.01, 95% CI 1.55 to 2.6), irregular night shift work (OR 3.04, 95% CI 2.37 to 3.9) and permanent night shift work (OR 2.49, 95% CI 1.67 to 3.7) were all associated with positive COVID-19 tests compared with participants that did not perform shift work. This relationship persisted after adding sleep duration, chronotype, premorbid disease, body mass index, alcohol and smoking to the model. The effects of workplace were controlled for in three ways: (1) by adding in work factors (proximity to a colleague combined with estimated disease exposure) to the multivariate model or (2) comparing participants within each job sector (non-essential, essential and healthcare) and (3) comparing shift work and non-shift working colleagues. In all cases, shift work was significantly associated with COVID-19. In 2017, 120 307 UK Biobank participants had their occupational history reprofiled. Using this updated occupational data shift work remained associated with COVID-19 (OR 4.48 (95% CI 1.8 to 11.18)., Conclusions: Shift work is associated with a higher likelihood of in-hospital COVID-19 positivity. This risk could potentially be mitigated via additional workplace precautions or vaccination., Competing Interests: Competing interests: MR has received speaker fees and research support from Novo Nordisk and Roche Diabetes Care for research unrelated to that presented here., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Shift work causes misalignment between internal circadian time and the external light/dark cycle and is associated with metabolic disorders and cancer. Approximately 20% of the working population in industrialised countries work permanent or rotating night shifts, exposing this large population to the risk of circadian misalignment-driven disease. Analysis of the impact of shift work on chronic inflammatory diseases is lacking. We investigated the association between shift work and asthma., Methods: We describe the cross-sectional relationship between shift work and prevalent asthma in >280000 UK Biobank participants, making adjustments for major confounding factors (smoking history, ethnicity, socioeconomic status, physical activity, body mass index). We also investigated chronotype., Results: Compared with day workers, 'permanent' night shift workers had a higher likelihood of moderate-severe asthma (OR 1.36 (95% CI 1.03 to 1.8)) and all asthma (OR 1.23 (95% CI 1.03 to 1.46)). Individuals doing any type of shift work had higher adjusted odds of wheeze/whistling in the chest. Shift workers who never or rarely worked on nights and people working permanent nights had a higher adjusted likelihood of having reduced lung function (FEV 1 <80% predicted). We found an increase in the risk of moderate-severe asthma in morning chronotypes working irregular shifts, including nights (OR 1.55 (95% CI 1.06 to 2.27))., Conclusions: The public health implications of these findings are far-reaching due to the high prevalence and co-occurrence of both asthma and shift work. Future longitudinal follow-up studies are needed to determine if modifying shift work schedules to take into account chronotype might present a public health measure to reduce the risk of developing inflammatory diseases such as asthma., Competing Interests: Competing interests: FS has received lecture fees from Bayer HealthCare (2016), Sentara HealthCare (2017), Philips (2017), Vanda Pharmaceuticals (2017) and Pfizer Pharmaceuticals (2018). DL has received research support from Medtronic Ltd and Roche Diagnostics for research unrelated to that presented here. MR has received speaker fees and research support from Novo Nordisk and Roche Diabetes Care for research unrelated to that presented here., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Background: The circadian clock powerfully regulates inflammation and the clock protein REV-ERBα is known to play a key role as a repressor of the inflammatory response. Asthma is an inflammatory disease of the airways with a strong time of day rhythm. Airway hyper-responsiveness (AHR) is a dominant feature of asthma; however, it is not known if this is under clock control., Objectives: To determine if allergy-mediated AHR is gated by the clock protein REV-ERBα., Methods: After exposure to the intra-nasal house dust mite (HDM) allergen challenge model at either dawn or dusk, AHR to methacholine was measured invasively in mice., Main Results: Wild-type (WT) mice show markedly different time of day AHR responses (maximal at dusk/start of the active phase), both in vivo and ex vivo , in precision cut lung slices. Time of day effects on AHR were abolished in mice lacking the clock gene Rev-erb α, indicating that such effects on asthma response are likely to be mediated via the circadian clock. We suggest that muscarinic receptors one ( Chrm 1 ) and three ( Chrm 3 ) may play a role in this pathway., Conclusions: We identify a novel circuit regulating a core process in asthma, potentially involving circadian control of muscarinic receptor expression, in a REV-ERBα dependent fashion., Clinical Implication: These insights suggest the importance of considering the timing of drug administration in clinic trials and in clinical practice (chronotherapy)., Competing Interests: Conflict of interest: K. Krakowiak has nothing to disclose. Conflict of interest: P. Meijer has nothing to disclose. Conflict of interest: N. Begley has nothing to disclose. Conflict of interest: R. Maidstone has nothing to disclose. Conflict of interest: L. Goosey has nothing to disclose. Conflict of interest: J.E. Gibbs has nothing to disclose. Conflict of interest: J.F. Blaikley has nothing to disclose. Conflict of interest: L.G. Gregory has nothing to disclose. Conflict of interest: C.M. Lloyd has nothing to disclose. Conflict of interest: A.S.I. Loudon has nothing to disclose. Conflict of interest: D.W. Ray has nothing to disclose. Conflict of interest: H.J. Durrington has nothing to disclose., (Copyright ©ERS 2020.)

The circadian clock regulates many aspects of immunity. Bacterial infections are affected by time of day, but the mechanisms involved remain undefined. Here we show that loss of the core clock protein BMAL1 in macrophages confers protection against pneumococcal pneumonia. Infected mice show both reduced weight loss and lower bacterial burden in circulating blood. In vivo studies of macrophage phagocytosis reveal increased bacterial ingestion following Bmal1 deletion, which was also seen in vitro. BMAL1 -/- macrophages exhibited marked differences in actin cytoskeletal organization, a phosphoproteome enriched for cytoskeletal changes, with reduced phosphocofilin and increased active RhoA. Further analysis of the BMAL1 -/- macrophages identified altered cell morphology and increased motility. Mechanistically, BMAL1 regulated a network of cell movement genes, 148 of which were within 100 kb of high-confidence BMAL1 binding sites. Links to RhoA function were identified, with 29 genes impacting RhoA expression or activation. RhoA inhibition restored the phagocytic phenotype to that seen in control macrophages. In summary, we identify a surprising gain of antibacterial function due to loss of BMAL1 in macrophages, associated with a RhoA-dependent cytoskeletal change, an increase in cell motility, and gain of phagocytic function., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

Pulmonary inflammatory responses lie under circadian control; however, the importance of circadian mechanisms in the underlying fibrotic phenotype is not understood. Here, we identify a striking change to these mechanisms resulting in a gain of amplitude and lack of synchrony within pulmonary fibrotic tissue. These changes result from an infiltration of mesenchymal cells, an important cell type in the pathogenesis of pulmonary fibrosis. Mutation of the core clock protein REVERBα in these cells exacerbated the development of bleomycin-induced fibrosis, whereas mutation of REVERBα in club or myeloid cells had no effect on the bleomycin phenotype. Knockdown of REVERBα revealed regulation of the little-understood transcription factor TBPL1. Both REVERBα and TBPL1 altered integrinβ1 focal-adhesion formation, resulting in increased myofibroblast activation. The translational importance of our findings was established through analysis of 2 human cohorts. In the UK Biobank, circadian strain markers (sleep length, chronotype, and shift work) are associated with pulmonary fibrosis, making them risk factors. In a separate cohort, REVERBα expression was increased in human idiopathic pulmonary fibrosis (IPF) lung tissue. Pharmacological targeting of REVERBα inhibited myofibroblast activation in IPF fibroblasts and collagen secretion in organotypic cultures from IPF patients, thus suggesting that targeting of REVERBα could be a viable therapeutic approach., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

Objective: To identify whether renal transplant activity varies in a reproducible manner across the year., Design: Retrospective cohort study using NHS Blood and Transplant data., Setting: All renal transplant centres in the UK., Participants: A total of 24 270 patients who underwent renal transplantation between 2005 and 2014., Primary Outcome: Monthly transplant activity was analysed to see if transplant activity showed variation during the year., Secondary Outcome: The number of organs rejected due to healthcare capacity was analysed to see if this affected transplantation rates., Results: Analysis of national transplant data revealed a reproducible yearly variance in transplant activity. This activity increased in late autumn and early winter (p=0.05) and could be attributed to increased rates of living (October and November) and deceased organ donation (November and December). An increase in deceased donation was attributed to a rise in donors following cerebrovascular accidents and hypoxic brain injury. Other causes of death (infections and road traffic accidents) were more seasonal in nature peaking in the winter or summer, respectively. Only 1.4% of transplants to intended recipients were redirected due to a lack of healthcare capacity, suggesting that capacity pressures in the National Health Service did not significantly affect transplant activity., Conclusion: UK renal transplant activity peaks in late autumn/winter in contrast to other countries. Currently, healthcare capacity, though under strain, does not affect transplant activity; however, this may change if transplantation activity increases in line with national strategies as the spike in transplant activity coincides with peak activity in the national healthcare system., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

The importance of circadian factors in managing patients is poorly understood. We present two retrospective cohort studies showing that lungs reperfused between 4 and 8 AM have a higher incidence (OR 1.12; 95% CI 1.03 to 1.21; p=0.01) of primary graft dysfunction (PGD) in the first 72 hours after transplantation. Cooling of the donor lung, occurring during organ preservation, shifts the donor circadian clock causing desynchrony with the recipient. The clock protein REV-ERBα directly regulates PGD biomarkers explaining this circadian regulation while also allowing them to be manipulated with synthetic REV-ERB ligands., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Asthma exhibits a marked time of day variation in symptoms, airway physiology, and airway inflammation. This is also seen in chronic obstructive pulmonary disease (COPD), but to a lesser extent. Our understanding of how physiological daily rhythms are regulated by the circadian clock is increasing, and there is growing evidence that the molecular clock is important in the pathogenesis of these two airway diseases. If time of day is important, then it follows that treatment of asthma and COPD should also be tailored to the most efficacious time of the day, a concept known as 'chronotherapy'. There have been a number of studies to determine the optimal time of day at which to take medications for asthma and COPD. Some of these agents are already used 'chronotherapeutically' in practice (often at night-time). However, several studies investigating systemic and inhaled corticosteroids have consistently shown that the best time of day to take these medications for treating asthma is in the afternoon or early evening and not in the morning, when these medications are often prescribed. Future, large, randomized, placebo-controlled studies of systemic and inhaled corticosteroids in asthma and COPD are needed to inform clinical practice.

Circadian rhythms regulate changes in physiology, allowing organisms to respond to predictable environmental demands varying over a 24 h period. A growing body of evidence supports a key role for the circadian clock in the regulation of immune functions and inflammatory responses, which influence the understanding of infections and inflammatory diseases and their treatment. A variety of experimental methods have been used to assess the complex bidirectional crosstalk between the circadian clock and inflammation. In this review, we summarize the organization of the molecular clock, experimental methods used to study circadian rhythms, and both the inflammatory and immune consequences of circadian disturbance., (© Society for Leukocyte Biology.)

It is characteristic of asthma that symptoms worsen overnight, particularly in the early hours of the morning. Nocturnal symptoms in asthma are common and are an important indicator for escalation of treatment. An extensive body of research has demonstrated that nocturnal symptoms of cough and dyspnea are accompanied by circadian variations in airway inflammation and physiologic variables, including airflow limitation and airways hyper-responsiveness. The molecular apparatus that underpins circadian variations, controlled by so called 'clock' genes, has recently been characterised. Clock genes control circadian rhythms both centrally, in the suprachiasmatic nucleus of the brain and peripherally, within every organ of the body. Here, we will discuss how clock genes regulate circadian rhythms. We will focus particularly on the peripheral lung clock and the peripheral immune clock and discuss how these might relate to both the pathogenesis and treatment of asthma.

Capillary malformation-arteriovenous malformation (CM-AVM) is a newly recognized clinical entity caused by mutation of the RASA1 gene, which encodes p120-RasGAP. Here we describe, for the first time, a patient with CM-AVM presenting during the late stages of pregnancy with pulmonary "capillary level" microvascular shunt, worsening cutaneous capillary malformations, and gross fluid overload. Sequencing revealed a novel mutation of the RASA1 gene involving a frameshift mutation in the RASGAP domain of RASA1. This report extends our current genetic and clinical understanding of CM-AVM., (Copyright © 2013 Wiley Periodicals, Inc.)

Bone morphogenetic proteins (BMPs) are critically involved in early development and cell differentiation. In humans, dysfunction of the bone morphogenetic protein type II receptor (BMPR-II) is associated with pulmonary arterial hypertension (PAH) and neoplasia. The ability of Kaposi sarcoma-associated herpesvirus (KSHV), the etiologic agent of Kaposi sarcoma and primary effusion lymphoma, to down-regulate cell surface receptor expression is well documented. Here we show that KSHV infection reduces cell surface BMPR-II. We propose that this occurs through the expression of the viral lytic gene, K5, a ubiquitin E3 ligase. Ectopic expression of K5 leads to BMPR-II ubiquitination and lysosomal degradation with a consequent decrease in BMP signaling. The down-regulation by K5 is dependent on both its RING domain and a membrane-proximal lysine in the cytoplasmic domain of BMPR-II. We demonstrate that expression of BMPR-II protein is constitutively regulated by lysosomal degradation in vascular cells and provide preliminary evidence for the involvement of the mammalian E3 ligase, Itch, in the constitutive degradation of BMPR-II. Disruption of BMP signaling may therefore play a role in the pathobiology of diseases caused by KSHV infection, as well as KSHV-associated tumorigenesis and vascular disease.

The hereditary spastic paraplegias (HSPs) are genetic conditions characterized by distal axonopathy of the longest corticospinal tract axons, and so their study provides an important opportunity to understand mechanisms involved in axonal maintenance and degeneration. A group of HSP genes encode proteins that localize to endosomes. One of these is NIPA1 (non-imprinted in Prader-Willi/Angelman syndrome 1) and we have shown recently that its Drosophila homologue spichthyin inhibits bone morphogenic protein (BMP) signalling, although the relevance of this finding to the mammalian protein was not known. We show here that mammalian NIPA1 is also an inhibitor of BMP signalling. NIPA1 physically interacts with the type II BMP receptor (BMPRII) and we demonstrate that this interaction does not require the cytoplasmic tail of BMPRII. We show that the mechanism by which NIPA1 inhibits BMP signalling involves downregulation of BMP receptors by promoting their endocytosis and lysosomal degradation. Disease-associated mutant versions of NIPA1 alter the trafficking of BMPRII and are less efficient at promoting BMPRII degradation than wild-type NIPA1. In addition, we demonstrate that two other members of the endosomal group of HSP proteins, spastin and spartin, are inhibitors of BMP signalling. Since BMP signalling is important for distal axonal function, we propose that dysregulation of BMP signalling could be a unifying pathological component in this endosomal group of HSPs, and perhaps of importance in other conditions in which distal axonal degeneration is found.

Research on the molecular basis of PAH caused by BMPR-II mutations is beginning to yield novel approaches to therapy, for example, small molecule inhibitors of ALK-5. Enhancement of BMP signalling may be possible with BMP-derived ligands or rescue of BMPR-II cell surface expression for some mutations. For mutations leading to nonsense mediated mRNA decay, approaches aimed at transcript stabilisation provide another possible intervention. To further our genetic understanding of this rare disease, large international collaborative studies are needed to generate the numbers of patients necessary to undertake meaningful genome wide association studies for novel susceptibility genes or disease modifying genes. In addition, to provide accurate information to families, longitudinal cohort studies, coupled with biomarker studies, are required of affected and unaffected individuals in families segregating BMPR-II mutations.

Background: The Norfolk and Norwich University Hospital (NNUH) is situated in rural Norfolk, and ambulance journey times are often >30 min. Longer ambulance journeys could lead to a greater risk of hypercapnia, if inappropriately high concentrations of oxygen are given during an exacerbation of COPD., Aim: To investigate the effect of high concentration oxygen (HCO, FiO(2) > 0.28) on COPD patients, and the outcome of instituting a simple protocol to reduce such exposure., Design: Retrospective audit., Method: An audit was conducted of all patients admitted with an exacerbation of COPD to the NNUH during the 2 months from 1 December 2001 to 31 January 2002 (n = 108). Results were shared with paramedics, and guidelines agreed for the initial provision of lower concentrations of oxygen (LCO, FiO(2) < or = 0.28). A second audit was conducted a year later between 1 December 2002 and 31 January 2003 (n = 103)., Results: HCO caused significant (p < 0.01) acidosis and inappropriately high PaO(2) and PaCO(2), compared to initial LCO therapy. There was a significantly increased complication rate during admission (p < 0.01) in those COPD patients receiving HCO compared to LCO, particularly when ambulance journeys exceeded 30 min. The second audit demonstrated a significant (p < 0.001) reduction in the number of patients initially receiving HCO, but the complication rate was unaltered., Discussion: A simple intervention, such as providing paramedics with 28% Venturi masks, can reduce the number of COPD patients exposed to HCO. A randomized controlled trial is long overdue to establish whether HCO or LCO as initial management is associated with the most favourable prognosis in different hospital settings.

1. Epithelia lining the nasal passages and descending colon of wild-type and cystic fibrosis (CF) mice were examined by the short-circuit current technique. Additionally, intracellular Ca2+ ion determinations were made in nasal epithelial cells. Forskolin produced anion secretory currents in wild-type and CF nasal epithelia. It produced similar effects in wild-type colonic epithelia, but not in colonic epithelia from CF mice. 2. After electrogenic Na+ transport was blocked with amiloride and electrogenic Cl- secretion was stimulated with forskolin, the ability of K+ channel blockers to inhibit the forskolin-induced Cl- current was determined. The order of efficiency for nasal epithelium was: Ba2+ > clofilium >>> TEA = azimilide >>> trans-6-cyano-4-(N-ethylsulphonyl-N-methylamino)-3-hydroxy-2, 2-dimethyl-chromane (293B) = charybdotoxin, whereas for the colonic epithelium the order was: Ba2+ = 293B >>> azimilide = TEA >>> clofilium = charybdotoxin. 3. 1-Ethyl-2-benzimdazolinone (1-EBIO) was able to generate large Cl--secretory currents in colonic epithelia which were partially sensitive to charybdotoxin, with the remaining current being inhibited by 293B. In nasal epithelia 1-EBIO produced only a small transient effect on current. 4. Forskolin released intracellular Ca2+ in nasal epithelial cells; this activity was attenuated when more powerful Ca2+-releasing agents were applied first. 5. It is concluded that an action on basolateral cAMP-sensitive K+ channels is an important determinant of the maintained responses to forskolin in nasal and colonic epithelia, in addition to the effects on the cystic fibrosis transmembrane conductance regulator (CFTR) in the apical membrane. In CF nasal epithelia the activation of calcium-activated chloride channels (CACs) substitutes for the effect on CFTR. On the basis of the different orders of potency of the blocking agents and the differential response to 1-EBIO it is concluded that the cAMP-sensitive K+ channels are different in the airways and the gut.