Investigation of the neural control of cough and cough suppression in humans using functional brain imaging

Excessive coughing is one of the mostcommonreasons for seeking medical advice, yet the available therapies for treating cough disorders are inadequate. Humans can voluntarily cough, choose to suppress their cough, and are acutely aware of an irritation that is present in their airways. This indicates a significant level of behavioral and conscious control over the basic cough reflex pathway. However, very little is known about the neural basis for higher brain regulation of coughing. The aim of the present study was to use functional brain imaging in healthy humans to describe the supramedullary control of cough and cough suppression. Our data show that the brain circuitry activated during coughing in response to capsaicin-evoked airways irritation is not simply a function of voluntarily initiated coughing and the perception of airways irritation. Rather, activations in several brain regions, including the posterior insula and posterior cingulate cortex, define the unique attributes of an evoked cough. Furthermore, the active suppression of irritant-evoked coughing is also associated with a unique pattern of brain activity, including an involvement of the anterior insula, anterior mid-cingulate cortex, and inferior frontal gyrus. These data demonstrate for the first time that evoked cough is not solely a brainstem-mediated reflex response to irritation of the airways, but rather requires active facilitation by cortical regions, and is further regulated by distinct higher order inhibitory processes. Copyright © 2011 the authors

HLA-DQA1*05 carriage associated with development of anti-drug antibodies to infliximab and adalimumab in patients with Crohn's Disease

Anti-tumor necrosis factor (anti-TNF) therapies are the most widely used biologic drugs for treating immune-mediated diseases, but repeated administration can induce the formation of anti-drug antibodies. The ability to identify patients at increased risk for development of anti-drug antibodies would facilitate selection of therapy and use of preventative strategies.This article is freely available via Open Access. Click on Publisher URL to access the full-text

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely

Pain perception and processing in ageing and Alzheimer's disease

© 2008 Dr. Leonie J. ColeThe prevalence of chronic pain is known to increase with advancing age, with over 50% of community dwelling older adults (aged 65 years and over) and up to 80% of those residing in nursing homes estimated to be suffering some form of persistent or recurring pain complaint. In addition to a greater likelihood of pain, advancing age is associated with increased reports of pain interference. It is possible to ascribe age-related changes in pain report and impact to increased disease prevalence and severity in older people. However, there is also evidence that ageing has effects on pain perception, central pain processing, and plasticity of pain responses that are not explained by co-morbid disease. The increased prevalence of chronic pain in older adults represents a major public health concern. As a result of increased life expectancy and the post-World War II baby boom, there will be a dramatic change in the demographic structure of our population over the coming decades, with older adults representing the fastest-growing segment of our communities. The proportion of the total population over the age of 65 in Australia has risen from 9% in 1976, to 12% in 2001, and is predicted to reach 16% by the year 2016. Pain that is undetected or under-treated can adversely affect quality of life for older adults, leading to diminished mood, impaired cognition, behavioural problems, as well as increased functional dependence. This in turn contributes to greater demands for daily personal care and a resultant increase in health-care costs. Pain management is a particularly salient issue in the case of older adults with dementia, who are at increased risk of undetected pain on account of impaired cognition and communication skills. Indeed, clinical reports show that patients with Alzheimer’s disease (AD) are routinely administered fewer pain-relief medications compared with their cognitively-intact peers. Understandably, reports of reduced analgesia in AD have sparked considerable research interest, and over recent years there has been a marked increase in the number of studies aimed at better characterising the experience of pain in patients with AD. However, despite these efforts, the effects of neurodegeneration on pain processing, and the specific ways in which the disease process impacts on brain responses to noxious stimulation and the ensuing experience of pain have not been previously determined. Improved management of pain is fundamental to the clinical care of older adults, particularly those with dementia. However, the potential to adequately counteract pro-nociceptive processes and facilitate endogenous inhibitory mechanisms in the treatment of ongoing pain in older adults will only become possible once the effects of ageing and age-related neurodegeneration on central pain processing are identified and described. The overarching goal of this thesis was therefore to improve current understanding of the ways in which normal ageing and Alzheimer’s disease impact on the perception and central nervous system processing of pain. The findings of this thesis provide valuable new insights into the impact of ageing and AD on the central mechanisms contributing to pain perception, and may therefore contribute toward better management and treatment of pain in this vulnerable and rapidly growing sector of our community. Thesis outline: Chapter 2 provides a review of the background literature and rationale for the thesis. The chapter begins with a discussion of current understanding of pain as a multidimensional phenomenon shaped by sensory, emotional and cognitive components, and leads into a description of neural mechanisms of nociception, as well as the supraspinal processes involved in the elaboration of nociceptive signals into these aspects of pain. The impact of ageing on the structure and function of central nervous system regions underlying these processes are discussed, along with the findings from previous clinical and empirical data which suggest age-related changes in pain perception. Current understanding of the neuropathological and clinical aspects of AD is reviewed, with particular emphasis on potential ways in which the disease may impact on central nociceptive processing and the behavioural response to pain. This is followed by a review of the previous clinical and empirical literature examining pain perception in AD. Finally, the aims of the current thesis are outlined. Chapter 3 describes the general methods which were employed in the subsequent empirical chapters in order to address the aims of the thesis. The equipment and psychophysical procedures used to assess pain perception in healthy young and older adults and patients with AD are described. The basic principals of magnetic resonance imaging (MRI) are then outlined, and the utility of structural and functional MRI for assessing age-related and disease-related changes to brain regions involved in pain perception and processing are discussed. The empirical studies which were undertaken to identify the impact of ageing and AD on central pain processing are presented in the next three chapters. Chapter 4 begins with psychophysical studies comparing sensory and emotional responses to pain in healthy young and older adults, and follows with MRI investigations of age-related differences in brain volumetry and pain-related brain activity. Studies of pain sensitivity and pain-evoked brain activity in patients with AD compared with age-matched controls are presented in Chapter 5. Following on from these findings of AD-related differences in pain-evoked brain activation, the study described in Chapter 6 used functional connectivity analysis in order to assess the impact of AD on the functional integration of brain regions underlying the sensory, emotional, and cognitive aspects of pain. The key findings presented in the preceding three chapters are summarized in a general discussion in Chapter 7. The implications of the findings, in terms of the clinical management of pain in older adults with and without Alzheimer’s disease are discussed. The opportunity is also taken to discuss some of the limitations of the present research, and finally, recommendations are made for future research directions

Teaching values

Teaching Values has been designed to support teachers to introduce the Nine Values for Australian Schooling (Australian Government 2005) to their students and to build on the work that they and their schools do in the name of values education. It does not set out to be the definitive text rather it contributes to the current and historical discourse in this area by providing a unique approach to this complex area of the school curriculum. Using a range of texts sourced from collections held by the National Museum of Australia the book uses textual analysis as an approach to teaching values. <br /

Central nervous system control of cough: pharmacological implications

For many years the idea of a cough center in the brain dominated discussions in the field without any substantial progress in defining what this cough center is or how it functions. Substantial progress has now been made and many of the central neural elements involved in coughing are being described. Furthermore, hypothesis driven research into the function of these neural elements is providing exciting new leads for possible therapeutic targets. The concept of a specific, centrally acting drug for cough suppression is fast becoming a reality. This review summarizes the key findings from the past few years and provides a perspective on future directions for the development of novel antitussives

Cipro e la memoria dell'antico fra Medioevo e Rinascimento. La percezione del passato romano dell'isola nel mondo occidentale

Cipro, crocevia di culture e culla di antiche civiltà, costituì nei secoli del Medioevo e del Rinascimento un baluardo dell'Occidente latino nello scacchiere del Mediterraneo orientale. Quale atteggiamento assunsero governanti e viaggiatori occidentali nei confronti del ricco passato classico dell'isola? Il libro affronta il tema secondo una prospettiva volutamente ampia, ricercando la nascita dell'archeologia e dell'epigrafia sul suolo cipriota, ripercorrendo le tappe della riscoperta dei testi classici relativi all'isola ed esaminando il rapporto sviluppatosi fra il XIII e il XVI secolo con i resti visibili dell'antico