Investigation of the neural basis of expectation-based analgesia in the human brainstem and spinal cord by means of functional magnetic resonance imaging.

PURPOSE: The expected intensity of pain resulting from a noxious stimulus has been observed to have a strong influence on the pain that is perceived. The neural basis of pain reduction, as a result of expecting lower pain, was investigated using functional magnetic resonance imaging (fMRI) in the brainstem and spinal cord. METHODS: Functional MRI studies were carried out in a region spanning the brainstem and cervical spinal cord in healthy participants. Participants were familiarized with a noxious heat stimulus and study procedures in advance, and were informed during each trial that either a heat calibrated to produce moderate pain (Base state), or a temperature 1 °C lower (Low state), would be applied to their hand. However, the Base temperature was applied in every trial. RESULTS: Pain ratings were significantly reduced as a result of expecting lower temperatures. FMRI results demonstrate blood oxygenation-level dependent (BOLD) signal variations in response to participants being informed of the stimulus to expect, in advance of stimulation, and in response to stimulation. Significant coordination of BOLD signals was also detected across specific brainstem and spinal cord regions, with connectivity strengths that varied significantly with the study condition, and with individual pain ratings. The results identify regions that are known to be involved with arousal and autonomic regulation. CONCLUSIONS: Expectation-based analgesia is mediated by descending regulation of spinal cord nociceptive responses. This regulation appears to be related to arousal and autonomic regulation, consistent with the cognitive/affective dimension of pain.

Anomalous collapses of Nares Strait ice arches leads to enhanced export of Arctic sea ice.

The ice arches that usually develop at the northern and southern ends of Nares Strait play an important role in modulating the export of Arctic Ocean multi-year sea ice. The Arctic Ocean is evolving towards an ice pack that is younger, thinner, and more mobile and the fate of its multi-year ice is becoming of increasing interest. Here, we use sea ice motion retrievals from Sentinel-1 imagery to report on the recent behavior of these ice arches and the associated ice fluxes. We show that the duration of arch formation has decreased over the past 20 years, while the ice area and volume fluxes along Nares Strait have both increased. These results suggest that a transition is underway towards a state where the formation of these arches will become atypical with a concomitant increase in the export of multi-year ice accelerating the transition towards a younger and thinner Arctic ice pack.

Human symptom responses to bioeffluents, short-chain carbonyls/acids, and long-chain carbonyls in a simulated aircraft cabin environment.

Occupants of aircraft have reported an array of symptoms related to general discomfort and irritation. Volatile organic compounds (VOCs) have been suggested to contribute to the reported symptoms. VOCs are from products used, bioeffluents from people and oxidation reaction products. Thirty-six healthy, young female subjects rated symptoms and environmental quality during an eight-hour exposure to groups of compounds often present in aircraft: (i) long-chain carbonyls, (ii) simulated bioeffluents, and (iii) short-chain carbonyls/organic acids. Statistically more symptoms were identified for the simulated bioeffluents and, to a lesser extent, short-chain carbonyls/organic acids compared to a control condition, although they remained in the acceptable range. There were three temporal patterns in the environmental quality and symptom reports: (i) an adaptive response (immediate increases followed by a decline); (ii) an apparent physiological effect (increases one to three hours into the exposure that remained elevated); and (iii) no statistical differences in reported environmental quality or symptom severity compared to the control air conditions. Typical concentrations found in aircraft can cause transitory symptoms in healthy individuals questioning the adequacy of current standards. Understanding the effects on individuals sensitive to air pollutants and methods to remove the compounds causing the greatest symptom responses are needed.

Factors Influencing Adoption of New Technologies into Dental Practice: A Qualitative Study.

The objective of this study was to explore factors affecting decisions to adopt new technologies into dental practice using a colorimetric rinse test for detection of periodontal disease as a model. Focus groups with key informants in Canadian dentistry and dental hygiene were conducted. A deductive approach used Rogers's diffusion of innovation theory as a framework for organizing codes and subcodes. Two members of the research team independently reviewed and analyzed the data using NVivo 10. The attributes of the technology itself emerged as primary influencers. Perceived relative advantages of the diagnostic mouth rinse over existing methods were potential time efficiency, low implementation cost, and utility of the tool. Low complexity, compatibility with existing routines/beliefs, and the potential for reinvention-the use of a technology for other than its intended purpose (i.e., patient education, monitoring of disease, screening tool in nondental settings)-were other important features enhancing adoption. An overarching concern was that any new technology benefit the patient. Contextual factors also play a role. Numerous communication channels, including opinion leaders, patients, marketing, continuing education courses, and strength of evidence, influenced clinicians, with peer interaction being a stronger influence than marketing. Similar themes arose from specialist, general dentist, and dental hygienist focus groups. Adopter characteristics also came into play: participants ranged in their self-reported innovativeness with many considering themselves "early adopters" of new technology. Findings of this study suggest that the innovation adoption process is not straightforward, but attributes of the innovation, contextual factors, and adopter characteristics play important roles in the process. Knowledge Transfer Statement: Various factors affect the adoption of new tools into clinical dental practice. These include attributes of the test or tool itself, the context of the settings in which the tool is introduced to practitioners, and the characteristics of the clinicians themselves. A qualitative study of dentists and dental hygienists investigated these factors. Situations in which dentists and hygienists interact with their peers and colleagues-through social networks, continuing education courses, conventions, or personal contact-were a major driver in the decision to adopt new technologies. However, even among "early adopters," most were reluctant to use new tests or tools unless they perceived a benefit to their patients or practice.

Exogenous administration of protease-resistant, non-matrix-binding IGFBP-2 inhibits tumour growth in a murine model of breast cancer.

BACKGROUND: Insulin-like growth factors (IGF-I and IGF-II) signal via the type 1 IGF receptor (IGF-1R) and IGF-II also activates the insulin receptor isoform A (IR-A). Signalling via both receptors promotes tumour growth, survival and metastasis. In some instances IGF-II action via the IR-A also promotes resistance to anti-IGF-1R inhibitors. This study assessed the efficacy of two novel modified IGF-binding protein-2 (IGFBP-2) proteins that were designed to sequester both IGFs. The two modified IGFBP-2 proteins were either protease resistant alone or also lacked the ability to bind extracellular matrix (ECM). METHODS: The modified IGFBP-2 proteins were tested in vitro for their abilities to inhibit cancer cell proliferation and in vivo to inhibit MCF-7 breast tumour xenograft growth. RESULTS: Both mutants retained low nanomolar affinity for IGF-I and IGF-II (0.8-2.1-fold lower than IGFBP-2) and inhibited cancer cell proliferation in vitro. However, the combined protease resistant, non-matrix-binding mutant was more effective in inhibiting MCF-7 tumour xenograft growth and led to inhibition of angiogenesis. CONCLUSIONS: By removing protease cleavage and matrix-binding sites, modified IGFBP-2 was effective in inhibiting tumour growth and reducing tumour angiogenesis.

Design and delivery of an e-learning curriculum for physicians involved in the management of pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH) is a condition that affects more than 25 million individuals worldwide and causes premature disability and death. Despite advances in our understanding of this condition, education and training of health professionals has not kept pace with the rapid changes in diagnosis and treatment. The net effects of this gap between advancing knowledge and limited educational opportunity likely include clinically significant delays in both the diagnosis and commencement of effective evidence-based treatment - an unacceptable outcome for patients with a lethal condition. AIM: The Actelion Clinical Excellence Programme (ACEP) is an e-learning postgraduate curriculum, the purpose of which is to educate and mentor healthcare professionals, both theoretically and practically, in the diagnosis and treatment of patients with all forms of PH. This article reports on the development and delivery of the programme and outcomes from its first year of operation. RESULTS: Forty-three healthcare professionals from 22 institutions were enroled in the first iteration of the programme. In the 6 months from May to October 2011, participants successfully completed 285 lectures and/or activities. Overall, the programme was considered easily accessible, comprehensive in terms of both quality and quantity, provided an efficient means of self-paced learning, and was a highly regarded as reference source. Ninety-five per cent of participants said that they intended to change their clinical practice as a result of the information presented in the programme. CONCLUSION: ACEP represents a successful physician-industry partnership, which has resulted in a significant impact on clinical teaching and awareness of PH.

Epilepsy in the Twitter era: a need to re-tweet the way we think about seizures.

Seizures have long been associated with misconceptions and stigma. Exponential growth in Internet use has seen the rapid expansion of social media, such as Twitter, for health promotion. In view of the popularity of Twitter, we sought to explore how seizures are being portrayed on this social networking website and to consider its potential for information dissemination. A 48-hour Twitter search was used as a preliminary data set to determine an appropriate classification scheme of "seizure"-related posts ("tweets"). Analysis was then conducted using "seizure" tweets from a 7-consecutive day sample period. Tweets were analyzed and coded by two independent reviewers. Predominant categories were Metaphorical (32%), Personal Accounts (31%), Informative (12%), and Ridicule/Joke (9%). This study supports the notion that stigmatization associated with seizures continues to flourish, as 41% of "seizure" tweets were derogatory in nature. Although Twitter could be used to disseminate accurate information on seizures and epilepsy, this study suggests that it is currently propagating negative attitudes toward seizures with potential for fueling stigma. In recent years there have been significant advancements in technology offering many new methods of sharing information. Social networking sites allow real-time communication while providing the opportunity for exchange of information and opinions. Twitter, a website launched in 2006, allows users to communicate through "tweets" limited to 140 characters. Twitter's popularity has drastically increased since its inception, with approximately 110 million tweets per day from 200 million users worldwide, as of January 2011 (http://blogs.forbes.com/oliverchiang/2011/01/19/twitter-hits-nearly-200m-users-110m-tweets-per-day-focuses-on-global-expansion/). Such social media facilitate communication about an array of health-related topics including seizures and epilepsy.

The Bosentan Patient Registry: long-term survival in pulmonary arterial hypertension.

BACKGROUND/AIMS: The Bosentan Patient Registry (BPR) was a prospective, multicentre, Australian registry funded by Actelion Pharmaceuticals. The primary aim of the registry was to collect survival data in patients with pulmonary arterial hypertension (PAH) treated with bosentan. METHODS: The BPR was initiated in 15 specialized PAH centres. All patients on or starting bosentan were invited to enrol. Treating physicians notified the registry if patients discontinued bosentan, because of either a change in therapy, transplantation, intervention or death. Survival data were validated against the Australian Institute of Health and Welfare National Death Index. RESULTS: Between 2004 and 2007, a total of 528 patients (mean age 59 ± 17 years) were enrolled representing 69% of patients either previously taking or initiated on bosentan during that time. The BPR population was generally older with more advanced functional deficit than patients enrolled in randomized, placebo-controlled trials. Aetiology was idiopathic (iPAH) in 58% and connective tissue disease related (scleroderma (SSc)-PAH) in 42%. For iPAH patients, World Health Organisation functional classes II, III and IV at enrolment was 8.2%, 66.4% and 20.5%, and for the SSc-PAH cohort, 3.2%, 75.8% and 17.9% respectively. The observed annual mortality was 11.8% in patients with iPAH and 16.6% in patients SSc-PAH. CONCLUSION: This large Australian registry provides 'real life' information on the characteristics and management of PAH in clinical practice. Treatment with bosentan improved survival outcomes in both iPAH and SSc-PAH compared with historical controls. Age, disease severity and aetiology were critical factors in determining clinical outcomes.

Endothelin receptor antagonists are an effective long term treatment option in pulmonary arterial hypertension associated with congenital heart disease with or without trisomy 21.

INTRODUCTION: Traditionally, treatment options for patients with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) are limited. Bosentan has been shown to improve pulmonary haemodynamics and exercise tolerance short term but long term clinical studies are lacking. AIM: To report long term efficacy and safety data with endothelin receptor antagonists (ERA) in patients with PAH associated CHD. METHODS: Prospective, open label, uncontrolled, single centre study of 53 patients (33 females, 17 Trisomy 21, mean age 34 ± 12 years) prescribed ERA (48 bosentan, 5 sitaxentan) from 2003 to August 2009. Outcome measurements of oxygen saturation (SaO2), WHO functional class, 6-minute walk test distance (6MWD) and adverse events were analysed. RESULTS: Mean duration of therapy was 15 ± 13 months in 53 patients with CHD. Four patients failed ERA, seven died (five progressive RHF) and one delisted from transplantation. No abnormal liver transaminases occurred on bosentan, with one case on sitaxentan. After 3, 6, 12, 18 and 24 months of treatment a significant improvement was seen in WHO functional class (mean 3.15 vs 2.8 vs 2.5 vs 2.5 vs 2.4 vs 2.4; p<0.01) and 6MWD (344 ± 18 vs 392 ± 17 vs 411 ± 17 vs 420 ± 17 vs 442 ± 18 vs 417 ± 23: p<0.0005, p<0.01) compared with baseline. The Trisomy 21 and PAH-CHD showed a significant improvement in 6MWD at 6 and 12 months (263 ± 24 vs 348 ± 29 vs 360 ± 32, p<0.01, p<0.05) respectively. No changes in SaO2, BNP, RV or LV function were demonstrated during follow-up. CONCLUSION: This large single centre study demonstrates that endothelin receptor antagonism is an effective and safe treatment in PAH associated CHD with or without Trisomy 21. The improvements in exercise tolerance are similar to reported benefits in other forms of PAH.

Improvement after angioplasty and stenting of pulmonary arteries due to sarcoid mediastinal fibrosis.

We describe a series of cases referred to our institution with working diagnoses of chronic thrombo-embolic pulmonary hypertension (CTEPH) for consideration of surgical pulmonary thrombo-endarterectomy (PTE). Investigations in two cases revealed extrinsic compression of the pulmonary arteries from massive mediastinal lymphadenopathy (mediastinal fibrosis) due to underlying sarcoidosis. Angioplasty and stenting of the pulmonary arteries were performed in all cases with sustained haemodynamic and functional improvement. This highlights the value of new imaging modalities in delineating causes of pulmonary hypertension, and demonstrates an interventional approach for selected cases.

Treatment options and strategies for acute severe pulmonary embolism.

Pulmonary thromboembolism (PE) is the third most frequent cause of cardiovascular death after ischaemic heart disease and stroke. In fatal PE, 2/3 of patients die within first hour of presentation. There is a clinical impetus to rapidly recognize, risk-stratify and appropriately treat patients with acute severe PE. Current recommendations present conflicting classification systems, and there is often some confusion in the clinical evaluation and management of patients with acute severe PE. This review presents a series of real clinical cases, which illustrate the available treatment options, ranging from conservative therapy to thrombolysis through to percutaneous catheter fragmentation and open surgical embolectomy. We evaluate the evidence for the various strategies and propose an algorithm for clinicians with a focus on early risk stratification and timely referral. This is particularly relevant to regional and remote centres, as well as secondary and tertiary institutions.

Pulmonary hypertension and left heart disease: emerging concepts and treatment strategies.

At least two thirds of patients with chronic severe left heart disease have associated pulmonary hypertension, and mortality associated with biventricular failure is >two-fold higher compared with isolated left ventricular failure. This review considers and discusses emerging concepts and strategies from recent studies of specific treatments in populations with pulmonary hypertension complicating overt left ventricular dysfunction. While the results reported in the studies considered are encouraging, to date there are no large randomised studies of specific treatments in populations with pulmonary hypertension complicating overt left ventricular dysfunction.

Resolution of severe ischemia-reperfusion injury post-lung transplantation after administration of endobronchial surfactant.

BACKGROUND: Ischemia-reperfusion injury (IRI) is a prominent cause of primary graft failure after lung transplantation and is associated with an altered surfactant profile. Experimental animal studies have found that replacement with exogenous surfactant administered via fiber-optic bronchoscopy (FOB) enhanced recovery from IRI with improved pulmonary compliance and gas exchange after lung transplantation. We report our clinical experience with FOB instillation of surfactant in severe IRI after human lung transplantation. METHODS: This study is a retrospective review of 106 consecutive lung or heart-lung transplants performed at a single institution. Severe IRI was defined as diffuse roentgenographic alveolar infiltrates, worsening hypoxemia and decreased lung compliance within 72 hours of lung transplantation. One vial of surfactant (20 mg/ml phospholipid) was instilled into each segmental bronchus upon diagnosis of IRI. RESULTS: Six patients (5 bilateral sequential and 1 re-do heart-lung transplant), mean age 46 years, were diagnosed with IRI and surfactant was administered at a mean of 37 hours (range 2.3 to 98) post-transplant. Mean graft ischemia time was 376 minutes (range 187 to 625) and cardiopulmonary bypass time 174 minutes (range 0 to 210). Mean Pao(2) [mm Hg]/Fio(2) ratio before and 48 hours after surfactant instillation was 70 and 223, respectively. Significant resolution of radiologic infiltrates was evident in all cases within 24 hours. Successful extubation occurred at a mean of 13.5 days and survival is presently 100% at 19 months (range 3 to 54). CONCLUSIONS: Bronchoscopic instillation of surfactant improves oxygenation and prognosis after severe IRI in lung transplant recipients. It represents a cost-effective, relatively non-invasive therapeutic alternative to extracorporeal membrane oxygenation.

Ex vivo monitoring of human cytomegalovirus-specific CD8+ T-cell responses using QuantiFERON-CMV.

We have developed a novel diagnostic technology to monitor the human cytomegalovirus (HCMV)-specific CD8+ T-cell responses that is based on the detection of secreted interferon-gamma (IFN-gamma) in the whole blood (referred to as QuantiFERON -CMV). Evaluation of QuantiFERON -CMV in healthy individuals revealed that this technology was at least as sensitive and with some HCMV epitopes more sensitive than the ELISPOT for detecting ex vivo IFN-gamma. Results from QuantiFERON -CMV assays showed 97% (36/37 individuals) agreement with the anti-HCMV serology test in healthy individuals. Furthermore, we also show that this technology can be used to assess HCMV-specific T-cell responses in transplant patients. This study shows that QuantiFERON -CMV is a simple, reproducible, and reliable test for the detection of IFN-gamma in response to HCMV CD8+ T-cell epitopes, and may be a valuable diagnostic test for the detection of HCMV infection and a useful clinical tool for monitoring the immune response in immunosuppressed patients during therapy.

Interaction of insulin-like growth factor (IGF)-I and -II with IGF binding protein-2: mapping the binding surfaces by nuclear magnetic resonance.

The interaction of IGF binding protein-2 (IGFBP-2) with IGF-I and -II has been investigated in solution using nuclear magnetic resonance (NMR) spectroscopy. Chemical shift perturbations in 15N- and 2H/15N-labelled IGF-I or -II upon binding to unlabelled thioredoxin-tagged bovine IGFBP-2 (Trx(1-279)IGFBP-2) have been monitored to identify residues involved directly in the binding interaction as well as any affected by conformational changes associated with the interaction. A key step in obtaining high-quality spectra of the complexes was the use of transverse relaxation optimised spectroscopy (TROSY) methods with partially deuterated ligands. Indeed, because the effects of conformational averaging and aggregation are eliminated in IGF-I and -II bound to IGFBP-2, the spectra of the complexes are actually superior to those of the free ligands. Comparison of our results with the crystal structure of the complex between IGF-I and an N-terminal fragment of IGFBP-5 allowed identification of those residues perturbed by the C-domain of IGFBP-2. Other perturbations, such as those of Gly 19 and Asp 20 of IGF-I (and the corresponding residues in IGF-II) - which are located in a reverse turn linking N-domain and C-domain interactive surfaces - are due to local conformational changes in the IGF-I and -II. Our results confirm that the C-domain of IGFBP-2 plays a key role in binding regions of IGF-I and -II that are also involved in binding to the type-1 IGF receptor and thereby blocking ligand binding to this receptor.

Extended ganciclovir prophylaxis in lung transplantation.

BACKGROUND: Positive cytomegaloviral status of the donor or of the recipient adversely affects survival and enhances the development of bronchiolitis obliterans syndrome (BOS) in lung transplant recipients. The role of ganciclovir prophylaxis in cytomegalovirus infection in respect to obliterative bronchiolitis or to BOS development is not known. METHODS: From the Papworth transplant database, we identified 146 patients who received organs from cytomegalovirus-positive donors. We classified patients into 3 groups as follows: Group 1 consisted of 42 patients who underwent transplantation between 1990 and 1992 when no prophylaxis was given; Group 2 consisted of 49 patients who underwent transplantation between 1992 and 1995 when 4 weeks of IV ganciclovir was given as prophylaxis; and Group 3 consisted of 55 patients who underwent transplantation between 1995 and 1998 when cytomegalovirus prophylaxis consisted of IV (1 week) followed by oral ganciclovir for a total of 3 months. Donor management, recipient management during and after surgery, and pharmacotherapy were uniform during the study period. We used survival and regression methods to compare these groups, adjusting for the transplantation type (single lung, double lung, or heart-lung) and for HLA typing. RESULTS: We found a significant difference among all 3 groups in numbers of cytomegaloviral disease episodes in the 1st year after transplantation. The number of rejection episodes in the 3 groups during the 1st post-transplant year gradually decreased from Group 1 to Group 3. We identified no statistically significant benefit in the time to BOS occurrence or in actuarial survival. CONCLUSION: Extended prophylaxis with IV and oral ganciclovir practically abolishes cytomegaloviral disease and is related to a decreased incidence of rejection episodes. However, ganciclovir prophylaxis is not related to a decreased incidence or progression of BOS or survival.

Lung transplant outcomes: a review of survival, graft function, physiology, health-related quality of life and cost-effectiveness.

The success of lung transplantation has improved over time as evidenced by better long-term survival and functional outcomes. Despite the success of this procedure, there are numerous problems and complications that may develop over the life of a lung transplant recipient. With proper monitoring and treatment, the frequency and severity of these problems can be decreased. However, significant improvement for the overall outcomes of lung transplantation will only occur when better methods exist to prevent or effectively treat chronic rejection.

Atrial septostomy in the treatment of severe pulmonary arterial hypertension.

BACKGROUND: Atrial septostomy (AS) may improve symptoms and haemodynamics in patients with severe pulmonary arterial hypertension (PAH). METHODS: Twenty AS performed in 17 patients with severe progressive PAH (13 primary pulmonary hypertension, two collagen vascular disease, one thromboembolic disease, one vaso-occlusive disease) were analysed. Seven patients were in NYHA class III and 10 in NYHA IV. Fifteen patients were on long term prostanoid treatment. AS was performed under fluoroscopy using graded balloon technique. RESULTS: AS improved clinical symptoms and increased the cardiac index from 1.8 to 2.2 l/min/m(2) and systemic oxygen transport from 263.2 to 329.6 ml/min/m(2) (p<0.001). Procedure related complications included one non-fatal atrial puncture and one unsuccessful septal puncture. Four patients died within 1 week of surgery from uncontrolled tachyarrhythmia (n=1), severe hypoxaemia (n=1), and multiorgan failure (n=2). One further patient died after voluntarily discontinuing renal dialysis. Twelve patients are alive 5-17 months after the operation with five patients undergoing heart-lung transplantation. There were no differences in haemodynamic and functional parameters between the non-survivors and the mid term survivors. However, the non-survivors were significantly older (52 v 36 years, p<0.01) and had a significantly lower creatinine clearance rate (70 ml/min v 48 ml/min, p<0.05). CONCLUSION: Atrial septostomy improves clinical symptoms, cardiac index, and systemic oxygen transport and has the potential to influence the prognosis in selected cases of severe PAH.