Pulmonary hypertension associated with COPD

Pulmonary hypertension is a common complication of chronic obstructive pulmonary disease (COPD). The increase in pulmonary artery pressures is often mild to moderate, but some patients may suffer from severe pulmonary hypertension, and present with a progressively downhill clinical course because of right-sided heart failure added to ventilatory handicap. The cause of pulmonary hypertension in COPD is generally assumed to be hypoxic pulmonary vasoconstriction leading to permanent medial hypertrophy. However, recent pathological studies point, rather, to extensive remodeling of the pulmonary arterial walls, with prominent intimal changes. These aspects account for minimal reversibility with supplemental oxygen. There may be a case for pharmacological treatment of pulmonary hypertension in selected patients with advanced COPD and right-sided heart failure. Candidate drugs include prostacyclin derivatives, endothelin antagonists and inhaled nitric oxide, all of which have been reported of clinical benefit in primary pulmonary hypertension. However, it will be a challenge for randomized controlled trials to overcome the difficulties of the diagnosis of right ventricular failure and the definition of a relevant primary endpoint in pulmonary hypertensive COPD patients

Treprostinil for pulmonary hypertension

Treprostinil is a stable, long-acting prostacyclin analogue which can be administered as a continuous subcutaneous infusion using a portable miniature delivery system. Subcutaneous treprostinil has been shown in a large multicenter randomized controlled trial to improve exercise capacity, clinical state, functional class, pulmonary hemodynamics, and quality of life in patients with pulmonary arterial hypertension, an uncommon disease of poor prognosis. Side effects include facial flush, headache, jaw pain, abdominal cramping, and diarrhea, all typical of prostacyclin, and manageable by symptom-directed dose adjustments, and infusion site pain which may make further treatment impossible in 7%–10% of the patients. Long-term survival in pulmonary arterial hypertension patients treated with subcutaneous treprostinil is similar to that reported with intravenous epoprostenol. There are uncontrolled data suggesting efficacy of subcutaneous treprostinil in chronic thromboembolic pulmonary hypertension. Treprostinil can also be administered intravenously, although increased doses, up to 2–3 times those given subcutaneously, appear to be needed to obtain the same efficacy. Preliminary results of a randomized controlled trial of inhaled treprostinil on top of bosentan and sildenafil therapies have shown significance on the primary endpoint, which was exercise capacity as assessed by the distance walked in 6 minutes. Trials of oral formulations of treprostinil have been initiated

"She said..." "He said...": Cross applications in NSW apprehended domestic violence order proceedings

This thesis examines the use of cross applications in civil protection order proceedings in New South Wales (NSW) (known as Apprehended Domestic Violence Orders, ADVOs). A cross application takes place when one person in an existing or former intimate relationship, usually the woman, applies for an ADVO and sometime afterwards the defendant in that originating application, usually the man, seeks an ADVO against the first person. The focus on cross applications provides a means to investigate the nature of men’s and women’s competing allegations about domestic violence, and to explore the way in which professionals working within the ADVO system approach, and seek to unravel, these competing claims. This thesis draws on the extensive debate within the sociological literature about ‘what is domestic violence’ and whether domestic violence is gendered in its perpetration. This debate has been paid scant attention in the legal literature. This thesis examines the assumptions underpinning the legal definitions and understandings of domestic violence in the civil protection order system, with reference to these theoretical debates about ‘what is domestic violence’ and ‘what counts as domestic violence’. To do so it draws on empirical work: semi-structured in-depth interviews with women involved in cross applications and key professionals working in the field, documentary analysis of court files, and observations of court proceedings. The key contribution of this thesis to this literature is threefold: (1) it explores the question of gender perpetration through the investigation of official data (a data source little explored in debates about gender and domestic violence), (2) it combines qualitative and quantitative methods in a single study, and (3) it extends questions about the gendered perpetration of domestic violence to the legal arena (in particular the prime legal arena that responds to domestic violence in NSW, the ADVO system, a system ostensibly designed to better respond to domestic violence). This thesis found that, like other studies in this field, the analysis of quantitative data alone reveals few differences between the types of violence men and women are alleged to use against their intimate partners. However when supplemented by qualitative data differences started to emerge particularly for men who lodged their application second in time. This qualitative analysis reveals not only that male second applicants appeared to make claims of a different nature, but that some men appeared to use the ADVO process to undermine women’s claims for legal protection. The differences that emerged between men and women’s alleged experiences of domestic violence resonated with feminist understandings of domestic violence that highlight its function of control and the repetitive, cumulative environment in which violence is perpetrated by men against women. While the study focussed on cross applications, its findings reveal a number of issues of concern for the ADVO system more broadly: its focus on incidents, the poor quality of complaint narratives, the brevity of court proceedings and the emphasis on settlement. These features undermine the progressive potential of the ADVO legislation to capture more than single incidents of largely physical violence. This was further compounded by the fact that while the professionals interviewed articulated broad definitions of domestic violence, this tended to be lost when responding to practice-orientated questions (here professionals returned to incident-based definitions). Perhaps more significantly the defining feature of domestic violence as a mechanism of control is not articulated in the NSW legislation, and hence (not unsurprisingly) was generally not articulated in the complaint narratives examined in this thesis. Yet control was the dominant way in which the women interviewed described their relationship with their former partner. The failure of complaint narratives to reflect the dimension of control, combined with the failure of key professionals to give sufficient emphasis to control in their practice under the ADVO legislation, an absence highlighted through the focus on cross applications, is an issue of concern for the ADVO system generally. This is important given the growing recognition in the research literature of the fundamental nature of control to the experience of domestic violence, particularly women’s experiences of domestic violence

Cognitive impairment in essential tremor assessed by the cerebellar cognitive affective syndrome scale

BackgroundEssential tremor (ET) is a movement disorder characterized by cerebellar neurodegenerative changes. ET is also associated with non-motor symptoms including cognitive impairment. The neuropsychologic profile of a patient with ET could relate to cerebellar cognitive affective syndrome (CCAS).ObjectiveThis study aimed to assess the prevalence of cognitive impairment in patients with ET and identify whether the cognitive impairment in ET corresponds to a CCAS.MethodsCognitive functions were evaluated with the CCAS-Scale (CCAS-S) in 20 patients with ET and 20 controls matched for age, sex, and level of education. The results of the CCAS-S were compared between patients and controls. The underlying determinant of CCAS inpatients with ET was identified through the correlation between the results of the CCAS-S and age at onset of symptoms, disease duration, and the Essential Tremor Rating Assessment Scale (TETRAS).ResultsOn a group level, ET patients performed significantly worse than matched controls. In total, 13 individuals with ET had a definite CCAS (CCAS-S failed items ≥ 3). ASO and TETRAS scores significantly correlated with CCAS-S performances in ET patients.ConclusionCCAS is highly prevalent in patients with ET which supports the cerebellar pathophysiology of associated cognitive impairment and supports a more systematic use of the CCAS-S to cognitively assessed patients with ET

Echocardiography combined with cardiopulmonary exercise testing for the prediction of outcome in idiopathic pulmonary arterial hypertension

BACKGROUND: Right ventricular (RV) function is a major determinant of exercise intolerance and outcome in idiopathic pulmonary arterial hypertension (IPAH). The aim of the study was to evaluate the incremental prognostic value of echocardiography of the RV and cardiopulmonary exercise testing (CPET) on long-term prognosis in these patients. METHODS: One hundred-thirty treatment-naïve IPAH patients were enrolled and prospectively followed. Clinical worsening (CW) was defined by a reduction in 6-minute walk distance plus an increase in functional class, or non elective hospitalization for PAH, or death. Baseline evaluation included clinical, hemodynamic, echocardiographic and CPET variables. Cox regression modeling with c-statistic and bootstrapping validation methods were done. RESULTS: During a mean period of 528 ± 304 days, 54 patients experienced CW (53%). Among demographic, clinical and hemodynamic variables at catheterization, functional class and cardiac index were independent predictors of CW (Model-1). With addition of echocardiographic and CPET variables (Model-2), peak O2 pulse (peak VO2/heart rate) and RV fractional area change (RVFAC) independently improved the power of the prognostic model (AUC: 0.81 vs 0.66, respectively; p=0.005). Patients with low RVFAC and low O2 pulse (low RVFAC + low O2 pulse) and high RVFAC+low O2 pulse showed 99.8 and 29.4 increase in the hazard ratio, respectively (relative risk -RR- of 41.1 and 25.3, respectively), compared with high RVFAC+high O2 pulse (p=0.0001). CONCLUSIONS: Echocardiography combined with CPET provides relevant clinical and prognostic information. A combination of low RVFAC and low O2 pulse identifies patients at a particularly high risk of clinical deterioration

Alignment effects in beer mugs: Automatic action activation or response competition?

Responses to objects with a graspable handle are faster when the response hand and handle orientation are aligned (e.g., a key press with the right hand is required and the object handle is oriented to the right) than when they are not aligned. This effect could be explained by automatic activation of specific motor programs when an object is viewed. Alternatively, the effect could be explained by competition at the response level. Participants performed a reach-and-grasp or reach-and-button-press action with their left or right hand in response to the color of a beer mug. The alignment effect did not vary as a function of the type of action. In addition, the alignment effect disappeared in a go/no-go version of the task. The same results were obtained when participants made upright/inverted decisions, so that object shape was task-relevant. Our results indicate that alignment effects are not due to automatic motor activation of the left or right limb

Altered neocortical tactile but preserved auditory early change detection responses in Friedreich ataxia

Available online 11 May 2019Objective: To study using magnetoencephalography (MEG) the spatio-temporal dynamics of neocortical responses involved in sensory processing and early change detection in Friedreich ataxia (FRDA). Methods: Tactile (TERs) and auditory (AERs) evoked responses, and early neocortical change detection responses indexed by the mismatch negativity (MMN) were recorded using tactile and auditory oddballs in sixteen FRDA patients and matched healthy subjects. Correlations between the maximal amplitude of each response, genotype and clinical parameters were investigated. Results: Evoked responses were detectable in all FRDA patients but one. In patients, TERs were delayed and reduced in amplitude, while AERs were only delayed. Only tactile MMN responses at the contralateral secondary somatosensory cortex were altered in FRDA patients. Maximal amplitudes of TERs, AERs and tactile MMN correlated with genotype, but did not correlate with clinical parameters. Conclusions: In FRDA, the amplitude of tactile MMN responses at SII cortex are reduced and correlate with the genotype, while auditory MMN responses are not altered. Significance: Somatosensory pathways and tactile early change detection are selectively impaired in FRDAThis study was financially supported by (i) the research grant ‘‘Les Voies du Savoir” from the Fonds Erasme (Brussels, Belgium) and (ii) the Fonds de la Recherche Scientifique (FRS-FNRS, Brussels, Belgium; research credit: J.0095.16.F). Gilles Naeije was supported by a research grant from the Fonds Erasme (Brussels, Belgium). Mathieu Bourguignon was supported by the program Attract of Innoviris (grant 2015-BB2B-10), by the Spanish Ministry of Economy and Competitiveness (grant PSI2016-77175-P), and by the Marie Skłodowska-Curie Action of the European Commission (grant 743562). Xavier De Tiège is Postdoctorate Clinical Master Specialist at the Fonds de la Recherche Scientifique (FRS-FNRS, Brussels, Belgium). The MEG project at the CUB Hôpital Erasme is financially supported by the Fonds Erasme (Research grant ‘‘Les Voies du Savoir”, Brussels, Belgium). The authors would like to thank Brice Marty for his help in MEG data acquisition

Proprioceptive and tactile processing in individuals with Friedreich ataxia: an fMRI study

ObjectiveFriedreich ataxia (FA) neuropathology affects dorsal root ganglia, posterior columns in the spinal cord, the spinocerebellar tracts, and cerebellar dentate nuclei. The impact of the somatosensory system on ataxic symptoms remains debated. This study aims to better evaluate the contribution of somatosensory processing to ataxia clinical severity by simultaneously investigating passive movement and tactile pneumatic stimulation in individuals with FA.MethodsTwenty patients with FA and 20 healthy participants were included. All subjects underwent two 6 min block-design functional magnetic resonance imaging (fMRI) paradigms consisting of twelve 30 s alternating blocks (10 brain volumes per block, 120 brain volumes per paradigm) of a tactile oddball paradigm and a passive movement paradigm. Spearman rank correlation tests were used for correlations between BOLD levels and ataxia severity.ResultsThe passive movement paradigm led to the lower activation of primary (cSI) and secondary somatosensory cortices (cSII) in FA compared with healthy subjects (respectively 1.1 ± 0.78 vs. 0.61 ± 1.02, p = 0.04, and 0.69 ± 0.5 vs. 0.3 ± 0.41, p = 0.005). In the tactile paradigm, there was no significant difference between cSI and cSII activation levels in healthy controls and FA (respectively 0.88 ± 0.73 vs. 1.14 ± 0.99, p = 0.33, and 0.54 ± 0.37 vs. 0.55 ± 0.54, p = 0.93). Correlation analysis showed a significant correlation between cSI activation levels in the tactile paradigm and the clinical severity (R = 0.481, p = 0.032).InterpretationOur study captured the difference between tactile and proprioceptive impairments in FA using somatosensory fMRI paradigms. The lack of correlation between the proprioceptive paradigm and ataxia clinical parameters supports a low contribution of afferent ataxia to FA clinical severity

Activation of apoptotic pathways in experimental acute afterload-induced right ventricular failure

Objective: The pathobiology of persistent right ventricular failure observed after an acute increase in right ventricular afterload remains incompletely understood. We hypothesized that persistent right ventricular dysfunction might be related to activation of apoptotic pathways. Design: Prospective, randomized, controlled animal study. Setting: University research laboratory. Subjects: Mongrel dogs. Interventions: Fourteen anesthetized dogs were randomized to a transient 90-min pulmonary artery constriction operation to induce persistent right ventricular failure or to a sham operation followed 30 mins later by hemodynamic measurements and sampling of cardiac tissue. Measurements and main results: We evaluated effective arterial elastance to estimate right ventricular afterload and end-systolic elastance to estimate right ventricular contractility. Transient increase in pulmonary artery pressure persistently increased effective arterial elastance from 0.75 ± 0.08 to 1.37 ± 0.18 mm Hg/mL and decreased end-systolic elastance from 1.06 ± 0.09 to 0.49 ± 0.09 mm Hg/mL, end-systolic elastance/effective arterial elastance from 1.44 ± 0.06 to 0.34 ± 0.03, and cardiac output from 3.78 ± 0.16 to 1.46 ± 0.10 L/min, indicating right ventricular failure. At the pathobiologic level, we assessed apoptosis by real-time quantitative polymerase chain reaction, Western blotting, enzyme-linked immunosorbent assay, and immunohistochemistry. As compared with the sham-operated group, and with the left ventricle in animals with persistent right ventricular failure, there were decreased right ventricular and septal expressions of Bcl-2 with no changes in expressions of Bax, resulting in an increased Bax/Bcl-2 ratio. Right ventricular and septal Bcl-XL, and right ventricular Bcl-w gene expressions were decreased as compared with the sham-operated group, whereas Bak gene expression did not change. There were activations of right ventricular caspases-8 and-9 and of right ventricular and septal caspase-3. Diffuse right ventricular and septal apoptosis was confirmed by terminal deoxynucleotidyl transferase dUTP nick-end labeling staining. There were also increased right ventricular and septal protein expressions of tumor necrosis factor-alpha. Conclusions: Acute afterload-induced persistent right ventricular failure appears to be related to an early activation of apoptotic pathways and to a local overexpression of tumor necrosis factor-alpha, a proinflammatory cytokine. Copyright © 2010 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.SCOPUS: ar.jinfo:eu-repo/semantics/publishe