Rationale: The impact of modern treatments of pulmonary arterial hypertension (PAH) on pulmonary vascular pathology remains unknown. Objectives: To assess the spectrum of pulmonary vascular remodeling in the modern era of PAH medication. Methods: Assessment of pulmonary vascular remodeling and inflammation in 62 PAH and 28 control explanted lungs systematically sampled. Measurements and Main Results: Intima and intima plus media fractional thicknesses of pulmonary arteries were increased in the PAH group versus the control lungs and correlated with pulmonary hemodynamic measurements. Despite a high variability of morphological measurements within a given PAH lung and among all PAH lungs, distinct pathological subphenotypes were detected in cohorts of PAH lungs. These included a subset of lungs lacking intima or, most prominently, media remodeling, which had similar numbers of profiles of plexiform lesions as those in lungs with more pronounced remodeling. Marked perivascular inflammation was present in a high number of PAH lungs and correlated with intima plus media remodeling. The number of profiles of plexiform lesions was significantly lower in lungs of male patients and those never treated with prostacyclin or its analogs. Conclusions: Our results indicate that multiple features of pulmonary vascular remodeling are present in patients treated with modern PAH therapies. Perivascular inflammation may have an important role in the processes of vascular remodeling, all of which may ultimately lead to increased pulmonary artery pressure. Moreover, our study provides a framework to interpret and design translational studies in PAH. Keywords: pulmonary circulation; vessel remodeling; angiogenesis; inflammationThe modern treatment of pulmonary arterial hypertension (PAH) has led to substantive advancements in patients' quality of life and survival, significantly improving on the grave prognosis historically associated with the disease (1, 2). With the restrictions regarding obtaining lung tissue for diagnosis, the endpoints for effectiveness of the current therapies are largely based on assessments of exercise performance and reported quality of life, time to clinical deterioration, and/or measured physiological performance (e.g., 6-min walk test). Whether prostacyclin and its analogs, endothelin receptor blockers, and phosphodiesterase type 5 inhibitors modify the spectrum of pulmonary vascular lesions in PAH has not been addressed with a large cohort of lungs with the disease.Several large series, heavily reliant on autopsy samples, highlighted pulmonary vascular alterations that characterize the pulmonary vascular remodeling in idiopathic PAH (IPAH) and PAH associated with congenital heart disease (CHD) (3-14) (see Table E1 in the online supplement). Eccentric and obliterative intima thickening are largely composed of smooth muscle cells and myofibroblasts. A similar cell composition underlies media thickening, which is regarded as the signature process in pulmonary hypertension (15). In addition, most of the cau...

Rationale: The impact of modern treatments of pulmonary arterial hypertension (PAH) on pulmonary vascular pathology remains unknown. Objectives: To assess the spectrum of pulmonary vascular remodeling in the modern era of PAH medication. Methods: Assessment of pulmonary vascular remodeling and inflammation in 62 PAH and 28 control explanted lungs systematically sampled. Measurements and Main Results: Intima and intima plus media fractional thicknesses of pulmonary arteries were increased in the PAH group versus the control lungs and correlated with pulmonary hemodynamic measurements. Despite a high variability of morphological measurements within a given PAH lung and among all PAH lungs, distinct pathological subphenotypes were detected in cohorts of PAH lungs. These included a subset of lungs lacking intima or, most prominently, media remodeling, which had similar numbers of profiles of plexiform lesions as those in lungs with more pronounced remodeling. Marked perivascular inflammation was present in a high number of PAH lungs and correlated with intima plus media remodeling. The number of profiles of plexiform lesions was significantly lower in lungs of male patients and those never treated with prostacyclin or its analogs. Conclusions: Our results indicate that multiple features of pulmonary vascular remodeling are present in patients treated with modern PAH therapies. Perivascular inflammation may have an important role in the processes of vascular remodeling, all of which may ultimately lead to increased pulmonary artery pressure. Moreover, our study provides a framework to interpret and design translational studies in PAH. Keywords: pulmonary circulation; vessel remodeling; angiogenesis; inflammationThe modern treatment of pulmonary arterial hypertension (PAH) has led to substantive advancements in patients' quality of life and survival, significantly improving on the grave prognosis historically associated with the disease (1, 2). With the restrictions regarding obtaining lung tissue for diagnosis, the endpoints for effectiveness of the current therapies are largely based on assessments of exercise performance and reported quality of life, time to clinical deterioration, and/or measured physiological performance (e.g., 6-min walk test). Whether prostacyclin and its analogs, endothelin receptor blockers, and phosphodiesterase type 5 inhibitors modify the spectrum of pulmonary vascular lesions in PAH has not been addressed with a large cohort of lungs with the disease.Several large series, heavily reliant on autopsy samples, highlighted pulmonary vascular alterations that characterize the pulmonary vascular remodeling in idiopathic PAH (IPAH) and PAH associated with congenital heart disease (CHD) (3-14) (see Table E1 in the online supplement). Eccentric and obliterative intima thickening are largely composed of smooth muscle cells and myofibroblasts. A similar cell composition underlies media thickening, which is regarded as the signature process in pulmonary hypertension (15). In addition, most of the cau...

This paper begins with a comprehensive review of the management literature on culture, and demonstrates close parallels with research and writings on organisational climate and values. The paper then reports the findings from an empirical investigation into the relationship between the organisational culture, climate, and managerial values of a large Australian public sector agency. The relative strengths of four dimensions of culture in this organisation were measured using Hofstede’s instrument. Added to this were items from a questionnaire developed by Ryder and Southey, derived from the Jones and James instrument measuring psychological climate and providing scores across six specific dimensions of organisational climate. Measures of managerial values, drawn from a questionnaire by Flowers and Hughes, were also incorporated. Results show that levels of culture within this particular organisation are at variance with those reported by Hofstede from his Australian data. Findings indicate a strong link between specific organisational climate items and a number of managerial values dimensions. Additional relationships between particular dimensions of culture, climate and managerial values are also reported. From this, a hypothesised, predictive model of linkages between the constructs is presented.

No abstract

α-1 anti-trypsin (AAT) is the most abundant circulating serine protease inhibitor (serpin) and an acute phase reactant. Systemic deficiency in AAT (AATD) due to genetic mutations can result in liver failure and chronic lung disease such as emphysema. Considered the prototypic serpin, the emphysema observed in patients with AATD, consisting of progressive destruction of the alveoli and small airway structures, formed the basis of the protease/anti-protease imbalance theory of chronic obstructive pulmonary disease (COPD). Over the past decade, however, investigations of AATD have described multiple functions of AAT beyond those generally attributed to its antiprotease activity. Evidence now suggests that AAT plays an important role in modulating immunity, inflammation, proteostasis, apoptosis, and possibly cellular senescence programs. When integrated in vivo, these processes contribute to the lung maintenance program which preserves the lung despite a constant bombardment by damage associated molecular patterns (DAMPs) and/or pathogenassociated molecular patterns (PAMPs) initiated by cigarette smoke, pollutants, or infections. In this review, we discuss the clinical aspects of AATD as they pertain to emphysema; including similarities and differences to cigarette smoke-induced emphysema. Examining the lung maintenance program, we next consider the multiple mechanisms of airspace destruction and explore the role AATD contributes. Finally, we consider the data regarding treatment of AATD, including AAT supplementation and its current limitations, and suggest further avenues of research informed by the multiple functions of AAT.

The ankle-brachial index (ABI) is the standard test used in clinical practice to detect peripheral artery disease (PAD) and is a powerful predictor of adverse cardiovascular outcomes. This study sought to measure the baseline knowledge of the ABI test among a sample of internal medicine residents and to examine the impact of an educational intervention on performance of the test. A total of 29 residents were asked to perform three tasks, with the performance of each task being assessed using a point-based scoring system: measure an ABI on a normal volunteer (15 points), calculate the ABI based on data from a hypothetical patient (3 points), and interpret a range of ABI values (6 points). A standardized educational intervention was then provided and post-education performance was assessed for each task using the same scoring system. At baseline, 4% of residents correctly measured the ABI, 10% correctly calculated the ABI, and 45% correctly interpreted the ABI. Baseline performance was unaffected by year of residency training. Following the educational intervention, 50% of residents correctly measured the ABI, 75% correctly calculated the ABI, and 88% correctly interpreted the ABI. The mean score for the tasks of ABI measurement, calculation and interpretation between baseline and post-education were 4.6 +/- 3 and 13.9 +/- 1.6 (p < 0.0001), 1 +/- 0.9 and 2.3 +/- 1.2 (p = 0.002), and 4.9 +/- 1.6 and 5.9 +/- 0.3 (p = 0.008), respectively. In conclusion, baseline knowledge of the ABI test was poor among a sample of internal medicine residents. These results suggest that instruction regarding the ABI test is deficient in medical school and residency programs and requires action by those responsible for the education of medical students and residents.

No abstract

No abstract