A comparison of the predictive accuracy of three screening models for pulmonary arterial hypertension in systemic sclerosis

IntroductionThere is evidence that early screening for pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc) improves outcomes. We compared the predictive accuracy of two recently published screening algorithms (DETECT 2013 and Australian Scleroderma Interest Group (ASIG) 2012) for SSc-associated PAH (SSc-PAH) with the commonly used European Society of Cardiology/European Respiratory Society (ESC/ERS 2009) guidelines.MethodsWe included 73 consecutive SSc patients with suspected PAH undergoing right heart catheterization (RHC). The three screening models were applied to each patient. For each model, contingency table analysis was used to determine sensitivity, specificity, and positive (PPV) and negative (NPV) predictive values for PAH. These properties were also evaluated in an ‘alternate scenario analysis’ in which the prevalence of PAH was set at 10%.ResultsRHC revealed PAH in 27 (36.9%) patients. DETECT and ASIG algorithms performed equally in predicting PAH with sensitivity and NPV of 100%. The ESC/ERS guidelines had sensitivity of 96.3% and NPV of only 91%, missing one case of PAH; these guidelines could not be applied to three patients who had absent tricuspid regurgitant (TR) jet. The ASIG algorithm had the highest specificity (54.5%). With PAH prevalence set at 10%, the NPV of the models was unchanged, but the PPV dropped to less than 20%.ConclusionsIn this cohort, the DETECT and ASIG algorithms out-perform the ESC/ERS guidelines, detecting all patients with PAH. The ESC/ERS guidelines have limitations in the absence of a TR jet. Ultimately, the choice of SSc-PAH screening algorithm will also depend on cost and ease of application.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0517-5) contains supplementary material, which is available to authorized users.     

Mechanobiology of embryonic skeletal development: Insights from animal models

A range of clinical conditions in which fetal movement is reduced or prevented can have a severe effect on skeletal development. Animal models have been instrumental to our understanding of the interplay between mechanical forces and skeletal development, particularly the mouse and the chick model systems. In the chick, the most commonly used means of altering the mechanical environment is by pharmaceutical agents which induce paralysis, whereas genetically modified mice with nonfunctional or absent skeletal muscle offer a valuable tool for examining the interplay between muscle forces and skeletogenesis in mammals. This article reviews the body of research on animal models of bone or joint formation in vivo in the presence of an altered or abnormal mechanical environment. In both immobilized chicks and “muscleless limb” mice, a range of effects are seen, such as shorter rudiments with less bone formation, changes in rudiment and joint shape, and abnormal joint cavitation. However, although all bones and synovial joints are affected in immobilized chicks, some rudiments and joints are unaffected in muscleless mice. We propose that extrinsic mechanical forces from movements of the mother or littermates impact on skeletogenesis in mammals, whereas the chick embryo is reliant on intrinsic movement for mechanical stimulation. The insights gained from animal models into the mechanobiology of embryonic skeletal development could provide valuable cues to prospective tissue engineers of cartilage and bone and contribute to new or improved treatments to minimize the impact on skeletal development of reduced movement in utero. Birth Defects Research (Part C) 90:203–213, 2010. © 2010 Wiley‐Liss, Inc.     

Scales of aboveground and below-ground competition in a semi-arid woodland detected from spatial pattern

Abstract. Semi-arid woodlands are two-phase mosaics of canopy and inter-canopy patches. We hypothesized that both aboveground competition (within canopy patches), and below-ground competition (between canopy patches), would be important structuring processes in these communities. We investigated the spatial pattern of trees in a Pinus edulis-Juniperus monosperma woodland in New Mexico using Ripley's K-function. We found strong aggregation of trees at scales of 2 to 4 m, which indicates the scale of canopy patches. Canopy patches were composed of individuals of both species. Crown centers of both species were always less aggregated than stem centers at scales less than canopy patch size, indicating morphological plasticity of competing crowns. In the smallest size classes of both species, aggregation was most intense, and occurred over a larger range of scales; aggregation decreased with increasing size as is consistent with density-dependent mortality from intraspecific competition. Within canopy patches, younger trees were associated with older trees of the other species. At scales larger than canopy patches, younger trees showed repulsion from older conspecifics, indicating below-ground competition. Hence, intraspecific competition was stronger than interspecific competition, probably because the species differ in rooting depth. Woodland dynamics depend on the scale and composition of canopy patches, aggregated seed deposition and facilitation, above- and below-ground competition, and temporal changes in the spatial scale of interactions. This woodland is intermediate in a grassland-forest continuum (a gradient of increasing woody canopy cover) and hence we expected, and were able to detect, the effects of both above- and below-ground competition.     

Predictors of mortality in connective tissue disease-associated pulmonary arterial hypertension: a cohort study

Introduction

Pulmonary arterial hypertension (PAH) is a major cause of mortality in connective tissue disease (CTD). We sought to quantify survival and determine factors predictive of mortality in a cohort of patients with CTD-associated PAH (CTD-PAH) in the current era of advanced PAH therapy.

Methods

Patients with right heart catheter proven CTD-PAH were recruited from six specialised PAH treatment centres across Australia and followed prospectively. Using survival methods including Cox proportional hazards regression, we modelled for all-cause mortality. Independent variables included demographic, clinical and hemodynamic data.

Results

Among 117 patients (104 (94.9%) with systemic sclerosis), during 2.6 ± 1.8 (mean ± SD) years of follow-up from PAH diagnosis, there were 32 (27.4%) deaths. One-, two- and three-year survivals were 94%, 89% and 73%, respectively. In multiple regression analysis, higher mean right atrial pressure (mRAP) at diagnosis (hazard ratio (HR) = 1.13, 95% CI: 1.04 to 1.24, P = 0.007), lower baseline six-minute walk distance (HR = 0.64, 95% CI: 0.43 to 0.97, P = 0.04), higher baseline World Health Organization functional class (HR = 3.42, 95% CI: 1.25 to 9.36, P = 0.04) and presence of a pericardial effusion (HR = 3.39, 95% CI: 1.07 to 10.68, P = 0.04) were predictive of mortality. Warfarin (HR = 0.20, 95% CI: 0.05 to 0.78, P = 0.02) and combination PAH therapy (HR = 0.20, 95% CI: 0.05 to 0.83, P = 0.03) were protective.

Conclusions

In this cohort of CTD-PAH patients, three-year survival was 73%. Independent therapeutic predictors of survival included warfarin and combination PAH therapy. Our findings suggest that anticoagulation and combination PAH therapy may improve survival in CTD-PAH. This observation merits further evaluation in randomised controlled trials.     

Analysis of the diet of Natterer's bat Myotis nattereri and the common long-eared bat Plecotus auritus in the West of Ireland

The diets of Natterer's bat Myotis nattereri and the common long-eared bat Plecotus auritus were investigated at a nursery colony of each species by analysis of droppings collected monthly from May to September. Respectively, 68% and 42% of the diets comprised items presumed to have been gleaned from foliage or other surfaces: diurnal insects, insects which rarely fly, and non-flying arthropods. Such surfaces included the ground: centipedes were eaten by both bats, and the muscid, Scatophaga stercoraria , usually associated with cattle dung, was a common prey. Indeed, the prevalence of cattle-farming around both of the bat roosts almost certainly contributed indirectly, in the form of S. stercoraria , to a significant part of the Diptera consumed. The chief food of M. nattereri was the larger Diptera, but Trichoptera, Hymenoptera and Arachnida were also important. Lepidoptera, Coleoptera and Hemiptera were minor prey, with Dermaptera and Chilopoda taken occasionally. Diptera, closely followed by Lepidoptera, together accounted for nearly two-thirds of the diet of P. auritus. Also taken, in descending order of importance, were Trichoptera, Arachnida, Chilopoda, Coleoptera, Dermaptera, Hymenoptera and Hemiptera. Plecotus auritus , but not M. nattereri , was evidently able to take a few small insects such as aphids and lesser nematoceran Diptera.     

Protein phosphatase 1α mediates ceramide-induced ERM protein dephosphorylation: a novel mechanism independent of phosphatidylinositol 4, 5-biphosphate (PIP2) and myosin/ERM phosphatase

ERM (ezrin, radixin, and moesin) proteins are cytoskeletal interacting proteins that bind cortical actin, the plasma membrane, and membrane proteins, which are found in specialized plasma membrane structures such as microvilli and filopodia. ERM proteins are regulated by phosphatidylinositol 4, 5-biphosphate (PIP(2)) and by phosphorylation of a C-terminal threonine, and its inactivation involves PIP(2) hydrolysis and/or myosin phosphatase (MP). Recently, we demonstrated that ERM proteins are also subject to counter regulation by the bioactive sphingolipids ceramide and sphingosine 1-phosphate. Plasma membrane ceramide induces ERM dephosphorylation whereas sphingosine 1-phosphate induces their phosphorylation. In this work, we pursue the mechanisms by which ceramide regulates dephosphorylation. We found that this dephosphorylation was independent of hydrolysis and localization of PIP(2) and MP. However, the results show that ERM dephosphorylation was blocked by treatment with protein phosphatase 1 (PP1) pharmacological inhibitors and specifically by siRNA to PP1α, whereas okadaic acid, a PP2A inhibitor, failed. Moreover, a catalytic inactive mutant of PP1α acted as dominant negative of the endogenous PP1α. Additional results showed that the ceramide mechanism of PP1α activation is largely independent of PIP(2) hydrolysis and MP. Taken together, these results demonstrate a novel, acute mechanism of ERM regulation dependent on PP1α and plasma membrane ceramide.     

Recognition of Leukaemia Cells as Foreign before and after Autoimmunization

Leukaemia cells in the peripheral blood of nine patients with acute leukaemia were removed and stored. When the patients had been brought into haematological remission these leukaemia cells were cultured with autologous lymphocytes both before and after the patients had been autoimmunized with their own irradiated leukaemia cells. The extent to which the leukaemia cells stimulated the “normal lymphocytes” was increased as the result of autoimmunization.The implications of the use of this test for determining the best regimen for “immunotherapy” in acute leukaemia are discussed.