Pulmonary Lymphangioleiomyomatosis originates in the pleural mesothelial cell population.

Lymphangioleiomyomatosis (LAM) is a cystic lung disease mainly affecting women, in which degradation of the lung parenchyma is associated with a cell of unknown provenance, known as a LAM cell. LAM cells carry TSC2 mutations and can be identified in the lung parenchyma by their expression of both smooth muscle actin and antigens characteristic of melanocytes and melanocytic tumors. The nature of the cell-of-origin of LAM is controversial, and despite continued research effort remains elusive. Further, it has not been possible to culture pulmonary LAM cells in vitro, and current research relies on cells and animal models which may not recapitulate all features of the disease. We noted aberrant expression of melanoma antigens in pleural mesothelial cells in lung tissue from LAM patients, indicating that these cells could be the precursors of parenchymal LAM cells. We hypothesise that loss of tuberin function following TSC2 mutation in the mesothelial cell lineage gives rise to the cell-of-origin of pulmonary LAM (P-LAM), and of other associated conditions commonly noted in LAM patients. The unique properties of mesothelial cells provide a straightforward explanation of the diverse presentation of LAM.

The UK guidelines for management and surveillance of Tuberous Sclerosis Complex.

BACKGROUND: The severity of Tuberous Sclerosis Complex (TSC) can vary among affected individuals. Complications of TSC can be life threatening, with significant impact on patients' quality of life. Management may vary dependent on treating physician, local and national policies, and funding. There are no current UK guidelines. We conducted a Delphi consensus process to reach agreed guidance for the management of patients with TSC in the UK. METHODS: We performed a literature search and reviewed the 2012/13 international guideline for TSC management. Based on these, a Delphi questionnaire was formed. We invited 86 clinicians and medical researchers to complete an online survey in two rounds. All the people surveyed were based in the UK. Clinicians were identified through the regional TSC clinics, and researchers were identified through publications. In round one, 55 questions were asked. In round two, 18 questions were asked in order to obtain consensus on the outstanding points that had been contentious in round one. The data was analysed by a core committee and subcommittees, which consisted of UK experts in different aspects of TSC. The Tuberous Sclerosis Association was consulted. RESULTS: About 51 TSC experts took part in this survey. Two rounds were required to achieve consensus. The responders were neurologists, nephrologists, psychiatrist, psychologists, oncologists, general paediatricians, dermatologist, urologists, radiologists, clinical geneticists, neurosurgeons, respiratory and neurodisability clinicians. CONCLUSIONS: These new UK guidelines for the management and surveillance of TSC patients provide consensus guidance for delivery of best clinical care to individuals with TSC in the UK.

Early symptoms of systemic lupus erythematosus (SLE) recalled by 339 SLE patients.

Objective The European League Against Rheumatism and the American College of Rheumatology jointly embarked on a new classification criteria for systemic lupus erythematosus (SLE) project. Its first phase involved generation of a broad set of items potentially useful for classification of SLE. This study was undertaken to add the patient perspective to an expert Delphi approach and an early patient cohort study. Methods A national cross-sectional study was conducted. A self-report questionnaire was published in the "Schmetterling" (Butterfly), the quarterly journal of the German SLE patient association. Individuals with SLE were asked to anonymously complete the questionnaire, which asked for demographic details, organ manifestations, autoantibodies and symptoms. Results A total of 339 completed questionnaires out of 2498 were returned, a response rate of 13.6%; 83.2% reported they were ANA positive and 81.7% reported joint, 66.1% skin and 33.0% renal involvement. For the time before and in the first year after their SLE diagnosis, the majority reported fatigue (89.4%), joint pain (86.7%), photosensitivity (79.4%) and myalgia (76.1%). Of interest, more than half of the patients reported fever as an early symptom (53.7%). Conclusion For a Caucasian European SLE patient population, the overall characteristics suggest meaningful representation. While many symptoms were reported as expected, the high percentage of patients reporting fever and the significant number of patients with unexpected gastrointestinal complaints are of particular interest. These data add to the information on early SLE symptoms informing the development process of new SLE classification criteria.

The impact of simulation education on self-efficacy towards teaching for nurse educators.

AIM: The objective of this study was to assess the impact of a simulation workshop on self-efficacy towards teaching for nurse educators in India. Additionally, we sought to revise and validate a tool to measure self-efficacy in teaching for use with a global audience. BACKGROUND: Simulation is an evidence-based teaching and learning method and is increasingly used in nursing education globally. INTRODUCTION: As new technology and teaching methods such as simulation continue to evolve, it is important for new as well as experienced nurse educators globally to have confidence in their teaching skills and abilities. METHODS: The study included (1) instrument revision, and measures of reliability and validation, (2) an 8-h faculty development workshop intervention on simulation, (3) pre- and post-survey of self-efficacy among nurse educators, and (4) investigation of relationship between faculty socio-demographics and degree of self-efficacy. RESULTS: The modified tool showed internal consistency (r = 0.98) and was validated by international faculty experts. There were significant improvements in total self-efficacy (P < 0.001) and subscale scores among nurse educators after the simulation workshop intervention when compared to pre-survey results. No significant relationships were found between socio-demographic variables and degree of self-efficacy. DISCUSSION: Strong self-efficacy in teaching among nurse educators is crucial for effective learning to occur. CONCLUSIONS AND IMPLICATIONS FOR NURSING: Results indicated the simulation workshop was effective in significantly improving self-efficacy towards teaching for nurse educators using an internationally validated tool. IMPLICATIONS FOR NURSING POLICY: The Minister of Health in India recently called for improvements in nursing education. Introducing nursing education on simulation as a teaching method in India and globally to improve self-efficacy among teachers is an example of a strategy towards meeting this call.

Whole-exome sequencing for mutation detection in pediatric disorders of insulin secretion: Maturity onset diabetes of the young and congenital hyperinsulinism.

BACKGROUND: To assess the utility of whole-exome sequencing (WES) for mutation detection in maturity-onset diabetes of the young (MODY) and congenital hyperinsulinism (CHI). MODY and CHI are the two commonest monogenic disorders of glucose-regulated insulin secretion in childhood, with 13 causative genes known for MODY and 10 causative genes identified for CHI. The large number of potential genes makes comprehensive screening using traditional methods expensive and time-consuming. METHODS: Ten subjects with MODY and five with CHI with known mutations underwent WES using two different exome capture kits (Nimblegen SeqCap EZ Human v3.0 Exome Enrichment Kit, Nextera Rapid Capture Exome Kit). Analysis was blinded to previously identified mutations, and included assessment for large deletions. The target capture of five exome capture technologies was also analyzed using sequencing data from >2800 unrelated samples. RESULTS: Four of five MODY mutations were identified using Nimblegen (including a large deletion in HNF1B). Although targeted, one mutation (in INS) had insufficient coverage for detection. Eleven of eleven mutations (six MODY, five CHI) were identified using Nextera Rapid (including the previously missed mutation). On reconciliation, all mutations concorded with previous data and no additional variants in MODY genes were detected. There were marked differences in the performance of the capture technologies. CONCLUSIONS: WES can be useful for screening for MODY/CHI mutations, detecting both point mutations and large deletions. However, capture technologies require careful selection.

There is a need for new systemic sclerosis subset criteria. A content analytic approach.

OBJECTIVES: Systemic sclerosis (SSc) is heterogenous. The objectives of this study were to evaluate the purpose, strengths and limitations of existing SSc subset criteria, and identify ideas among experts about subsets. METHODS: We conducted semi-structured interviews with randomly sampled international SSc experts. The interview transcripts underwent an iterative process with text deconstructed to single thought units until a saturated conceptual framework with coding was achieved and respondent occurrence tabulated. Serial cross-referential analyses of clusters were developed. RESULTS: Thirty experts from 13 countries were included; 67% were male, 63% were from Europe and 37% from North America; median experience of 22.5 years, with a median of 55 new SSc patients annually. Three thematic clusters regarding subsetting were identified: research and communication; management; and prognosis (prediction of internal organ involvement, survival). The strength of the limited/diffuse system was its ease of use, however 10% stated this system had marginal value. Shortcomings of the diffuse/limited classification were the risk of misclassification, predictions/generalizations did not always hold true, and that the elbow or knee threshold was arbitrary. Eighty-seven percent use more than 2 subsets including: SSc sine scleroderma, overlap conditions, antibody-determined subsets, speed of progression, and age of onset (juvenile, elderly). CONCLUSIONS: We have synthesized an international view of the construct of SSc subsets in the modern era. We found a number of factors underlying the construct of SSc subsets. Considerations for the next phase include rate of change and hierarchal clustering (e.g. limited/diffuse, then by antibodies).

Impact of Left Ventricular Diastolic Dysfunction on Lung Transplantation Outcome in Patients With Pulmonary Arterial Hypertension.

Diastolic dysfunction may influence perioperative outcome, early graft function, and long-term survival. We compared the outcomes of double lung transplantation (DLTx) for patients with pulmonary arterial hypertension (PAH) with preoperative left ventricular (LV) diastolic dysfunction with the outcomes of patients without diastolic dysfunction. Of 116 consecutive patients with PAH (who underwent transplantation between January 1995 and December 2013), 44 met our inclusion and exclusion criteria. Fourteen (31.8%) patients with diastolic dysfunction pretransplantation had a higher body mass index (29 [IQR 21.5-32.6] vs 22.4 [IQR 19.9-25.3] kg/m2 ) and mean pulmonary arterial pressure (54.6 ± 10 mmHg vs 47 ± 11.3 mmHg) and right atrial pressure (16.5 ± 5.2 mmHg vs 10.6 ± 5.2 mmHg). The patients received extracorporeal life support more frequently (33% vs 7% [p = 0.02]), had worse APACHE II scores (21.7 ± 7.4 vs 15.3 ± 5.3 [p = 0.02]), and a trend toward worse ventilator-free days (2.5 [IQR 6.5-32.5] vs 17 [IQR 3-23] [p = 0.08]). There was no effect on development of primary graft dysfunction or intensive care unit/hospital survival. One-year survival was worse (hazard ratio [HR] 4.45, 95% confidence interval [CI] 1.3-22, p = 0.02). Diastolic dysfunction was the only variable that correlated with overall survival (HR 5.4, 95% CI 1.3-22, p = 0.02). Diastolic dysfunction leads to early postoperative morbidity and worse survival in patients with PAH after DLTx.

Defining Skin Ulcers in Systemic Sclerosis: Systematic Literature Review and Proposed World Scleroderma Foundation (WSF) definition.

PURPOSE: There is a lack of a valid, definition for skin ulcers in SSc to be used in clinical trials. Our aim was to develop a consensus definition for SSc-skin ulcers based on the results of a systematic literature review (SLR) for skin ulcer definitions and expert opinion; and to evaluate its face validity, reliability and feasibility. METHODS: SLR for skin ulcer definitions was conducted using PubMed, Web of Science, and Cochrane library for articles published from inception to January 1st, 2016. SSc experts were to discuss the definitions' categories and vote for the relevant terms. Reliability of the definition were tested in a second expert meeting, seven SSc experts evaluated 7 SSc pts with skin lesions twice. Face validity and feasibility evaluated by sending out case report forms(CRFs) to 4 SSc experts, they were asked to use the definition in 5 pts each. RESULTS: A total of 3464 abstracts and titles were screened, and 446 articles were fully evaluated. Of these, 66 met eligibility criteria and skin ulcer definitions were extracted. SSc experts discussed, refined and voted on the consensus definition using nominal process. Kappa for inter-, intra-rater rater agreement was 0.51, 0.90 respectively. The mean time to decide if the lesion is an ulcer was 7.4 sec. All investigators endorsed the face validity of the new definition in the CRFs. CONCLUSION: Using a SLR and a nominal technique, we developed a preliminary consensus-based definition of SSc-skin ulcers. Face validity, feasibility and reliability were demonstrated for the developed definition.

Toward new criteria for systemic lupus erythematosus-a standpoint.

While clearly different in their aims and means, classification and diagnosis both try to accurately label the disease patients are suffering from. For systemic lupus erythematosus (SLE), this is complicated by the multi-organ nature of the disease and by our incomplete understanding of its pathophysiology. Hallmarks of SLE are the presence of antinuclear antibodies (ANA), and multiple immune-mediated organ symptoms that are largely independent. In an attempt to overcome limitations of the current sets of SLE classification criteria, a new four-phase approach is being developed, which is jointly supported by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). This review attempts to delineate the performance of the current sets of criteria, the reasons for the decision for classification, and not diagnostic, criteria, and to provide a background of the current approach taken.

Tranexamic acid: optimal blood loss management in surface replacement arthroplasty.

AIMS: This study investigated whether the use of tranexamic acid (TXA) decreased blood loss and transfusion related cost following surface replacement arthroplasty (SRA). METHODS: A retrospective review of patients treated with TXA during a SRA, who did not receive autologous blood (TXA group) was performed. Two comparison groups were established; the first group comprised of patients who donated their own blood pre-operatively (auto group) and the second of patients who did not donate blood pre-operatively (control). Outcomes included transfusions, post-operative haemoglobin (Hgb), complications, and length of post-operative stay. RESULTS: Between 2009 and 2013, 150 patients undergoing SRA were identified for inclusion: 51 in the auto, 49 in the control, and 50 in the TXA group. There were no differences in the pre-operative Hgb concentrations between groups. The mean post-operative Hgb was 11.3 g/dL (9.1 to 13.6) in the auto and TXA groups, and 10.6 g/dL (8.1 to 12.1)in the control group (p = 0.001). Accounting for cost of transfusions, administration of TXA, and length of stay, the cost per patient was $1731, $339, and $185 for the auto, control and TXA groups, respectively. DISCUSSION: TXA use demonstrated higher post-operative Hgb concentrations when compared with controls and decreased peri-operative costs. TAKE HOME MESSAGE: Tranexamic acid safely limits allogeneic transfusion, maintains post-operative haemoglobin, and decreases direct and indirect transfusion related costs in surface replacement arthroplasty.

Levels of circulating MMP-7 degraded elastin are elevated in pulmonary disorders.

OBJECTIVES: Elastin is a signature protein of the lungs. Matrix metalloproteinase-7 (MMP-7) is important in lung defence mechanisms and degrades elastin. However, MMP-7 activity in regard to elastin degradation has never been quantified serologically in patients with lung diseases. An assay for the quantification of MMP-7 generated elastin fragments (ELM7) was therefore developed to investigate MMP-7 derived elastin degradation in pulmonary disorders such as idiopathic pulmonary fibrosis (IPF) and lung cancer. DESIGN AND METHODS: Monoclonal antibodies (mABs) were raised against eight carefully selected MMP-7 cleavage sites on elastin. After characterisation and validation of the mABs, one mAB targeting the ELM7 fragment was chosen. ELM7 fragment levels were assessed in serum samples from patients diagnosed with IPF (n=123, baseline samples, CTgov reg. NCT00786201), and lung cancer (n=40) and compared with age- and sex-matched controls. RESULTS: The ELM7 assay was specific towards in vitro MMP-7 degraded elastin and the ELM7 neoepitope but not towards other MMP-7 derived elastin fragments. Serum ELM7 levels were significantly increased in IPF (113%, p<0.0001) and lung cancer (96%, p<0.0001) compared to matched controls. CONCLUSIONS: MMP-7-generated elastin fragments can be quantified in serum and may reflect pathological lung tissue turnover in several important lung diseases.

Clinical outcomes following re-admission for non-infectious wound complications after primary total knee replacement.

Haematomas, drainage, and other non-infectious wound complications following total knee replacement (TKR) have been associated with long-term sequelae, in particular, deep infection. However, the impact of these wound complications on clinical outcome is unknown. This study compares results in 15 patients re-admitted for wound complications within 90 days of TKR to 30 matched patients who underwent uncomplicated total knee replacements. Patients with wound complications had a mean age of 66 years (49 to 83) and mean body mass index (BMI) of 37 (21 to 54), both similar to that of patients without complications (mean age 65 years and mean BMI 35). Those with complications had lower mean Knee Society function scores (46 (0 to 100 vs. 66 (20 to 100), p = 0.047) and a higher incidence of mild or greater pain (73% vs. 33%, p = 0.01) after two years compared with the non re-admitted group. Expectations in patients with wound complications following TKR should be tempered, even in those who do not develop an infection.

Reliability of the American Society of Anesthesiologists physical status scale in clinical practice.

BACKGROUND: Previous studies, which relied on hypothetical cases and chart reviews, have questioned the inter-rater reliability of the ASA physical status (ASA-PS) scale. We therefore conducted a retrospective cohort study to evaluate its inter-rater reliability and validity in clinical practice. METHODS: The cohort included all adult patients (≥18 yr) who underwent elective non-cardiac surgery at a quaternary-care teaching institution in Toronto, Ontario, Canada, from March 2010 to December 2011. We assessed inter-rater reliability by comparing ASA-PS scores assigned at the preoperative assessment clinic vs the operating theatre. We also assessed the validity of the ASA-PS scale by measuring its association with patients' preoperative characteristics and postoperative outcomes. RESULTS: The cohort included 10 864 patients, of whom 5.5% were classified as ASA I, 42.0% as ASA II, 46.7% as ASA III, and 5.8% as ASA IV. The ASA-PS score had moderate inter-rater reliability (κ 0.61), with 67.0% of patients (n=7279) being assigned to the same ASA-PS class in the clinic and operating theatre, and 98.6% (n=10 712) of paired assessments being within one class of each other. The ASA-PS scale was correlated with patients' age (Spearman's ρ, 0.23), Charlson comorbidity index (ρ=0.24), revised cardiac risk index (ρ=0.40), and hospital length of stay (ρ=0.16). It had moderate ability to predict in-hospital mortality (receiver-operating characteristic curve area 0.69) and cardiac complications (receiver-operating characteristic curve area 0.70). CONCLUSIONS: Consistent with its inherent subjectivity, the ASA-PS scale has moderate inter-rater reliability in clinical practice. It also demonstrates validity as a marker of patients' preoperative health status.

Bone disease in systemic sclerosis: outcomes and associations.

OBJECTIVES: The relationship between systemic sclerosis (SSc) and low bone mineral density (BMD) is poorly understood. The aim of this study is to improve our understanding of low bone density in SSc and its potential consequences. METHODS: Fifty consecutive unselected SSc patients were approached. Demographics, disease manifestations, BMD (lumbar spine and femoral neck) were collected at baseline and occurrence of fracture and death were collected over 2 years. The 10-year risk of osteoporotic fracture was estimated using the fracture risk assessment tool (FRAX) v2.0 with the Canadian population reference. Fisher's Exact and Student's t-tests were used to evaluate differences between patients with and without low BMD. Logistic regression was used for multivariate analysis. RESULTS: Forty-five patients had complete BMD data. Twenty-eight patients (62%) had low BMD, of those 10 (36%) had osteoporosis. There was no difference in age, sex, or disease duration between both groups. Low BMD was associated with non-Caucasian race (57% vs. 18%, p=0.01), postmenopausal status (83% vs. 47%, p<0.01), low body mass index (24.5 vs. 26.2, p=0.05). The mean 10-year risk of developing a major osteoporotic fracture and a femoral neck fracture was higher in the low BMD group (10.2% vs. 4.8%, p=0.12) and (4.1% vs. 0.5%, p = 0.16) respectively. Fourteen percent (4/28) of SSc patients with low BMD had a fracture, compared to 6% (1/17) SSc patients without low BMD. Fracture-related mortality did not occur in any patients. CONCLUSIONS: Low BMD and fracture are frequently seen in SSc patients. A number of clinically relevant factors are associated with low BMD. Further research is needed to evaluate these factors and the role of bone-specific treatments in SSc.

Hypoglycaemia, fear of hypoglycaemia and quality of life in children with Type 1 diabetes and their parents.

AIM: To evaluate the association between fear of hypoglycaemia, episodes of hypoglycaemia and quality of life in children with Type 1 diabetes and their parents. METHODS: This was a cross-sectional, population-based study of 325 children with Type 1 diabetes and their parents. The children were aged 2-18 years. A total of 325 parents of the patients aged 2-18 years and 196 of the patients themselves (aged 8-18 years) completed questionnaires including the PedsQL Diabetes Module, the Hypoglycaemia Fear Survey and Clarke's hypoglycaemia awareness questionnaire. Data were compared with HbA1c results and the history of severe hypoglycaemia episodes. RESULTS: Parents with the highest levels of fear of hypoglycaemia reported that their children had a reduced quality of life (P < 0.001). Similarly children with the greatest fear also reported a reduced quality of life (P < 0.001); however a history of severe hypoglycaemia was not associated with the child's quality of life as perceived by the child or parent. Episodes of severe hypoglycaemia were associated with an increased fear of hypoglycaemia for the parents (P = 0.004) but not the children. Children in the highest fear quartile also had a higher HbA(1c) concentration compared with those in the lowest fear quartile [increase in HbA(1c) 7 mmol/mol (0.6%), P < 0.01]. CONCLUSIONS: Fear of hypoglycaemia and not episodes of hypoglycaemia per se is associated with increased psychological burden for children with Type 1 diabetes. Interventions to reduce fear of hypoglycaemia in these families may improve their quality of life.

Multidisciplinary approach to epizootiology and pathogenesis of bat rabies viruses in the United States.

Zoonotic disease surveillance is typically initiated after an animal pathogen has caused disease in humans. Early detection of potentially high-risk pathogens within animal hosts may facilitate medical interventions to cope with an emerging disease. To effectively spillover to a novel host, a pathogen may undergo genetic changes resulting in varying transmission potential in the new host and potentially to humans. Rabies virus (RABV) is one model pathogen to consider for studying the dynamics of emerging infectious diseases under both laboratory and field conditions. The evolutionary history of RABV is characterized by regularly documented spillover infections and a series of notable host shifts. Within this context, enhanced field surveillance to improve detection of spillover infections will require validated techniques to non-invasively differentiate infected from non-infected individuals. In this study, we evaluate the use of infrared thermography to detect thermal changes associated with experimental RABV infection in big brown bats (Eptesicus fuscus) in a captive colony. Our results indicated that 62% of rabid bats had detectable facial temperature decreases (-4.6°C, SD ± 2.5) compared with pre-inoculation baseline values. These data suggest potential utility for discriminating rabid bats in natural field settings. In addition, focusing upon RABV circulating in the United States between 2008 and 2011, we confirmed spillover events of bat RABV among carnivores and identified cross-species transmission events caused by four lineages of RABV associated with insectivorous bats. Additionally, our analysis of RABV glycoprotein sequences identified substitutions in antigenic sites that may affect neutralizing activity associated with monoclonal antibodies proposed for use in human post-exposure prophylaxis. This study provides a glimpse into RABV pathobiology and spillover dynamics among and between bats and a variety of mesocarnivores.

The structure, thermal properties and phase transformations of the cubic polymorph of magnesium tetrahydroborate.

The structure of the cubic polymorph of magnesium tetrahydroborate (γ-Mg(BH(4))(2)) has been determined in space group Ia3d from a structural database of the isoelectronic compound SiO(2); this has been corroborated by DFT calculations. The structure is found to concur with that recently determined by Filinchuk et al. (Y. Filinchuk, B. Richter, T. R. Jensen, V. Dmitriev, D. Chernyshov and H. Hagemann, Angew. Chem. Int. Ed., 2011, DOI: 10.1002/anie.201100675). The phase transformations and subsequent decomposition of γ-Mg(BH(4))(2) on heating have been ascertained from variable-temperature synchrotron X-ray diffraction data combined with thermogravimetric and mass spectrometry measurements. At ~160 °C, conversion to a disordered variant of the ß-Mg(BH(4))(2) phase (denoted as ß') is observed along with a further unidentified polymorph. There is evidence of amorphous phases during decomposition but there is no direct crystallographic indication of the existence of Mg(B(12)H(12)) or other intermediate Mg-B-H compounds. MgH(2) and finally Mg are observed in the X-ray diffraction data after decomposition.

CCR3 induced-p42/44 MAPK activation protects against staurosporine induced-DNA fragmentation but not apoptosis in airway smooth muscle cells.

BACKGROUND: Chemokine receptors (CCRs) are expressed on airway smooth muscle (ASM) cells. As their ligands are present in the airways in asthma, we hypothesized that ASM CCR activation could promote the increase in ASM mass seen in patients with chronic asthma. OBJECTIVE: To determine which CCRs are expressed by ASM cells and their potential functional relevance to the chronic airway changes seen in asthma. METHODS: CCR expression in primary ASM cell cultures and airway biopsies from patients with and without asthma was examined by RT-PCR, fluorescence-activated cell sorting and immunohistochemistry. ASM p42/44 MAPK activity, proliferation, migration and apoptosis were examined by western blotting, thymidine incorporation, transwell assay and TUNEL assay respectively. RESULTS: CCR3 was the most frequently expressed CCR protein and was present on 79 ± 14% of cells. CX3CR1 and CXCR6 were present on 6% and 11% of cells respectively. CCR3 ligands CCL11 and CCL24 caused rapid activation of p42/44 MAPK but not Akt. CCR3 activation did not affect ASM proliferation, migration or VEGF secretion. DNA fragmentation detected by TUNEL staining could be induced by staurosporine and Fas activation although only Fas activation resulted in caspase 3 cleavage. CCL11 and CCL24 protected ASM cells against DNA fragmentation dependent upon p42/44 MAPK activity only via caspase 3 independent pathways. CCR3 was expressed in the smooth muscle and epithelium in the airways of patients with and without asthma. Smooth muscle cell DNA fragmentation in the airways of patients with stable asthma and controls was very uncommon. CONCLUSIONS AND CLINICAL RELEVANCE: CCR3 is strongly expressed by ASM cells in vitro and in vivo. Protection against cell death by CCR3 activation is dependent on p42/44 MAPK but does not affect caspase 3 mediated apoptosis.

Prognostic factors for survival in systemic lupus erythematosus associated pulmonary hypertension.

OBJECTIVE: Pulmonary hypertension (PH) is a rare but severe manifestation of systemic lupus erythematosus (SLE) that can ultimately result in death. The identification of factors that prognosticate survival in SLE-PH is necessary for appropriate monitoring, timing of therapeutics and lung transplantation. The primary objective of this study was to identify prognostic factors for survival in SLE-PH through review of the literature. The methodological quality of the prognostic studies was also evaluated. METHODS: A systematic review of the literature was performed to identify studies evaluating prognostic factors for survival in SLE-PH. Medline, EMBASE, CINAHL, and Cochrane Central Registry of Controlled Trials (inception - week 2 2010) were searched. A standardized abstraction form was used by two independent reviewers to extract prognostic factors. Methodological quality was evaluated using a validated quality index. RESULTS: Twenty-three observational studies from 375 citations were evaluated. Elevated mean pulmonary artery pressure, Raynaud's phenomenon, thrombocytopenia, plexiform lesion, infection, thrombosis, pregnancy, pulmonary vasculitis and anticardiolipin antibodies were associated with decreased survival. Lupus disease activity, nephritis and central nervous system disease were not associated with survival. The sample sizes were small and methodological quality of the studies was variable. CONCLUSION: This study summarizes factors that may be associated with decreased survival in SLE-PH. The small sample sizes and variable methodological quality preclude definitive conclusions. This study provides the groundwork for further research using large cohorts.

Pulmonary hypertension in systemic sclerosis and systemic lupus erythematosus.

Pulmonary arterial hypertension (PAH) is a severe manifestation of systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). Due to improvements in the understanding of the pathogenesis of these diseases, improved methodological rigour in the conduct of epidemiological studies and the advent of successful therapies, our understanding of SSc-PAH and SLE-PAH has evolved considerably. In this review we will review the current evidence regarding the prevalence, prognostic factors and survival estimates for SSc-PAH and SLE-PAH. In doing so, we will compare and contrast these two diseases, highlight clinically useful features, discuss methodological limitations of existing data, and draw attention to areas where research is needed.