Computational Construction of Toxicant Signaling Networks.

Humans and animals are regularly exposed to compounds that may have adverse effects on health. The Toxicity Forecaster (ToxCast) program was developed to use high throughput screening assays to quickly screen chemicals by measuring their effects on many biological end points. Many of these assays test for effects on cellular receptors and transcription factors (TFs), under the assumption that a toxicant may perturb normal signaling pathways in the cell. We hypothesized that we could reconstruct the intermediate proteins in these pathways that may be directly or indirectly affected by the toxicant, potentially revealing important physiological processes not yet tested for many chemicals. We integrate data from ToxCast with a human protein interactome to build toxicant signaling networks that contain physical and signaling protein interactions that may be affected as a result of toxicant exposure. To build these networks, we developed the EdgeLinker algorithm, which efficiently finds short paths in the interactome that connect the receptors to TFs for each toxicant. We performed multiple evaluations and found evidence suggesting that these signaling networks capture biologically relevant effects of toxicants. To aid in dissemination and interpretation, interactive visualizations of these networks are available at http://graphspace.org.

Acute Vasoreactivity Testing and Outcomes in Pulmonary Arterial Hypertension: A Call for Increased Testing.

BACKGROUND: Pulmonary arterial hypertension (PAH) has a progressive, unremitting clinical course. Vasoreactivity testing (VdT) during right heart catheterisation (RHC) identifies a subgroup with excellent long-term response to calcium channel blockade (CCB). Reporting on these patients is limited. Established in 2011, the Pulmonary Hypertension Society of Australia and New Zealand (PHSANZ) registry offers the opportunity to assess the frequency of VdT during RHC, treatment and follow up of PAH patients. METHODS: Registry data from 3,972 PAH patients with index RHC revealed 1,194 VdT appropriate patients. Data was analysed in three groups: 1) VdT+CCB+: VdT positive, CCB treated; 2) VdT+CCB-: VdT positive, no CCB prescribed, 3) VdT-/noVdT: VdT negative, or VdT not tested. Data was reviewed for adherence to guidelines, clinical response (World Health Organization functional class [WHO FC], 6-minute-walk-distance [6MWD], RHC), and outcomes (survival or lung transplantation). RESULTS: Patients included had idiopathic (IPAH=1,087), heritable (HPAH=67) and drug or toxin-induced PAH (DPAH=40). A VdT was performed in 22% (268/1,194), with incomplete data in 26% (70/268); 28% (55/198) were VdT+. Analysis group allocation was: VdT+CCB+ (33/55), VdT+CCB- (22/55), VdT- (143)/noVdT (996). From patients with 1-year data VdT+CCB+ and VdT-/noVdT patients improved WHO FC, 6MWD and cardiac index (CI); VdT+CCB- data remained similar. Within the VdT+CCB+ group, 30% (10/33) were long-term CCB responders with a 100% 5-year survival; non-responders had a 61% survival at 5.4 years. Long-term responders were younger at diagnosis (40 yrs vs 54 yrs). CONCLUSION: Use of VdT testing and documentation is poor in this contemporary patient cohort. Nonetheless, survival in VdT+CCB+ patients from the PHSANZ registry is excellent, supporting guidelines promoting VdT testing. Strategies to promote the use of VdT are warranted.

Cognitive strengths in first episode psychosis: a thematic analysis of clinicians' perspectives.

BACKGROUND: Cognitive deficits are associated with poor functional outcomes in individuals recovering from a first episode of psychosis (FEP). Existing treatments that target cognitive deficits in FEP may enhance cognitive function, but improvements to real-world functioning are less consistent. Furthermore, these treatments may not adequately address the personal recovery goals of young people attending FEP services. A novel cognitive strengths-based approach may overcome these shortcomings. METHODS: This qualitative study used semi-structured interviews to explore clinicians' (N = 12) perspectives toward the potential development of a cognitive strengths-based assessment or treatment in FEP. The interviews were analysed using thematic analysis. RESULTS: Five higher-order themes emerged: (1) pro-strengths attitude despite unfamiliarity and minimal use, (2) default to a cognitive deficit lens, (3) potential benefits of a cognitive strengths approach, (4) potential risks and barriers, and (5) considerations for successful implementation. While clinicians acknowledged their current deficit approach, they supported implementing a cognitive strengths assessment or treatment and highlighted their potential benefits for the personal recovery needs of young people with FEP. CONCLUSIONS: These findings suggest that a deficit-focused approach to cognitive function amongst clinicians may be common practice in FEP services. Nevertheless, a cognitive strengths approach was viewed favourably by clinicians and may represent a novel method of supporting personal recovery. Thus, the design and implementation of a cognitive strengths approach may be worthwhile. Future exploration of other stakeholder perspectives, such as young people with FEP, is essential.

Presentation and surgical management of a superficial temporal artery pseudoaneurysm: A case report.

INTRODUCTION AND IMPORTANCE: A Superficial Temporal Artery Pseudoaneurysm is an uncommon, but important, differential diagnosis for masses in the head and neck region. This work has been reported in line with SCARE 2020 criteria [1]. CASE PRESENTATION: An 81-year-old male presented to the Oral and Maxillofacial Department with a facial swelling that had been present for a duration of three weeks. A provisional diagnosis of a haematoma was made and an ultrasound carried out to confirm diagnosis. Ultrasonography and CT Angiography confirmed a pseudoaneurysm arising from the left superficial temporal artery. CLINICAL DISCUSSION: Although this is a relatively uncommon diagnosis it is important to be aware of the key diagnostic tools used to identify a pseudoaneurysm. Specifically, their potential to exclude a pseudoaneurysm prior to diagnosing a simple post-traumatic haematoma. This is important as the treatment strategies for the two pathologies differ considerably. Useful learning points from this case include diagnostic aids such as the unique pulsatile nature of the mass and the role of ultrasonography and CT Angiography in confirming diagnosis and guiding surgical management. CONCLUSION: Pseudoaneurysms are an important consideration as a differential diagnosis of masses in the head and neck region. This case report may impact upon management of future similar cases by highlighting significant aspects of their clinical diagnosis and surgical management, enabling early identification and appropriate management.

Left ventricular ischemia in pre-capillary pulmonary hypertension: a cardiovascular magnetic resonance study.

BACKGROUND: Prognosis in pulmonary arterial hypertension (PAH) is largely dependent on right ventricular (RV) function. However, recent studies have suggested the presence of left ventricular (LV) dysfunction in PAH patients. The potential role of LV ischemia, as a contributor to progressive LV dysfunction, has not been systematically studied in PAH. We aim to assess the presence and extent of LV myocardial ischemia in patients with known PH and without obstructive coronary artery disease (CAD), using oxygen-sensitive (OS) cardiovascular magnetic resonance (CMR) and stress/rest CMR T1 mapping. METHODS: We prospectively recruited 28 patients with right heart catheter-proven PH and no significant CAD, 8 patients with known CAD and 11 normal age-matched controls (NC). OS-CMR images were acquired using a T2* sequence and T1 maps were acquired using Shortened Modified Look-Locker Inversion recovery (ShMOLLI) at rest and adenosine-induced stress vasodilatation; ΔOS-CMR signal intensity (SI) index (stress/rest SI) and ΔT1 reactivity (stress-rest/rest T1 mapping) were calculated. RESULTS: Global LV ΔOS SI index was significantly lower in PH patients compared with controls (11.1%±6.7% vs. 20.5%±10.5%, P=0.016), as was ΔT1 reactivity (5.2%±4.5% vs. 8.0%±2.9%, P=0.047). The ischemic segments of CAD patients had comparable ΔOS SI (10.3%±6.4% vs. 11.1%±6.7%, P=0.773) to PH patients, but lower ΔT1 reactivity (1.1%±4.2% vs. 5.2%±4.5%, P=0.036). CONCLUSIONS: Decreased OS-CMR SI and T1 reactivity signify the presence of impaired myocardial oxygenation and vasodilatory response in PH patients. Given their unobstructed epicardial coronary arteries, this is likely secondary to coronary microvascular dysfunction (CMD).

Cognitive strengths-based assessment and intervention in first-episode psychosis: A complementary approach to addressing functional recovery?

People who have experienced psychosis describe functional and personal recovery as a key goal of treatment. To date, the early, pervasive and influential role of cognitive impairments in functional recovery in psychosis has been predominantly addressed using approaches aiming to remediate clinically-defined cognitive deficits. Despite acceptance of the recovery and strengths-based model of care for first-episode psychosis (FEP), there has been minimal attention paid to the potential for strengths-based approaches to be extended to cognitive function. The purpose of this review is to present the case for supplementary strengths-based approaches to addressing cognition and functioning in FEP. In this review we appraise current approaches to addressing cognition in FEP that have primarily focused on remediating cognitive impairment, showing evidence for inconsistent engagement and generally small treatment effects. We describe the important role of psychological factors such as motivation and self-efficacy in mediating the relationship between cognitive performance and functional outcome, and draw on positive psychology and self-determination theory as models for potential application in relation to a cognitive-strengths paradigm. Our review supports the argument for complementing approaches for remediating cognitive deficits by applying strengths-based or positive psychology approaches to the domain of cognition as a promising avenue for further enhancing personal and functional recovery from FEP.

Pharmacological Treatment of Pulmonary Arterial Hypertension in Australia: Current Trends and Challenges.

BACKGROUND: Combination drug therapy for pulmonary arterial hypertension (PAH) is the international standard of care for most patients, however in Australia there are barriers to drug access. This study evaluates current treatment of PAH patients in Australia and the consistency of therapy with international guidelines. METHODS: Cross-sectional analysis of patients with Group 1 PAH enrolled in the Pulmonary Hypertension Society of Australia and New Zealand Registry (PHSANZ) at 31 December 2017. Drug treatment was classified as monotherapy or combination therapy and adequacy of treatment was determined by risk status assessment using the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) 2.0 risk calculator. Predictors of monotherapy were assessed using a generalised linear model with Poisson distribution and logarithmic link function. RESULTS: 1,046 patients met the criteria for analysis. Treatment was classified as monotherapy in 536 (51%) and combination therapy in 510 (49%) cases. Based on REVEAL 2.0, 184 (34%) patients on monotherapy failed to meet low-risk criteria and should be considered inadequately treated. Independent predictors of monotherapy included age greater than 60 years (risk ratio [RR] 1.23, 95% confidence interval [CI] 1.09-1.38; p=0.001), prevalent enrolment in the registry (RR 1.21 [95%CI 1.08-1.36]; p=0.001) and comorbid systemic hypertension (RR 1.17 [95%CI 1.03-1.32]; p=0.014), while idiopathic/heritable/drug-induced PAH subtype (RR 0.85 [95%CI 0.76-0.96]; p=0.006), functional class IV (RR 0.50 [95%CI 0.29-0.86]; p=0.012), increased right ventricular systolic pressure (RR 0.99 [95%CI 0.99-1.00]; p<0.001) and increased pulmonary vascular resistance (RR 0.96 [95%CI 0.95-0.98]; p<0.001) were less likely to be associated with monotherapy. CONCLUSIONS: Most Australian PAH patients are treated with monotherapy and a significant proportion remain at risk of poor outcomes. This is below the standard of care recommended by international guidelines and at risk patients should be escalated to combination therapy.

Diagnostic delay in pulmonary arterial hypertension: Insights from the Australian and New Zealand pulmonary hypertension registry.

BACKGROUND AND OBJECTIVE: Early diagnosis of PAH is clinically challenging. Patterns of diagnostic delay in Australian and New Zealand PAH populations have not been explored in large-scale studies. We aimed to evaluate the magnitude, risk factors and survival impact of diagnostic delay in Australian and New Zealand PAH patients. METHODS: A cohort study of PAH patients from the PHSANZ Registry diagnosed from 2004 to 2017 was performed. Diagnostic interval was the time from symptom onset to diagnostic right heart catheterization as recorded in the registry. Factors associated with diagnostic delay were analysed in a multivariate logistic regression model. Survival rates were compared across patients based on the time to diagnosis using Kaplan-Meier method and Cox regression. RESULTS: A total of 2044 patients were included in analysis. At diagnosis, median age was 58 years (IQR: 43-69), female-to-male ratio was 2.8:1 and majority of patients were in NYHA FC III-IV (82%). Median diagnostic interval was 1.2 years (IQR: 0.6-2.7). Age, CHD-PAH, obstructive sleep apnoea and peripheral vascular disease were independently associated with diagnostic interval of ≥1 year. No improvement in diagnostic interval was seen during the study period. Longer diagnostic interval was associated with decreased 5-year survival. CONCLUSION: PAH patients experience significant diagnostic interval, which has not improved despite increased community awareness. Age, cardiovascular and respiratory comorbidities are significantly associated with longer time to diagnosis. Mortality rates appear higher in patients who experience longer diagnostic interval.

Retrospective Validation of the REVEAL 2.0 Risk Score With the Australian and New Zealand Pulmonary Hypertension Registry Cohort.

BACKGROUND: Pulmonary arterial hypertension (PAH) prognosis has improved with targeted therapies; however, the long-term outlook remains poor. Objective multiparametric risk assessment is recommended to identify patients at risk of early morbidity and mortality, and for optimization of treatment. The US Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) 2.0 risk score is a new model proposed for the follow-up of patients with PAH but has not been externally validated. METHODS: The REVEAL 2.0 risk score was applied to a mixed prevalent and incident cohort of patients with PAH (n = 1,011) from the Pulmonary Hypertension Society of Australia and New Zealand (PHSANZ) Registry. Kaplan-Meier survival was estimated for each REVEAL 2.0 risk score strata and for a simplified three-category (low, intermediate, and high risk) model. Sensitivity analysis was performed on an incident-only cohort. RESULTS: The REVEAL 2.0 model effectively discriminated risk in the large external PHSANZ Registry cohort, with a C statistic of 0.74 (both for full eight-tier and three-category models). When applied to incident cases only, the C statistic was 0.73. The three-category REVEAL 2.0 model demonstrated robust separation of 12- and 60-month survival estimates (all risk category comparisons P < .001). Although the full eight-tier REVEAL 2.0 model separated patients at low, intermediate, and high risk, survival estimates overlapped within some of the intermediate- and high-risk strata. CONCLUSIONS: The REVEAL 2.0 risk score was validated in a large external cohort from the PHSANZ Registry. The REVEAL 2.0 model can be applied for risk assessment of patients with PAH at follow-up. The simplified three-category model may be preferred for clinical use and for future comparison with other prognostic models.

Feasibility of oxygen sensitive cardiac magnetic resonance of the right ventricle in pulmonary artery hypertension.

BACKGROUND: Progressive right ventricular (RV) dysfunction in pulmonary arterial hypertension (PAH) which is contributed by RV ischemia leads to adverse clinical outcomes. Oxygen-sensitive (OS) cardiovascular magnetic resonance (CMR) has been used to determine the in vivo myocardial oxygenation of the left ventricle (LV). The aims of the present study were therefore to determine the feasibility of RV targeted rest/stress OS-CMR imaging in PAH patients and healthy volunteers. METHODS: We prospectively recruited 20 patients with right heart catheter proven PAH and 9 healthy age matched controls (NC). The CMR examination involved standard functional imaging and OS-CMR imaging. An OS-CMR signal intensity (SI) index (stress/rest SI) was acquired at RV anterior, RV free-wall and RV inferior segments. In the LV, the OS-CMR SI index was acquired globally. RESULTS: Reliable OS SI changes were only obtained from the RV inferior segment. As RV dysfunction in PAH is a global process, hence this segment was used in both patients and NC for further comparison. RV OS-CMR SI change between rest and stress in the NC was 17%±5% (mean ± SD). Nine of 20 (45%) of the PAH patients had a mean OS SI change of less than 9% (or ≥2 SD different from the mean values in NC). Overall, RV OS SI index between the PAH patients and NC was 11%±9% vs. 17%±5% (P=0.045) in the RV inferior segment. In the LV, the global OS-CMR SI index between the PAH patients and NC was 11%±7% vs. 21%±9% (P=0.019). There was a strong correlation between RV Inf OS-CMR SI and LV OS-CMR SI (r=0.86, P<0.001). CONCLUSIONS: In this small pilot study, pharmacological induced OS-CMR is a feasible and safe technique to identify and study myocardial oxygenation in the RV of PAH patients.

Survival of Idiopathic Pulmonary Arterial Hypertension Patients in the Modern Era in Australia and New Zealand.

BACKGROUND: Epidemiology and treatment strategies continue to evolve in pulmonary arterial hypertension (PAH). We sought to define the characteristics and survival of patients with idiopathic, heritable and drug-induced PAH in the current management era. METHODS: Consecutive cases of idiopathic, heritable and drug-induced PAH were prospectively enrolled into an Australian and New Zealand Registry. RESULTS: Between January 2012 and December 2016, a total of 220 incident cases were enrolled (mean age 57.2±18.7years, female 69.5%) and followed for a median duration of 26 months (IQR17-39). Co-morbidities were common such as obesity (34.1%), systemic hypertension (30.5%), coronary artery disease (16.4%) and diabetes mellitus (19.5%). Initial combination therapy was used in 54 patients (dual, n=50; triple, n=4). Estimated survival rates at 1-year, 2-years and 3-years were 95.6% (CI 92.8-98.5%), 87.3% (CI 82.5-92.4%) and 77.0% (CI 70.3-84.3%), respectively. Multivariate analysis showed that male sex and lower 6-minute distance at diagnosis independently predicted worse survival, whereas obesity was associated with improved survival. Co-morbidities other than obesity did not impact survival. Initial dual oral combination therapy was associated with a trend towards better survival compared with initial oral monotherapy (adjusted HR=0.27, CI 0.06-1.18, p=0.082) CONCLUSIONS: The epidemiology and survival of patients with idiopathic PAH in Australia and New Zealand are similar to contemporary registries reported in Europe and North America. Male sex and poorer exercise capacity are predictive of mortality whereas obesity appears to exert a protective effect. Despite current therapies, PAH remains a life-threatening disease associated with significant early mortality.

The predictive capabilities of a novel cardiovascular magnetic resonance derived marker of cardiopulmonary reserve on established prognostic surrogate markers in patients with pulmonary vascular disease: results of a longitudinal pilot study.

BACKGROUND: No unified method exists to effectively predict and monitor progression of pulmonary arterial hypertension (PAH). We assessed the longitudinal relationship between a novel marker of cardiopulmonary reserve and established prognostic surrogate markers in patients with pulmonary vascular disease. METHODS AND RESULTS: Twenty participants with confirmed (n = 14) or at high risk (n = 6) for PAH underwent cardiovascular magnetic resonance (CMR) at baseline and after ~6 months of guideline-appropriate management. Ten PAH participants underwent RHC within 48 h of each CMR. RHC (mean pulmonary arterial pressure, mPAP; pulmonary vascular resistance index, PVRI; cardiac index, CI) and phase-contrast CMR (mean pulmonary arterial blood flow velocity, meanPAvel) measurements were taken at rest and during continuous adenosine infusion (70/140/210 mcg/kg/min). Initial meanPAvel's (rest and hyperemic) were correlated with validated surrogate prognostic parameters (CMR: RV ejection fraction, RVEF; RV end systolic volume indexed, RVESVI; RHC: PVRI, CI; biomarker: NT-pro brain natriuretic peptide, NTpBNP; clinical: 6-min walk distance, 6MWD), a measure of pulmonary arterial stiffness (elastic modulus) and volumetric estimation of RV ventriculoarterial (VA) coupling. Changes in meanPAvel's were correlated with changes in comparator parameters over time. At initial assessment, meanPAvel at rest correlated significantly with PVRI (inversely), CI (positively) and elastic modulus (inversely) (R 2 > 0.37,P < 0.05 for all), whereas meanPAvel at peak hyperemia correlated significantly with PVRI, RVEF, RVESVI, 6MWD, elastic modulus and VA coupling (R 2 > 0.30,P < 0.05 for all). Neither resting or hyperemia-derived meanPAvel correlated with NTpBNP levels. Initial meanPAvel at rest correlated significantly with RVEF, RVESVI, CI and VA coupling at follow up assessment (R 2 > 0.2,P < 0.05 for all) and initial meanPAvel at peak hyperemia correlated with RVEF, RVESVI, PVRI and VA coupling (R 2 > 0.37,P < 0.05 for all). Change in meanPAvel at rest over time did not show statistically significant correlation with change in prognostic parameters, while change in meanPAvel at peak hyperemia did show a significant relationship with ΔRVEF, ΔRVESVI, ΔNTpBNP and ΔCI (R 2 > 0.24,P < 0.05 for all). CONCLUSION: MeanPAvel during peak hyperemia correlated with invasive, non-invasive and clinical prognostic parameters at different time points. Further studies with predefined clinical endpoints are required to evaluated if this novel tool is a marker of disease progression in patients with pulmonary vascular disease.

Kounis syndrome and hypersensitivity myocarditis - One and the same? Insights from cardiac magnetic resonance imaging.

Myocarditis and acute coronary syndrome are both described in the setting of concurrent hypersensitivity reactions to a variety of allergenic triggers (hypersensitivity myocarditis and Kounis syndrome respectively). Mast cell degranulation is thought to be pivotal in the pathogenesis of both clinical entities. Cardiac magnetic resonance imaging (CMR) has assumed a key role in the assessment of chest pain syndromes, providing a useful non-invasive tool to aid clinical decision-making. Despite increasing availability and uptake of CMR, only a small fraction of published Kounis syndrome cases report CMR findings, and confirmation of myocardial infarction remains elusive. We present a case of presumed Kounis syndrome with comprehensive CMR imaging that provides an insight into why these two well-described clinical entities share many clinical features - perhaps they are one and the same. .

Ex vivo paracrine properties of cardiac tissue: Effects of chronic heart failure.

BACKGROUND: Cardiac regenerative responses are responsive to paracrine factors. We hypothesize that chronic heart failure (HF) in pediatric patients affects cardiac paracrine signaling relevant to resident c-kit(+)cluster of differentiation (CD)34- cardiac stem cells (CSCs). METHODS: Discarded atrial septum (huAS) and atrial appendages (huAA) from pediatric patients with HF (huAA-HF; n = 10) or without HF (n = 3) were explanted and suspension explant cultured in media. Conditioned media were screened for 120 human factors using unedited monoclonal antibody-based arrays. Significantly expressed (relative chemiluminescence >30 of 100) factors are reported (secretome). Emigrated cells were immunoselected for c-kit and enumerated as CSCs. RESULTS: After culture Day 7, CSCs emigrate from huAA but not huAS. The huAA secretome during CSC emigration included hepatocyte growth factor (HGF), epithelial cell-derived neutrophil attractant-78 (ENA-78)/chemokine (C-X-C motif) ligand (CXCL) 5, growth-regulated oncogene-α (GRO-α)/CXCL1, and macrophage migration inhibitory factor (MIF), candidate pro-migratory factors not present in the huAS secretome. Survival/proliferation of emigrated CSCs required coculture with cardiac tissue or tissue-conditioned media. Removal of huAA (Day 14) resulted in the loss of all emigrated CSCs (Day 28) and in decreased expression of 13 factors, including HGF, ENA-78/CXCL5, urokinase-type plasminogen activator receptor (uPAR)/CD87, and neutrophil-activating protein-2 (NAP-2)/CXCL7 candidate pro-survival factors. Secretomes of atrial appendages from HF patients have lower expression of 14 factors, including HGF, ENA-78/CXCL5, GRO-α/CXCL1, MIF, NAP-2/CXCL7, uPAR/CD87, and macrophage inflammatory protein-1α compared with AA from patients without HF. CONCLUSIONS: Suspension explant culturing models paracrine and innate CSC interactions in the heart. In pediatric patients, heart failure has an enduring effect on the ex vivo cardiac-derived secretome, with lower expression of candidate pro-migratory and pro-survival factors for CSCs.

Heart cells with regenerative potential from pediatric patients with end stage heart failure: a translatable method to enrich and propagate.

Background. Human cardiac-derived progenitor cells (hCPCs) have shown promise in treating heart failure (HF) in adults. The purpose of this study was to describe derivation of hCPCs from pediatric patients with end-stage HF. Methods. At surgery, discarded right atrial tissues (hAA) were obtained from HF patients (n = 25; hAA-CHF). Minced tissues were suspended in complete (serum-containing) DMEM. Cells were selected for their tissue migration and expression of stem cell factor receptor (hc-kit). Characterization of hc-kit(positive) cells included immunohistochemical screening with a panel of monoclonal antibodies. Results. Cells, including phase-bright cells identified as hc-kit(positive), spontaneously emigrated from hAA-CHF in suspended explant cultures (SEC) after Day 7. When cocultured with tissue, emigrated hc-kit(positive) cells proliferated, first as loosely attached clones and later as multicellular clusters. At Day 21~5% of cells were hc-kit(positive). Between Days 14 and 28 hc-kit(positive) cells exhibited mesodermal commitment (GATA-4(positive) and NKX2.5(positive)); then after Day 28 cardiac lineages (flk-1(positive), smooth muscle actin(positive), troponin-I(positive), and myosin light chain(positive)). Conclusions. C-kit(positive) hCPCs can be derived from atrial tissue of pediatric patients with end-stage HF. SEC is a novel culture method for derivation of migratory hc-kit(positive) cells that favors clinical translation by reducing the need for exogenously added factors to expand hCPCs in vitro.

Abdominal wall abscess due to penetrating caecal cancer: an unusual presentation.

INTRODUCTION: The common presentations of caecal cancer are anaemia, weight loss and obstructive symptoms. Caecal cancer perforation and abscess formation are rare and mostly intra- or retroperitoneal. CASE REPORT: We present a case of abdominal wall abscess secondary to penetrating caecal cancer, the inability of computed tomography scan in aiding the diagnosis and successful surgical excision. DISCUSSION: When caecal cancer presents atypically, the preoperative diagnosis is difficult, but complete excision is possible even with abdominal wall penetration.

Hemodynamics in pulmonary arterial hypertension (PAH): do they explain long-term clinical outcomes with PAH-specific therapy?

BACKGROUND: Pulmonary arterial hypertension (PAH) has witnessed dramatic treatment advances over the past decade. However, with the exception of epoprostenol, data from short-term randomized controlled trials (RCTs) have not shown a benefit of these drugs on survival. There remains a need to differentiate between available therapies and current endpoint responses which in turn, could be used to guide treatment selection and provide long-term prognostic information for patients. METHODS: We performed a systematic literature search of MEDLINE and EMBASE databases for RCTs of PAH-specific therapy published between January 1980 and May 2009. Articles were selected if they contained a placebo comparator and described hemodynamic changes from baseline. We applied the weighted mean change in hemodynamic variables to the equation developed by the National Institutes of Health (NIH) Registry to estimate long-term survival with each therapy. RESULTS: Ten RCTs involving 1,635 patients met the inclusion criteria. Suitable hemodynamic data were identified for bosentan, sitaxentan, sildenafil, epoprostenol, beraprost and treprostinil. 77.6% of patients were female and the mean (SD) age was 46.5 +/- 4.9 years. 55.5% of patients had idiopathic PAH (iPAH), 23.9% PAH related to connective tissue disease, and 18.2% PAH related to congenital heart disease. Based on the effects observed in short-term trials and, relative to placebo, all analyzed therapies improved survival. The estimated 1-year survival was 78.4%, 77.8%, 76.1%, 75.8%, 75.2%, and 74.1% for epoprostenol, bosentan, treprostinil, sitaxentan, sildenafil, and beraprost, respectively. These estimates are considerably lower than the 1-year observed survival reported in several open-label and registry studies with PAH-specific therapies: 88% - 97%. CONCLUSION: When applied to the NIH Registry equation, hemodynamic changes from baseline appear to underestimate the survival benefits observed with long-term PAH therapy.