Diagnostic performance and reference values of novel biomarkers of paediatric heart failure

Objective: Biomarkers play a pivotal role in heart failure (HF) management. Reference values and insights from studies in adults cannot be extrapolated to the paediatric population due to important differences in pathophysiology and compensatory reserve. We assessed the diagnostic utility of four novel biomarkers in paediatric HF. Methods: Midregional (MR) pro-atrial natriuretic peptide (proANP), soluble ST2 (sST2), growth differentiation factor-15 (GDF-15), MR-pro-adrenomedullin (proADM) and N-terminal pro-B natriuretic peptide (NT-proBNP) were measured in 114 patients and 89 controls. HF was defined as the presence of HF symptoms and/or abnormal systolic ventricular function. Receiver-operating characteristics were plotted, and the area under the curve (AUC) was measured. This was repeated for subgroups with cardiomyopathy and congenital heart disease (CHD). Ventricular systolic function was measured by magnetic resonance or echocardiography. Reference values were calculated according to the current guidelines. Results: The AUC for diagnosing HF was 0.76 for MR-proANP (CI 0.70 to 0.84) and 0.82 for NT-proBNP (CI 0.75 to 0.88). These parameters performed similarly in the subgroups with CHD and cardiomyopathy. By contrast, MR-proADM, GDF-15 and sST2 performed poorly. When used in conjunction with NT-proBNP, no parameter added significantly to its diagnostic accuracy. NT-proBNP, MR-proANP, GDF-15 and sST2 could accurately discriminate between patients with preserved and patients with poor functional status. In a subset of patients with dilated cardiomyopathy, NT-proBNP, MR-proANP, MR-proADM and GDF-15 were associated with poor LV function. Conclusions: MR-proANP could accurately detect HF in children and adolescents. Its diagnostic performance was comparable with that of NT-proBNP, regardless of the underlying condition. Reference values are presented

Fitness Ranking of Individual Mutants Drives Patterns of Epistatic Interactions in HIV-1

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Experiences of wearing support garments by people living with a urostomy

BACKGROUND:support garments are commonly worn by people with a urostomy but there are no published data about their experiences of doing so. AIMS:to identify the views of people living with a urostomy on the role of support garments. METHODS:a cross-sectional survey of the stoma population's experiences of support garments was conducted in 2018. Recruitment was by social media. The free-text responses provided by a sub-sample of 58 people out of 103 respondents with a urostomy, were analysed. FINDINGS:thematic analysis revealed four themes: physical self-management; psychosocial self-management; lifestyle; and healthcare advice and support. There were mixed feelings about the value of support garments. Many cited a sense of reassurance and confidence and being able to be more sociable and active; others reported discomfort and uncertainty about their value. CONCLUSION:these findings add new understanding of experiences of support garments and provide novel theoretical insights about life with a urostomy

MAGE-A cancer/testis antigens inhibit MDM2 ubiquitylation function and promote increased levels of MDM4

Melanoma antigen A (MAGE-A) proteins comprise a structurally and biochemically similar sub-family of Cancer/Testis antigens that are expressed in many cancer types and are thought to contribute actively to malignancy. MAGE-A proteins are established regulators of certain cancer-associated transcription factors, including p53, and are activators of several RING finger-dependent ubiquitin E3 ligases. Here, we show that MAGE-A2 associates with MDM2, a ubiquitin E3 ligase that mediates ubiquitylation of more than 20 substrates including mainly p53, MDM2 itself, and MDM4, a potent p53 inhibitor and MDM2 partner that is structurally related to MDM2. We find that MAGE-A2 interacts with MDM2 via the N-terminal p53-binding pocket and the RING finger domain of MDM2 that is required for homo/hetero-dimerization and for E2 ligase interaction. Consistent with these data, we show that MAGE-A2 is a potent inhibitor of the E3 ubiquitin ligase activity of MDM2, yet it does not have any significant effect on p53 turnover mediated by MDM2. Strikingly, however, increased MAGE-A2 expression leads to reduced ubiquitylation and increased levels of MDM4. Similarly, silencing of endogenous MAGE-A expression diminishes MDM4 levels in a manner that can be rescued by the proteasomal inhibitor, bortezomid, and permits increased MDM2/MDM4 association. These data suggest that MAGE-A proteins can: (i) uncouple the ubiquitin ligase and degradation functions of MDM2; (ii) act as potent inhibitors of E3 ligase function; and (iii) regulate the turnover of MDM4. We also find an association between the presence of MAGE-A and increased MDM4 levels in primary breast cancer, suggesting that MAGE-A-dependent control of MDM4 levels has relevance to cancer clinically

A patient with Graves' disease who survived despite developing thyroid storm and lactic acidosis

A 56-year-old woman with Graves' disease presented with the complaints of diarrhea and palpitations. Physical examination and laboratory data revealed hypothermia and signs of mild hyperthyroidism, heart failure, hepatic dysfunction with jaundice, hypoglycemia, and lactic acidosis. The patient was diagnosed as having developed the complication of thyroid storm in the absence of marked elevation of the thyroid hormone levels, because of the potential hepatic and cardiac dysfunctions caused by heavy alcohol drinking. A year later, after successful treatment, the patient remains well without any clinical evidence of heart failure or hepatic dysfunction. Thyroid storm associated with lactic acidosis and hypothermia is a serious condition and has rarely been reported. Prompt treatment is essential even if the serum thyroid hormone levels are not markedly elevated. We present a report about this patient, as her life could eventually be saved

The effect of bone marrow microenvironment on the functional properties of the therapeutic bone marrow-derived cells in patients with acute myocardial infarction

<p>Abstract</p> <p>Background</p> <p>Treatment of acute myocardial infarction with stem cell transplantation has achieved beneficial effects in many clinical trials. The bone marrow microenvironment of ST-elevation myocardial infarction (STEMI) patients has never been studied even though myocardial infarction is known to cause an imbalance in the acid-base status of these patients. The aim of this study was to assess if the blood gas levels in the bone marrow of STEMI patients affect the characteristics of the bone marrow cells (BMCs) and, furthermore, do they influence the change in cardiac function after autologous BMC transplantation. The arterial, venous and bone marrow blood gas concentrations were also compared.</p> <p>Methods</p> <p>Blood gas analysis of the bone marrow aspirate and peripheral blood was performed for 27 STEMI patients receiving autologous stem cell therapy after percutaneous coronary intervention. Cells from the bone marrow aspirate were further cultured and the bone marrow mesenchymal stem cell (MSC) proliferation rate was determined by MTT assay and the MSC osteogenic differentiation capacity by alkaline phosphatase (ALP) activity assay. All the patients underwent a 2D-echocardiography at baseline and 4 months after STEMI.</p> <p>Results</p> <p>As expected, the levels of pO₂, pCO₂, base excess and HCO₃were similar in venous blood and bone marrow. Surprisingly, bone marrow showed significantly lower pH and Na⁺and elevated K⁺levels compared to arterial and venous blood. There was a positive correlation between the bone marrow pCO₂and HCO₃levels and MSC osteogenic differentiation capacity. In contrast, bone marrow pCO₂and HCO₃levels displayed a negative correlation with the proliferation rate of MSCs. Patients with the HCO₃level below the median value exhibited a more marked change in LVEF after BMC treatment than patients with HCO₃level above the median (11.13 ± 8.07% vs. 2.67 ± 11.89%, P = 0.014).</p> <p>Conclusions</p> <p>Low bone marrow pCO₂and HCO₃levels may represent the optimal environment for BMCs in terms of their efficacy in autologous stem cell therapy in STEMI patients.</p

Rat model of metastatic breast cancer monitored by MRI at 3 tesla and bioluminescence imaging with histological correlation

<p>Abstract</p> <p>Background</p> <p>Establishing a large rodent model of brain metastasis that can be monitored using clinically relevant magnetic resonance imaging (MRI) techniques is challenging. Non-invasive imaging of brain metastasis in mice usually requires high field strength MR units and long imaging acquisition times. Using the brain seeking MDA-MB-231BR transfected with luciferase gene, a metastatic breast cancer brain tumor model was investigated in the nude rat. Serial MRI and bioluminescence imaging (BLI) was performed and findings were correlated with histology. Results demonstrated the utility of multimodality imaging in identifying unexpected sights of metastasis and monitoring the progression of disease in the nude rat.</p> <p>Methods</p> <p>Brain seeking breast cancer cells MDA-MB-231BR transfected with firefly luciferase (231BRL) were labeled with ferumoxides-protamine sulfate (FEPro) and 1-3 × 10⁶cells were intracardiac (IC) injected. MRI and BLI were performed up to 4 weeks to monitor the early breast cancer cell infiltration into the brain and formation of metastases. Rats were euthanized at different time points and the imaging findings were correlated with histological analysis to validate the presence of metastases in tissues.</p> <p>Results</p> <p>Early metastasis of the FEPro labeled 231BRL were demonstrated onT2*-weighted MRI and BLI within 1 week post IC injection of cells. Micro-metastatic tumors were detected in the brain on T2-weighted MRI as early as 2 weeks post-injection in greater than 85% of rats. Unexpected skeletal metastases from the 231BRL cells were demonstrated and validated by multimodal imaging. Brain metastases were clearly visible on T2 weighted MRI by 3-4 weeks post infusion of 231BRL cells, however BLI did not demonstrate photon flux activity originating from the brain in all animals due to scattering of the photons from tumors.</p> <p>Conclusion</p> <p>A model of metastatic breast cancer in the nude rat was successfully developed and evaluated using multimodal imaging including MRI and BLI providing the ability to study the temporal and spatial distribution of metastases in the brain and skeleton.</p

Going Coastal: Shared Evolutionary History between Coastal British Columbia and Southeast Alaska Wolves (Canis lupus)

Many coastal species occupying the temperate rainforests of the Pacific Northwest in North America comprise endemic populations genetically and ecologically distinct from interior continental conspecifics. Morphological variation previously identified among wolf populations resulted in recognition of multiple subspecies of wolves in the Pacific Northwest. Recently, separate genetic studies have identified diverged populations of wolves in coastal British Columbia and coastal Southeast Alaska, providing support for hypotheses of distinct coastal subspecies. These two regions are geographically and ecologically contiguous, however, there is no comprehensive analysis across all wolf populations in this coastal rainforest.By combining mitochondrial DNA datasets from throughout the Pacific Northwest, we examined the genetic relationship between coastal British Columbia and Southeast Alaska wolf populations and compared them with adjacent continental populations. Phylogenetic analysis indicates complete overlap in the genetic diversity of coastal British Columbia and Southeast Alaska wolves, but these populations are distinct from interior continental wolves. Analyses of molecular variation support the separation of all coastal wolves in a group divergent from continental populations, as predicted based on hypothesized subspecies designations. Two novel haplotypes also were uncovered in a newly assayed continental population of interior Alaska wolves.We found evidence that coastal wolves endemic to these temperate rainforests are diverged from neighbouring, interior continental wolves; a finding that necessitates new international strategies associated with the management of this species

Multiscale Currents Observed by MMS in the Flow Braking Region

We present characteristics of current layers in the off-equatorial near-Earth plasma sheet boundary observed with high time-resolution measurements from the Magnetospheric Multiscale mission during an intense substorm associated with multiple dipolarizations. The four Magnetospheric Multiscale spacecraft, separated by distances of about 50 km, were located in the southern hemisphere in the dusk portion of a substorm current wedge. They observed fast flow disturbances (up to about 500 km/s), most intense in the dawn-dusk direction. Field-aligned currents were observed initially within the expanding plasma sheet, where the flow and field disturbances showed the distinct pattern expected in the braking region of localized flows. Subsequently, intense thin field-aligned current layers were detected at the inner boundary of equatorward moving flux tubes together with Earthward streaming hot ions. Intense Hall current layers were found adjacent to the field-aligned currents. In particular, we found a Hall current structure in the vicinity of the Earthward streaming ion jet that consisted of mixed ion components, that is, hot unmagnetized ions, cold E × B drifting ions, and magnetized electrons. Our observations show that both the near-Earth plasma jet diversion and the thin Hall current layers formed around the reconnection jet boundary are the sites where diversion of the perpendicular currents take place that contribute to the observed field-aligned current pattern as predicted by simulations of reconnection jets. Hence, multiscale structure of flow braking is preserved in the field-aligned currents in the off-equatorial plasma sheet and is also translated to ionosphere to become a part of the substorm field-aligned current system