A Rash Decision. The Hazards of the Wrongful Use of Adrenaline

Anaphylaxis is life-threatening and should be addressed urgently. Its treatment is not without side effects and an accurate diagnosis must be made to prevent potential harm by the wrongful use of medication. A 46-year-old woman with hypertension treated with angiotensin converting enzyme inhibitor (ACEI) presented to the emergency department with non-pitting oedema of the face and limbs. A hasty diagnosis of anaphylaxis was made and intravenous adrenaline administered. The patient developed a myocardial infarction caused by coronary artery spasm that required invasive intervention. The initial clinical picture was resolved when the ACEI was discontinued unmasking a case of ACEI-induced angioedema. The correct differentiation of these two apparently similar clinical entities is of utmost importance in the management of emergency department patients.info:eu-repo/semantics/publishedVersio

Doing research with children and young people who do not use speech for communication

Despite emphasis in policy on participation of disabled children, we still know relatively little about how to obtain the views of disabled children with significant communication impairment and their views are often overlooked in planning and service provision. This article describes how the views of children who do not use speech were accessed in research aiming to identify disabled children and young people's priorities regarding outcomes of social care and support services. The main challenge was to develop a method that was reliable, non-threatening, enjoyable and relevant to individual children, as well as enabling children to think beyond their everyday life and express what they aspire to

Mechanism of catalysis and inhibition of Mycobacterium tuberculosis SapM, implications for the development of novel antivirulence drugs.

Mycobacterium tuberculosis (Mtb) SapM is a secreted virulence factor critical for intracellular survival of the pathogen. The role of SapM in phagosome maturation arrest in host macrophages suggests its potential as a drug target to assist in the clearance of tuberculosis infection. However, the mechanism of action of SapM at the molecular level remains unknown. In this study, we provide new insights into the mechanism of catalysis, substrate specificity and inhibition of SapM, and we identify the critical residues for catalysis and substrate binding. Our findings demonstrate that SapM is an atypical monoester alkaline phosphatase, with a serine-based mechanism of catalysis probably metal-dependent. Particularly relevant to SapM function and pathogenesis, is its activity towards PI(4,5)P2 and PI3P, two phosphoinositides that function at the early stages of microbial phagocytosis and phagosome formation. This suggests that SapM may have a pleiotropic role with a wider importance on Mtb infection than initially thought. Finally, we have identified two inhibitors of SapM, L-ascorbic acid and 2-phospho-L-ascorbic, which define two different mechanisms by which the catalytic activity of this phosphatase could be regulated. Critically, we demonstrate that 2-phospho-L-ascorbic reduces mycobacterial survival in macrophage infections, hence confirming the potential of SapM as a therapeutic drug target

Self-consistent stability analysis of spherical shocks.

In this paper, we study self-similar solutions, and their linear stability as well, describing the flow within a spherical shell with finite thickness, expanding according to a power law of time, t q , where q>0. The shell propagates in a medium with initially uniform density and it is bounded by a strong shock wave at its outer border while the inner face is submitted to a time-dependent uniform pressure. For q=2/5, the well-known Sedov–Taylor solution is recovered. In addition, although both accelerated and decelerated shells can be unstable against dynamic perturbations, they exhibit highly different behaviors. Finally, the dispersion relation derived earlier by Vishniac (Vishniac, E.T. in Astrophys. J. 274:152, 1983) for an infinitely thin shell is obtained in the limit of an isothermal shock wave

Interleukin-10 polymorphisms in Spanish IgA deficiency patients: a case-control and family study

BACKGROUND: IgA deficiency (IgAD) is the most common primary immunodeficiency in Caucasians. Genetic and environmental factors are suspected to be involved in the development of the disease. Interleukin-10 (IL-10) is a cytokine with stimulatory activity on immunoglobulin production and it may be an important regulator in IgAD pathogenesis. The IL-10 gene contains several single nucleotide polymorphisms (SNPs) and two polymorphic microsatellites located in the 5'-flanking region. Our aim was to ascertain if any of these polymorphic markers are associated or linked to IgAD in Spanish patients. METHODS: We genotyped 278 patients with IgAD and 573 ethnically matched controls for the microsatellites IL-10R and IL-10G and for three single nucleotide polymorphisms at positions -1082, -819 and -592 in the proximal promoter of the gene. We also included in this study the parents of 194 patients in order to study the IL-10 haplotypes transmitted and not transmitted to the affected offspring. RESULTS: The only allele where a significant difference was observed in the comparison between IgA deficiency patients and controls was the IL-10G12 allele (OR = 1.58 and p = 0.021). However, this p value could not withstand a Bonferroni correction. None of the IL-10R or promoter SNP alleles was found at a different frequency when patients were compared with controls. CONCLUSION: Our data do not show any significant difference in IL-10 polymorphism frequencies between control and IgAD patient samples. Their haplotype distribution among patients and controls was also equivalent and therefore these microsatellites and SNPs do not seem to influence IgAD susceptibility

IL10 and IL10 receptor gene variation and outcomes after unrelated and related hematopoietic cell transplantation.

BACKGROUND: Results of a previous study with human leukocyte antigen (HLA)-identical siblings showed individual and synergistic associations of single nucleotide polymorphisms in the promoter region of the recipient's IL10 gene and the donor's IL10 receptor beta (IL-10RB) gene with development of grades III-IV acute graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation. METHODS: In this study of 936 patients who had unrelated donors, genotypes of single nucleotide polymorphisms in the IL10 gene and the IL-10RB gene were evaluated as correlates with outcomes after transplantation. RESULTS: We found no statistically significant associations of polymorphisms at positions -3575, -2763, -1082, and -592 of the IL10 gene or codon 238 of the IL10RB gene with severe acute GVHD, extensive chronic GVHD or nonrelapse mortality after hematopoietic cell transplantation. Among HLA-matched unrelated pairs, the patient's IL10/-592 genotype and donor's IL10RB/c238 genotype showed trends suggesting individual and combined associations with grades III-IV acute GVHD similar to those observed among patients with HLA-identical sibling donors. CONCLUSIONS: Although genetic variation in IL10 pathway affects risk of acute GVHD and non-relapse mortality in HLA-identical sibling transplants, the current results indicate that genetic variation in the IL10 pathway does not significant affect these outcomes in unrelated donor transplants suggesting that the strength of the alloimmune response in the latter exceeds the anti-inflammatory activity of IL10

MycoRRdb: A Database of Computationally Identified Regulatory Regions within Intergenic Sequences in Mycobacterial Genomes

The identification of regulatory regions for a gene is an important step towards deciphering the gene regulation. Regulatory regions tend to be conserved under evolution that facilitates the application of comparative genomics to identify such regions. The present study is an attempt to make use of this attribute to identify regulatory regions in the Mycobacterium species followed by the development of a database, MycoRRdb. It consist the regulatory regions identified within the intergenic distances of 25 mycobacterial species. MycoRRdb allows to retrieve the identified intergenic regulatory elements in the mycobacterial genomes. In addition to the predicted motifs, it also allows user to retrieve the Reciprocal Best BLAST Hits across the mycobacterial genomes. It is a useful resource to understand the transcriptional regulatory mechanism of mycobacterial species. This database is first of its kind which specifically addresses cis-regulatory regions and also comprehensive to the mycobacterial species. Database URL: http://mycorrdb.uohbif.in

Comparative Genomic Analyses of Copper Transporters and Cuproproteomes Reveal Evolutionary Dynamics of Copper Utilization and Its Link to Oxygen

Copper is an essential trace element in many organisms and is utilized in all domains of life. It is often used as a cofactor of redox proteins, but is also a toxic metal ion. Intracellular copper must be carefully handled to prevent the formation of reactive oxygen species which pose a threat to DNA, lipids, and proteins. In this work, we examined patterns of copper utilization in prokaryotes by analyzing the occurrence of copper transporters and copper-containing proteins. Many organisms, including those that lack copper-dependent proteins, had copper exporters, likely to protect against copper ions that inadvertently enter the cell. We found that copper use is widespread among prokaryotes, but also identified several phyla that lack cuproproteins. This is in contrast to the use of other trace elements, such as selenium, which shows more scattered and reduced usage, yet larger selenoproteomes. Copper transporters had different patterns of occurrence than cuproproteins, suggesting that the pathways of copper utilization and copper detoxification are independent of each other. We present evidence that organisms living in oxygen-rich environments utilize copper, whereas the majority of anaerobic organisms do not. In addition, among copper users, cuproproteomes of aerobic organisms were larger than those of anaerobic organisms. Prokaryotic cuproproteomes were small and dominated by a single protein, cytochrome c oxidase. The data are consistent with the idea that proteins evolved to utilize copper following the oxygenation of the Earth

Structure-based design of MptpB inhibitors that reduce multi-drug-resistant mycobacterium tuberculosis survival and infection burden in vivo

Mycobacterium tuberculosis protein-tyrosine-phosphatase B (MptpB) is a secreted virulence factor that subverts antimicrobial activity in the host. We report here the structure-based design of selective MptpB inhibitors that reduce survival of multidrug-resistant tuberculosis strains in macrophages and enhance killing efficacy by first-line antibiotics. Monotherapy with an orally bioavailable MptpB inhibitor reduces infection burden in acute and chronic guinea pig models and improves the overall pathology. Our findings provide a new paradigm for tuberculosis treatmen