Characterization of the active site and calcium binding in cytochromecnitrite reductases

The decahaem homodimeric cytochrome c nitrite reductase (NrfA) is expressed within the periplasm of a wide range of Gamma-, Delta- and Epsilon-proteobacteria and is responsible for the six-electron reduction of nitrite to ammonia. This allows nitrite to be used as a terminal electron acceptor, facilitating anaerobic respiration while allowing nitrogen to remain in a biologically available form. NrfA has also been reported to reduce nitric oxide (a reaction intermediate) and sulfite to ammonia and sulfide respectively, suggesting a potential secondary role as a detoxification enzyme. The protein sequences and crystal structures of NrfA from different bacteria and the closely related octahaem nitrite reductase from Thioalkalivibrio nitratireducens (TvNir) reveal that these enzymes are homologous. The NrfA proteins contain five covalently attached haem groups, four of which are bis-histidine-co-ordinated, with the proximal histidine being provided by the highly conserved CXXCH motif. These haems are responsible for intraprotein electron transfer. The remaining haem is the site for nitrite reduction, which is ligated by a novel lysine residue provided by a CXXCK haem-binding motif. The TvNir nitrite reductase has five haems that are structurally similar to those of NrfA and three extra bis-histidine-coordinated haems that precede the NrfA conserved region. The present review compares the protein sequences and structures of NrfA and TvNir and discusses the subtle differences related to active-site architecture and Ca2+ binding that may have an impact on substrate reduction

A national survey on violence and discrimination among people with disabilities

Background: The aim of the study was to quantify levels of violence and discrimination among people with disabilities and analyze the effects of gender and the type and degree of disability. Methods: The study analyzed data on self-reported violence and discrimination from a Danish national survey of 18,019 citizens, of whom 4519 reported a physical disability and 1398 reported a mental disability. Results: Individuals with disabilities reported significantly higher levels of violence than those without. Specifically, individuals reporting a mental disability reported higher levels of violence and discrimination. Significant gender differences were found with regard to type of violence: while men with disabilities were more likely to report physical violence, women with disabilities were more likely to report major sexual violence, humiliation and discrimination. Neither severity nor visibility of disability was found to be a significant factor for risk of violence. Conclusions: This large-scale study lends support to existing research showing that people with disabilities are at greater risk of violence than people without disabilities. Further, the study found that people with mental disabilities were significantly more likely to report all types of violence and discrimination than those with physical disabilities. The findings also show that gender is significant in explaining the type of violence experienced and the experience of discrimination

Leprosy in a patient infected with HIV

A 60-year-old Nigerian man, who had lived in Europe for 30 years but had returned home frequently, presented with right frontalis muscle weakness and right ulnar nerve palsy, without skin lesions. Neurophysiology showed a generalised neuropathy with demyelinating features. Blood tests were positive for HIV, with a normal CD4 count. There was nerve thickening both clinically and on MRI. Nerve biopsy showed chronic endoneuritis and perineuritis (indicating leprosy) without visible mycobacteria. His neuropathy continued to deteriorate (lepra reaction) before starting treatment with WHO multidrug therapy, highly active antiretroviral therapy and corticosteroids. There are 10 new cases of leprosy diagnosed annually in the UK. Coinfection with HIV is rare but paradoxically does not usually adversely affect the outcome of leprosy or change treatment. However, permanent nerve damage in leprosy is common despite optimal therapy. Leprosy should be considered in patients from endemic areas who present with mononeuritis multiplex

Four priority areas to advance invasion science in the face of rapid environmental change

Unprecedented rates of introduction and spread of non-native species pose burgeoning challenges to biodiversity, natural resource management, regional economies, and human health. Current biosecurity efforts are failing to keep pace with globalization, revealing critical gaps in our understanding and response to invasions. Here, we identify four priority areas to advance invasion science in the face of rapid global environmental change. First, invasion science should strive to develop a more comprehensive framework for predicting how the behavior, abundance, and interspecific interactions of non-native species vary in relation to conditions in receiving environments and how these factors govern the ecological impacts of invasion. A second priority is to understand the potential synergistic effects of multiple co-occurring stressors— particularly involving climate change—on the establishment and impact of non-native species. Climate adaptation and mitigation strategies will need to consider the possible consequences of promoting non-native species, and appropriate management responses to non-native species will need to be developed. The third priority is to address the taxonomic impediment. The ability to detect and evaluate invasion risks is compromised by a growing deficit in taxonomic expertise, which cannot be adequately compensated by new molecular technologies alone. Management of biosecurity risks will become increasingly challenging unless academia, industry, and governments train and employ new personnel in taxonomy and systematics. Fourth, we recommend that internationally cooperative biosecurity strategies consider the bridgehead effects of global dispersal networks, in which organisms tend to invade new regions from locations where they have already established. Cooperation among countries to eradicate or control species established in bridgehead regions should yield greater benefit than independent attempts by individual countries to exclude these species from arriving and establishing

Pathogen- and Host-Directed Antileishmanial Effects Mediated by Polyhexanide (PHMB)

BACKGROUND:Cutaneous leishmaniasis (CL) is a neglected tropical disease caused by protozoan parasites of the genus Leishmania. CL causes enormous suffering in many countries worldwide. There is no licensed vaccine against CL, and the chemotherapy options show limited efficacy and high toxicity. Localization of the parasites inside host cells is a barrier to most standard chemo- and immune-based interventions. Hence, novel drugs, which are safe, effective and readily accessible to third-world countries and/or drug delivery technologies for effective CL treatments are desperately needed. METHODOLOGY/PRINCIPAL FINDINGS:Here we evaluated the antileishmanial properties and delivery potential of polyhexamethylene biguanide (PHMB; polyhexanide), a widely used antimicrobial and wound antiseptic, in the Leishmania model. PHMB showed an inherent antileishmanial activity at submicromolar concentrations. Our data revealed that PHMB kills Leishmania major (L. major) via a dual mechanism involving disruption of membrane integrity and selective chromosome condensation and damage. PHMB's DNA binding and host cell entry properties were further exploited to improve the delivery and immunomodulatory activities of unmethylated cytosine-phosphate-guanine oligodeoxynucleotides (CpG ODN). PHMB spontaneously bound CpG ODN, forming stable nanopolyplexes that enhanced uptake of CpG ODN, potentiated antimicrobial killing and reduced host cell toxicity of PHMB. CONCLUSIONS:Given its low cost and long history of safe topical use, PHMB holds promise as a drug for CL therapy and delivery vehicle for nucleic acid immunomodulators

A new classification method using array Comparative Genome Hybridization data, based on the concept of Limited Jumping Emerging Patterns

<p>Abstract</p> <p>Background</p> <p>Classification using aCGH data is an important and insufficiently investigated problem in bioinformatics. In this paper we propose a new classification method of DNA copy number data based on the concept of limited Jumping Emerging Patterns. We present the comparison of our limJEPClassifier to SVM which is considered the most successful classifier in the case of high-throughput data.</p> <p>Results</p> <p>Our results revealed that the classification performance using limJEPClassifier is significantly higher than other methods. Furthermore, we show that application of the limited JEP's can significantly improve classification, when strongly unbalanced data are given.</p> <p>Conclusion</p> <p>Nowadays, aCGH has become a very important tool, used in research of cancer or genomic disorders. Therefore, improving classification of aCGH data can have a great impact on many medical issues such as the process of diagnosis and finding disease-related genes. The performed experiment shows that the application of Jumping Emerging Patterns can be effective in the classification of high-dimensional data, including these from aCGH experiments.</p

Post-Kala-azar Dermal Leishmaniasis in Nepal: A Retrospective Cohort Study (2000–2010)

Post-kala-azar dermal leishmaniasis (PKDL) is a skin disorder seen in patients treated for Leishmania donovani visceral leishmaniasis (VL), a neglected tropical disease that is fatal if left untreated. In the Indian subcontinent, PKDL is seen in 5–10% of all past VL cases and is also reported in some without history of VL. As persons with PKDL do not feel sick, the disease has only cosmetic significance for the individual and treatment is rarely sought. However, PKDL lesions harbour parasites and therefore could represent a source of transmission, through the bite of female sand flies. Our study shows that the occurrence of PKDL in patients with past treated VL is low in Nepal compared to neighboring countries. Treatment of the original VL episode with SSG (sodium stibogluconate), inadequate treatment and treatment on ambulatory basis were significantly associated with PKDL. Though SSG has since been replaced by other drugs, counseling and supervision of adherence to the prescribed VL treatment is of vital importance to reduce risk of treatment failure and relapse as well as later development of PKDL. Policy makers should include surveillance and case management of PKDL in the VL elimination program

Development and validation of a severity scale for leprosy Type 1 Reactions

Objectives: To develop a valid and reliable quantitative measure of leprosy Type 1 reactions.Methods: A scale was developed from previous scales which had not been validated. The face and content validity were assessed following consultation with recognised experts in the field. The construct validity was determined by applying the scale to patients in Bangladesh and Brazil who had been diagnosed with leprosy Type 1 reaction. An expert categorized each patient's reaction as mild or moderate or severe. Another worker applied the scale. This was done independently. In a subsequent stage of the study the agreement between two observers was assessed.Results: The scale had good internal consistency demonstrated by a Cronbach's alpha &gt;0.8. Removal of three items from the original scale resulted in better discrimination between disease severity categories. Cut off points for Type 1 reaction severities were determined using Receiver Operating Characteristic curves. A mild Type 1 reaction is characterized using the final scale by a score of 4 or less. A moderate reaction is a score of between 4.5 and 8.5. A severe reaction is a score of 9 or more.Conclusions: We have developed a valid and reliable tool for quantifying leprosy Type 1 reaction severity and believe this will be a useful tool in research of this condition, in observational and intervention studies, and in the comparison of clinical and laboratory parameters.<br/