Drug treatment in the development of mismatch repair defective acute leukemia and myelodysplastic syndrome

DNA from therapy-related acute leukemia/myelodysplastic syndrome cases (tAL/MDS) from the GIMEMA [Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto] Archive was examined for the microsatellite instability (MSI(+)) phenotype that is diagnostic for defective DNA mismatch repair. More than 60% (16/25) of tAL/MDS cases were MSI(+) in contrast to <4% (0/28) of de novo cases. hMLH1 gene silencing was rare and evidence of promoter methylation was found in less than one-third of the MSI(+) cases. Among the GIMEMA patients who had been treated for breast cancer there was an apparent trend towards early onset primary breast disease. This suggests that there might be common predisposing factors for breast cancer and tAL/MDS. There were also three examples of mutations in the MRE11 gene among the 25 tAL/MDS cases suggesting that defective recombinational DNA repair may promote the development of secondary malignancy. MSI(+) tAL/MDS was significantly associated with previous chemotherapy and the frequency of MSI(+) among radiotherapy patients was considerably lower. In view of the established relationship between drug resistance and mismatch repair defects, we suggest that selection for therapeutic drug resistance may contribute to the incidence of MSI(+) tAL/MDS.     

Conformational changes involved in thermal aggregation processes of bovine serum albumin

We report a kinetic study on thermal aggregation process of the model protein bovine serum albumin (BSA) in low concentration regime. Aim of this study is to provide information on relationship between conformational changes and initial step of aggregation. The experimental approach is based on steady-state fluorescence spectra of the two tryptophans located in two different domains, in way to study conformational changes in the surrounding of these residues. We also follow emission spectra of Fluorescein-5-Maleimide dye bound to the single free cysteine of BSA. Complementary information on the extent of aggregation and on the structural changes is obtained by Rayleigh scattering and circular dichroism measurements. These data contribute to clarify the connection between conformational changes at tertiary and secondary structure level during the aggregation and how the different domains are involved. We also discuss the relevant role played by cysteine 34 in the aggregation pathways.     

The effect of Cyclosporine A chronic administration on the antioxidant pattern of rat liver mitochondria: structural and functional consequences

Cyclosporine A (CsA) plays a pivotal role in controlling Ca2+ movement in the cell modulating also the mitochondrial permeability transition pore. We investigated if chronic administration of CsA may have some effects on the lipophilic and hydrophilic antioxidant pattern of rat liver mitochondria and on their morphological structure. It seems that CsA administration does not statistically affect the redox status of the antioxidants investigated and their amounts (vitamin E, CoQ9, CoQ10, glutathione, uric acid and ascorbic acid) despite the variety of effects that this treatment produces at physiological and morphological levels. However, some kind of derangement could occur in the liver biochemical machinery since CsA treatment induces a markedly increased variability in antioxidant contents.     

Activation of extracellular signal-regulated kinase (ERK) and Akt by human serotonin 5-HT(1B) receptors in transfected BE(2)-C neuroblastoma cells is inhibited by RGS4

Regulator of G protein signaling (RGS) proteins are GTPase-activating proteins for heterotrimeric G proteins. One of the best-studied RGS proteins, RGS4, accelerates the rate of GTP hydrolysis by all G(i) and G(q) alpha subunits yet has been shown to exhibit receptor selectivity. Although RGS4 is expressed primarily in brain, its effect on modulating the activity of serotonergic receptors has not yet been reported. In the present study, transfected BE(2)-C human neuroblastoma cells expressing human 5-HT(1B) receptors were used to demonstrate that RGS4 can inhibit the coupling of 5-HT(1B) receptors to cellular signals. Serotonin and sumatriptan were found to stimulate activation of extracellular signal-regulated kinase. This activation was attenuated, but not completely inhibited, by RGS4. Similar inhibition by RGS4 of the protein kinase Akt was also observed. As RGS4 is expressed at high levels in brain, these results suggest that it may play a role in regulating serotonergic pathways.     

Wild Sicilian Rosemary: Phytochemical and Morphological Screening and Antioxidant Activity Evaluation of Extracts and Essential Oils

To identify the best biotypes, an extensive survey of Sicilian wild rosemary was carried out by collecting 57 samples from various sites, followed by taxonomic characterization from an agronomic perspective. All the biotypes collected were classified as Rosmarinus officinalis L. A cluster analysis based on the morphological characteristics of the plants allowed the division of the biotypes into seven main groups, although the characteristics examined were found to be highly similar and not area‐dependent. Moreover, all samples were analyzed for their phytochemical content, applying an extraction protocol to obtain the nonvolatile components and hydrodistillation to collect the essential oils for the volatile components. The extracts were characterized by LC‐UV‐DAD/ESI‐MS, and the essential oils by GC‐FID and GC/MS analyses. In the nonvolatile fractions, 18 components were identified, namely, 13 flavones, two organic acids, and three diterpenes. In the volatile fractions, a total of 82 components were found, with as predominant components α‐pinene and camphene among the monoterpene hydrocarbons and 1,8‐cineole, camphor, borneol, and verbenone among the oxygenated monoterpenes. Cluster analyses were carried out on both phytochemical profiles, allowing the separation of the rosemary samples into different chemical groups. Finally, the total phenol content and the antioxidant activity of the essential oils and extracts were determined with the Folin–Ciocalteu (FC) colorimetric assay, the UV radiation‐induced peroxidation in liposomal membranes (UV‐IP test), and the scavenging activity of the superoxide radical (O$\rm{{_{2}^{{^\cdot} -}}}$ ). The present study confirmed that the essential oils and organic extracts of the Sicilian rosemary samples analyzed showed a considerable antioxidant/free radical‐scavenging activity.     

Emergency Department Presentations following Tropical Cyclone Yasi

Introduction

Emergency departments see an increase in cases during cyclones. The aim of this study is to describe patient presentations to the Emergency Department (ED) of a tertiary level hospital (Townsville) following a tropical cyclone (Yasi). Specific areas of focus include changes in: patient demographics (age and gender), triage categories, and classification of diseases.

Methods

Data were extracted from the Townsville Hospitals ED information system (EDIS) for three periods in 2009, 2010 and 2011 to coincide with formation of Cyclone Yasi (31 January 2011) to six days after Yasi crossed the coast line (8 February 2012). The analysis explored the changes in ICD10-AM 4-character classification and presented at the Chapter level.

Results

There was a marked increase in the number of patients attending the ED during Yasi, particularly those aged over 65 years with a maximum daily attendance of 372 patients on 4 Feb 2011. The most marked increases were in: Triage categories - 4 and 5; and ICD categories - diseases of the skin and subcutaneous tissue (L00-L99), and factors influencing health care status (Z00-Z99). The most common diagnostic presentation across all years was injury (S00-T98).

Discussion

There was an increase in presentations to the ED of TTH, which peaked in the first 24 – 48 hours following the cyclone and returned to normal over a five-day period. The changes in presentations were mostly an amplification of normal attendance patterns with some altered areas of activity. Injury patterns are similar to overseas experience.     

Leptospirosis in Rio Grande do Sul,Brazil: An Ecosystem Approach in the Animal-Human Interface

Background

Leptospirosis is an epidemic-prone neglected disease that affects humans and animals, mostly in vulnerable populations. The One Health approach is a recommended strategy to identify drivers of the disease and plan for its prevention and control. In that context, the aim of this study was to analyze the distribution of human cases of leptospirosis in the State of Rio Grande do Sul, Brazil, and to explore possible drivers. Additionally, it sought to provide further evidence to support interventions and to identify hypotheses for new research at the human-animal-ecosystem interface.

Methodology and findings

The risk for human infection was described in relation to environmental, socioeconomic, and livestock variables. This ecological study used aggregated data by municipality (all 496). Data were extracted from secondary, publicly available sources. Thematic maps were constructed and univariate analysis performed for all variables. Negative binomial regression was used for multivariable statistical analysis of leptospirosis cases. An annual average of 428 human cases of leptospirosis was reported in the state from 2008 to 2012. The cumulative incidence in rural populations was eight times higher than in urban populations. Variables significantly associated with leptospirosis cases in the final model were: Parana/Paraiba ecoregion (RR: 2.25; CI_95%: 2.03–2.49); Neossolo Litolítico soil (RR: 1.93; CI_95%: 1.26–2.96); and, to a lesser extent, the production of tobacco (RR: 1.10; CI_95%: 1.09–1.11) and rice (RR: 1.003; CI_95%: 1.002–1.04).

Conclusion

Urban cases were concentrated in the capital and rural cases in a specific ecoregion. The major drivers identified in this study were related to environmental and production processes that are permanent features of the state. This study contributes to the basic knowledge on leptospirosis distribution and drivers in the state and encourages a comprehensive approach to address the disease in the animal-human-ecosystem interface.