Epidemiological and clinical characteristics of scorpionism in Shiraz (2012-2016); development of a clinical severity grading for Iranian scorpion envenomation

Background: Scorpionism is a public health problem in some provinces in Iran. The present study aimed to assess the clinical manifestations of scorpion envenomation in Shiraz and determine a clinical severity grading for Iranian scorpion envenomation in order to suggest a treatment guideline for emergency physicians. Methods: In this analytic retrospective study, all medical charts of patients with scorpion sting admitted in the adult medical toxicology center in Shiraz during July 2012 to July 2016 were assessed. Data regarding the patient's age, gender, sting site, month of envenomation, time of sting, clinical manifestations, vital signs, presence of blood or hemoglobin in urine analysis, duration of admission, color of scorpion, received treatments, and administration of scorpion antivenin were recorded. Results: The scorpions in Shiraz and its suburban area were classified into two groups: yellow scorpions (Mesobuthus eupeus, Mesobuthus caucasicus, and Compsobuthus matthiesseni) and Hottentotta scorpions (Hottentotta jayakari and Hottentotta zagrosensis). A total of 126 cases of scorpion stings were assessed. About 59% (n=74) were males. The patients aged 8-63 years (mean age, 33.8±11.5 years). About 38.4% (n=48) of the stings occurred during summer. More than 40% of patients (n=51) referred to the emergency department (ED) at night. Localized pain was the most frequent presenting complaint (76.2%). The most frequent general symptom was nausea (6.3%). The most prevalent envenomation site was the lower extremities followed by upper extremities (43.5% and 41.9%, respectively). Based on the clinical severity grading for Iranian scorpion envenomation, 65, 43, and 18 patients (51.6%, 34.1%, and 14.3%) were classified in the grades I, II, and III, respectively. Eighty-one (73%) patients stayed in the ED from 1 to 6 hours, and 30 (27%) patients stayed for >6 hours for observation. Severe localized pain was more prevalent in stings with Hottentotta scorpions than yellow scorpions (P=0.01). The season of envenomation with Hottentotta scorpions was summer in all cases, but envenomation with yellow scorpions was seen throughout the year. All patients received symptomatic treatment, and five were given scorpion antivenin. No death was reported. Conclusion: Hottentotta jayakari is recommended to be listed among the medically important scorpions in Iran. Moreover, scorpion- stung patients in geographical regions where Hemiscorpius lepturus and Androctonus crassicauda are not prevalent may be treated in outpatient departments. The presented grading system can be used for treating patients with scorpion envenomation. © Iran University of Medical Sciences

Novel heart valve prosthesis with self-endothelialization potential made of modified polyhedral oligomeric silsesquioxane-nanocomposite material

In the cardiovascular system, the endothelial layer provides a natural antithrombogenic surface on the inner portion of the heart and associated vessels. For a synthetic material therefore, the ability to attract and retain endothelial or endothelial progenitor cells (EPCs), ultimately creating a single endothelial layer on its surface, is of prime importance. The authors have developed a nanocomposite polymer, based on a combination of polyhedral oligomeric silsesquioxane nanoparticles and polycarbonate urea urethane (POSS-PCU), which is biocompatible and has been used in human for the world's first synthetic trachea, tear duct, and bypass graft. In this study, the authors modified the surface of this casted nanocomposite by grafting fibronectin derived bioactive peptides [glycine-arginine-glycine-aspartic acid-glycine (GRGDG) and lauric acid conjugated GRGDG (GRGDG-LA)] to enhance the endothelialization for using heart valves leaflets from circulating EPCs. Human peripheral blood mononuclear cells were separated using Ficoll-Paque centrifugation, with harvested EPCs purified using CD34 microbead labeling and magnetic-activated cell sorting. Cells were seeded onto 96 well plates coated with POSS-PCU, GRGDG/GRGDG-LA modified POSS-PCU and PCU polymers, for a period of 21 days. Cells were studied under light, confocal, and scanning electron microscope (SEM). Fluorescence-activated cell sorting was used to analyze cell surface markers. Cell attachment and proliferation was observed in all POSS-PCU samples, significantly higher than the activity seen within the control PCU polymers (p < 0.05). Microscopic examination revealed clonal expansion and morphological changes in cells seeded on POSS-PCU. The cells expressed increasing levels of mature endothelial cell markers over time with a concurrent reduction in hematopoietic stem cell marker expression. SEM showed a mixed population of morphologically differentiated endothelial cells and EPCs. These results support the use of heart valve made with the POSS-PCU polymer and demonstrate that suitable chemical modification of this nanocomposite could increase self-endothelialization potential and reduce associated thrombotic events

Efficient inhibition of human immunodeficiency virus replication using novel modified microRNA-30a targeting 3'-untranslated region transcripts

RNA interference (RNAi)-based gene therapy is currently considered to be a combinatorial anti-human immunodeficiency virus-1 (HIV-1) therapy. Although arti­ficial polycistronic microRNAs (miRs) can reduce HIV-1 escape mutant variants, this approach may increase the risk of side effects. The present study aimed to optimize the efficiency of anti-HIV RNAi gene therapy in order to reduce the cell toxicity induced by multi-short hairpin RNA expression. An artificial miR-30a-3'-untranslated region (miR-3'-UTR) obtained from a single RNA polymerase II was used to simultaneously target all viral transcripts. The results of the present study demonstrated that HIV-1 replication was signifi­cantly inhibited in the cells with the miR-3'-UTR construct, suggesting that miR-3'-UTR may serve as a promising tool for RNAi-based gene therapy in the treatment of HIV-1. © 2016, Spandidos Publications. All Rights Reserved

Enhancing clinical decision support with genomic tools in breast cancer: a Scottish perspective

Introduction: The Oncotype DX Breast RS test has been adopted in Scotland and has been the subject of a large population-based study by a Scottish Consensus Group to assess the uptake of the recurrence score (RS), evaluate co-variates associated with the RS and to analyse the effect it may have had on clinical practice. Materials &amp; Methods: Pan-Scotland study between August 2018–August 2021 evaluating 833 patients who had a RS test performed as part of their diagnostic pathway. Data was extracted retrospectively from electronic records and analysis conducted to describe change in chemotherapy administration (by direct comparison with conventional risk assessment tools), and univariate/multivariate analysis to assess relationship between covariates and the RS. Results: Chemotherapy treatment was strongly influenced by the RS (p &lt; 0.001). Only 30 % of patients received chemotherapy treatment in the intermediate and high risk PREDICT groups, where chemotherapy is considered. Additionally, 55.5 % of patients with a high risk PREDICT had a low RS and did not receive chemotherapy. There were 17 % of patients with a low risk PREDICT but high RS who received chemotherapy. Multivariate regression analysis showed the progesterone receptor Allred score (PR score) to be a strong independent predictor of the RS, with a negative PR score being associated with high RS (OR 4.49, p &lt; 0.001). Increasing grade was also associated with high RS (OR 3.81, p &lt; 0.001). Classic lobular pathology was associated with a low RS in comparison to other tumour pathology (p &lt; 0.01). Nodal disease was associated with a lower RS (p = 0.012) on univariate analysis, with menopausal status (p = 0.43) not influencing the RS on univariate or multivariate analysis. Conclusions: Genomic assays offer the potential for risk-stratified decision making regarding the use of chemotherapy. They can help reduce unnecessary chemotherapy treatment and identify a subgroup of patients with more adverse genomic tumour biology. A recent publication by Health Improvement Scotland (HIS) has updated guidance on use of the RS test for NHS Scotland [1].It suggests to limit its use to the intermediate risk PREDICT group. Our study shows the impact of the RS test in the low and high risk PREDICT groups. The implementation across Scotland has resulted in a notable shift in practice, leading to a significant reduction in chemotherapy administration in the setting of high risk PREDICT scores returning low risk RS. There has also been utility for the test in the low risk PREDICT group to detect a small subgroup with a high RS. We have found the PR score to have a strong independent association with high risk RS. This finding was not evaluated by the key RS test papers, and the potential prognostic information provided by the PR score as a surrogate biomarker is an outstanding question that requires more research to validate

Applying refinement to the use of mice and rats in rheumatoid arthritis research

Rheumatoid arthritis (RA) is a painful, chronic disorder and there is currently an unmet need for effective therapies that will benefit a wide range of patients. The research and development process for therapies and treatments currently involves in vivo studies, which have the potential to cause discomfort, pain or distress. This Working Group report focuses on identifying causes of suffering within commonly used mouse and rat ‘models’ of RA, describing practical refinements to help reduce suffering and improve welfare without compromising the scientific objectives. The report also discusses other, relevant topics including identifying and minimising sources of variation within in vivo RA studies, the potential to provide pain relief including analgesia, welfare assessment, humane endpoints, reporting standards and the potential to replace animals in RA research

Formyl Peptide Receptor as a Novel Therapeutic Target for Anxiety-Related Disorders

Formyl peptide receptors (FPR) belong to a family of sensors of the immune system that detect microbe-associated molecules and inform various cellular and sensorial mechanisms to the presence of pathogens in the host. Here we demonstrate that Fpr2/3-deficient mice show a distinct profile of behaviour characterised by reduced anxiety in the marble burying and light-dark box paradigms, increased exploratory behaviour in an open-field, together with superior performance on a novel object recognition test. Pharmacological blockade with a formyl peptide receptor antagonist, Boc2, in wild type mice reproduced most of the behavioural changes observed in the Fpr2/3(-/-) mice, including a significant improvement in novel object discrimination and reduced anxiety in a light/dark shuttle test. These effects were associated with reduced FPR signalling in the gut as shown by the significant reduction in the levels of p-p38. Collectively, these findings suggest that homeostatic FPR signalling exerts a modulatory effect on anxiety-like behaviours. These findings thus suggest that therapies targeting FPRs may be a novel approach to ameliorate behavioural abnormalities present in neuropsychiatric disorders at the cognitive-emotional interface

Amino Acid Usage Is Asymmetrically Biased in AT- and GC-Rich Microbial Genomes.

INTRODUCTION: Genomic base composition ranges from less than 25% AT to more than 85% AT in prokaryotes. Since only a small fraction of prokaryotic genomes is not protein coding even a minor change in genomic base composition will induce profound protein changes. We examined how amino acid and codon frequencies were distributed in over 2000 microbial genomes and how these distributions were affected by base compositional changes. In addition, we wanted to know how genome-wide amino acid usage was biased in the different genomes and how changes to base composition and mutations affected this bias. To carry this out, we used a Generalized Additive Mixed-effects Model (GAMM) to explore non-linear associations and strong data dependences in closely related microbes; principal component analysis (PCA) was used to examine genomic amino acid- and codon frequencies, while the concept of relative entropy was used to analyze genomic mutation rates. RESULTS: We found that genomic amino acid frequencies carried a stronger phylogenetic signal than codon frequencies, but that this signal was weak compared to that of genomic %AT. Further, in contrast to codon usage bias (CUB), amino acid usage bias (AAUB) was differently distributed in AT- and GC-rich genomes in the sense that AT-rich genomes did not prefer specific amino acids over others to the same extent as GC-rich genomes. AAUB was also associated with relative entropy; genomes with low AAUB contained more random mutations as a consequence of relaxed purifying selection than genomes with higher AAUB. CONCLUSION: Genomic base composition has a substantial effect on both amino acid- and codon frequencies in bacterial genomes. While phylogeny influenced amino acid usage more in GC-rich genomes, AT-content was driving amino acid usage in AT-rich genomes. We found the GAMM model to be an excellent tool to analyze the genomic data used in this study

Enhanced formation of giant cells in common variable immunodeficiency: Relation to granulomatous disease.

Peripheral monocytes from patients with common variable immunodeficiency (CVID) had on average a 2 fold greater tendency to form giant cells in medium without additional cytokines. Giant cell formation was faster and 3 to 5 fold higher in most CVID cells compared to normal. Addition of IL4, GMCSF, IFNγ, TNFa and both T cell and monocyte conditioned media promoted monocyte fusion of some CVID individuals over 5 fold the normal average level, with combinations of cytokines and monokines acting synergistically. The reduction of normal giant cell formation by anti-IFNγ antibody and a greater tendency of CVID cells to fuse in immunoglobulin conditioned media suggests that standard IVIg treatment contributes to granuloma formation. CVID and normal giant cells expressed similar levels of phenotypic molecules and had similar phagocytic activity. Monocytes from many CVID patients have an elevated tendency to fuse which may explain the high incidence of granulomatous complications in CVID

Fast splice site detection using information content and feature reduction

Background: Accurate identification of splice sites in DNA sequences plays a key role in the prediction of gene structure in eukaryotes. Already many computational methods have been proposed for the detection of splice sites and some of them showed high prediction accuracy. However, most of these methods are limited in terms of their long computation time when applied to whole genome sequence data. Results: In this paper we propose a hybrid algorithm which combines several effective and informative input features with the state of the art support vector machine (SVM). To obtain the input features we employ information content method based on Shannon\u27s information theory, Shapiro\u27s score scheme, and Markovian probabilities. We also use a feature elimination scheme to reduce the less informative features from the input data. Conclusion: In this study we propose a new feature based splice site detection method that shows improved acceptor and donor splice site detection in DNA sequences when the performance is compared with various state of the art and well known method