Proteomic Analyses of Snake Venoms with an Examination of the Biological Roles and Anti-cancer Effects of Venom Disintegrins

For decades, snakes and snake venoms have been utilized in numerous aspects of biological and biomedical research. Behaviorally, snakes have been examined for their extraordinary chemosensory capabilities, providing a detailed understanding of their foraging ecology and predatory responses. The presence of a highly complex vomeronasal organ has enabled snakes to not only respond to, but also discriminate between a high-range of heterospecific, conspecific, predatory, and prey-derived chemical odors. Snake venom has allowed for a transition in predatory behaviors, and this often complex mixture of proteins and peptides has provided researchers with an ever growing catalog of natural compounds that may be applicable as novel therapeutics or as biomedical reagents. Research into venomous systems also provides a detailed understanding of the biological roles of venom compounds, as well as providing critical information necessary for the proper assessment and treatment of snakebite. The current work addresses several aspects of snake behavior and snake venom toxinology and has four major objectives: i) to examine the chemosensory responses of neonate, subadult and adult Prairie Rattlesnake (Crotalus viridis viridis) to various prey chemical stimuli, ii) to identify the chemical component(s) of venom which allows for prey recovery during viperid predatory episodes, iii) to examine the anti-cancer effects of a novel snake venom disintegrin towards various human derived cancer cell lines and iv) to complete in-depth proteomic analyses of the neonate and adult C. v. viridis and examine the efficacy of the current anti-venom treatment CroFab® against this species’ venom. Chapter I presents the objectives and aims of my dissertation work, and provides background on chemosensory systems in squamates, and the numerous studies examining prey relocation in viperid snakes. Further, this chapter addresses the importance of examining the potential medicinal values of disintegrins as anti-cancer therapeutics, and the utilization of proteomics to develop a better understanding of venom composition and anti-venom efficacy. Chapters II focuses on the chemosensory responses of wild-caught neonate, subadult, and adult C. v. viridis to natural and non-natural prey-derived chemical odors. Results indicate that responses to chemical stimuli shift with snake age, correlating with ontogenetic changes in snake diet. Chapter III examines this phenomenon in more detail with a group of “stunted” C. v. viridis which had been in captivity since birth and had only consumed neonate lab mice (Mus musculus). Further, these snakes were the age of adults yet only the size of large juveniles, therefore they could not consume larger prey normally taken by adult snakes. Results suggest that ontogenetic shifts in responsiveness to natural prey chemical cues are innately programmed and are not based on body size or feeding experience. Chapter IV identifies the venom component, disintegrins, which are responsible for prey recovery during strike-induced chemosensory searching in Western Diamondback Rattlesnakes (Crotalus atrox). In Chapter V, a novel disintegrin protein (named tzabcanin) was isolated from the venom of the Middle American Rattlesnake (Crotalus simus tzabcan) and the cytotoxic and anti-adhesion properties of this protein toward Colo-205 and MCF-7 cell lines was examined. Chapter VI also examines the anticancer effects of tzabcanin towards A-375 and A-549 cell lines, and by specifically binding integrin αvβ3, tzabcanin inhibits cell migration and cell adhesion to vitronectin. In Chapter VII, a detailed proteomic analysis of the venoms of four individual C. v. viridis is presented, showing a novel trend in ontogenetic changes in venom composition, as well as identifying which compounds are, and which are not, effectively immunocaptured by the current anti-venom therapy used in the United States, CroFab®

Hubungan Beban Kerja, Lingkungan Kerja dan Job Insecurity dengan stres kerja pada perawat Instalasi Gawat Darurat RSUP SR. M Djamil Padang Tahun 2018

FAKULTAS KESEHATAN MASYARAKAT UNIVERSITAS ANDALAS Skripsi, Juni 2018 FEBBY SAVIOLA, No.BP. 1411211037 HUBUNGAN BEBAN KERJA, LINGKUNGAN KERJA DAN JOB INSECURITY DENGAN STRES KERJA PADA PERAWAT INSTALASI GAWAT DARURAT RSUP DR. M DJAMIL PADANG TAHUN 2018 xii + 86 halaman, 11 tabel, 2 gambar, 9 lampiran ABSTRAK Tujuan Stres akibat kerja merupakan suatu respon emosional dan fisik yang bersifat mengganggu dikarenakan tuntutan tugas tidak sesuai dengan kemampuan individu. Stres kerja dapat menjadi masalah yang serius karena dapat berpengaruh terhadap pelayanan yang akan diberikan oleh perawat. Penelitian ini bertujuan untuk mengetahui hubungan antara beban kerja, lingkungan kerja dan job insecuirty dengan stres kerja pada perawat Instalasi Gawat Darurat RSUP DR. M Djamil Padang Tahun 2018. Metode Jenis penelitian kuantitatif dengan pendekatan cross sectional. Penelitian dilakukan pada bulan Desember 2017 hingga April 2018. Populasi adalah seluruh perawat IGD RSUP DR. M Djamil Padang. Jumlah sampel 33 responden dengan metode pengambilan sampel secara total sampling. Pengolahan data dilakukan secara univariat dan bivariat. Analisis data dengan uji chi-square dengan derajat kepercayaan 95% (α=0.05). Hasil Hasil penelitian menunjukkan 72,7% perawat instalasi gawat darurat RSUP DR. M Djamil Padang mengalami stres berat, 66,7% mengalami beban kerja berat, 54,5% mengalami lingkungan kerja buruk, dan 36,4% mengalami job insecurity tinggi. Hasil uji statistik didapatkan hubungan antara beban kerja (p value=0,033) dan lingkungan kerja (p value=0,047) dengan stres kerja. Tidak ada hubungan bermakna antara job insecurity (p value=0,429) dengan stres kerja. Kesimpulan Terdapat hubungan antara beban kerja dan lingkungan kerja dengan stres kerja pada perawat IGD RSUP DR. M Djamil Padang. Untuk meminimalisir terjadinya stres kerja, disarankan kepada RSUP DR. M Djamil untuk dapat melakukan pemeriksaan stres akibat kerja kepada perawat baik awal maupun berkala sehingga dapat diketahui kondisi psikologis perawat. Daftar Pustaka : 39 (1992-2017) Kata Kunci : perawat, IGD, stres kerj

Diagnostic Delay in Oncology: A Case Report of Metastatic Seminoma

Germ cell tumours are the most common malignancy among young men; cryptorchidism is a possible risk factor for the development of testicular cancer. Psycho-oncology studies indicate that diagnostic delay can often be explained by different social conditions and that symptoms worsened under lack of appropriate treatment can lead to an urgent admission to the hospital. Nevertheless, germ cell tumours are considered curable malignancies even in advanced stages since the introduction of a chemotherapy regimen based on bleomycin, etoposide and cisplatin. Cell lines derived from germ cell tumours are sensitive to cisplatin-based treatment more than other solid cancers, which is reflected in the good clinical response. We report an unusual manifestation of malignancy in an adult man presenting with a metastatic seminoma of the left testicle. The large ulcerate and necrotic mass suggested a secondary infection from a tumour site. The patient reported surgical orchiopexy for left cryptorchidism in his childhood. Despite worsening of physical features, he had not sought help at the hospital for social reasons. The patient achieved complete clinical remission after receiving standard chemotherapy, and a good objective response of the primitive mass was clearly visible. Complete response was persistent at the 30-month clinical follow-up. The chemotherapy administration was later complicated by acute haemorrage in the site of the primitive tumour that needed urgent surgical management; in addition to this, the artificial graft material was rejected and the arterial prosthesis had to be removed

Cost Effectiveness Analysis of Disease-Modifying Antirheumatic Drugs in Rheumatoid Arthritis. A Systematic Review Literature

The cost effectiveness of treatments that have changed the “natural history” of a chronic progressive disease needs to be evaluated over the long term. Disease-modifying antirheumatic drugs (DMARDs) are the standard treatment of rheumatoid arthritis (RA) and should be started as early as possible. A number of studies have shown that they are effective in improving disease activity and function, and in joint damage. Our review was focused on revision and critical evaluation of the studies including the literature on cost effectiveness of DMARDs (cyclosporine A, sulphasalazine, leflunomide, and methotrexate). The European League Against Rheumatism (EULAR) recommendations showed that traditional DMARDs are cost effective at the time of disease onset. They are less expensive than biological DMARDs and can be useful in controlling disease activity in early RA

The Economic Burden of Biological Therapy in Rheumatoid Arthritis in Clinical Practice: Cost-Effectiveness Analysis of Sub-Cutaneous Anti-TNFα Treatment in Italian Patients:

Rheumatoid arthritis (RA), with a prevalence of 0.46%, is found in about 272,004 patients in Italy. The socioeconomic cost of rheumatoid arthritis in Italy in 2002 has been estimated at €1,600 million. Cost-effectiveness evaluations have been based on the concept that, with treatment, patients will not progress to the next level(s) of disease severity or will take a longer time to progress, thus avoiding or delaying the high costs and low utility associated with more severe disease. Many cost-effective studies have been based on the variation of Health Assessment Questionnaire (HAQ) in clinical trials. The objective of this study is to perform a cost-effective analysis of 86 patients with rheumatoid arthritis in therapy with adalimumab 40 mg every other week and etanercept 50 mg/week for two years in a population of patients observed in clinical practice. The group of patients in therapy with adalimumab had also taken methotrexate, mean dose 12.4±2.5 mg/week (22 patients) or leflunomide 20 mg/day (16 patients). The group of patients in therapy with etanercept had also taken methotrexate, mean dose 11.7±2.6 mg/week (24 patients) or leflunomide 20 mg/day (24 patients). Incremental costs and QALYs (quality adjusted life years) gains are calculated compared with baseline, assuming that without biologic treatment patients would remain at the baseline level through the year. Conversion HAQ scores to utility were based on the Bansback algorithm. The results after two years showed: in the group methotrexate+adalimumab the QALY gained was 0.62±0.15 with a treatment cost of €26,517.62 and a QALY/cost of €42,521.13. In the group methotrexate+etanercept the QALY gained was 0.64±0.26 with a treatment cost of €25,020.96 and a QALY/cost of €39,171.76. The result of using etanercept in association with methotrexate is cost-effectiveness with a QALY gained under the acceptable threshold of €50,000. These are important data for discussion from an economic point of view when we choose a biologic therapy for rheumatoid arthritis in clinical practice

Determinants of Risk Infection During Therapy with Anti TNF-Alpha Blocking Agents in Rheumatoid Arthritis

The use of TNF-alpha antagonists (infliximab, etanercept, adalimumab) has changed the course of many rheumatic diseases including rheumatoid arthritis (RA). Since their approval, some questions regarding their safety including infections have been observed. The aim of the study was to evaluate the changes in cytokines levels and cells subsets in patients with RA during anti TNF blocking agents treatment and the possible effect on infections’ development. We evaluated in 89 RA patients [39 treated with etanercept (ETN), 29 with adalimumab (ADA) and 21 with infliximab (IFN)] at baseline and after 6 months the following parameters: procalcitonin, ESR, CRP, cytokines as TNF, IL-6, IL-10, IL-8 and the TNF/IL-10 ratio, and peripheral mononuclear cells as CD3+, CD3+/CD4+, CD3+/CD8+, CD19+, CD3- /CD16+/56+, CD14+HLADR+, CD20+, CD19+/CD38+. Peripheral mononuclear cells were detected by flow cytometric system Cytomics FC500 and cytokines circulating levels by a quantitative sandwich enzyme immunoassay technique (Human IL-8 Instant ELISAe Bioscience, Human IL-6 Instant ELISA e Bioscience, Human IL-10 Instant ELISAe Bioscience and Human TNF-a Quantikine immunoassay RD system). A lower reduction of CD14+HLADR+ in ADA group 54.6±10.4% vs ETA 48.4±15.7% vs INF 40.7±16.5%, p<0.039 was found. No differences in all three groups on peripheral mononuclear cells CD3+, CD3+/CD4+, CD3+/CD8+, CD19+, CD 20+, CD19+/CD38+, CD3-/CD16+/56+, and cytokine circulating levels were found. The number of infections at 6 months was: 10.3% in ADA group, 12.8% in ETN group and 19.04% in IFN group. A correlation was found between the reduction in CD14+HLADR+ cells and IFN treatment. Our data showed that the level of CD14+HLADR+ cells was reduced during therapy with IFN. ADA and ETN don’t reduce lymphocyte populations and their subsets such as CD14+HLADR+ cells that play an important role host defence