Complicações da infecção por EBV em doentes transplantados

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2016Paralelamente à crescente utilização de transplantes de órgão sólido ou de células estaminais no tratamento de uma miríade de doenças, tem crescido a investigação de patologias relacionadas com a imunossupressão associada. As doenças linfoproliferativas pós-transplante (PTLD, do inglês post-transplant lymphoproliferative disorders), frequentemente associadas à reactivação do vírus de Epstein-Barr nestes doentes, podem representar uma complicação grave da imunossupressão. Nesta revisão pretende-se sumarizar o mecanismo de desenvolvimento destas patologias, apresentar as classificações, enumerar os factores de risco, assim como os sinais e sintomas de apresentação de PTLD. Para orientação clínica, expõem-se ainda os exames complementares de diagnóstico úteis para o seu rastreio e monitorização, terminando por discutir os principais esquemas terapêuticos usados com intenção preventiva ou curativa, segundo as guidelines mais actuais.The rising usage of solid organ transplants and stem cell transplant in the treatment of various diseases has been accompanied by a growing research into the consequences of the associated imunossupression. Post-Transplant Lymphoproliferative Disorders (PTLD), frequently linked to the reactivation of the Epstein-Barr virus, may represent a serious complication of immunossupression. This review summarizes the mechanism inherent to the development of these disorders, describes their current classification system, lists the risk factors and the signs and symptoms associated with PTLD. To guide the clinical approach to these disorders, this review scrutinizes the most important diagnostic tests for screening and monitoring the development of PTLD, and also discusses the main therapeutic approach to prevention or cure, according to the most recent guidelines

Prediction of paraquat exposure and toxicity in clinically ill poisoned patients: a model based approach

Aims Paraquat poisoning is a medical problem in many parts of Asia and the Pacific. The mortality rate is extremely high as there is no effective treatment. We analyzed data collected during an ongoing cohort study on self-poisoning and from a randomized controlled trial assessing the efficacy of immunosuppressive therapy in hospitalized paraquat-intoxicated patients. The aim of this analysis was to characterize the toxicokinetics and toxicodynamics of paraquat in this population. Methods A non-linear mixed effects approach was used to perform a toxicokinetic/toxicodynamic population analysis in a cohort of 78 patients. Results The paraquat plasma concentrations were best fitted by a two compartment toxicokinetic structural model with first order absorption and first order elimination. Changes in renal function were used for the assessment of paraquat toxicodynamics. The estimates of toxicokinetic parameters for the apparent clearance, the apparent volume of distribution and elimination half-life were 1.17 l h−1, 2.4 l kg−1 and 87 h, respectively. Renal function, namely creatinine clearance, was the most significant covariate to explain between patient variability in paraquat clearance.This model suggested that a reduction in paraquat clearance occurred within 24 to 48 h after poison ingestion, and afterwards the clearance was constant over time. The model estimated that a paraquat concentration of 429 μg l−1 caused 50% of maximum renal toxicity. The immunosuppressive therapy tested during this study was associated with only 8% improvement of renal function. Conclusion The developed models may be useful as prognostic tools to predict patient outcome based on patient characteristics on admission and to assess drug effectiveness during antidote drug development

Effects of exposure to glyphosate on oxidative stress, inflammation, and lung function in maize farmers, Northern Thailand

Abstract Background Glyphosate is a herbicide which is commonly used in agricultural areas. However, previous studies on glyphosate exposure in farmers and their health are still scarce. Methods A longitudinal pre-post study was performed among maize farmers. Information from questionnaires, urine and blood samples, and lung function were collected a day before and a day after glyphosate application in the morning. The urine samples were analyzed using liquid chromatography-tandem mass spectrometry to detect glyphosate levels. Serum samples were analyzed to detect malondialdehyde (MDA), glutathione (GHS), and C-reactive protein (CRP) levels using thiobarbituric acid, dithiobisnitrobenzoic acid, and nephelometry, respectively. Lung function performances were measured using a spirometer. Results A total of 180 maize farmers met the study inclusion criteria. After glyphosate application, it was found that increased urinary glyphosate levels contributed to increased serum MDA (β = 0.024, 95% CI = 0.000, 0.0047) and decreased serum GHS (β = -0.022, 95% CI = -0.037, -0.007), FEV1 (β = -0.134, 95% CI = -0.168, -0.100), FEV1/FVC (β = -0.062, 95% CI = -0.082, -0.042) and PEF (β = -0.952, 95% CI = -1.169, -0.735). Conclusions Exposure to glyphosate during glyphosate application had significant effects on oxidative stress and lung function in maize farmers

Urinary Levels of Sirtuin-1, π-Glutathione S-Transferase, and Mitochondrial DNA in Maize Farmer Occupationally Exposed to Herbicide

Epidemiologic studies have suggested an association between agrochemical exposure and risk of renal injury. Farmers face great risks to developing adverse effects. The most appropriate biomarker related to renal injury needs to be developed to encounter earlier detection. We aim to study the association between early renal biomarker and occupational herbicide exposure in maize farmers, Thailand. Sixty-four farmers were recruited and interviewed concerning demographic data, herbicide usage, and protective behavior. Two spot urines before (pre-work task) and after (post-work task) herbicide spraying were collected. To estimate the intensity of exposure, the cumulative herbicide exposure intensity index (cumulative EII) was also calculated from activities on the farm, type of personal protective equipment (PPE) use, as well as duration and frequency of exposure. Four candidate renal biomarkers including π-GST, sirtuin-1, mitochondrial DNA (mtDNA) were measured. Most subjects were male and mostly sprayed three herbicides including glyphosate-based herbicides (GBH), paraquat, and 2,4-dichlorophenoxyacetic acid (2,4-D). A type of activity in farm was mixing and spraying herbicide. Our finding demonstrated no statistical significance of all biomarker levels between pre- and post-work task urine. To compare between single and cocktail use of herbicide, there was no statistical difference in all biomarker levels between pre- and post-work task urine. However, the urinary mtDNA seems to be increased in post-work task urine. Moreover, the cumulative EII was strongly associated with change in mtDNA content in both ND-1 and COX-3 gene. The possibility of urinary mtDNA as a valuable biomarker was promising as a noninvasive benchmark for early detection of the risk of developing renal injury from herbicide exposure

How to protect agricultural workers from exposure to pesticides: Effectiveness of woven and natural resin-coated fabrics

Agricultural workers in low and middle-income countries usually wear their everyday clothing made of woven fabrics during pesticide application. Different characteristics of various woven fabrics have different abilities to prevent the penetration of pesticides through to the skin. Therefore, the ultimate goal of this study is that agricultural workers in Thailand can choose a suitable fabric of protective clothing to protect themselves from pesticide exposure. This study aims to investigate pesticide penetration levels in different woven fabrics, and to explore factors affecting levels of pesticide penetration through fabrics. In addition, our study aims to produce cotton fabrics coated with a natural resin to obtain water-repellent characteristics and evaluate their effectiveness in protecting against pesticides. Four pesticides used in the testing process were chlorpyrifos, cypermethrin, paraquat, and glyphosate. The results found that a suitable fabric to protect agricultural workers from pesticide exposure is a fabric which made of 100% cotton and have greater weight. With regard to natural resin-coated fabrics, fabric C1-R showed the highest levels of effectiveness in protecting against the pesticides (range between 89%-95%). The natural resin-coated fabric is an alternative fabric in the protection against pesticides for agricultural workers in low and middle-income countries when commercial PPE are prohibitively expensive

Renal biomarkers predict nephrotoxicity after paraquat

Drug-induced nephrotoxicity contributes to the failure rate of investigational drugs during clinical trials. We are still not able to accurately predict drug-induced nephrotoxicity during early drug discovery and development. There is an urgent need for a robust screening system that can identify nephrotoxic compounds before they reach the clinic

Simple and sensitive liquid chromatography-tandem mass spectrometry methods for quantification of paraquat in plasma and urine: Application to experimental and clinical toxicological studies

Simple, sensitive and specific liquid chromatography–tandem mass spectrometry (LC–MS/MS) methods have been developed and validated for quantification of paraquat (PQ) in plasma and urine. Plasma and urine sample preparation were carried out by one-step protein precipitation using cold acetonitrile (−20 to −10 °C). After centrifugation, an aliquot of 10 μL of supernatant was injected into a Kinetex™ hydrophilic interaction chromatography (HILIC) column with a KrudKatcher™ Ultra in-line filter. The chromatographic separation was achieved using the mobile phase mixture of 250 mM ammonium formate (with 0.8% aqueous formic acid) in water and acetonitrile at a flow rate of 0.3 mL/min. Detection was performed using an API2000 triple quadrupole tandem mass spectrometer in multiple reaction monitoring (MRM) mode via an electrospray ionization (ESI) source. The calibration curve was linear over the concentration range of 10–5000 ng/mL, with an LLOQ of 10 ng/mL. The inter- and intra-day precision (% R.S.D.) wer