Os danos, efeitos adversos e agravos á saúde mental gerados pela atividade policial

A atividade policial vem impactando na saúde mental dos agentes, conectando traumas adquiridos em ocorrências, vivência diária na violência descontrolada, fatores estressores, condições insalubres de trabalho, e como há uma repercussão desfavorável na mente. Constatando assim, mudanças comportamentais indissociáveis à atividade laboral exercida: alcoolismo, uso de drogas, ansiedade, depressão, Síndrome de Burnout, TEPT.  O trabalho visa realizar revisão bibliográfica narrativa, utilizando conceitos números, dados, pesquisas, questionários em instituições policiais. Fato inconteste, é que o tema encontra-se cada dia mais presente no dia a dia da sociedade com ocorrências policiais que acabam saindo fora do planejado, com uso excessivo da força, emprego em desconformidade da técnica, formas letais de ação em possíveis intervenções menos vigorosas, sendo advindas, em sua maioria, de aspectos de cunho psicológico mal resolvidos. Assim, resta também prejuízo para a própria Instituição que tem seu reconhecimento social abalado, convive com atestados, tem bons servidores fora de sua área, chegando à fase máxima de chegar ao ponto de aposentadorias e uma exacerbada e grave quantidade crescente de suicídios

Transport Mechanisms and Their Pathology-Induced Regulation Govern Tyrosine Kinase Inhibitor Delivery in Rheumatoid Arthritis

<div><h3>Background</h3><p>Tyrosine kinase inhibitors (TKIs) are effective in treating malignant disorders and were lately suggested to have an impact on non-malignant diseases. However, in some inflammatory conditions like rheumatoid arthritis (RA) the <em>in vivo</em> effect seemed to be moderate. As most TKIs are taken up actively into cells by cell membrane transporters, this study aimed to evaluate the role of such transporters for the accumulation of the TKI Imatinib mesylates in RA synovial fibroblasts as well as their regulation under inflammatory conditions.</p> <h3>Methodology/Principal Findings</h3><p>The transport and accumulation of Imatinib was investigated in transporter-transfected HEK293 cells and human RA synovial fibroblasts (hRASF). Transporter expression was quantified by qRT-PCR. In transfection experiments, hMATE1 showed the highest apparent affinity for Imatinib among all known Imatinib transporters. Experiments quantifying the Imatinib uptake in the presence of specific transporter inhibitors and after siRNA knockdown of hMATE1 indeed identified hMATE1 to mediate Imatinib transport in hRASF. The anti-proliferative effect of Imatinib on PDGF stimulated hRASF was quantified by cell counting and directly correlated with the uptake activity of hMATE1. Expression of hMATE1 was investigated by Western blot and immuno-fluorescence. Imatinib transport under disease-relevant conditions, such as an altered pH and following stimulation with different cytokines, was also investigated by HPLC. The uptake was significantly reduced by an acidic extracellular pH as well as by the cytokines TNFα, IL-1β and IL-6, which all decreased the expression of hMATE1-mRNA and protein.</p> <h3>Conclusion/Significance</h3><p>The regulation of Imatinib uptake via hMATE1 in hRASF and resulting effects on their proliferation may explain moderate <em>in vivo</em> effects on RA. Moreover, our results suggest that investigating transporter mediated drug processing under normal and pathological conditions is important for developing intracellular acting drugs used in inflammatory diseases.</p> </div

Inflammatory conditions reduce Imatinib uptake and hMATE1 expression in hRASF.

<p>Influence of (A) extracellular pH and (B/E) pro-inflammatory cytokines (each at 10 ng/ml) on specific Imatinib uptake (10 µM) given as difference of HPLC detected accumulation at 4°C and 37°C and on (C/D) hMATE1 expression. A) Imatinib uptake in dependence of extracellular pH shown as percentage of uptake at pH 7.4. B, C, and D) Effect of 18 hours incubation with a TNFα, IL-1β and IL-6 (+sIL-6R) cocktail and with single cytokines (each at 10 ng/ml) on Imatinib uptake in hRASF (B), hMATE1-mRNA expression (C), hMATE1-protein expression by immunofluorescence staining (upper part of D) and by Western Blot analysis of biotynilated plasma membrane fractions hMATE1 (lower part of D showing an example of a typical Western blot together with the quantitative analysis of three independent experiments). E) Uptake in hRASF after incubation with cytokine cocktail and inhibition of hMATE1 (by pyrimethamine at 200 nM), hOCT1 (by MPP⁺ at 20 µM) or hOCTN1 (by ergothioneine at 40 µM), measured by HPLC. All values are mean ± SEM. * indicates statistically significant effects (P<0.05).</p

hRASF actively accumulate Imatinib and express several OCTs.

<p>A) Temperature dependent uptake of Imatinib (10 µM) in hRASF at 4°C (black column) and 37°C (white column) measured by HPLC. B) Expression of investigated transporters in hRASF (white columns) and hOASF (black columns) determined by qRT-PCR. Values are mean ± SEM. n.d. = not detected.</p

hMATE1 mediates the Imatinib uptake in hRASF and governs anti-proliferating effects.

<p>A) Specific uptake of Imatinib (10 µM) in hRASF given as difference of accumulation at 4°C and 37°C with inhibition of hMATE1 (by 200 nM pyrimethamine), hOCT1 (by 20 µM MPP⁺) or hOCTN1 (by 40 µM ergothioneine). Data are given as percentage of uptake without inhibition. B) Specific Imatinib uptake, hMATE1 Western Blot and PCR in hRASF after transfection with hMATE1- or scrambled (scr)-siRNA for 72 and 192 hours. Number of transfections is given in brackets. C) Proliferation on hRASF quantified by cell counting after stimulation with PDGF in the presence and absence of Imatinib and the hMATE1 inhibitor pyrimethamine with number of transfections given in brackets. All values are mean ± SEM. * indicates statistically significant effects (P<0.05).</p

Properties of Imatinib transport by hOCTN1, hOCTN2 and hMATE1.

<p>A) Specific Imatinib uptake (10 µM) in transfected HEK293 cells given as difference of accumulation at 4°C and at 37°C measured by HPLC. B) Effect of extracellular pH on the specific Imatinib uptake (10 µM) in hMATE1 transfected HEK293 cells. C) Apparent affinities of Imatinib on hOCT1 (IC₅₀ = 5 µM), hOCTN1 (IC₅₀ = 31 µM) and hMATE1 (IC₅₀ = 118 nM) measured by concentration dependent inhibition of ASP⁺ uptake. Results show number of observation in brackets. Values are mean ± SEM. * indicates statistically significant effects (P<0.05).</p

Regulation of matrixmetalloproteinase-3 and matrixmetalloproteinase-13 by SUMO-2/3 through the transcription factor NF-κB

OBJECTIVE: Based on previous data that have linked the small ubiquitin-like modifier-1 (SUMO-1) to the pathogenesis of rheumatoid arthritis (RA), we have investigated the expression of the highly homologous SUMO family members SUMO-2/3 in human RA and in the human tumour necrosis factor α transgenic (hTNFtg) mouse model of RA and studied their role in regulating disease specific matrixmetalloproteinases (MMPs). METHODS: Synovial tissue was obtained from RA and osteoarthritis (OA) patients and used for histological analyses as well as for the isolation of synovial fibroblasts (SFs). The expression of SUMO-2/3 in RA and OA patients as well as in hTNFtg and wild type mice was studied by PCR, western blot and immunostaining. SUMO-2/3 was knocked down using small interfering RNA in SFs, and TNF-α induced MMP production was determined by ELISA. Activation of nuclear factor-κB (NF-κB) was determined by a luciferase activity assay and a transcription factor assay in the presence of the NF-κB inhibitor BAY 11-7082. RESULTS: Expression of SUMO-2 and to a lesser extent of SUMO-3 was higher in RA tissues and RASFs compared with OA controls. Similarly, there was increased expression of SUMO-2 in the synovium and in SFs of hTNFtg mice compared with wild type animals. In vitro, the expression of SUMO-2 but not of SUMO-3 was induced by TNF-α. The knockdown of SUMO-2/3 significantly increased the TNF-α and interleukin (IL)-1β induced expression of MMP-3 and MMP-13, accompanied by increased NF-κB activity. Induction of MMP-3 and MMP-13 was inhibited by blockade of the NF-κB pathway. TNF-α and IL-1β mediated MMP-1 expression was not regulated by SUMO-2/3. CONCLUSIONS: Collectively, we show that despite their high homology, SUMO-2/3 are differentially regulated by TNF-α and selectively control TNF-α mediated MMP expression via the NF-κB pathway. Therefore, we hypothesise that SUMO-2 contributes to the specific activation of RASF