Indoleamine 2,3-dioxygenase (IDO1) - Can dendritic cells and monocytes expressing this moonlight enzyme change the phase of Parkinson's Disease?

Parkinson's Disease (PD) is the second most common neurodegenerative disease where central and peripheral immune dysfunctions have been pointed out as a critical component of susceptibility and progression of this disease. Dendritic cells (DCs) and monocytes are key players in promoting immune response regulation and can induce the enzyme indoleamine 2,3-dioxygenase 1 (IDO1) under pro-inflammatory environments. This enzyme with catalytic and signaling activity supports the axis IDO1-KYN-aryl hydrocarbon receptor (AhR), promoting disease-specific immunomodulatory effects. IDO1 is a rate-limiting enzyme of the kynurenine pathway (KP) that begins tryptophan (Trp) catabolism across this pathway. The immune functions of the pathway, which are extensively described in cancer, have been forgotten so far in neurodegenerative diseases, where a chronic inflammatory environment underlines the progression of the disease. Despite dysfunctions of KP have been described in PD, these are mainly associated with neurotoxic functions. With this review, we aim to focus on the immune properties of IDO1+DCs and IDO1+monocytes as a possible strategy to balance the pro-inflammatory profile described in PD. We also highlight the importance of exploring the role of dopaminergic therapeutics in IDO1 modulation to possibly optimize current PD therapeutic strategies.

A peripheral blood mononuclear cell-based in vitro model: A tool to explore indoleamine 2, 3-dioxygenase-1 (IDO1).

BACKGROUND: Proinflammatory cytokines powerfully induce the rate-limiting enzyme indoleamine 2, 3-dioxygenase-1 (IDO-1) in dendritic cells (DCs) and monocytes, it converts tryptophan (Trp) into L-kynurenine (KYN), along the kynurenine pathway (KP). This mechanism represents a crucial innate immunity regulator that can modulate T cells. This work explores the role of IDO1 in lymphocyte proliferation within a specific pro-inflammatory milieu. METHODS: Peripheral blood mononuclera cells (PBMCs) were isolated from buffy coats taken from healthy blood donors and exposed to a pro-inflammatory milieu triggered by a double-hit stimulus: lipopolysaccharide (LPS) plus anti-CD3/CD28. The IDO1 mRNA levels in the PBMCs were measured by RT-PCR; the IDO1 activity was analyzed using the KYN/Trp ratio, measured by HPLC-EC; and lymphocyte proliferation was measured by flow cytometry. Trp and epacadostat (EP) were used as an IDO1 substrate and inhibitor, respectively. KYN, which is known to modulate Teffs, was tested as a positive control in lymphocyte proliferation. RESULTS: IDO1 expression and activity in PBMCs increased in an in vitro pro-inflammatory milieu. The lymphoid stimulus increased IDO1 expression and activity, which supports the interaction between the activated lymphocytes and the circulating myeloid IDO1-expressing cells. The addition of Trp decreased lymphocyte proliferation but EP, which abrogated the IDO1 function, had no impact on proliferation. Additionally, incubation with KYN seemed to decrease the lymphocyte proliferation. CONCLUSION: IDO1 inhibition did not change T lymphocyte proliferation. We present herein an in vitro experimental model suitable to measure IDO1 expression and activity in circulating myeloid cells.

Medications used in paediatric intensive care by continuous infusion: Do the technical aspects of the package inserts corroborate scientific evidence?

WHAT IS KNOWN AND OBJECTIVE: Hospitalized paediatric patients are three times more likely to experience medication errors with the potential to cause harm, when they are compared to adults. The lack of research in paediatrics, difficulties that are derived as indications and the parameters of safety and effectiveness of pharmacological therapy in children. To analyse whether the technical and legal aspects of the package insert for medicines used in paediatric intensive care units (ICU) using a continuous infusion (CI) pump corroborate the recommendations of clinical protocols and legal provisions. METHODS: A documentary study, in which technical and legal information contained in the package inserts of medications commonly used via CI in neopediatric ICUs was analysed. The consultation of the medication package insert was carried out through the electronic portal of the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária - ANVISA). Information on the use of medications in the neonatal and paediatric populations via CI was sought in the medication package insert. To analyse the legal aspects, ANVISA's RDC no. 47/2009 was used. In order to compare the technical information, the Micromedex NeoFax®, Micromedex Paediatrics®, and Lexicomp® databases were consulted. RESULTS AND DISCUSSION: Of the 13 medications analysed, 46% (n = 6) had some non-compliance with RDC 47/2009. Only 46% (n = 6) of the medications are indicated for paediatric use and only the medication package insert for midazolam (7.7%) contained the information considered essential for use via CI in paediatrics. WHAT IS NEW AND CONCLUSION: This is an innovative study that identifies the weaknesses of the medication package inserts for medications used by CI in paediatric ICUs. Failure to comply with legal recommendations can make medication administration difficult and increase the probability that errors will occur; and the absence of specific technical information can make care difficult and compromise patient safety. It is important that there is supervision by regulatory agencies and the contribution of health professionals so that non-conformities are reported and corrected, to guarantee safe care for paediatric patients in intensive care.

Soroprevalence of rapid tests in leprosy cases and household contacts in endemic municipalities of Pará state / Soroprevalência de testes rápidos em caso de hanseníase e contatos intradomiciliares em municípios endêmicos do estado do Pará.

Objective:This is a transversal study of series of cases in endemic areas for leprosy in the Sate of Pará, estimating the seroprevalence of antiPGL-1, through ML-Flow rapid test in leprosy cases and their household contacts. Method: from april 2011 to october 2012, 73 new leprosy cases and 165 household contacts were recruited in the reference units for treatment of leprosy in the municipalities of Marituba, Belém, Igarapé-Açú and Santarém. Results: seropositivity was observed in 53.42% of index cases; of them were MB cases and among 12.1% household contacts. Conclusions: the results indicate that the introduction of the rapid test, as auxiliary instrument, serves for classification of index cases and household contacts of cases involved in this study, allowing to conclude that leprosy cases and their contacts are important elements in the epidemiology of the disease.

Objetivo: Trata-se de um estudo transversal, do tipo série de casos em áreas endêmicas para hanseníase no estado do Pará, estimando a soroprevalência de anticorpos antiPGL-1 através do teste rápido ML-Flow em casos de hanseníase e seus contactos intradomiciliares. Método: de abril de 2011 a outubro de 2012, 73 novos casos de hanseníase e 165 contactos intradomiciliares foram recrutados nas unidades de referência para tratamento da hanseníase nos municípios de Marituba, Belém, Igarapé-Açú e Santarém. Resultados: a soropositividade foi observada em 53,42% dos casos índices; deles eram casos MB e 12,1% entre os contactos intradomiciliares. Conclusões: os resultados indicam que a introdução do teste rápido, como instrumento auxiliar, serve para a classificação dos casos índices e contactos intradomiciliares dos casos envolvidos no estudo, o que permite concluir que os casos de hanseníase e seus contactos são elementos importantes na epidemiologia da doença.