Tracking and considerations on the therapeutic management of neuropathic pain in adult patients with sickle cell disease / Rastreamento e considerações sobre a conduta terapêutica na dor neuropática em pacientes adultos com doença falciforme

ABSTRACT BACKGROUND AND OBJECTIVES: Sickle cell disease is considered the most common hereditary disorder in Brazil. The chronic pain resulting from some complications of sickle cell disease is still poorly understood, inadequately described, and under-researched. This study aimed to characterize chronic pain in individuals with sickle cell disease, evaluate its treatment, and discuss the importance of studying it as a distinct pathology. METHODS: A cross-sectional study based on comparative analysis between two associations of sickle cell disease patients, one in Brazil and the other in France. The Pain Detect Questionnaire was used to assess neuropathic pain, and Odds Ratio was used to evaluate the strength of the association between opioid use and the recurrence of chronic painful crises. RESULTS: In Brazil, the Pain Detect questionnaire revealed that 55% of patients had a probable neuropathic component, 23% negative, and 22% uncertain. In France, the application resulted in 51% for probable presence, 29% for negative, and 20% for uncertain. All patients reported constant pain. As for the frequent use of opioids, the results were 62% in Brazil and 32% in France. The Odds Ratio calculation results were: OR 15.14 (95% CI = 4.777- 41.4, p < 0.0001) in Brazil; and OR 7.5 (95% CI = 2.121- 25.74, p = 0.0013) in France. CONCLUSION: While it is commonly believed that pain in sickle cell disease is primarily related to somatic and visceral tissue damage after vaso-occlusive events, this study indicated emerging evidence of neuropathic processes involved. Thus, there should be a significant concern about the management of chronic pain and particularly opioid dependence in Brazil.

RESUMO JUSTIFICATIVA E OBJETIVOS: Dentre as alterações hereditárias, a doença falciforme é considerada a mais comum no Brasil. A dor crônica decorrente de suas complicações ainda é mal compreendida, inadequadamente descrita e pouco pesquisada. O presente estudo teve como finalidade caracterizar a dor crônica em indivíduos com doença falciforme, avaliar o seu tratamento e discutir a importância de seu estudo como uma doença em si. METODOS: Estudo transversal, baseado na análise comparativa entre duas associações de indivíduos acometidos pela doença falciforme, com sede no Brasil e na França. Foi aplicado o questionário Pain Detect para avaliação da dor neuropática e a Odds Ratio para avaliar a intensidade de associação entre o uso de opioides e a recorrência de crises álgicas de cunho crônico. RESULTADOS: O questionário Pain Detect apontou que no Brasil 55% de pacientes da doença calciforme apresentam componente neuropático provável, 23% negativo e 22% incerto. Na França, os resultaram foram de 51% para componente provável, 29% negativo e 20% incerto. Dos acometidos pela doença, 100% relataram dores constantes, sendo que fizeram uso frequente de opioides 62% no Brasil e 32% na França. O cálculo do Odds Ratio apontou os seguintes resultados: OR 15,14 (IC 95% = 4,777- 41,4, p < 0,0001) no Brasil; e OR 7,5 (IC 95% = 2,121- 25,74, p = 0,0013) na França. CONCLUSÃO: Embora haja uma crença de que a dor na doença falciforme seja primariamente relacionada à lesão tecidual a nível somático e visceral após os eventos vasoclusivos, o estudo apontou evidências emergentes de processos neuropáticos envolvidos. Assim, deve haver uma preocupação quanto ao manejo da dor crônica e em especial à dependência química pelos opioides no Brasil.

Biotransformations, Antioxidant System Responses, and Histopathological Indexes in the Liver of Fish Exposed to Cyanobacterial Extract.

Radiocystis fernandoi, a microcystin (MC) producer, has been common in cyanobacterial blooms in tropical regions. Microcystin is a hepatotoxin that causes tissue damage and even death in animals, including humans; its detoxification process may involve biotransformation and activation of the antioxidant defense system. We evaluated the detoxification pathway, examined the antioxidant defense system responses, and determined the alterations and the organ histopathological indexes in the liver of the tropical fish Hoplias malabaricus after acute and subchronic intraperitoneal exposure to microcystin. The crude microcystin extract of R. fernandoi had predominantly MC-RR and MC-YR. The detoxification process was activated by increasing ethoxyresorufin-O-deethylase activity, whereas glutathione S-transferase was inhibited. The activity of the antioxidant defense enzymes superoxide dismutase (SOD) and glutathione peroxidase decreased after acute exposure; the SOD-catalase system and the glutathione level increased after subchronic exposure. The carbonyl protein level, lipid peroxidation (LPO), and DNA damage were unchanged after acute exposure, whereas protein carbonyl was unchanged, LPO decreased, and DNA damage increased after subchronic exposure. Histopathological alteration indexes differed between acute and subchronic exposure, but the histopathological organ indexes indicate liver dysfunction in both exposure periods. We conclude that MC-RR and MC-YR induce different liver responses depending on the time of exposure, and the antioxidant defense responses after subchronic exposure may help to partially restore the liver function. Environ Toxicol Chem 2020;39:1041-1051. © 2020 SETAC.

Crude extract of cyanobacterium Radiocystis fernandoi strain R28 induces anemia and oxidative stress in fish erythrocytes.

The cyanobacterium Radiocystis fernandoi has been frequently identified in cyanobacterial blooms in Brazil. Recently, R. fernandoi strain R28, which produces microcystin (MC)-RR and MC-YR, was isolated from the Furnas reservoir, Minas Gerais, Brazil. The present study evaluated the hematological variables and erythrocyte antioxidant responses, lipid peroxidation (LPO), and genotoxicity in a neotropical fish (Hoplias malabaricus) after acute and subchronic exposure to a crude extract (CE) of R. fernandoi strain R28. Acute exposure (12 or 96 h) consisted of a single intraperitoneal (i.p.) CE injection, and subchronic exposure consisted of one i.p. CE injection every 72 h for 30 days. After acute exposure, fish exhibited macrocytic anemia (12 h post-injection) followed by normocytic anemia (96 h post-injection). The increased activity of superoxide dismutase, glutathione peroxidase, glutathione-S-transferase, and the glutathione level in the erythrocytes did not prevent oxidative stress, manifested as lipid peroxidation and elevated DNA damage after acute exposure. After subchronic exposure, the hematological variables recovered, and the absence of erythrocyte oxidative stress suggests possible modulation by other biological factors, including a possible decrease in MC uptake by the cells and/or increasing detoxification efficiency that precludes erythrocyte damage.

Overview of the toxic effects of titanium dioxide nanoparticles in blood, liver, muscles, and brain of a Neotropical detritivorous fish.

The toxicity of titanium dioxide nanoparticles (TiO2 -NP) in the blood, liver, muscle, and brain of a Neotropical detritivorous fish, Prochilodus lineatus, was tested. Juvenile fish were exposed to 0, 1, 5, 10, and 50 mg L-1 of TiO2 -NP for 48 hours (acute exposure) or 14 days (subchronic exposure) to evaluate changes in hematology, red blood cell (RBC) genotoxicity/mutagenicity, liver function (reactive oxygen species (ROS) production, antioxidant responses, detoxification, and histopathology), acetylcholinesterase (AChE) activity in muscles and brain, and Ti bioaccumulation. TiO2 -NP did not cause genetic damage to RBC, but acutely decreased white blood cells (WBC) and increased monocytes. Subchronically, RBC decreased, mean cell volume and hemoglobin increased, and WBC and lymphocytes decreased. Therefore, NP has the potential to affect immune system and increase energy expenditure, reducing the fish's ability to avoid predator and to resist pathogens. In the liver, acute exposure decreased ROS and increased glutathione (GSH) content, while subchronic exposure decreased superoxide dismutase activity and increased glutathione-S-transferase (GST) activity and GSH content. GSH and GST seem to play an essential role in metabolizing NP and ROS, likely increasing hepatocytes' metabolic rate, which may be the cause of observed cell hypertrophy, disarrangement of hepatic cords and degenerative morphological alterations. Although most studies indicate that the kidney is responsible for metabolizing and/or eliminating TiO2 -NP, this study shows that the liver also has a main role in these processes. Nevertheless, Ti still accumulated in the liver, muscle, and brain and decreased muscular AChE activity after acute exposure, showing neurotoxic potential. More studies are needed to better understand the biochemical pathways TiO2 -NP are metabolized and how its bioaccumulation may affect fish homeostasis and survival in the environment.