Evaluation of urinary cysteinyl leukotrienes as biomarkers of severity and putative therapeutic targets in COVID-19 patients.

BACKGROUND: Cysteinyl leukotrienes (CysLT) are potent inflammation-promoting mediators, but remain scarcely explored in COVID-19. We evaluated urinary CysLT (U-CysLT) relationship with disease severity and their usefulness for prognostication in hospitalized COVID-19 patients. The impact on U-CysLT of veno-venous extracorporeal membrane oxygenation (VV-ECMO) and of comorbidities such as hypertension and obesity was also assessed. METHODS: Blood and spot urine were collected in "severe" (n = 26), "critically ill" (n = 17) and "critically ill on VV-ECMO" (n = 17) patients with COVID-19 at days 1-2 (admission), 3-4, 5-8 and weekly thereafter, and in controls (n = 23) at a single time point. U-CysLT were measured by ELISA. Routine markers, prognostic scores and outcomes were also evaluated. RESULTS: U-CysLT did not differ between groups at admission, but significantly increased along hospitalization only in critical groups, being markedly higher in VV-ECMO patients, especially in hypertensives. U-CysLT values during the first week were positively associated with ICU and total hospital length of stay in critical groups and showed acceptable area under curve (AUC) for prediction of 30-day mortality (AUC: 0.734, p = 0.001) among all patients. CONCLUSIONS: U-CysLT increase during hospitalization in critical COVID-19 patients, especially in hypertensives on VV-ECMO. U-CysLT association with severe outcomes suggests their usefulness for prognostication and as therapeutic targets.

Outcomes of thrombotic thrombocytopenic purpura patients submitted to therapeutic plasma exchange in a single center in Brazil.

INTRODUCTION: Immune thrombotic thrombocytopenic purpura (iTTP) is characterized by acute systemic microvascular thrombosis and is associated with a high morbidity and mortality, especially in delayed diagnosis (later than 6-7 days from symptoms). iTTP data in Brazil is scarce, so we aimed to characterize the clinical presentation and identify predictors of death risk in patients with this disease in Brazil. METHODS: In this single-center retrospective study the patients who underwent therapeutic plasma exchange (TPE) for presumptive or confirmed iTTP were evaluated regarding the epidemiological, clinical, laboratorial characteristics and management. RESULTS: A total of 50 patients (90 % female), with median age (IQR) of 34.1 (27-47) years, were enrolled, of which 12 (24 %) died. The most frequent symptoms were neurological (96 %), bleeding (76 %), gastrointestinal (52 %), fever (38 %), and cardiovascular (22 %). Neurological focal deficit and cardiovascular symptoms were more frequently observed in the non-survivor group (P = 0.0019 and P = 0.007, respectively). The mean ± SD number of days from beginning of symptoms to first TPE was 12.22 ± 7.91. We identified an association regarding mortality rate with a score MITS ≥ 2 points (P = 0.04), a higher indirect bilirubin (P = 0.0006), a higher number of transfused red blood cell units (P = 0.025), and platelet transfusion (P = 0.027). CONCLUSION: Delayed diagnosis appears to be associated with a higher frequency of neurological symptoms and mortality. Intensity of hemolysis and signs of organ ischemia, such as cardiovascular symptoms and focal neurological deficit, are indicators of death risk.

Urinary Cysteinyl Leukotrienes as Biomarkers of Endothelial Activation, Inflammation and Oxidative Stress and Their Relationship with Organ Dysfunction in Human Septic Shock.

Cysteinyl leukotrienes (CysLT) are potent vascular leakage-promoting agents but have been scarcely explored in human septic shock (SS). We evaluated CysLT at admission and during hospitalization and their correlation with endothelial dysfunction, inflammation, oxidative stress, the renin-angiotensin-aldosterone system, and cardiac, renal, respiratory, and hepatic parameters in SS patients. Blood and spot-urine samples were collected at days 1-2 (admission), 3-4, and 5-8 in SS patients (n = 13) and at a single time point in controls (n = 22). Urinary CysLT (u-CysLT) and isoprostanes, plasma, and urinary angiotensinogen, serum myeloperoxidase, and IL-10 were quantified by ELISA. Serum intercellular-adhesion molecule-1, vascular cell-adhesion molecule-1, E-selectin, tumor necrosis factor-α, IL-1ß, and IL-6 were measured by multiplex immunoassays. Routine markers were evaluated using automated analyzers. At admission, SS patients had increased u-CysLT, endothelial activation, inflammation, oxidative stress, and plasma and urinary angiotensinogen, as well as cardiac, respiratory, hepatic, and renal injury/dysfunction. There were no changes in u-CysLT during hospitalization. Both correlation and multivariate analyses showed positive relationships of u-CysLT with endothelial activation, inflammation, oxidative stress, proteinuria, and hepatic injury/dysfunction markers. These results suggest that u-CysLT may be potential non-invasive biomarkers for monitoring the pathophysiological mechanisms underlying SS, as well as putative therapeutic targets.

Endothelitis profile in acute heart failure and cardiogenic shock patients: Endocan as a potential novel biomarker and putative therapeutic target.

Aims: Inflammation-driven endothelitis seems to be a hallmark of acute heart failure (AHF) and cardiogenic shock (CS). Endocan, a soluble proteoglycan secreted by the activated endothelium, contributes to inflammation and endothelial dysfunction, but has been scarcely explored in human AHF. We aimed to evaluate serum (S-Endocan) and urinary endocan (U-Endocan) profiles in AHF and CS patients and to correlate them with biomarkers/parameters of inflammation, endothelial activation, cardiovascular dysfunction and prognosis. Methods: Blood and spot urine were collected from patients with AHF (n = 23) or CS (n = 25) at days 1-2 (admission), 3-4 and 5-8 and from controls (blood donors, n = 22) at a single time point. S-Endocan, U-Endocan, serum IL-1ß, IL-6, tumour necrosis factor-α (S-TNF-α), intercellular adhesion molecule-1 (S-ICAM-1), vascular cell adhesion molecule-1 (S-VCAM-1) and E-selectin were determined by ELISA or multiplex immunoassays. Serum C-reactive protein (S-CRP), plasma B-type natriuretic peptide (P-BNP) and high-sensitivity troponin I (P-hs-trop I), lactate, urea, creatinine and urinary proteins, as well as prognostic scores (APACHE II, SAPS II) and echocardiographic left ventricular ejection fraction (LVEF) were also evaluated. Results: Admission S-Endocan was higher in both patient groups, with CS presenting greater values than AHF (AHF and CS vs. Controls, p < 0.001; CS vs. AHF, p < 0.01). Admission U-Endocan was only higher in CS patients (p < 0.01 vs. Controls). At admission, S-VCAM-1, S-IL-6 and S-TNF-α were also higher in both patient groups but there were no differences in S-E-selectin and S-IL-1ß among the groups, nor in P-BNP, S-CRP or renal function between AHF and CS. Neither endocan nor other endothelial and inflammatory markers were reduced during hospitalization (p > 0.05). S-Endocan positively correlated with S-VCAM-1, S-IL-6, S-CRP, APACHE II and SAPS II scores and was positively associated with P-BNP in multivariate analyses. Admission S-Endocan raised in line with LVEF impairment (p = 0.008 for linear trend). Conclusion: Admission endocan significantly increases across AHF spectrum. The lack of reduction in endothelial and inflammatory markers throughout hospitalization suggests a perpetuation of endothelial dysfunction and inflammation. S-Endocan appears to be a biomarker of endothelitis and a putative therapeutic target in AHF and CS, given its association with LVEF impairment and P-BNP and its positive correlation with prognostic scores.

Neutrophil-to-lymphocyte ratio and D-dimer are biomarkers of death risk in severe COVID-19: A retrospective observational study.

BACKGROUND AND AIMS: Over 4 million deaths from coronavirus disease (COVID)-19 have been reported in the world. Several biomarkers have been identified that predict disease severity, but there is still a need to identify biomarkers for death risk in severe COVID-19. We aim to define amongst the biomarkers already identified those which are mostly associated with increased death rate in patients with severe COVID-19. METHODS: In this retrospective study conducted in three public hospitals linked to the Medical School of Ribeirão Preto, Brazil, patients with severe COVID-19 were evaluated regarding biomarkers (neutrophil-to-lymphocyte ratio-NLR, D-dimer, fibrinogen) of death risk, obtained before administration of corticosteroids. RESULTS: Thirty-nine (32.8%) of the 119 patients included (104 [87.4%] on mechanical ventilation) died during hospitalization. Non-survivor group had higher median (range) NLR (12.63 [2.6-115] vs 7.43 [0.43-31.8]; P = .001), D-dimer (2.17 [0.27-20.00] vs 1.57 [0.28-20.00]; P = .03), but lower fibrinogen (631 [353-1078] vs 705 [407-1200]; P = .02). The group with NLR ≥ 10 and D-dimer ≥ 2 µg/mL had a higher death risk than the group with NLR < 10 and D-dimer < 2 µg/mL (OR: 5.39; CI 95%: 1.5-19.42; P = .01). CONCLUSION: High NLR and D-dimer, especially when combined, are predictors of death risk for patients with severe COVID-19 and should be incorporated into their evaluation.

Inflammation in Human Heart Failure: Major Mediators and Therapeutic Targets.

Inflammation has been recognized as a major pathophysiological contributor to the entire spectrum of human heart failure (HF), including HF with reduced ejection fraction, HF with preserved ejection fraction, acute HF and cardiogenic shock. Nevertheless, the results of several trials attempting anti-inflammatory strategies in HF patients have not been consistent or motivating and the clinical implementation of anti-inflammatory treatments for HF still requires larger and longer trials, as well as novel and/or more specific drugs. The present work reviews the different inflammatory mechanisms contributing to each type of HF, the major inflammatory mediators involved, namely tumor necrosis factor alpha, the interleukins 1, 6, 8, 10, 18, and 33, C-reactive protein and the enzymes myeloperoxidase and inducible nitric oxide synthase, and their effects on heart function. Furthermore, several trials targeting these mediators or involving other anti-inflammatory treatments in human HF are also described and analyzed. Future therapeutic advances will likely involve tailored anti-inflammatory treatments according to the patient's inflammatory profile, as well as the development of resolution pharmacology aimed at stimulating resolution of inflammation pathways in HF.

Synthesis of a Small Library of Nature-Inspired Xanthones and Study of Their Antimicrobial Activity.

A series of thirteen xanthones 3-15 was prepared based on substitutional (appendage) diversity reactions. The series was structurally characterized based on their spectral data and HRMS, and the structures of xanthone derivatives 1, 7, and 8 were determined by single-crystal X-ray diffraction. This series, along with an in-house series of aminated xanthones 16-33, was tested for in-vitro antimicrobial activity against seven bacterial (including two multidrug-resistant) strains and five fungal strains. 1-(Dibromomethyl)-3,4-dimethoxy-9H-xanthen-9-one (7) and 1-(dibromomethyl)-3,4,6-trimethoxy-9H-xanthen-9-one (8) exhibited antibacterial activity against all tested strains. In addition, 3,4-dihydroxy-1-methyl-9H-xanthen-9-one (3) revealed a potent inhibitory effect on the growth of dermatophyte clinical strains (T. rubrum FF5, M. canis FF1 and E. floccosum FF9), with a MIC of 16 µg/mL for all the tested strains. Compounds 3 and 26 showed a potent inhibitory effect on two C. albicans virulence factors: germ tube and biofilm formation.

New marine-derived indolymethyl pyrazinoquinazoline alkaloids with promising antimicrobial profiles.

Due to the emergence of multidrug-resistant pathogenic microorganisms, the search for novel antimicrobials is urgent. Inspired by marine alkaloids, a series of indolomethyl pyrazino [1,2-b]quinazoline-3,6-diones was prepared using a one-pot microwave-assisted multicomponent polycondensation of amino acids. The compounds were evaluated for their antimicrobial activity against a panel of nine bacterial strains and five fungal strains. Compounds 26 and 27 were the most effective against Staphylococcus aureus ATCC 29213 reference strain with MIC values of 4 µg mL-1, and a methicillin-resistant Staphylococcus aureus (MRSA) isolate with MIC values of 8 µg mL-1. It was possible to infer that enantiomer (-)-26 was responsible for the antibacterial activity (MIC 4 µg mL-1) while (+)-26 had no activity. Furthermore, compound (-)-26 was able to impair S. aureus biofilm production and no significant cytotoxicity towards differentiated and non-differentiated SH-SY5Y cells was observed. Compounds 26, 28, and 29 showed a weak antifungal activity against Trichophyton rubrum clinical isolate with MIC 128 µg mL-1 and presented a synergistic effect with fluconazole.

Prenatal microRNA miR-200b Therapy Improves Nitrofen-induced Pulmonary Hypoplasia Associated With Congenital Diaphragmatic Hernia.

OBJECTIVE: We aimed to evaluate the use of miR-200b as a prenatal transplacental therapy in the nitrofen rat model of abnormal lung development and congenital diaphragmatic hernia (CDH). BACKGROUND: Pulmonary hypoplasia (PH) and pulmonary hypertension determine mortality and morbidity in CDH babies. There is no safe medical prenatal treatment available. We previously discovered that higher miR-200b is associated with better survival in CDH babies. Here, we investigate the role of miR-200b in the nitrofen rat model of PH and CDH and evaluate its use as an in vivo prenatal therapy. METHODS: We profiled miR-200b expression during nitrofen-induced PH using RT-qPCR and in situ hybridization in the nitrofen rat model of PH and CDH. The effects of nitrofen on downstream miR-200b targets were studied in bronchial lung epithelial cells using a SMAD luciferase assay, Western blotting and Immunohistochemistry. We evaluated miR-200b as a lung growth promoting therapy ex vivo and in vivo using lung explant culture and transplacental prenatal therapy in the nitrofen rat model. RESULTS: We show that late lung hypoplasia in CDH is associated with (compensatory) upregulation of miR-200b in less hypoplastic lungs. Increasing miR-200b abundance with mimics early after nitrofen treatment decreases SMAD-driven TGF-ß signaling and rescues lung hypoplasia both in vitro and in vivo. Also, prenatal miR-200b therapy decreases the observed incidence of CDH. CONCLUSIONS: Our data indicate that miR-200b improves PH and decreases the incidence of CDH. Future studies will further exploit this newly discovered prenatal therapy for lung hypoplasia and CDH.

Lichen Xanthones as Models for New Antifungal Agents.

Due to the emergence of multidrug-resistant pathogenic microorganisms, the search for new antimicrobial compounds plays an important role in current medicinal chemistry research. Inspired by lichen antimicrobial xanthones, a series of novel chlorinated xanthones was prepared using five chlorination methods (Methods A⁻E) to obtain different patterns of substitution in the xanthone scaffold. All the synthesized compounds were evaluated for their antimicrobial activity. Among them, 3-chloro-4,6-dimethoxy-1-methyl-9H-xanthen-9-one 15 showed promising antibacterial activity against E. faecalis (ATCC 29212 and 29213) and S. aureus ATCC 29213. 2,7-Dichloro-3,4,6-trimethoxy-1-methyl-9H-xanthen-9-one 18 revealed a potent fungistatic and fungicidal activity against dermatophytes clinical strains (T. rubrum, M. canis, and E. floccosum (MIC = 4⁻8 µg/mL)). Moreover, when evaluated for its synergistic effect for T. rubrum, compound 18 exhibited synergy with fluconazole (ΣFIC = 0.289). These results disclosed new hit xanthones for both antibacterial and antifungal activity.

Neuroendocrine factors regulate retinoic acid receptors in normal and hypoplastic lung development.

KEY POINTS: Retinoic acid (RA) and ghrelin levels are altered in human hypoplastic lungs when compared to healthy lungs. Although considerable data have been obtained about RA, ghrelin and bombesin in the congenital diaphragmatic hernia (CDH) rat model, neuroendocrine factors have never been associated with the RA signalling pathway in this animal model. In this study, the interaction between neuroendocrine factors and RA was explored in the CDH rat model. The authors found that normal fetal lung explants treated with RA, bombesin and ghrelin showed an increase in lung growth. Hypoplastic lungs presented higher expression levels of the RA receptors α and γ. Moreover bombesin and ghrelin supplementation, in vitro, to normal lungs increased RA receptor α/γ expression whereas administration of bombesin and ghrelin antagonists to normal and hypoplastic lungs decreased it. These data reveal for the first time that there is a link between neuroendocrine factors and RA, and that neuroendocrine factors sensitise the lung to the RA action through RA receptor modulation. ABSTRACT: Congenital diaphragmatic hernia (CDH) is characterised by a spectrum of lung hypoplasia and consequent pulmonary hypertension, leading to high morbidity and mortality rates. Moreover, CDH has been associated with an increase in the levels of pulmonary neuroendocrine factors, such as bombesin and ghrelin, and a decrease in the action of retinoic acid (RA). The present study aimed to elucidate the interaction between neuroendocrine factors and RA. In vitro analyses were performed on Sprague-Dawley rat embryos. Normal lung explants were treated with bombesin, ghrelin, a bombesin antagonist, a ghrelin antagonist, dimethylsulfoxide (DMSO), RA dissolved in DMSO, bombesin plus RA and ghrelin plus RA. Hypoplastic lung explants (nitrofen model) were cultured with bombesin, ghrelin, bombesin antagonist or ghrelin antagonist. The lung explants were analysed morphometrically, and retinoic acid receptor (RAR) α, ß and γ expression levels were assessed via Western blotting. Immunohistochemistry analysis of RAR was performed in normal and hypoplastic lungs 17.5 days post-conception (dpc). Compared with the controls, hypoplastic lungs exhibited significantly higher RARα/γ expression levels. Furthermore considering hypoplastic lungs, bombesin and ghrelin antagonists decreased RARα/γ expression. Normal lung explants (13.5 dpc) treated with RA, bombesin plus RA, ghrelin plus RA, bombesin or ghrelin exhibited increased lung growth. Moreover, bombesin and ghrelin increased RARα/γ expression levels, whereas the bombesin and ghrelin antagonists decreased RARα/γ expression. This study demonstrates for the first time that neuroendocrine factors function as lung growth regulators, sensitising the lung to the action of RA through up-regulation of RARα and RARγ.

Lower NPAS3 expression during the later stages of abnormal lung development in rat congenital diaphragmatic hernia.

PURPOSE: Congenital diaphragmatic hernia (CDH) is characterized by a developmental defect in the diaphragm, pulmonary hypoplasia and pulmonary hypertension. NPAS3 is a PAS domain transcription factor regulating Drosophila tracheogenesis. NPAS3 null mice develop pulmonary hypoplasia in utero and die after birth due to respiratory failure. We aimed to evaluate NPAS3 expression during normal and abnormal lung development due to CDH. METHODS: CDH was induced by administering 100 mg/ml nitrofen to time-pregnant dams on embryonic day (E) 9 of gestation. Lungs were isolated on E15, E18 and E21 and NPAS3 localization was determined by immunohistochemistry and quantified using Western blotting. RESULTS: We found that only E21 hypoplastic CDH lungs have reduced expression of NPAS3 in the terminal saccules. Western blotting confirmed the down-regulation of NPAS3 protein in the nitrofen-induced hypoplastic lungs. CONCLUSIONS: We demonstrate for the first time that nitrofen-induced hypoplastic CDH lungs have reduced NPAS3 expression in the terminal saccules during the later stages of abnormal lung development. Our findings suggest that NPAS3 is associated with pulmonary hypoplasia in CDH.

Unique Tracheal Fluid MicroRNA Signature Predicts Response to FETO in Patients With Congenital Diaphragmatic Hernia.

OBJECTIVE AND BACKGROUND: Our objective was to determine the fetal in vivo microRNA signature in hypoplastic lungs of human fetuses with severe isolated congenital diaphragmatic hernia (CDH) and changes in tracheal and amniotic fluid of fetuses undergoing fetoscopic endoluminal tracheal occlusion (FETO) to reverse severe lung hypoplasia due to CDH. METHODS: We profiled microRNA expression in prenatal human lungs by microarray analysis. We then validated this signature with real-time quantitative polymerase chain reaction in tracheal and amniotic fluid of CDH patients undergoing FETO. We further explored the role of miR-200b using semiquantitative in situ hybridization and immunohistochemistry for TGF-ß2 in postnatal lung sections. We investigated miR-200b effects on TGF-ß signaling using a SMAD-luciferase reporter assay and Western blotting for phospho-SMAD2/3 and ZEB-2 in cultures of human bronchial epithelial cells. RESULTS: CDH lungs display an increased expression of 2 microRNAs: miR-200b and miR-10a as compared to control lungs. Fetuses undergoing FETO display increased miR-200 expression in their tracheal fluid at the time of balloon removal. Future survivors of FETO display significantly higher miR-200 expression than those with a limited response. miR-200b was expressed in bronchial epithelial cells and vascular endothelial cells. TGF-ß2 expression was lower in CDH lungs. miR-200b inhibited TGF-ß-induced SMAD signaling in cultures of human bronchial epithelial cells. CONCLUSIONS: Human fetal hypoplastic CDH lungs have a specific miR-200/miR-10a signature. Survival after FETO is associated with increased miR-200 family expression. miR-200b overexpression in CDH lungs results in decreased TGF-ß/SMAD signaling.

The role of ephrins-B1 and -B2 during fetal rat lung development.

UNLABELLED: BACKGROUND/ AIMS: The knowledge of the molecular network that governs fetal lung branching is an essential step towards the discovery of novel therapeutic targets against pulmonary pathologies. Lung consists of two highly branched systems: airways and vasculature. Ephrins and its receptors, Eph, have been implicated in cardiovascular development, angiogenesis and vascular remodeling. This study aims to clarify the role of these factors during lung morphogenesis. METHODS: Ephrins-B1, -B2 and receptor EphB4 expression pattern was assessed in fetal rat lungs between 15.5 and 21.5 days post-conception, by immunohistochemistry. Fetal rat lungs were harvested at 13.5 dpc, cultured during 4 days and treated with increasing doses of ephrins-B1 and -B2 and the activity of key signaling pathways was assessed. RESULTS: Ephrin-B1 presents mesenchymal expression, whereas ephrin-B2 and its receptor EphB4 were expressed by the epithelium. Both ephrins stimulated pulmonary branching. Moreover, while ephrin-B1 did not affect the pathways studied, ephrin-B2 supplementation decreased activity of JNK, ERK and STAT. This study characterizes the expression pattern of ephrins-B1, -B2 and EphB4 receptor throughout rat lung development. CONCLUSION: Our data highlight a possible role of ephrins as molecular stimulators of lung morphogenesis. Moreover, it supports the idea that classical vascular factors might play a role as airway growth promoters.

Anestesia em paciente com saturnismo: relato de caso / Anesthesia in patient with lead poisoning: case report / Anestesia en paciente con saturnismo: relato de caso

JUSTICATIVA E OBJETIVOS: O saturnismo decorre da intoxicação crônica pelo chumbo, comum após exposição ocupacional. Projéteis retidos no corpo podem resultar em elevados níveis plasmáticos de chumbo com inúmeras repercussões clínicas, principalmente neurológicas. Apresentamos um caso de paciente sintomático, sem diagnóstico, que foi detectado durante visita pré-anestésica. RELATO DO CASO: Paciente apresentado para retirada de projétil alojado em joelho esquerdo há 14 anos, com polineuropatia sem investigação. Durante visita pré-anestésica foi levantada a hipótese de saturnismo, confirmada pelos altos níveis plasmáticos de chumbo (129 µg.dL-1). A cirurgia foi realizada sob anestesia geral antes do início da quelação do chumbo. Durante indução anestésica, o paciente evoluiu com apneia, sem rigidez torácica após 50 µg de fentanil. CONCLUSÃO: A intoxicação por chumbo interfere com a função de diversos órgãos e sistemas, altera o metabolismo oxidativo e os mecanismos intracelulares de sinalização. O acometimento neurológico, com redução da condução neural merece especial atenção do anestesiologista.

BACKGROUND AND OBJECTIVES: Lead poisoning, also Saturnism, results from chronic lead poisoning, common after occupational exposure. Projectiles retained in the body may result in increased levels of plasma lead with numerous clinical implications, particularly neurological. We report a case of a symptomatic patient, undiagnosed, whose diagnosis was made during the preanesthesia evaluation. CASE REPORT: The patient was attended at our hospital to remove a bullet lodged in his left knee 14 years ago, presenting with polyneuropathy without investigation. During the preanesthetic visit, saturnism was hypothesized and confirmed by high plasma lead levels (129 µg.dL-1). Surgery was performed under general anesthesia before starting lead chelation. During anesthesia, the patient developed apnea, without chest-wall rigidity after administration of fentanyl (50 mg). CONCLUSION: Lead poisoning interferes with the function of various organs and systems, alters oxidative metabolism and intracellular signaling mechanisms. Neurological involvement, with reduced neural conduction, deserves special attention from anesthesiologists.

JUSTIFICATIVA Y OBJETIVOS: El saturnismo proviene de la intoxicación crónica por el plomo común después de la exposición ocupacional. Los proyectiles que el cuerpo retiene pueden traer como resultado elevados niveles plasmáticos de plomo con innumerables repercusiones clínicas, principalmente neurológicas. Presentamos aquí un caso de paciente sintomático, sin diagnóstico, y que fue detectado durante la visita preanestésica. RELATO DEL CASO: Paciente que se presentó para la retirada de una bala que se había alojado en la rodilla izquierda hacía 14 años, con polineuropatía sin investigación. Durante la visita preanestésica se pensó en saturnismo, lo que fue confirmado por los altos niveles plasmáticos de plomo (129 µg.dL-1). La cirugía fue realizada bajo anestesia general antes del inicio de la quelación del plomo. Durante la inducción anestésica, el paciente evolucionó con apnea sin rigidez torácica después de 50 µg de fentanilo. CONCLUSIONES: La intoxicación por plomo interfiere con la función de diversos órganos y sistemas, altera el metabolismo oxidativo y los mecanismos intracelulares de señalización. El compromiso neurológico, con la reducción de la conducción neural, merece una especial atención por parte del anestesiólogo.

Anesthesia in patient with lead poisoning: case report.

BACKGROUND AND OBJECTIVES: Lead poisoning, also Saturnism, results from chronic lead poisoning, common after occupational exposure. Projectiles retained in the body may result in increased levels of plasma lead with numerous clinical implications, particularly neurological. We report a case of a symptomatic patient, undiagnosed, whose diagnosis was made during the preanesthesia evaluation. CASE REPORT: The patient was attended at our hospital to remove a bullet lodged in his left knee 14 years ago, presenting with polyneuropathy without investigation. During the preanesthetic visit, saturnism was hypothesized and confirmed by high plasma lead levels (129 µg.dL(-1)). Surgery was performed under general anesthesia before starting lead chelation. During anesthesia, the patient developed apnea, without chest-wall rigidity after administration of fentanyl (50 µg). CONCLUSION: Lead poisoning interferes with the function of various organs and systems, alters oxidative metabolism and intracellular signaling mechanisms. Neurological involvement, with reduced neural conduction, deserves special attention from anesthesiologists.

Changes in serotoninergic and noradrenergic descending pain pathways during painful diabetic neuropathy: the preventive action of IGF1.

Painful diabetic neuropathy (PDN) induces neuronal hyperactivity at the spinal cord and periaqueductal gray (PAG), a key area in descending nociceptive modulation. Since the PAG uses relay stations at serotoninergic and noradrenergic brainstem areas, we determined the serotonin and noradrenaline levels at the spinal cord of streptozotocin-diabetic rats and at those brainstem areas (serotoninergic rostroventromedial medulla and noradrenergic A(5) and A(7) cell groups). Since, during diabetes, the levels of insulin growth factor 1 (IGF1) decrease, reducing its neurotrophic effect in the brain, we also studied the effects of IGF1 treatment. One week after diabetes induction, subcutaneous injections of IGF1 (2.5mg/kg) were performed during 3 weeks. Body weights, glycemia, and mechanical nociception were weekly evaluated until the end of the study, the time when the animals were subjected to a modified formalin test to study chemical allodynia. Serotonin and noradrenaline levels were quantified by ELISA at the spinal cord, whereas at the brainstem, the quantification was performed by immunohistochemistry against, respectively, tryptophan hydroxylase (TpH) or tyrosine hydroxylase (TH). STZ-diabetic rats exhibited mechanical hyperalgesia and chemical allodynia, along with higher spinal levels of serotonin and noradrenaline and higher numbers of neurons expressing TpH at the RVM and TH at the A(5) noradrenergic cell group. Treatment with IGF1 prevented the behavioral signs of PDN and reversed the neuronal hyperactivity at the spinal cord and ventrolateral PAG and the neurochemical changes at the spinal cord and at the brainstem. Based on the facilitatory role of serotoninergic and noradrenergic descending modulation during chronic pain, the increased serotonin and noradrenaline innervation of the dorsal horn in STZ-diabetic rats may probably account for enhanced pain during PDN. The benefits of IGF1 in PDN are probably due to blockade of the increased peripheral input to the somatosensory system, but direct central actions cannot be discarded. The value of IGF1 in PDN treatment deserves further evaluation.

Neuronal hyperactivity at the spinal cord and periaqueductal grey during painful diabetic neuropathy: effects of gabapentin.

Painful diabetic neuropathy may be due to impairments in descending modulation of nociceptive transmission at the spinal cord. In the present study, streptozotocin diabetic rats (STZ rats) with neuropathic symptoms (mechanical hypersensitivity) were used to perform a time-course evaluation of neuronal activity at the spinal dorsal horn and at the periaqueductal grey matter (PAG), a major brainstem area of pain modulation. The expression of Fos protein, a marker of nociceptive activation, progressively increased at the spinal dorsal horn at 4 and 10 weeks. At the PAG, increases in Fos expression were detected until the 4th week, with a reversal to baseline values at 10 weeks in all areas except the ventrolateral PAG. Co-localisation of Fos with NeuN ascertained the neuronal nature of Fos-expressing cells at the spinal cord and PAG. Four weeks after diabetes induction, the effects of gabapentin (i.p. injection of 50mg/kg, daily during 3 days) were assessed. Gabapentin decreased Fos expression at the spinal cord and PAG and reversed mechanical hypersensitivity. The present study shows that diabetic neuropathy is accompanied by a progressive increase of the spontaneous neuronal activity at the spinal cord. Changes in descending modulation of nociceptive transmission from the PAG are likely to occur during diabetic neuropathy, probably with exacerbation of facilitatory actions. The effects of gabapentin in reversing the behavioural signs of diabetic neuropathy and neuronal hyperactivity in the spinal cord and PAG reinforce the central causes of diabetic neuropathy and point to the central targets of the drug.

Cortical asymmetry: catching an object in free fall.

The main goal of the present study was to analyze theta asymmetry through quantitative electroencephalography (qEEG) when individuals were exposed to a sequential motor task, i.e. catching a ball. The sample was composed of 23 healthy subjects, male and female, between 25 and 40 years of age. A two-way factor Anova was applied to compare pre and post moments related to the balls' drop and scalp regions (i.e., frontal and parieto-occipital cortices). The first analysis of the frontal region compared electrodes in the left, right and left/right hemispheres combined, with the frontal midline electrode (FZ) included in the analysis. The results showed moment and region main effects. The second analysis compared left versus right hemisphere without the FZ site. The findings demonstrated an interaction effect between moment and region. The first parieto-occipital analysis, comparing left, right and central regions, with PZ included in all regions, showed main effects of moment and region. The second analysis, comparing left, right (without Pz) and central regions strictly demonstrated a region main effect. Thus, we observed an asymmetric pattern in the frontal cortex (i.e., planning and response selection) when the subjects were waiting for the balls' drop. Moreover, the left hemisphere seems to engage differently from the other regions when the central nervous system needs to prepare for a motor action. On the other hand, the parieto-occipital cortex, which is related to attentive processes, demonstrated a more asymmetric activity towards the right region which implies a participation of this area in cognitive strategies in this particular task. Taken together, we concluded that the adopted experimental approach can be useful to explore several others directions combining sensorimotor integration tasks with different pathologies, such as depression, Alzheimer's and Parkinson's diseases.

Changes in quantitative EEG absolute power during the task of catching an object in free fall.

The aim of this study was to verify changes in absolute power (qEEG), in theta, during the catch of a free falling object. The sample consisted of 10 healthy individuals, of both genders, with ages between 25 and 40 years. A three-way ANOVA followed by Post-Hoc analysis was applied. The results demonstrated main effects for time and position. In conclusion, a motor task that involves expectation produces deactivation of non-relevant areas in the ipsilateral hemisphere of the active limb. On the other hand, the patterns of results showed activation in areas responsible for planning and selection of motor repertoires in the contralateral hemisphere.