A partial agonist of PPARγ prevents paclitaxel-induced peripheral neuropathy in mice, by inhibiting neuroinflammation.

BACKGROUND AND PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of paclitaxel, affecting 30-50% of patients. Increased survival and concern with patients' quality of life have encouraged the search for new tools to prevent paclitaxel-induced neuropathy. This study presents the glitazone 4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-N-phenylbenzene-sulfonamide (TZD-A1) as a partial agonist of peroxisome proliferator-activated receptor γ (PPARγ), its toxicological profile and effects on paclitaxel-induced CIPN in mice. EXPERIMENTAL APPROACH: Interactions of TZD-A1 with PPARγ were analysed using in silico docking and in vitro reporter gene assays. Pharmacokinetics and toxicity were evaluated using in silico, in vitro and in vivo (C57Bl/6 mice) analyses. Effects of TZD-A1 on CIPN were investigated in paclitaxel-injected mice. Axonal and dorsal root ganglion damage, mitochondrial complex activity and cytokine levels, brain-derived neurotrophic factor (BDNF), nuclear factor erythroid 2-related factor 2 (Nrf2) and PPARγ, were also measured. KEY RESULTS: Docking analysis predicted TZD-A1 interactions with PPARγ compatible with partial agonism, which were corroborated by in vitro reporter gene assays. Good oral bioavailability and safety profile of TZD-A1 were shown in silico, in vitro and in vivo. Paclitaxel-injected mice, concomitantly treated with TZD-A1 by i.p. or oral administration, exhibited decreased mechanical and thermal hypersensitivity, effects apparently mediated by inhibition of neuroinflammation and mitochondrial damage, through increasing Nrf2 and PPARγ levels, and up-regulating BDNF. CONCLUSION AND IMPLICATIONS: TZD-A1, a partial agonist of PPARγ, provided neuroprotection and reduced hypersensitivity induced by paclitaxel. Allied to its safety profile and good bioavailability, TZD-A1 is a promising drug candidate to prevent and treat CIPN in cancer patients.

Multiple extremity necrosis in fatal calciphylaxis: Case report / Necrose de múltiplas extremidades em quadro fatal de calcifilaxia: Relato de caso

ABSTRACT Introduction: The clinical impact of vascular calcification is well established in the context of cardiovascular morbidity and mortality, but other clinical syndromes, such as calciphylaxis, although less frequent, have a significant impact on chronic kidney disease. Methods: Case report of a 27-year-old woman, who had complained of bilateral pain in her toes for 3 days, with the presence of small necrotic areas in the referred sites. She had a history of type 1 diabetes (25 years ago), with chronic kidney disease, on peritoneal dialysis, in addition to rheumatoid arthritis. She was admitted to the hospital, which preceded the current condition, due to exacerbation of rheumatoid arthritis, evolving with intracardiac thrombus due to venous catheter complications, when she started using warfarin. Ischemia progressed to her feet, causing the need for bilateral amputations. Her chirodactyls were also affected. Thrombophilia, vasculitis, endocarditis or other embolic sources were investigated and discarded. Her pathology report evidenced skin necrosis and superficial soft parts with recent arterial thrombosis, and Monckeberg's medial calcification. We started treatment with bisphosphonate and sodium thiosulfate, conversion to hemodialysis and replacement of warfarin with unfractionated heparin. Despite all the therapy, the patient died after four months of evolution. Discussion: Calciphylaxis is a rare microvasculature calcification syndrome that results in severe ischemic injuries. It has pathogenesis related to the mineral and bone disorder of chronic kidney disease combined with the imbalance between promoters and inhibitors of vascular calcification, with particular importance to vitamin K antagonism. Conclusion: The preventive strategy is fundamental, since the therapy is complex with poorly validated effectiveness.

RESUMO Introdução: O impacto clínico da calcificação vascular está bem estabelecido no âmbito de morbimortalidade cardiovascular, mas outras síndromes clínicas, como a calcifilaxia, apesar de menos frequente, têm significante impacto na doença renal crônica. Métodos: Relato de caso de mulher, 27 anos, com queixa de dor em pododáctilos bilateralmente havia 3 dias, com presença de pequenas áreas necróticas nos locais referidos. Antecedente pessoal de diabetes tipo 1 (há 25 anos), com doença renal crônica, em diálise peritoneal, além de artrite reumatoide. Teve internação hospitalar, que antecedeu o quadro atual, devido à exacerbação da artrite reumatoide, evoluindo com trombo intracardíaco por complicação de cateter venoso, quando iniciou uso de varfarina. A isquemia progrediu para pés com necessidade de amputações bilaterais. Quirodáctilos também foram acometidos. Trombofilias, vasculites, endocardite ou outras fontes emboligênicas foram pesquisadas e descartadas. Anatomopatológico evidenciou: necrose de pele e partes moles superficiais com trombose arterial recente e calcificação medial de Monckeberg. Tratamento foi instituído com bisfosfonato e tiossulfato de sódio, conversão para hemodiálise e substituição de varfarina por heparina não fracionada. Apesar de toda a terapia, a paciente foi a óbito após quatro meses de evolução. Discussão: A calcifilaxia é uma rara síndrome de calcificação da microvasculatura que resulta em graves lesões isquêmicas. Tem patogênese relacionada ao distúrbio mineral e ósseo da doença renal crônica combinado com o desbalanço entre promotores e inibidores de calcificação vascular, com particular importância ao antagonismo da vitamina K. Conclusão: A estratégia preventiva é fundamental, uma vez que a terapia é complexa e de eficácia pouco validada.

How efficient is graphene-based nanocomposite to adsorb Hg from seawater. A laboratory assay to assess the toxicological impacts induced by remediated water towards marine bivalves.

Advanced investigations on the use of graphene based nanomaterials have highlighted the capacity of these materials for wastewater treatment. Research on this topic revealed the efficiency of the nanocomposite synthetized by graphene oxide functionalized with polyethyleneimine (GO-PEI) to adsorb mercury (Hg) from contaminated seawater. However, information on the environmental risks associated with these approaches are still lacking. The focus of this study was to evaluate the effects of Hg in contaminated seawater and seawater remediated by GO-PEI, using the species Ruditapes philippinarum, maintained at two different warming scenarios: control (17 °C) and increased (22 °C) temperatures. The results obtained showed that organisms exposed to non-contaminated and remediated seawaters at control temperature presented similar biological patterns, with no considerable differences expressed in terms of biochemical and histopathological alterations. Moreover, the present findings revealed increased toxicological effects in clams under remediated seawater at 22 °C in comparison to those subjected to the equivalent treatment at 17 °C. These results confirm the capability of GO-PEI to adsorb Hg from water with no noticeable toxic effects, although temperature could alter the responses of mussels to remediated seawater. These materials seem to be a promise eco-friendly approach to remediate wastewater, with low toxicity evidenced by remediated seawater and high regenerative capacity of this nanomaterial, keeping its high removal performance after successive sorption-desorption cycles.

Multiple extremity necrosis in fatal calciphylaxis: Case report.

INTRODUCTION: The clinical impact of vascular calcification is well established in the context of cardiovascular morbidity and mortality, but other clinical syndromes, such as calciphylaxis, although less frequent, have a significant impact on chronic kidney disease. METHODS: Case report of a 27-year-old woman, who had complained of bilateral pain in her toes for 3 days, with the presence of small necrotic areas in the referred sites. She had a history of type 1 diabetes (25 years ago), with chronic kidney disease, on peritoneal dialysis, in addition to rheumatoid arthritis. She was admitted to the hospital, which preceded the current condition, due to exacerbation of rheumatoid arthritis, evolving with intracardiac thrombus due to venous catheter complications, when she started using warfarin. Ischemia progressed to her feet, causing the need for bilateral amputations. Her chirodactyls were also affected. Thrombophilia, vasculitis, endocarditis or other embolic sources were investigated and discarded. Her pathology report evidenced skin necrosis and superficial soft parts with recent arterial thrombosis, and Monckeberg's medial calcification. We started treatment with bisphosphonate and sodium thiosulfate, conversion to hemodialysis and replacement of warfarin with unfractionated heparin. Despite all the therapy, the patient died after four months of evolution. DISCUSSION: Calciphylaxis is a rare microvasculature calcification syndrome that results in severe ischemic injuries. It has pathogenesis related to the mineral and bone disorder of chronic kidney disease combined with the imbalance between promoters and inhibitors of vascular calcification, with particular importance to vitamin K antagonism. CONCLUSION: The preventive strategy is fundamental, since the therapy is complex with poorly validated effectiveness.

Listeria monocytogenes meningoencephalitis in a patient with Systemic Lupus Erythematosus / Meningoencefalite por Listeria monocytogenes em paciente com Lúpus Eritematoso Sistêmico

Abstract Introduction: Infectious complications are common in systemic lupus erythematosus. Although uncommon, central nervous system infections do occur and have significant lethality, with several etiological agents. Methods: We report on the case of a 29-year-old woman recently diagnosed with systemic lupus erythematosus with hematological, cutaneous, serous and renal manifestations (class IV lupus nephritis), who underwent corticosteroid pulse therapy and mycophenolate induction therapy. After 3 months of evolution, she developed headache and altered mental status. Computed tomography showed an area of hypoattenuation in the left frontal white matter and her cerebrospinal fluid examination showed pleocytosis and hyperproteinorrhachia. Peripheral blood and CSF culture identified Listeria monocytogenes. The patient presented deterioration of her neurological status, requiring invasive mechanical ventilation, monitoring of intracranial pressure and, despite all the intensive support, persisted in a comatose state and developed multiple organ failure, evolving to death due to nosocomial bloodstream infection. Discussion: Infection from L. monocytogenes usually occurs after eating contaminated food, manifesting itself with diarrhea and, occasionally, invasively, such as neurolisteriosis. Further investigation with CSF analysis and MRI is necessary, and the diagnosis consists of isolating the bacteria in sterile body fluid. Conclusion: The case presents a patient whose diagnosis of meningoencephalitis became an important differential with neuropsychiatric disorder. The poor outcome reinforces the need to remember this infectious condition as a serious complication in the natural history of SLE.

Resumo Introdução: As complicações infecciosas são frequentes no lúpus eritematoso sistêmico. Apesar de incomum, infecções do sistema nervoso central ocorrem e têm significativa letalidade, apresentando diversos agentes etiológicos. Métodos: Descrevemos aqui o caso de uma mulher de 29 anos recentemente diagnosticada com lúpus eritematoso sistêmico com manifestações hematológica, cutânea, serosa e renal (nefrite lúpica classe IV), submetida a pulsoterapia com corticoide e terapia de indução com micofenolato. Após 3 meses de evolução, apresentou quadro de cefaleia e alteração de estado mental. Tomografia computadorizada evidenciou área de hipoatenuação em substância branca frontal esquerda e exame de líquido cefalorraquidiano mostrava pleocitose e hiperproteinorraquia. Cultura de sangue periférico e do liquor identificaram Listeria monocytogenes. Paciente apresentou deterioração do quadro neurológico, necessitando de ventilação mecânica invasiva, monitorização de pressão intracraniana e, apesar de todo o suporte intensivo, persistiu em estado comatoso e disfunção de múltiplos órgãos, evoluindo a óbito por infecção de corrente sanguínea nosocomial. Discussão: Infecção por L. monocytogenes ocorre geralmente após ingestão de alimentos contaminados, manifestando-se por diarreia e, eventualmente, de forma invasiva como a neurolisteriose. Investigação complementar com análise de liquor e ressonância magnética faz-se necessária, sendo o diagnóstico confirmado por isolamento da bactéria em líquido corporal estéril. Conclusão: O caso representa uma paciente cujo diagnóstico de meningoencefalite tornou-se importante diferencial com atividade de doença neuropsiquiátrica. A evolução insatisfatória reforça a necessidade de se lembrar desta condição infecciosa como complicação grave na história natural do LES.

Multiple regression analysis to assess the contamination with metals and metalloids in surface sediments (Aveiro Lagoon, Portugal).

An innovative multiple regression analysis was used to evaluate metal/metalloid contamination in the surface sediments of a coastal lagoon. The concentrations of metals/metalloids were represented as a function of geochemical characteristics of the sediments (fine fraction, concentrations of organic carbon, Ca, Al, Mn) and distances between sampling points. The effect of distances on the concentrations were negligible for Li, Co, Ni, Ba, V, Cr, and only geochemical variables specific for each element explained its spatial variation. The concentrations of As, Cu, Zn and Pb were influenced by both geochemical and geographical distance variables, the latter representing the anthropogenic influence and the extent of transport of contaminants away from the upstream source. Enrichment of the sediment with Ba, As, Co, Cr and V was determined mainly by enrichment with Mn. The proposed approach is supplementary to the traditional utilization of enrichment factors, and is better suited for systems with anthropogenic influence.

Maternal and fetal parameters in pregnant woman undergoing tocolysis with nifedipine / Parâmetros maternos e fetais em gestante submetida a tocólise com nifedipina

Abstract Objectives: to evaluate the effects of nifedipine with tocolysis under maternal and fetal parameters. Methods: a cohort study with 40 pregnant women admitted at a high-risk pregnancy ward to inhibit premature labor between September/2010 to May/2012. Nifedipine was used as a 20mg sublingual attack dose and maintained 20mg every six and eight hours orally. The variables of the analysis were fetal heart rate (FHR), maternal heart rate (MHR), systolic blood pressure (SBP) and diastolic blood pressure (DBP), and amniotic fluid index (AFI). All the variables were evaluated prior to administrating nifedipine and approximately after 6 hours and every 24 hours, until hospital discharge. Results: there were no modification of the FHR (p=0.48) and the SBP (p=0.29). The MHR increased after 24 hours, but with no statistical difference (p=0.08), returning to similar levels as at admission within 48 hours. The DBP decreased at 6 (p=0.04) to 72 hours, being stable afterwards. The AFI decreased significantly at 24, 48 and 72 hours. Conclusions: the use of high doses of nifedipine with tocolysis causes a decrease of the maternal's diastolic blood pressure and consequently decreases the amniotic fluid index, but probably without any clinical repercussions.

Resumo Objetivos: avaliar os efeitos da nifedipina utilizada na tocólise sobre os parâmetros maternos e fetais. Métodos: estudo de coorte incluindo 40 gestantes admitidas na enfermaria de alto risco para inibição do trabalho de parto prematuro entre setembro/2010 a maio/2012. Utilizou-se a nifedipina sublingual na dose de ataque de 20mg e uma manutenção de 20mg por via oral a cada seis e oito horas. As variáveis avaliadas foram os batimentos cardio-fetais (BCF), frequência cardíaca materna (FCM), pressão arterial sistólica (PAS) e diastólica (PAD) e índice de líquido amniótico (ILA). Todas as variáveis foram avaliadas antes da administração da nifedipina e aproximadamente após 6h e cada 24h até alta hospitalar. Resultados: não houve modificação dos BCF (p=0,48) e da PAS (p=0,29). A FCM aumentou após 24h, mas sem significância estatística (p=0,08) retornando a níveis similares ao da admissão com 48h. A PAD diminuiua partir de 6h (p = 0,04)até 72h, mantendo-se constante. O ILA diminuiu significativamente em 24h, 48h e 72h. Conclusão: a utilização de altas doses de nifedipina para tocóliseocasio na diminuição dos níveis pressóricos diastólicos maternos e consequentemente diminuição do ILA, mas provavelmente sem repercussões clínicas.

Listeria monocytogenes meningoencephalitis in a patient with Systemic Lupus Erythematosus.

INTRODUCTION: Infectious complications are common in systemic lupus erythematosus. Although uncommon, central nervous system infections do occur and have significant lethality, with several etiological agents. METHODS: We report on the case of a 29-year-old woman recently diagnosed with systemic lupus erythematosus with hematological, cutaneous, serous and renal manifestations (class IV lupus nephritis), who underwent corticosteroid pulse therapy and mycophenolate induction therapy. After 3 months of evolution, she developed headache and altered mental status. Computed tomography showed an area of hypoattenuation in the left frontal white matter and her cerebrospinal fluid examination showed pleocytosis and hyperproteinorrhachia. Peripheral blood and CSF culture identified Listeria monocytogenes. The patient presented deterioration of her neurological status, requiring invasive mechanical ventilation, monitoring of intracranial pressure and, despite all the intensive support, persisted in a comatose state and developed multiple organ failure, evolving to death due to nosocomial bloodstream infection. DISCUSSION: Infection from L. monocytogenes usually occurs after eating contaminated food, manifesting itself with diarrhea and, occasionally, invasively, such as neurolisteriosis. Further investigation with CSF analysis and MRI is necessary, and the diagnosis consists of isolating the bacteria in sterile body fluid. CONCLUSION: The case presents a patient whose diagnosis of meningoencephalitis became an important differential with neuropsychiatric disorder. The poor outcome reinforces the need to remember this infectious condition as a serious complication in the natural history of SLE.

Dual nanofibrillar-based bio-sorbent films composed of nanocellulose and lysozyme nanofibrils for mercury removal from spring waters.

The present study explores the preparation of dual nanofibrillar-based bio-sorbent films composed of cellulose nanofibrils (CNFs) and lysozyme nanofibrils (LNFs) for application in the removal of Hg(II) from aqueous solutions. The free-standing films were fabricated via simple vacuum filtration of water suspensions of CNFs and LNFs and disclose good mechanical and thermal properties. The Hg(II) removal efficiency was evaluated by atomic fluorescence spectroscopy in ultra-pure and natural spring waters contaminated with environmental realistic levels of mercury (50 µg L-1). The removal efficiency is pH-dependent reaching a maximum of 99 % after 24 h at a pH value close to the isoelectric point of the protein. Under the experimental conditions, the sorption kinetics are well described by the pseudo-second-order and Elovich models, suggesting a chemisorption mechanism. These results demonstrate the ability of the dual nanofibrillar-based films to remove Hg(II) from water samples reaching a residual concentration lower than the guideline value for water intended for human consumption (1 µg L-1). Therefore, the CNFs/LNFs bio-sorbents might be a solution to treat low-concentrated mercury-contaminated waters.

Body feather mercury and arsenic concentrations in five species of seabirds from the Falkland Islands.

Several pollutants, including heavy metals, magnify along the food chain, and top predators such as seabirds can be used to monitor their trends in the marine environment. We studied mercury and arsenic contamination in body feathers in penguins, petrels and cormorants in three islands of the Falklands Islands. There were significant differences among species and sites in the concentration of trace elements in feathers. Black-browed albatrosses and gentoo penguins had consistently high mercury concentrations on New Island, while Rockhopper penguins and imperial shags presented considerably higher concentrations at Beauchene Island. Mercury levels in black-browed albatrosses increased since 1986 on one of the islands, probably reflecting world-wide emission trends. Rockhopper penguins exhibited high arsenic levels, but levels were less variable among species, and were not correlated with mercury levels, suggesting low biomagnification. These results provide a reference line for bioindication studies using feathers from species on the Falkland Islands.

Palliative care for end-of-life patients in a basic emergency service.

This research sought to describe the care provided by the nursing staff of the Western Department of the Basic Emergency Service for end-of-life patients. This was a retrospective, quantitative, exploratory and descriptive (level I) study, which sought to research the nursing records of 83 patients from admission to death. Patients who met the following inclusion criteria were considered eligible: adults; had an oncological or nononcological, advanced and irreversible chronic disease; and died in the Basic Emergency Service in the period from January 2011 to December 2012. An instrument was created for data collection, the content, relevance and adequacy of which was validated by a panel of experts in the area of palliative care. The study protocol was approved by the Institutional Ethics Committee. The main results indicate that the majority of patients died in the Observation Room in a period between the first two and twenty-four hours. Nursing interventions favoured technical-instrumental care related to medical prescriptions and service routines such as venous punctures, catheterisations, taking blood samples for analysis, aspiration of secretions, intravenous administration of fluids and drugs for symptomatic control, and monitoring of vital parameters and the state of consciousness. With the proximity of death, the nurses favoured the registration of cardiorespiratory arrest, cardiopulmonary resuscitation manoeuvres and aspiration of secretions. In the recognition of predictive factors of imminent death, the nurses favoured the patient's entry into a comatose state and aggravation of asthenia. In most patients, the entry into agony phase was not diagnosed.

Anatomical relation between nasal septum deviation and oropharynx volume in different facial patterns evaluated through cone beam computed tomography.

INTRODUCTION: The objective of this study was to establish the anatomical relation between nasal septum deviation (NSD) and oropharynx volume in different facial patterns using cone beam computed tomography (CBCT). METHODS: Ninety CBCT examinations were analyzed. InVivoDental software was used to evaluate cephalometric image reconstructions in terms of facial type, determined from cephalometric measurements indicative of growth direction; the presence of NSD was also evaluated. ITK-SNAP software was employed for delimitation of the oropharynx. Intra-examiner error methods were recorded. The results were subjected to parametric and non-parametric tests using Bioestat 5.0. RESULTS: A comparison of facial types revealed a significantly lower prevalence of NSD in the dolichofacial group compared with the brachyfacial and mesofacial groups (P = 0.0101 and 0.0149, respectively). In the total sample, there was a very strong positive relation between the presence of NSD and oropharynx space volume (P = 0.0162). The oropharynx volume was larger in all facial patterns in the presence of NSD. CONCLUSION: The presence of NSD was not associated with facial type, although the oropharynx volume in patients with NSD increased. Therefore, deviation of the septum influences oropharynx volume.

Sources of potentially toxic elements and organic pollutants in an urban area subjected to an industrial impact.

Urban and industrial development has caused a major impact on environmental soil quality. This work assesses the extent and severity of contamination in a small urban area subjected to an industrial impact and identifies the major anthropogenic inputs. Twenty-six soil samples were collected from agricultural and urban sites, and concentrations of potentially toxic elements (As, Cd, Cu, Cr, Fe, Mn, Ni, Pb and Zn), PAHs and PCBs, were determined. In spite of the low median concentrations observed, some sites represent a potential hazard for human health and ecosystems. Concentrations of contaminants were higher than those found in a nearby city, indicating that the study area is affected by the surrounding industry. The use of multivariate statistical analyses allowed for the identification of the main factors controlling the variability of potentially toxic elements and organic pollutants in the soils. The presence of Cr, Fe, Mn and Ni was associated with geogenic inputs, and Cu, Pb, Zn, As, PAHs and PCBs were associated with anthropogenic inputs. Industry and traffic were the most important anthropogenic sources. Soil characteristics were identified as important factors controlling the spatial variability of elements, both from recognised natural and anthropogenic origin. Differences between land uses were observed, which may be attributed to both management practices and proximity to sources.

Mercury organotropism in feral European sea bass (Dicentrarchus labrax).

The knowledge of mercury (Hg) burdens in a wide set of tissues and organs of exposed fish is crucial to understand the internal distribution dynamics and thus predict Hg bioavailability and implications for ecosystem and human health. Total Hg was measured in six tissues of Dicentrarchus labrax captured along an estuarine contamination gradient, revealing the following pattern: liver > kidney > muscle > brain ≈ gills > blood. All of the tissues displayed intersite differences, although brain and muscle seemed to better reflect the extent of contamination. Hg speciation showed that liver presented higher concentrations than muscle for both organic and inorganic forms. Furthermore, liver seemed to exert a protective action in relation to Hg accumulation in the other tissues and organs. This protection seems to be particularly marked in relation to the brain, whereas liver is assisted in that action by kidney and muscle.

Mercury distribution in key tissues of fish (Liza aurata) inhabiting a contaminated estuary-implications for human and ecosystem health risk assessment.

This study brings a new viewpoint based on multiple-tissue analyses to form the basis for a predictive mode of mercury accumulation dynamics in fish body under field conditions. Total mercury (T-Hg) was determined in key tissues of Liza aurata captured along an estuarine contamination gradient, displaying the following hierarchy: kidney > liver > muscle > brain > gills > blood. Brain was the tissue that better reflected the mercury contamination extent, closely followed by liver and muscle. Organic mercury (O-Hg) measured in muscle and liver represented more than 85% and less than 30% of the T-Hg, respectively. The lowest O-Hg percentage was found in the most contaminated area, for both muscle and liver. Mercury distribution and accumulation patterns showed dependence on the specific tissue. The high mercury levels found in organs involved in vital physiological processes point out the risk to autochthonous fish fauna. Human risk associated to the ingestion of fish living in the surveyed areas cannot be excluded.