Subprodutos do metabolismo da hemoglobina se associam com resposta inflamatória em pacientes com acidente vascular cerebral hemorrágico / Hemoglobin metabolism by-products are associated with an inflammatory response in patients with hemorrhagic stroke

RESUMO Objetivo: Avaliar o relacionamento entre os níveis cerebrais de ferro e heme e a resposta inflamatória sistêmica e no sistema nervoso central, assim como o papel dos sistemas de defesa contra a toxicidade do ferro e do heme, no sistema nervoso central. Métodos: Avaliamos uma coorte prospectiva de pacientes com quadro de hemorragia intracraniana e subaracnóidea. Realizamos ensaios em amostras de plasma e líquido cefalorraquidiano quanto à presença de ferro, heme, hemopexina, haptoglobina, enolase, S100-β e citocinas nos primeiros 3 dias após um acidente vascular cerebral hemorrágico. Analisamos também as alterações dinâmicas em todos os componentes de ambos os líquidos e seu relacionamento com as taxas de mortalidade precoce. Resultados: As concentrações de hemopexina e haptoglobina foram quase desprezíveis no cérebro após hemorragia intracraniana e subaracnóidea. As concentrações de ferro e heme no líquido cefalorraquidiano se correlacionaram com resposta pró-inflamatória no sistema nervoso central, e os perfis inflamatórios no líquido cefalorraquidiano no terceiro dia após acidente vascular cerebral hemorrágico se correlacionaram com as taxas de mortalidade precoce. Identificamos que os níveis de interleucina 4 no líquido cefalorraquidiano durante as primeiras 24 horas após acidente vascular cerebral hemorrágico foram mais altos nos sobreviventes do que nos que não sobreviveram. Conclusão: Os níveis de ferro e heme se associaram com resposta pró-inflamatória no sistema nervoso central após acidente vascular cerebral hemorrágico, e o cérebro humano não tem proteção contra hemoglobina e heme. Os perfis inflamatórios dos pacientes se associaram com prognósticos piores, e as respostas inflamatórias locais pareceram ter um papel protetor.

ABSTRACT Objective: To evaluate the relationships of brain iron and heme with the inflammatory response of the systemic and central nervous systems and to investigate the role of defensive systems against the toxicity of iron and heme in the central nervous system. Methods: We assessed a prospective cohort of patients presenting with intracerebral and subarachnoid hemorrhage. We assayed plasma and cerebrospinal fluid samples for the presence of iron, heme, hemopexin, haptoglobin, enolase, S100-β and cytokines for the first three days following hemorrhagic stroke. We also analyzed the dynamic changes in these components within both fluids and their relationship with early mortality rates. Results: Hemopexin and haptoglobin concentrations were nearly negligible in the brain after intracerebral and subarachnoid hemorrhage. Cerebrospinal fluid iron and heme concentrations correlated with a pro-inflammatory response in the central nervous system, and plasmatic and cerebrospinal fluid inflammatory profiles on the third day after hemorrhagic stroke were related to early mortality rates. Interleukin 4 levels within the cerebrospinal fluid during the first 24 hours after hemorrhagic stroke were found to be higher in survivors than in non-survivors. Conclusion: Iron and heme are associated with a pro-inflammatory response in the central nervous system following hemorrhagic stroke, and protections against hemoglobin and heme are lacking within the human brain. Patient inflammatory profiles were associated with a poorer prognosis, and local anti-inflammatory responses appeared to have a protective role.

Oseltamivir-resistant influenza A(H1N1)pdm2009 strains found in Brazil are endowed with permissive mutations, which compensate the loss of fitness imposed by antiviral resistance

The 2009 pandemic influenza A virus outbreak led to the systematic use of the neuraminidase (NA) inhibitor oseltamivir (OST). Consequently, OST-resistant strains, carrying the mutation H275Y, emerged in the years after the pandemics, with a prevalence of 1-2%. Currently, OST-resistant strains have been found in community settings, in untreated individuals. To spread in community settings, H275Y mutants must contain additional mutations, collectively called permissive mutations. We display the permissive mutations in NA of OST-resistant A(H1N1)pdm09 virus found in Brazilian community settings. The NAs from 2013 are phylogenetically distinct from those of 2012, indicating a tendency of positive selection of NAs with better fitness. Some previously predicted permissive mutations, such as V241I and N369K, found in different countries, were also detected in Brazil. Importantly, the change D344N, also predicted to compensate loss of fitness imposed by H275Y mutation, was found in Brazil, but not in other countries in 2013. Our results reinforce the notion that OST-resistant A(H1N1)pdm09 strains with compensatory mutations may arise in an independent fashion, with samples being identified in different states of Brazil and in different countries. Systematic circulation of these viral strains may jeopardise the use of the first line of anti-influenza drugs in the future. (AU)

Chest computed tomography findings in severe influenza pneumonia occurring in neutropenic cancer patients

OBJECTIVE: To describe the chest computed tomography findings for severe influenza H1N1 infection in a series of hospitalized neutropenic cancer patients. METHODS: We performed a retrospective systematic analysis of chest computed tomography scans for eight hospitalized patients with fever, neutropenia, and confirmed diagnoses of influenza H1N1. The clinical data had been prospectively collected. RESULTS: Six of eight patients (75%) developed respiratory failure and required intensive care. Prolonged H1N1 shedding was observed in the three mechanically ventilated patients, and overall hospital mortality in our series was 25%. The most frequent computed tomography findings were ground-glass opacity (all patients), consolidation (7/8 cases), and airspace nodules (6/8 cases) that were frequently moderate or severe. Other parenchymal findings were not common. Five patients had features of pneumonia, two had computed tomography findings compatible with bronchitis and/or bronchiolitis, and one had tomographic signs of chronicity. CONCLUSION: In this series of neutropenic patients with severe influenza H1N1 infection, chest computed tomography demonstrated mainly moderate or severe parenchymatous disease, but bronchiolitis was not a common feature. These findings associated with febrile neutropenia should elicit a diagnosis of severe viral infection.

Revisiting steroid treatment for septic shock: molecular actions and clinical effects - a review

Corticosteroids are widely used to treat a diversity of pathological conditions including allergic, autoimmune and some infectious diseases. These drugs have complex mechanisms of action involving both genomic and non-genomic mechanisms and interfere with different signal transduction pathways in the cell. The use of corticosteroids to treat critically ill patients with acute respiratory distress syndrome and severe infections, such as sepsis and pneumonia, is still a matter of intense debate in the scientific and medical community with evidence both for and against its use in these patients. Here, we review the basic molecular mechanisms important for corticosteroid action as well as current evidence for their use, or not, in septic patients. We also present an analysis of the reasons why this is still such a controversial point in the literature.

Cutaneous periumbilical purpura in disseminated strongyloidiasis in cancer patients: a pathognomonic feature of potentially lethal disease?

Cutaneous manifestations in disseminated strongyloidiasis are infrequent but should raise the suspicion for its diagnosis. We retrospectively evaluated the charts of six patients with cancer and a proven diagnosis of disseminated strongyloidiasis. All patients had received prophylaxis with albendazole before starting antineoplastic therapy, which included high-dose steroids. They presented with septic shock, acute respiratory failure and characteristic purpuric periumbilical skin lesions. Strongyloides larvae were identified in tracheal aspirates (n=5), gastric aspirates (n=4), lung (n=2) and skin biopsies (n=2). All patients died despite antihelminthic therapy and intensive care support.

Beyond sepsis pathophysiology with cytokines: what is their value as biomarkers for disease severity?

Sepsis is a major challenge in medicine. It is a common and frequently fatal infectious condition. The incidence continues to increase, with unacceptably high mortality rates, despite the use of specific antibiotics, aggressive operative intervention, nutritional support, and anti-inflammatory therapies. Typically, septic patients exhibit a high degree of heterogeneity due to variables such as age, weight, gender, the presence of secondary disease, the state of the immune system, and the severity of the infection. We are at urgent need for biomarkers and reliable measurements that can be applied to risk stratification of septic patients and that would easily identify those patients at the highest risk of a poor outcome. Such markers would be of fundamental importance to decision making for early intervention therapy or for the design of septic clinical trials. In the present work, we will review current biomarkers for sepsis severity and especially the use of cytokines as biomarkers with important pathophysiological role.

Controle automático da ventilação mecânica para minimizar a lesão pulmonar induzida pela ventilação / Automatic control of the mechanical ventilation for minimizing the ventilation induced lung injury

O ajuste de parâmetros dos ventiladores mecânicos pulmonares para evitar a reabertura cíclica de unidades alveolares e pequenas vias aéreas, assim como a hiperdistensão dos septos alveolares, tem sido motivo de atenção nos últimos anos. Este trabalho utiliza um modelo de lesão pulmonar aguda (ALI) em suínos para testar um controlador de ventiladores em malha fechada baseado em regras e modelos discutidos na literatura. Utiliza-se um modelo polinomial da cursa pressão-volume do sistema respiratório para o ajuste da pressão positiva ao final da expiração (PEEP), visando evitar a reabertura cíclica de unidades alveolares, e o ajuste do volume corrente, visando evitar a hiperdistensão pulmonar. Um índice de hiperdistensão baseado na identificação de uma elastância não linear para o sistema respiratório permite o uso do controlador com qualquer forma de onda de ventilação constrolada. Os resultados do controlador proposto foram confrontados com resultados obtidos na ventilação de um grupo controle, manualmente ventilados com base nas mesmas premissas. Como resultado, o controlador automático obteve valores de PEEP dentro da faixa de valores obtidos no grupo controle, porém com menor dispersão. O índice de hiperdistensão calculado ficou abaixo do limiar de hiperdistensão em 5 dos 6 animais do grupo ventilado automaticamente, e em 3 dos 6 animais ventilados do grupo controle. O controlador se comportou de forma estável e os resultados recomendam seu uso em ALI.