Stress oxydant chez l'enfant prématuré : causes, biomarqueurs et possibilités thérapeutiques [Oxidative stress after preterm birth: Origins, biomarkers, and possible therapeutic approaches].

The survival of preterm babies has increased over the last few decades. However, disorders associated with preterm birth, known as oxygen radical diseases of neonatology, such as retinopathy, bronchopulmonary dysplasia, periventricular leukomalacia, and necrotizing enterocolitis are severe complications related to oxidative stress, which can be defined by an imbalance between oxidative reactive species production and antioxidant defenses. Oxidative stress causes lipid, protein, and DNA damage. Preterm infants have decreased antioxidant defenses in response to oxidative challenges, because the physiologic increase of antioxidant capacity occurs at the end of gestation in preparation for the transition to extrauterine life. Therefore, preterm infants are more sensitive to neonatal oxidative stress, notably when supplemental oxygen is being delivered. Furthermore, despite recent advances in the management of neonatal respiratory distress syndrome, controversies persist concerning the oxygenation saturation targets that should be used in caring for preterm babies. Identification of adequate biomarkers of oxidative stress in preterm infants such as 8-iso-prostaglandin F2α, and adduction of malondialdehyde to hemoglobin is important to promote specific therapeutic approaches. At present, no therapeutic strategy has been validated as prevention or treatment against oxidative stress. Breastfeeding should be considered as the main measure to improve the antioxidant status of preterm infants. In the last few years, melatonin has emerged as a protective molecule against oxidative stress, with antioxidant and free-radical scavenger roles, in experimental and preliminary human studies, giving hope that it can be used in preterm infants in the near future.

Perspectives thérapeutiques dans la prise en charge de l'acouphène subjectif chronique [Therapeutic perspectives in the treatment of chronic subjective tinnitus].

There are no effective therapies for the treatment of chronic subjective tinnitus. The present study aims to compare two therapeutic approaches: Tinnitus Retraining Therapy (TRT) and a Biopsychosocial Approach (BPS). Results show no difference in evolution of tinnitus' perception between the beginning of the study and after 12 months of treatment in both treatment groups. Important anxiety could be a factor contributed towards the abandonment or ineffectiveness of treatments. Patients with more biopsychosocial comorbidities are more receptive to therapies. The practicioners therefore must assess specific needs, comorbidities and biopsychosocial profiles of patients suffering from tinnitus.

Estudo da circulação hepatomesentérica pela angiografia por ressonância magnética com gadolínio: comparação entre doses simples e dupla no estudo de pacientes esquistossomóticos

OBJETIVO: Determinar a freqüência de visualização dos segmentos da circulação hepatomesentérica pela angiografia por ressonância magnética (angio-RM) com contraste e comparar o valor do método, utilizando-se duas diferentes dosagens de gadolínio (doses simples e dupla). MATERIAIS E MÉTODOS: Estudo prospectivo de 36 pacientes esquistossomóticos submetidos a angio-RM. Os exames foram realizados em equipamento de RM de 1,5 T, usando-se bobina de corpo e bomba injetora para a administração endovenosa do contraste. Foram utilizadas, de maneira randomizada, dose dupla do contraste paramagnético (0,2 mmol/kg de Gd-DTPA) em 21 pacientes e dose simples (0,1 mmol/kg) em outros 15 pacientes. Os exames foram interpretados por dois observadores em consenso, que classificaram o grau de visualização de 25 segmentos vasculares estabelecidos para análise, sem conhecimento da dose de gadolínio utilizada. RESULTADOS: Os segmentos vasculares proximais e de maior calibre foram as estruturas com melhor grau de visualização na maioria da amostra em estudo. O tronco celíaco, a artéria hepática comum, a artéria esplênica, a croça e terço médio da artéria mesentérica superior, a veia porta, a veia esplênica e a veia mesentérica superior apresentaram grau 2 de visualização em mais de 70% da amostra. Quanto à comparação das diferentes dosagens, não houve diferença significante (p < 0,05) no grau de visualização das diversas estruturas analisadas entre os grupos dose simples e dose dupla, com uma exceção isolada: na avaliação da artéria hepática direita (p = 0,008), o grupo dose simples apresentou maior freqüência de visualização grau 2, com valor significante. CONCLUSÃO: O grau de visualização dos segmentos vasculares hepatomesentéricos pela angio-RM com contraste é elevado, sendo maior nos segmentos proximais e de maior calibre. A comparação entre os grupos que utilizaram dose simples e dupla de contraste demonstrou resultados semelhantes.

Repeated doses of methylone, a new drug of abuse, induce changes in serotonin and dopamine systems in the mouse

Rationale Methylone, a new drug of abuse sold as"bath salts' has similar effects to ecstasy or cocaine. Objective We have investigated changes in dopaminergic and serotoninergic markers, indicative of neuronal damage, induced by methylone in the frontal cortex, hippocampus and striatum of mice and according two different treatment schedules. Methods Methylone was given subcutaneously to male Swiss CD1 mice and at an ambient temperature of 26ºC. Treatment A: three doses of 25 mg/Kg at 3.5 h interval between doses for two consecutive days. Treatment B: four doses of 25 mg/Kg at 3 h interval in one day. Results Repeated methylone administration induced hyperthermia and a significant loss in body weight. Following treatment A, methylone induced transient dopaminergic (frontal cortex) and serotoninergic (hippocampus) impairment. Following treatment B, transient dopaminergic (frontal cortex) and serotonergic (frontal cortex and hippocampus) changes 7 days after treatment were found. We found evidence of astrogliosis in the CA1 and the dentate gyrus of the hippocampus following treatment B. The animals also showed an increase in immobility time in the forced swim test, pointing to a depressive-like behavior. In cultured cortical neurons, methylone (for 24 and 48 h) did not induce a remarkable cytotoxic effect. Conclusions The neural effects of methylone differ depending upon the treatment schedule. Neurochemical changes elicited by methylone are apparent when administered at an elevated ambient temperature, four times per day at 3 h intervals, which is in accordance with its short half-life.

STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity.

Spontaneous CD8 T-cell responses occur in growing tumors but are usually poorly effective. Understanding the molecular and cellular mechanisms that drive these responses is of major interest as they could be exploited to generate a more efficacious antitumor immunity. As such, stimulator of IFN genes (STING), an adaptor molecule involved in cytosolic DNA sensing, is required for the induction of antitumor CD8 T responses in mouse models of cancer. Here, we find that enforced activation of STING by intratumoral injection of cyclic dinucleotide GMP-AMP (cGAMP), potently enhanced antitumor CD8 T responses leading to growth control of injected and contralateral tumors in mouse models of melanoma and colon cancer. The ability of cGAMP to trigger antitumor immunity was further enhanced by the blockade of both PD1 and CTLA4. The STING-dependent antitumor immunity, either induced spontaneously in growing tumors or induced by intratumoral cGAMP injection was dependent on type I IFNs produced in the tumor microenvironment. In response to cGAMP injection, both in the mouse melanoma model and an ex vivo model of cultured human melanoma explants, the principal source of type I IFN was not dendritic cells, but instead endothelial cells. Similarly, endothelial cells but not dendritic cells were found to be the principal source of spontaneously induced type I IFNs in growing tumors. These data identify an unexpected role of the tumor vasculature in the initiation of CD8 T-cell antitumor immunity and demonstrate that tumor endothelial cells can be targeted for immunotherapy of melanoma.

Severity and burden of partial-onset seizures in a phase III trial of eslicarbazepine acetate.

OBJECTIVE: The objective of this study was to compare posttreatment seizure severity in a phase III clinical trial of eslicarbazepine acetate (ESL) as adjunctive treatment of refractory partial-onset seizures. METHODS: The Seizure Severity Questionnaire (SSQ) was administered at baseline and posttreatment. The SSQ total score (TS) and component scores (frequency and helpfulness of warning signs before seizures [BS]; severity and bothersomeness of ictal movement and altered consciousness during seizures [DS]; cognitive, emotional, and physical aspects of postictal recovery after seizures [AS]; and overall severity and bothersomeness [SB]) were calculated for the per-protocol population. Analysis of covariance, adjusted for baseline scores, estimated differences in posttreatment least square means between treatment arms. RESULTS: Out of 547 per-protocol patients, 441 had valid SSQ TS both at baseline and posttreatment. Mean posttreatment TS for ESL 1200mg/day was significantly lower than that for placebo (2.68 vs 3.20, p<0.001), exceeding the minimal clinically important difference (MCID: 0.48). Mean DS, AS, and SB were also significantly lower with ESL 1200mg/day; differences in AS and SB exceeded the MCIDs. The TS, DS, AS, and SB were lower for ESL 800mg/day than for placebo; only SB was significant (p=0.013). For both ESL arms combined versus placebo, mean scores differed significantly for TS (p=0.006), DS (p=0.031), and SB (p=0.001). CONCLUSIONS: Therapeutic ESL doses led to clinically meaningful, dose-dependent reductions in seizure severity, as measured by SSQ scores. CLASSIFICATION OF EVIDENCE: This study presents Class I evidence that adjunctive ESL (800 and 1200mg/day) led to clinically meaningful, dose-dependent seizure severity reductions, measured by the SSQ.

Efeitos de baixas doses de radiação-X no desenvolvimento do sistema nervoso central: estudo experimental em ratos

OBJETIVO: Este trabalho analisa as conseqüências da irradiação-X no desenvolvimento do sistema nervoso de fetos de ratos. MATERIAIS E MÉTODOS: O trabalho foi constituído de 10 Rattus norvegicus albinos, Wistar, fêmeas, grávidas, com idade de oito semanas. Cinco ratas fêmeas constituíram o grupo controle e outras cinco tiveram suas regiões abdominais expostas por 30 segundos a uma dose de 0,3 Gy proveniente de um aparelho odontológico Gnatus de 70 kV e 10 mA. No 17º dia gestacional, ambos os grupos foram submetidos a histerectomia. As seções selecionadas foram examinadas para análise cerebral comparativa entre os grupos. RESULTADOS: O exame clínico revelou não haver diferenças morfológicas entre os grupos controle e experimental e nenhum dos animais apresentou anormalidades grosseiras. Vinte e sete por cento dos animais do grupo experimental apresentaram hemorragia cerebral moderada e 73% apresentaram hemorragia severa e danos no tecido nervoso. Nenhum animal do grupo controle apresentou hemorragia cerebral ou danificações de tecido nervoso. CONCLUSÃO: Estas evidências demonstram que pequenas doses de radiação-X podem causar hemorragias cerebrais e, conseqüentemente, lesão tecidual nervosa.

Cysteine cathepsin proteases: regulators of cancer progression and therapeutic response.

Cysteine cathepsin protease activity is frequently dysregulated in the context of neoplastic transformation. Increased activity and aberrant localization of proteases within the tumour microenvironment have a potent role in driving cancer progression, proliferation, invasion and metastasis. Recent studies have also uncovered functions for cathepsins in the suppression of the response to therapeutic intervention in various malignancies. However, cathepsins can be either tumour promoting or tumour suppressive depending on the context, which emphasizes the importance of rigorous in vivo analyses to ascertain function. Here, we review the basic research and clinical findings that underlie the roles of cathepsins in cancer, and provide a roadmap for the rational integration of cathepsin-targeting agents into clinical treatment.

Avaliação das doses de radiação em uretrocistografia miccional de crianças

OBJETIVO: Analisar o produto dose-área, a dose de entrada na pele do paciente e as doses relativas à fluoroscopia e às radiografias em exames de cistouretrografia miccional em crianças. MATERIAIS E MÉTODOS: Foram avaliados os procedimentos em 37 pacientes, realizados por quatro médicos do serviço. As medições foram realizadas com um equipamento composto de uma câmara de ionização acoplada diretamente à saída do tubo de raios X e um eletrômetro (Diamentor) ligado diretamente ao computador, para a coleta dos dados. RESULTADOS: Foi observada alguma heterogeneidade na realização do procedimento, que não segue padrão de técnica radiográfica. São realizadas em média 11 radiografias por exame, usando tempo longo de fluoroscopia, com dose média final mais alta que a encontrada em referências da literatura. CONCLUSÃO: A adoção da técnica de alta quilovoltagem nas radiografias e o uso restrito da fluoroscopia podem proporcionar importante redução das doses durante a realização deste procedimento, porque o maior contribuinte para as altas doses verificadas foi a utilização da fluoroscopia.

Further molecular profiling of tumors harboring therapeutic targets within non-small cell lung cancer

Background: Treatment of NSCLC has been revolutionized in recent years with the introduction of several targeted therapies for selected genetically altered subtypes of NSCLC. A better understanding of molecular characteristics of NSCLC, which features common drug targets, may identify new therapeutic options. Methods: Over 6,700 non-small cell lung cancer cases referred to Caris Life Sciences between 2009 and 2014. Diagnoses and history were collected from referring physicians. Specific testing was performed per physician request and included a combination of sequencing (Sanger, NGS or pyrosequencing), protein expression (IHC), gene amplification/rearrangement (CISH or FISH), and/or RNA fragment analysis. Results: Tumors profiles from patients with hormone receptor positive disease (HER2, ER, PR, or AR positive by IHC) (n=629), HER2 mutations (n=8) ALK rearrangements (n=55), ROS1 rearrangement (n=17), cMET amplification or mutation (n=126), and cKIT mutation (n=11) were included in this analysis and compared to the whole cohort. Tumors with ALK rearrangement overexpressed AR in 18% of cases, and 7% presented with concomitant KRAS mutation. Lower rates of PTEN loss, as assessed by IHC, were observed in ALK positive (20%), ROS1 positive (9%) and cKIT mutated tumors (25%) compared to the overall NSCLC population (58%). cMET was overexpressed in 66% of ROS1 translocated and 57% of HER2 mutated tumors. cKIT mutations were found co-existing with APC (20%) and EGFR (20%) mutations. Pathway analysis revealed that hormone receptor positive disease carried more mutations in the ERK pathway (32%) compared to 9% in the mTOR pathway. 25% of patients with HER2 mutations harbored a co-existing mutation in the mTOR pathway. Conclusions: Pathway profiling reveals that NSCLC tumors present more often than reported with several concomitant alterations affecting the ERK or AKT pathway. Additionally, they are also characterized by the expression of potential biological modifiers of the cell cycle like hormonal receptors, representing a rationale for dual inhibition strategies in selected patients. Further refining of the understanding of NSCLC biomarker profile will optimize research for new treatment strategies.

Efeito da filtração adicional nas doses de radiação e na qualidade das imagens nos exames videofluoroscópicos

OBJETIVO: Investigar o efeito da adição de filtros de alumínio (1 mm) e cobre (0,4 mm) na redução das doses efetivas de radiação e na qualidade das imagens em exames videofluoroscópicos. MATERIAIS E MÉTODOS: Ao tubo de raios X adicionou-se câmara de ionização conectada a um eletrômetro para medir o produto kerma-área, com técnica de 65 kVp e 0,7 mA, sem e com adição dos filtros. Foi medida resolução espacial, a de baixo contraste e tons de cinza, utilizando os objetos de teste de Leeds. Quinze voluntários tiveram o produto kerma-área/minuto do estudo faríngeo comparados, dez com filtração e base e cinco com adição dos filtros associados. RESULTADOS: A adição dos filtros separados ou associados produziu expressiva redução do produto kerma-área, com ganho na qualidade das imagens videofluoroscópicas determinado pela maior separação dos tons de cinza e aumento da relação brilho/contraste da curva de cinza. CONCLUSÃO: A interposição adicional de filtros de alumínio e cobre, em especial quando associados, melhora a qualidade das imagens, com expressiva redução das doses de radiação necessárias à sua geração.

The paracaspase MALT1: biological function and potential for therapeutic inhibition.

The paracaspase MALT1 has a central role in the activation of lymphocytes and other immune cells including myeloid cells, mast cells and NK cells. MALT1 activity is required not only for the immune response, but also for the development of natural Treg cells that keep the immune response in check. Exaggerated MALT1 activity has been associated with the development of lymphoid malignancies, and recently developed MALT1 inhibitors show promising anti-tumor effects in xenograft models of diffuse large B cell lymphoma. In this review, we provide an overview of the present understanding of MALT1's function, and discuss possibilities for its therapeutic targeting based on recently developed inhibitors and animal models.