Rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART): Study protocol for a randomized controlled trial

Background: Acute respiratory distress syndrome (ARDS) is associated with high in-hospital mortality. Alveolar recruitment followed by ventilation at optimal titrated PEEP may reduce ventilator-induced lung injury and improve oxygenation in patients with ARDS, but the effects on mortality and other clinical outcomes remain unknown. This article reports the rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART). Methods/Design: ART is a pragmatic, multicenter, randomized (concealed), controlled trial, which aims to determine if maximum stepwise alveolar recruitment associated with PEEP titration is able to increase 28-day survival in patients with ARDS compared to conventional treatment (ARDSNet strategy). We will enroll adult patients with ARDS of less than 72 h duration. The intervention group will receive an alveolar recruitment maneuver, with stepwise increases of PEEP achieving 45 cmH(2)O and peak pressure of 60 cmH2O, followed by ventilation with optimal PEEP titrated according to the static compliance of the respiratory system. In the control group, mechanical ventilation will follow a conventional protocol (ARDSNet). In both groups, we will use controlled volume mode with low tidal volumes (4 to 6 mL/kg of predicted body weight) and targeting plateau pressure <= 30 cmH2O. The primary outcome is 28-day survival, and the secondary outcomes are: length of ICU stay; length of hospital stay; pneumothorax requiring chest tube during first 7 days; barotrauma during first 7 days; mechanical ventilation-free days from days 1 to 28; ICU, in-hospital, and 6-month survival. ART is an event-guided trial planned to last until 520 events (deaths within 28 days) are observed. These events allow detection of a hazard ratio of 0.75, with 90% power and two-tailed type I error of 5%. All analysis will follow the intention-to-treat principle. Discussion: If the ART strategy with maximum recruitment and PEEP titration improves 28-day survival, this will represent a notable advance to the care of ARDS patients. Conversely, if the ART strategy is similar or inferior to the current evidence-based strategy (ARDSNet), this should also change current practice as many institutions routinely employ recruitment maneuvers and set PEEP levels according to some titration method.

Adaptation and validation of the Patient Expectations and Satisfaction with Prenatal Care instrument among Brazilian pregnant women

Objective: to adapt and validate the Patient Expectations and Satisfaction with Prenatal Care instrument for use in Brazil. It contains 41 items divided into two dimensions: expectations and satisfaction. The adapted version was submitted to analysis for stability, convergent construct validity, and internal consistency (Cronbach’s alpha) for distinct groups and dimensions. Method: 119 pregnant women receiving prenatal care were interviewed and 26 of these women answered the instrument twice (retest). Internal consistency was appropriate (Cronbach’s alpha ≥ 0.70); test-retest presented strong correlation (r=0.82; p<0.001) for the domain expectations and moderate correlation (r=0.66; p<0.001) for the satisfaction domain. The analysis confirmed that the instrument’s adapted version is valid in the studied group. Results: there is strong evidence for the validity and reliability of the instrument’s adaptation. Conclusion: the instrument needs to be tested in groups of pregnant women with different social characteristics.

Global gene expression profiling of oral cavity cancers suggests molecular heterogeneity within anatomic subsites

Abstract Background Oral squamous cell carcinoma (OSCC) is a frequent neoplasm, which is usually aggressive and has unpredictable biological behavior and unfavorable prognosis. The comprehension of the molecular basis of this variability should lead to the development of targeted therapies as well as to improvements in specificity and sensitivity of diagnosis. Results Samples of primary OSCCs and their corresponding surgical margins were obtained from male patients during surgery and their gene expression profiles were screened using whole-genome microarray technology. Hierarchical clustering and Principal Components Analysis were used for data visualization and One-way Analysis of Variance was used to identify differentially expressed genes. Samples clustered mostly according to disease subsite, suggesting molecular heterogeneity within tumor stages. In order to corroborate our results, two publicly available datasets of microarray experiments were assessed. We found significant molecular differences between OSCC anatomic subsites concerning groups of genes presently or potentially important for drug development, including mRNA processing, cytoskeleton organization and biogenesis, metabolic process, cell cycle and apoptosis. Conclusion Our results corroborate literature data on molecular heterogeneity of OSCCs. Differences between disease subsites and among samples belonging to the same TNM class highlight the importance of gene expression-based classification and challenge the development of targeted therapies.

Toll-like receptor 1 N248S single-nucleotide polymorphism is associated with leprosy risk and regulates immune activation during mycobacterial infection

Conflicting findings about the association between leprosy and TLR1 variants N248S and I602S have been reported. Here, we performed case-control and family based studies, followed by replication in 2 case-control populations from Brazil, involving 3162 individuals. Results indicated an association between TLR1 248S and leprosy in the case-control study (SS genotype odds ratio [OR], 1.81; P = .004) and the family based study (z = 2.02; P = .05). This association was consistently replicated in other populations (combined OR, 1.51; P < .001), corroborating the finding that 248S is a susceptibility factor for leprosy. Additionally, we demonstrated that peripheral blood mononuclear cells (PBMCs) carrying 248S produce a lower tumor necrosis factor/interleukin-10 ratio when stimulated with Mycobacterium leprae but not with lipopolysaccharide or PAM3cysK4. The same effect was observed after infection of PBMCs with the Moreau strain of bacillus Calmette-Guerin but not after infection with other strains. Finally, molecular dynamics simulations indicated that the Toll-like receptor 1 structure containing 248S amino acid is different from the structure containing 248N. Our results suggest that TLR1 248S is associated with an increased risk for leprosy, consistent with its hypoimmune regulatory function.

Characterization and optimization of ArtinM lectin expression in Escherichia coli

Background ArtinM is a D-mannose-specific lectin from Artocarpus integrifolia seeds that induces neutrophil migration and activation, degranulation of mast cells, acceleration of wound healing, induction of interleukin-12 production by macrophages and dendritic cells, and protective T helper 1 immune response against Leishmania major, Leishmania amazonensis and Paracoccidioides brasiliensis infections. Considering the important biological properties of ArtinM and its therapeutic applicability, this study was designed to produce high-level expression of active recombinant ArtinM (rArtinM) in Escherichia coli system. Results The ArtinM coding region was inserted in pET29a(+) vector and expressed in E. coli BL21(DE3)-Codon Plus-RP. The conditions for overexpression of soluble ArtinM were optimized testing different parameters: temperatures (20, 25, 30 or 37°C) and shaking speeds (130, 200 or 220 rpm) during induction, concentrations of the induction agent IPTG (0.01-4 mM) and periods of induction (1-19 h). BL21-CodonPlus(DE3)-RP cells induced under the optimized conditions (incubation at 20°C, at a shaking speed of 130 rpm, induction with 0.4 mM IPTG for 19 h) resulted in the accumulation of large amounts of soluble rArtinM. The culture provided 22.4 mg/L of rArtinM, which activity was determined by its one-step purification through affinity chromatography on immobilized D-mannose and glycoarray analysis. Gel filtration showed that rArtinM is monomeric, contrasting with the tetrameric form of the plant native protein (jArtinM). The analysis of intact rArtinM by mass spectrometry revealed a 16,099.5 Da molecular mass, and the peptide mass fingerprint and esi-cid-ms/ms of amino acid sequences of peptides from a tryptic digest covered 41% of the total ArtinM amino acid sequence. In addition, circular dichroism and fluorescence spectroscopy of rArtinM indicated that its global fold comprises β-sheet structure. Conclusions Overall, the optimized process to express rArtinM in E. coli provided high amounts of soluble, correctly folded and active recombinant protein, compatible with large scale production of the lectin.

Space-time cluster analysis of American visceral leishmaniasis in Bauru, São Paulo State, Brazil

A space-time analysis of American visceral leishmaniasis (AVL) in humans in the city of Bauru, São Paulo State, Brazil was carried out based on 239 cases diagnosed between June 2003 and October 2008. Spatial analysis of the disease showed that cases occurred especially in the city's urban areas. AVL annual incidence rates were calculated, demonstrating that the highest rate occurred in 2006 (19.55/100,000 inhabitants). This finding was confirmed by the time series analysis, which also showed a positive tendency over the period analyzed. The present study allows us to conclude that the disease was clustered in the Southwest side of the city in 2006, suggesting that this area may require special attention with regard to control and prevention measures.

Rômulo Almeida e o Brasil desenvolvimentista (1946-1964): ensaio de reinterpretação

Este artigo empreende um esforço de reintrepretação sobre o desenvolvimentismo no Brasil. Procura repensá-lo a partir da tríade estruturante que lhe confere sentido: um consenso ideológico sobre as potencialidades nacionais, um estilo de reflexão sobre o país e uma aposta no planejamento democrático e descentralizado. A política econômica é encarada mais como ferramenta do que um fim em si mesmo. Para tanto, acompanhou-se a trajetória Rômulo Almeida, de modo a traçar o pano de fundo do Brasil desenvolvimentista entre 1946 e 1964. Um esforço de coleta de material inédito produzido pelo economista baiano ao longo dos anos 1970 permitiu mostrar como ele revê sua rica trajetória de servidor público e oferece uma crítica à política econômica da ditadura militar, partindo de um pensamento sistêmico e de uma dialética planejadora. Ao final, são tecidas algumas considerações acerca das possibilidades de emergência de uma nova perspectiva desenvolvimentista para o país no contexto atual.

Resultados da ressecção de hemangiomas infantis nasais em fase proliferativa: abordagem segura para os tumores centrais da face

INTRODUÇÃO: O hemangioma infantil é o tumor benigno mais comum da infância, predominando na região cervicofacial. É caracterizado por apresentar 3 fases distintas, observando-se frequentemente regressão espontânea dessas lesões. No entanto, sequelas residuais ou deformidades das estruturas anatômicas em crescimento podem ocorrer. A abordagem cirúrgica precoce e definitiva é indicada, em decorrência da localização dos hemangiomas nasais e seu potencial desfigurante, visando à obtenção de bons resultados estéticos e preservação anatômica. O objetivo do presente estudo foi analisar os resultados da abordagem cirúrgica definitiva para hemangiomas proliferativos nasais, com base em uma avaliação objetiva. MÉTODO: No período de 1997 a 2009, 20 pacientes portadores de hemangiomas nasais em fase proliferativa foram submetidos a tratamento cirúrgico. As lesões foram avaliadas segundo local de acometimento e tratamento realizado. Foram analisados índices de complicações e necessidade de procedimentos adicionais. Os resultados estéticos foram avaliados por avaliadores independentes. RESULTADOS: As lesões estavam localizadas na ponta nasal em 50% dos pacientes; no dorso, em 20%; em todas as subunidades, em 15%; nas áreas paranasais, em 10%; e na unidade alar, em 5%. A ressecção foi total em 60% dos pacientes e subtotal em 40%. O período médio de acompanhamento foi de 42,6 meses. A média de procedimentos cirúrgicos por paciente foi de 1,3 + 0,7. Nenhuma complicação importante foi observada. Os resultados foram positivamente avaliados quanto a redução do volume da lesão e melhora do contorno facial, corroborando a conduta proposta. CONCLUSÕES: No manejo dos hemangiomas nasais, o tratamento cirúrgico definitivo pode ser considerado uma alternativa segura e eficaz, com baixas taxas de complicação.

Biphasic positive airway pressure minimizes biological impact on lung tissue in mild acute lung injury independent of etiology

Abstract Introduction Biphasic positive airway pressure (BIVENT) is a partial support mode that employs pressure-controlled, time-cycled ventilation set at two levels of continuous positive airway pressure with unrestricted spontaneous breathing. BIVENT can modulate inspiratory effort by modifying the frequency of controlled breaths. Nevertheless, the optimal amount of inspiratory effort to improve respiratory function while minimizing ventilator-associated lung injury during partial ventilatory assistance has not been determined. Furthermore, it is unclear whether the effects of partial ventilatory support depend on acute lung injury (ALI) etiology. This study aimed to investigate the impact of spontaneous and time-cycled control breaths during BIVENT on the lung and diaphragm in experimental pulmonary (p) and extrapulmonary (exp) ALI. Methods This was a prospective, randomized, controlled experimental study of 60 adult male Wistar rats. Mild ALI was induced by Escherichia coli lipopolysaccharide either intratracheally (ALIp) or intraperitoneally (ALIexp). After 24 hours, animals were anesthetized and further randomized as follows: (1) pressure-controlled ventilation (PCV) with tidal volume (Vt) = 6 ml/kg, respiratory rate = 100 breaths/min, PEEP = 5 cmH2O, and inspiratory-to-expiratory ratio (I:E) = 1:2; or (2) BIVENT with three spontaneous and time-cycled control breath modes (100, 75, and 50 breaths/min). BIVENT was set with two levels of CPAP (Phigh = 10 cmH2O and Plow = 5 cmH2O). Inspiratory time was kept constant (Thigh = 0.3 s). Results BIVENT was associated with reduced markers of inflammation, apoptosis, fibrogenesis, and epithelial and endothelial cell damage in lung tissue in both ALI models when compared to PCV. The inspiratory effort during spontaneous breaths increased during BIVENT-50 in both ALI models. In ALIp, alveolar collapse was higher in BIVENT-100 than PCV, but decreased during BIVENT-50, and diaphragmatic injury was lower during BIVENT-50 compared to PCV and BIVENT-100. In ALIexp, alveolar collapse during BIVENT-100 and BIVENT-75 was comparable to PCV, while decreasing with BIVENT-50, and diaphragmatic injury increased during BIVENT-50. Conclusions In mild ALI, BIVENT had a lower biological impact on lung tissue compared to PCV. In contrast, the response of atelectasis and diaphragmatic injury to BIVENT differed according to the rate of spontaneous/controlled breaths and ALI etiology.