Impact of daily evaluation and spontaneous breathing test on the duration of pediatric mechanical ventilation: a randomized controlled trial

Objectives: To assess whether the combination of daily evaluation and use of a spontaneous breathing test could shorten the duration of mechanical ventilation as compared with weaning based on our standard of care. Secondary outcome measures included extubation failure rate and the need for noninvasive ventilation.Design: A prospective, randomized controlled trial.Setting: Two pediatric intensive care units at university hospitals in Brazil.Patients: the trial involved children between 28 days and 15 yrs of age who were receiving mechanical ventilation for at least 24 hrs.Interventions: Patients were randomly assigned to one of two weaning protocols. in the test group, the children underwent a daily evaluation to check readiness for weaning with a spontaneous breathing test with 10 cm H(2)O pressure support and a positive end-expiratory pressure of 5 cm H(2)O for 2 hrs. the spontaneous breathing test was repeated the next day for children who failed it. in the control group, weaning was performed according to standard care procedures.Measurements and Main Results: A total of 294 eligible children were randomized, with 155 to the test group and 139 to the control group. the time to extubation was shorter in the test group, where the median mechanical ventilation duration was 3.5 days (95% confidence interval, 3.0 to 4.0) as compared to 4.7 days (95% confidence interval, 4.1 to 5.3) in the control group (p = .0127). This significant reduction in the mechanical ventilation duration for the intervention group was not associated with increased rates of extubation failure or noninvasive ventilation. It represents a 30% reduction in the risk of remaining on mechanical ventilation (hazard ratio: 0.70).Conclusions: A daily evaluation to check readiness for weaning combined with a spontaneous breathing test reduced the mechanical ventilation duration for children on mechanical ventilation for > 24 hrs, without increasing the extubation failure rate or the need for noninvasive ventilation. (Crit Care Med 2011; 39: 2526-2533)Hosp Sirio Libanes, Intens Care Unit, São Paulo, BrazilUniv São Paulo, Sch Med, Dept Pediat, Hosp Clin, São Paulo, BrazilUniv São Paulo, Sch Med, Dept Pneumol, Hosp Clin, São Paulo, BrazilHosp Albert Einstein, Intens Care Unit, São Paulo, BrazilUniv Buenos Aires, Hosp Ninos R Gutierrez, Intens Care Unit, Buenos Aires, DF, ArgentinaUniv São Paulo, Sch Med, Intens Care Unit, Univ Hosp, São Paulo, BrazilWeb of Scienc

CF2 Represses Actin 88F Gene Expression and Maintains Filament Balance during Indirect Flight Muscle Development in Drosophila

The zinc finger protein CF2 is a characterized activator of muscle structural genes in the body wall muscles of the Drosophila larva. To investigate the function of CF2 in the indirect flight muscle (IFM), we examined the phenotypes of flies bearing five homozygous viable mutations. The gross structure of the IFM was not affected, but the stronger hypomorphic alleles caused an increase of up to 1.5X in the diameter of the myofibrils. This size increase did not cause any disruption of the hexameric arrangement of thick and thin filaments. RT-PCR analysis revealed an increase in the transcription of several structural genes. Ectopic overexpression of CF2 in the developing IFM disrupts muscle formation. While our results indicate a role for CF2 as a direct negative regulator of the thin filament protein gene Actin 88F (Act88F), effects on levels of transcripts of myosin heavy chain (mhc) appear to be indirect. This role is in direct contrast to that described in the larval muscles, where CF2 activates structural gene expression. The variation in myofibril phenotypes of CF2 mutants suggest the CF2 may have separate functions in fine-tuning expression of structural genes to insure proper filament stoichiometry, and monitoring and/or controlling the final myofibril size

Competing Neural Responses for Auditory and Visual Decisions

Why is it hard to divide attention between dissimilar activities, such as reading and listening to a conversation? We used functional magnetic resonance imaging (fMRI) to study interference between simple auditory and visual decisions, independently of motor competition. Overlapping activity for auditory and visual tasks performed in isolation was found in lateral prefrontal regions, middle temporal cortex and parietal cortex. When the visual stimulus occurred during the processing of the tone, its activation in prefrontal and middle temporal cortex was suppressed. Additionally, reduced activity was seen in modality-specific visual cortex. These results paralleled impaired awareness of the visual event. Even without competing motor responses, a simple auditory decision interferes with visual processing on different neural levels, including prefrontal cortex, middle temporal cortex and visual regions

Differential Functional Constraints on the Evolution of Postsynaptic Density Proteins in Neocortical Laminae

The postsynaptic density (PSD) is a protein dense complex on the postsynaptic membrane of excitatory synapses that is implicated in normal nervous system functions such as synaptic plasticity, and also contains an enrichment of proteins involved in neuropsychiatric disorders. It has recently been reported that the genes encoding PSD proteins evolved more slowly than other genes in the human brain, but the underlying evolutionary advantage for this is not clear. Here, we show that cortical gene expression levels could explain most of this effect, indicating that expression level is a primary contributor to the evolution of these genes in the brain. Furthermore, we identify a positive correlation between the expression of PSD genes and cortical layers, with PSD genes being more highly expressed in deep layers, likely as a result of layer-enriched transcription factors. As the cortical layers of the mammalian brain have distinct functions and anatomical projections, our results indicate that the emergence of the unique six-layered mammalian cortex may have provided differential functional constraints on the evolution of PSD genes. More superficial cortical layers contain PSD genes with less constraint and these layers are primarily involved in intracortical projections, connections that may be particularly important for evolved cognitive functions. Therefore, the differential expression and evolutionary constraint of PSD genes in neocortical laminae may be critical not only for neocortical architecture but the cognitive functions that are dependent on this structure

The 4C5 Cell-Impermeable Anti-HSP90 Antibody with Anti-Cancer Activity, Is Composed of a Single Light Chain Dimer

MAb 4C5 is a cell impermeable, anti-HSP90 murine monoclonal antibody, originally produced using hybridoma technology. We have previously shown that mAb 4C5 specifically recognizes both the α- and to a lesser extent the β-isoform of HSP90. Additionally, in vitro and in vivo studies revealed that by selectively inhibiting the function of cell-surface HSP90, mAb 4C5 significantly impairs cancer cell invasion and metastasis. Here we describe the reconstitution of mAb 4C5 into a mouse-human chimera. More importantly we report that mAb 4C5 and consequently its chimeric counterpart are completely devoid of heavy chain and consist only of a functional kappa light chain dimer. The chimeric antibody is shown to retain the original antibody's specificity and functional properties. Thus it is capable of inhibiting the function of surface HSP90, leading to reduced cancer cell invasion in vitro. Finally, we present in vivo evidence showing that the chimeric 4C5 significantly inhibits the metastatic deposit formation of MDA-MB-453 cells into the lungs of SCID mice. These data suggest that a chimeric kappa light chain antibody could be potentially used as an anti-cancer agent, thereby introducing a novel type of antibody fragment, with reduced possible adverse immunogenic effects, into cancer therapeutics

Interpretation and Visualization of Non-Linear Data Fusion in Kernel Space: Study on Metabolomic Characterization of Progression of Multiple Sclerosis

Contains fulltext : 93904.pdf (publisher's version ) (Open Access

Medial prefrontal cortex serotonin 1A and 2A receptor binding interacts to predict threat-related amygdala reactivity

Background\ud The amygdala and medial prefrontal cortex (mPFC) comprise a key corticolimbic circuit that helps shape individual differences in sensitivity to threat and the related risk for psychopathology. Although serotonin (5-HT) is known to be a key modulator of this circuit, the specific receptors mediating this modulation are unclear. The colocalization of 5-HT1A and 5-HT2A receptors on mPFC glutamatergic neurons suggests that their functional interactions may mediate 5-HT effects on this circuit through top-down regulation of amygdala reactivity. Using a multimodal neuroimaging strategy in 39 healthy volunteers, we determined whether threat-related amygdala reactivity, assessed with blood oxygen level-dependent functional magnetic resonance imaging, was significantly predicted by the interaction between mPFC 5-HT1A and 5-HT2A receptor levels, assessed by positron emission tomography.\ud \ud Results\ud 5-HT1A binding in the mPFC significantly moderated an inverse correlation between mPFC 5-HT2A binding and threat-related amygdala reactivity. Specifically, mPFC 5-HT2A binding was significantly inversely correlated with amygdala reactivity only when mPFC 5-HT1A binding was relatively low.\ud \ud Conclusions\ud Our findings provide evidence that 5-HT1A and 5-HT2A receptors interact to shape serotonergic modulation of a functional circuit between the amygdala and mPFC. The effect of the interaction between mPFC 5-HT1A and 5-HT2A binding and amygdala reactivity is consistent with the colocalization of these receptors on glutamatergic neurons in the mPFC

Functional sex differences in human primary auditory cortex

Background We used PET to study cortical activation during auditory stimulation and found sex differences in the human primary auditory cortex (PAC). Regional cerebral blood flow (rCBF) was measured in 10 male and 10 female volunteers while listening to sounds (music or white noise) and during a baseline (no auditory stimulation). Results and discussion We found a sex difference in activation of the left and right PAC when comparing music to noise. The PAC was more activated by music than by noise in both men and women. But this difference between the two stimuli was significantly higher in men than in women. To investigate whether this difference could be attributed to either music or noise, we compared both stimuli with the baseline and revealed that noise gave a significantly higher activation in the female PAC than in the male PAC. Moreover, the male group showed a deactivation in the right prefrontal cortex when comparing noise to the baseline, which was not present in the female group. Interestingly, the auditory and prefrontal regions are anatomically and functionally linked and the prefrontal cortex is known to be engaged in auditory tasks that involve sustained or selective auditory attention. Thus we hypothesize that differences in attention result in a different deactivation of the right prefrontal cortex, which in turn modulates the activation of the PAC and thus explains the sex differences found in the activation of the PAC. Conclusion Our results suggest that sex is an important factor in auditory brain studies

Robust Reproducible Resting State Networks in the Awake Rodent Brain

Resting state networks (RSNs) have been studied extensively with functional MRI in humans in health and disease to reflect brain function in the un-stimulated state as well as reveal how the brain is altered with disease. Rodent models of disease have been used comprehensively to understand the biology of the disease as well as in the development of new therapies. RSN reported studies in rodents, however, are few, and most studies are performed with anesthetized rodents that might alter networks and differ from their non-anesthetized state. Acquiring RSN data in the awake rodent avoids the issues of anesthesia effects on brain function. Using high field fMRI we determined RSNs in awake rats using an independent component analysis (ICA) approach, however, ICA analysis can produce a large number of components, some with biological relevance (networks). We further have applied a novel method to determine networks that are robust and reproducible among all the components found with ICA. This analysis indicates that 7 networks are robust and reproducible in the rat and their putative role is discussed