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At present, effective therapies to repair the central nervous system do not exist. Biomaterials might represent a new frontier for the development of neurorestorative therapies after brain injury and degeneration. In this study, an in situ gelling silk fibroin hydrogel was developed via the sonication-induced gelation of regenerated silk fibroin solutions. An adequate timeframe for the integration of the biomaterial into the brain tissue was obtained by controlling the intensity and time of sonication. After the intrastriatal injection of silk fibroin the inflammation and cell death in the implantation area were transient. We did not detect considerable cognitive or sensorimotor deficits, either as examined by different behavioral tests or an electrophysiological analysis. The sleep and wakefulness states studied by chronic electroencephalogram recordings and the fitness of thalamocortical projections and the somatosensory cortex explored by evoked potentials were in the range of normality. The methodology used in this study might serve to assess the biological safety of other biomaterials implanted into the rodent brain. Our study highlights the biocompatibility of native silk with brain tissue and extends the current dogma of the innocuousness of this biomaterial for therapeutic applications, which has repercussion in regenerative neuroscience. Statement of Significance The increasingly use of sophisticated biomaterials to encapsulate stem cells has changed the comprehensive overview of potential strategies for repairing the nervous system. Silk fibroin (SF) meets with most of the standards of a biomaterial suitable to enhance stem cell survival and function. However, a proof-of-principle of the in vivo safety and tolerability of SF implanted into the brain tissue is needed. In this study we have examined the tissue bioresponse and brain function after implantation of SF hydrogels. We have demonstrated the benign coexistence of silk with the complex neuronal circuitry that governs sensorimotor coordination and mechanisms such as learning and memory. Our results have repercussion in the development of advances strategies using this biomaterial in regenerative neuroscience. [ABSTRACT FROM AUTHOR]

Objectives: To determine the feasibility of conducting a sedation wake-up trial (SWT) plus a spontaneous breathing trial (SBT) in critically ill trauma patients based on the ability to implement the combined intervention; to measure and describe patients' physiological responses; and to maintain patient safety. Methods: A secondary analysis of the intervention group from a trial of 20 mechanically ventilated patients receiving SWT plus SBT in a trauma-intensive care unit. Results: Patients passed 67% of the 39 SWTs performed; those who failed presented RASS scores of +1 and +2 (70%), tachycardia (15%) or ventilator asynchrony (15%). Eighteen patients tolerated their first SBT, and after the second SBT, more than half of the patients were discontinued from the mechanical ventilator. A significant increase from the beginning to the end of the SWT was found in heart rate (p=.021), respiratory rate (p = .043) and systolic blood pressure (p=.04). Although these measures increased significantly, their overall mean did not increase by 20%. Conclusion: SWT plus SBT was well tolerated and successfully implemented. Our data showed that it is not necessary to withhold continuous-infusion analgesia during the SWT. [ABSTRACT FROM AUTHOR]

Summary: The purpose of this secondary data analysis of findings from a larger procedural pain study was to examine several factors related to pain during tracheal suctioning. In addition to tracheal suctioning, other procedures studied included turning, wound drain removal, femoral catheter removal, placement of a central venous catheter, and wound dressing change. A total of 755 patients underwent the tracheal suctioning procedure that was performed primarily in intensive care units (93%). A 0–10 numeric rating scale, a behavioural observation tool, and a modified McGill Pain Questionnaire-Short Form were used for pain assessment. Pain intensity scores were significantly greater during the tracheal suctioning procedure (M =3.96, S.D.=3.3) than prior to (M =2.14, S.D.=2.8) or after (M =1.98, S.D.=2.7) tracheal suctioning. Few patients received analgesics prior to or during the procedure. Surgical, younger, and non-white patients reported higher pain intensities. Although mean pain intensity during tracheal suctioning was mild, almost the half of the patients reported moderate-to-severe pain. Individualized pain management must be performed by healthcare providers in order to respond to patients’ needs as they undergo painful procedures such as tracheal suctioning. [Copyright &y& Elsevier]

Aralar1 and citrin are two isoforms of the mitochondrial carrier of aspartate–glutamate (AGC), a calcium regulated carrier, which is important in the malate–aspartate NADH shuttle. The expression and cell distribution of aralar1 and citrin in brain cells has been studied during development in vitro and in vivo. Aralar1 is the only isoform expressed in neurons and its levels undergo a marked increase during in vitro maturation, which is higher than the increase in mitochondrial DNA in the same time window. The enrichment in aralar1 per mitochondria during neuronal maturation is associated with a prominent rise in the function of the malate–aspartate NADH shuttle. Paradoxically, during in vivo development of rat or mouse brain there is very little postnatal increase in total aralar1 levels per mitochondria. This is explained by the fact that astrocytes develop postnatally, have aralar1 levels much lower than neurons, and their increase masks that of aralar1. Aralar1 mRNA and protein are widely expressed throughout neuron-rich areas in adult mouse CNS with clear enrichments in sets of neuronal nuclei in the brainstem and, particularly, in the ventral horn of the spinal cord. These aralar1-rich neurons represent a subset of the cytochrome oxidase-rich neurons in the same areas. The presence of aralar1 could reflect a tonic activity of these neurons, which is met by the combination of high malate–aspartate NADH shuttle and respiratory chain activities. [Copyright &y& Elsevier]

A reply by Milagros I. Figueroa-Ramos to a letter to the editor about her article "Feasibility of a Sedation Wake-Up Trial and Spontaneous Breathing Trial in Critically Ill Trauma Patients: A Secondary Analysis," in the 2013 issue is presented.

Human neural stem cells derived from the ventral mesencephalon (VM) are powerful research tools and candidates for cell therapies in Parkinson disease. Previous studies with VM dopaminergic neuron (DAn) precursors indicated poor growth potential and unstable phenotypical properties. Using the model cell line hVM1 (human ventral mesencephalic neural stem cell line 1; a new human fetal VM stem cell line), we have found that Bcl-XL enhances the generation of DAn from VM human neural stem cells. Mechanistically, Bcl-XL not only exerts the expected antiapoptotic effect but also induces proneural (NGN2 and NEUROD1) and dopamine-related transcription factors, resulting in a high yield of DAn with the correct phenotype of substantia nigra pars compacta (SNpc). The expression of key genes directly involved in VM/SNpc dopaminergic patterning, differentiation, and maturation (EN1, LMX1B, PITX3, NIJRR1, VMAT2, GIRK2, and dopamine transporter) is thus enhanced by Bcl-XL. These effects on neurogenesis occur in parallel to a decrease in glia generation. These in vitro Bcl-XL effects are paralleled in vivo, after transplantation in hemiparkinsonian rats, where hVM1-Bcl-XL cells survive, integrate, and differentiate into DAn, alleviating behavioral motor asymmetry. Bcl-XL then allows for human fetal VM stem cells to stably generate mature SNpc DAn both in vitro and in vivo and is thus proposed as a helpful factor for the development of cell therapies for neurodegenerative conditions, Parkinson disease in particular. [ABSTRACT FROM AUTHOR]

Aralar, the neuronal Ca2+-binding mitochondrial aspartate-glutamate carrier, has Ca2+ binding domains facing the extramitochondrial space and functions in the malate-aspartate NADH shuttle (MAS). Here we showed that MAS activity in brain mitochondria is stimulated by extramitochondrial Ca2+ with an S0.5 of 324 nM. By employing primary neuronal cultures from control and aralar-deficient mice and NAD(P)H imaging with two-photon excitation microscopy, we showed that lactate utilization involves a substantial transfer of NAD(P)H to mitochondria in control but not aralar-deficient neurons, in agreement with the lack of MAS activity associated with aralar deficiency. The increase in mitochondrial NAD(P)H was greatly potentiated by large [Ca2+]t signals both in control and aralar-deficient neurons, showing that these large signals activate the Ca2+ uniporter and mitochondrial dehydrogenases but not MAS activity. On the other hand, small [Ca2+]j signals potentiate the increase in mitochondrial NAD(P)H only in control but not in aralar-deficient neurons. We concluded that neuronal MAS activity is selectively activated by small Ca2+ signals that fall below the activation range of the Ca2+ uniporter and plays an essential role in mitochondrial Ca2+ signaling. [ABSTRACT FROM AUTHOR]

Aralar is a mitochondrial calcium-regulated aspartate-glutamate carrier mainly distributed in brain and skeletal muscle, involved in the transport of aspartate from mitochondria to cytosol, and in the transfer of cytosolic reducing equivalents into mitochondria as a member of the malate-aspartate NADH shuttle. In the present study, we describe the characteristics of aralar-deficient (Aralar-/-) mice, generated by a gene-trap method, showing no aralar mRNA and protein, and no detectable malate-aspartate shuttle activity in skeletal muscle and brain mitochondria. Aralar-/- mice were growth-retarded, exhibited generalized tremoring, and had pronounced motor coordination defects along with an impaired myelination in the central nervous system. Analysis of lipid components showed a marked decrease in the myelin lipid galactosyl cerebroside. The content of the myelin lipid precursor, N-acetylaspartate, and that of aspartate are drastically decreased in the brain of Aralar-/- mice. The defect in N-acetylaspartate production was also observed in cell extracts from primary neuronal cultures derived from Aralar-/- mouse embryos. These results show that aralar plays an important role in myelin formation by providing aspartate for the synthesis of N-acetylaspartate in neuronal cells. [ABSTRACT FROM AUTHOR]