Spinal N-methyl-D-aspartate (NMDA) receptor-mediated mechanisms may contribute to reduced opioid sensitivity in conditions of pain. The effectiveness of spinal opioids in inhibiting NMDA-mediated ...nociceptive events was assessed with two models. In addition, opioid dose-response curves with preemptive administration were compared with early and late postadministrations.
Dorsal horn nociceptive neuronal responses were recorded in the intact halothane anesthetized rat to acute repetitive C-fiber electrical stimulation (0.1 and 0.5 Hz) and to the peripheral injection of 5% formalin. At 0.5 Hz but not at 0.1 Hz, there was an enhanced C-fiber evoked response of dorsal horn neurons elicited by repetitive C-fiber stimulation (wind-up), which is mediated by the NMDA receptor. Formalin produced a biphasic response; the late protracted inflammatory phase was NMDA receptor-mediated.
With 0.5-Hz stimulation a large degree of wind-up was elicited; it was less sensitive to 5 micrograms morphine compared with the effect of the same dose on the residual wind-up elicited at 0.1 Hz. Preadministration and early postadministration of morphine were equieffective at inhibiting the second-phase formalin response. In contrast, administration of the fast-acting mu opioid, D-Ala-Gly-MePHe-Gly-ol, given late postadministration (during the second phase) was less effective than preadministration. Increasing the dose of D-Ala-Gly-MePHe-Gly-ol produced complete inhibitions.
NMDA receptor-mediated neuronal responses, such as wind-up and the established second phase of the formalin response, are poorly responsive to opioids. Dose increases and preemptive opioids effectively inhibit these NMDA receptor-mediated events.
The purpose of this study was to describe mechanical ventilation weaning outcomes for children with chronic respiratory failure discharged from one of six post-acute rehabilitation facilities. ...Demographic, clinical and outcome data were collected from the medical record. Forty-four children were included in this prospective series; 20 (45%) were weaned off the ventilator at discharge. Children required significantly lower levels of ventilatory support at discharge than admission. Hourly use on the ventilator decreased from admission to discharge for the full cohort and for the subgroup who required a ventilator at discharge. Seventy-five percent of the children discharged with a ventilator had a portable unit. We conclude that nearly half of the children using mechanical ventilation achieve weaning during a postacute rehabilitation admission, whereas others have positive outcomes in severity, hours off the ventilator or portability of equipment.
Therapies that might delay degeneration of synapses offer an appealing strategy for treatment of neurodegenerative diseases, including Alzheimer's disease and related dementias, prion diseases, ...schizophrenia and amyotrophic lateral sclerosis. Analysis of mouse mutants provides one possible avenue towards identifying relevant mechanisms. Here, we used quantitative and serial section electron microscopy to find out whether the onset and time course of pre-synaptic nerve terminal degeneration is delayed in the striatum of Wallerian degeneration slow (Wlds) mutant mice. Synaptic degeneration was observed within 48 h of cortical ablation in wild-type mice but was delayed by approximately 1 week in Wlds mice. However, the morphological characteristics of degenerating nerve terminals in wild-type and Wlds mice were indistinguishable, in contrast to the differences reported previously in studies of the PNS. Surprisingly, the delayed onset of synaptic degeneration was accompanied by an increased incidence of complex synaptic morphologies on post-synaptic spines in the denervated WldS striatum indicating an enhanced plastic response at both injured and uninjured synapses. The data suggest that targeting Wallerian-like mechanisms of synaptic degeneration could lead to the development of new therapies for the treatment of CNS disorders where synapse loss is a primary feature.
The Wlds mouse mutant demonstrates a remarkable phenotype of delayed axonal and synaptic degeneration after nerve lesion. In this study, the authors tested the hypothesis that expression of Wld ...protein is neuroprotective in an in vivo mouse model of global cerebral ischemia. This model is associated with selective neuronal degeneration in specific brain regions such as the caudate nucleus and CA2 hippocampal pyramidal cell layer. The extent of neuronal damage was quantified in Wlds compared to wild-type mice after an identical episode of global cerebral ischemia. The results demonstrated a significant and marked reduction in the extent of neuronal damage in Wlds as compared to wild-type C57Bl/6 mice. In the caudate nucleus, Wld expression significantly reduced the percentage of ischemic neuronal damage after global ischemia (Wlds, 27.7 ± 16.8%; wild-type mice, 58.7 ± 32.3%; P = 0.036). Similarly, in the CA2 pyramidal cell layer, there was a significant reduction of neuronal damage in the Wlds mice as compared to wild-type mice after ischemia (Wlds, 17.7 ± 23.0%; wild-type mice, 41.9 ± 28.0%; P < 0.023). Thus, these results clearly demonstrate that the Wld gene confers substantial neuroprotection after cerebral ischemia, and suggest a new role to that previously described for Wlds.
Slow Wallerian degeneration (Wld(S)) mutant mice express a chimeric nuclear protein that protects sick or injured axons from degeneration. The C-terminal region, derived from NAD(+) synthesizing ...enzyme Nmnat1, is reported to confer neuroprotection in vitro. However, an additional role for the N-terminal 70 amino acids (N70), derived from multiubiquitination factor Ube4b, has not been excluded. In wild-type Ube4b, N70 is part of a sequence essential for ubiquitination activity but its role is not understood. We report direct binding of N70 to valosin-containing protein (VCP; p97/Cdc48), a protein with diverse cellular roles including a pivotal role in the ubiquitin proteasome system. Interaction with Wld(S) targets VCP to discrete intranuclear foci where ubiquitin epitopes can also accumulate. Wld(S) lacking its N-terminal 16 amino acids (N16) neither binds nor redistributes VCP, but continues to accumulate in intranuclear foci, targeting its intrinsic NAD(+) synthesis activity to these same foci. Wild-type Ube4b also requires N16 to bind VCP, despite a more C-terminal binding site in invertebrate orthologues. We conclude that N-terminal sequences of Wld(S) protein influence the intranuclear location of both ubiquitin proteasome and NAD(+) synthesis machinery and that an evolutionary recent sequence mediates binding of mammalian Ube4b to VCP.
As medical and technological advances have made it possible to prolong the life of children with chronic respiratory failure, children are being referred to post-acute inpatient rehabilitation ...programmes. In these settings, children can be weaned from their ventilators and receive medical and rehabilitative care in a developmentally supportive environment at a lower financial cost than in an intensive care unit. There is strong evidence that weaning children from mechanical ventilation has beneficial effects on their functionality, ease of care and quality of life. There is, however, little scientific evidence describing how often successful weaning is achieved or the most effective methods. The purpose of this article is to present a consensus report detailing a structured approach to weaning children from mechanical ventilation in a post-acute care setting. This study proposes a Weaning Severity Index and a Weaning Algorithm for use in the assessment and implementation of the weaning process in post-acute rehabilitation. Future clinical studies are needed to validate the suggested approach to ventilator weaning and to determine whether or not the weaning algorithm results in beneficial patient outcomes.
A raíz de que los avances médicos y tecnológicos han hecho posible prolongar la vida de los niños con falla respiratoria crónica, estos están siendo referidos a programas de rehabilitación postaguda intrahospitalaria. En esta situación, los niños pueden ser separados de sus ventiladores y recibir un manejo médico y de rehabilitación en un medio ambiente de apoyo en desarrollo, con un costo financiero más bajo que el de una unidad de cuidados intensivos. Existe fuerte evidencia de que la separación de los niños de la ventilación mecánica tiene efectos benéficos en su función, facilidad de manejo y calidad de vida. Sin embargo hay poca evidencia científica que describa que tan frecuente se obtiene una separación del ventilador en forma exitosa o el método más efectivo. El propósito de este artículo es presentar un reporte consensuado, detallando una estrategia estructurada para separar a los niños de la ventilación mecánica en una situación de manejo postagudo.
Proponemos el Weaning Severity Index y Weaning Algorithm para su uso en la evaluación e implementación del proceso de separación del ventilador, en la rehabilitación post aguda. Se necesitan estudios clínicos en un futuro para validar la estrategia que sugerimos en la separación del ventilador, y para determinar si el algoritmo de separación tiene un resultado benéfico en los pacientes.
Palabras clave: destete, ventilación mecánica en niños, rehabilitación.
Wallerian degeneration of injured neuronal axons and synapses is blocked in WldS mutant mice by expression of an nicotinamide mononucleotide adenylyl transferase 1 (Nmnat-1)/truncated-Ube4b chimeric ...gene. The protein product of the WldS gene localizes to neuronal nuclei. Here we show that WldS protein expression selectively alters mRNA levels of other genes in WldS mouse cerebellum in vivo and following transfection of human embryonic kidney (HEK293) cells in vitro. The largest changes, identified by microarray analysis and quantitative real-time polymerase chain reaction of cerebellar mRNA, were an approximate 10-fold down-regulation of pituitary tumour-transforming gene-1 (pttg1) and an approximate 5-fold up-regulation of a structural homologue of erythroid differentiation regulator-1 (edr1l-EST). Transfection of HEK293 cells with a WldS-eGFP construct produced similar changes in mRNA levels for these and seven other genes, suggesting that regulation of gene expression by WldS is conserved across different species, including humans. Similar modifications in mRNA levels were mimicked for some of the genes (including pttg1) by 1 mm nicotinamide adenine dinucleotide (NAD). However, expression levels of most other genes (including edr1l-EST) were insensitive to NAD. Pttg1−/− mutant mice showed no neuroprotective phenotype. Transfection of HEK293 cells with constructs comprising either full-length Nmnat-1 or the truncated Ube4b fragment (N70-Ube4b) demonstrated selective effects of Nmnat-1 (down-regulated pttg1) and N70-Ube4b (up-regulated edr1l-EST) on mRNA levels. Similar changes in pttg1 and edr1l-EST were observed in the mouse NSC34 motor neuron-like cell line following stable transfection with WldS. Together, the data suggest that the WldS protein co-regulates expression of a consistent subset of genes in both mouse neurons and human cells. Targeting WldS-induced gene expression may lead to novel therapies for neurodegeneration induced by trauma or by disease in humans.
Medical records were reviewed to describe characteristics, report clinical and resource measures, and determine if differences exist between the diagnostic groups of prematurity and multiple ...congenital anomalies/neurologic conditions for initial admissions of 37 infants and toddlers to an inpatient pulmonary rehabilitation program. More than 75% of the children had a tracheostomy at admission and discharge. Forty-six percent of the sample was admitted requiring only oxygen, whereas 51% were discharged requiring only oxygen and not mechanical ventilation. Thirty percent of the children weaned to a less invasive mode of ventilation while just under half of the children were discharged home. Between-group comparisons indicated statistically significant differences for nutritional support at discharge (p < = 0.05) and discharge disposition (P = 0.04). Complete weaning of oxygen or ventilator support during an initial inpatient pulmonary rehabilitation admission occurred less frequently than weaning to a less invasive mode of ventilation. This is an important consideration for referring children to rehabilitation programs, for clinical program improvement activities, and for setting realistic expectations for referral sources, patients and families, clinical staff, and payers. Further study is recommended using clinical data in program planning, in program improvements, and for setting outcome expectations for infants and toddlers dependent on pulmonary technology.
Subcutaneous injection of formalin into the hindpaw peripheral receptive field of deep dorsal horn multireceptive (convergent) nociceptive neurones was used to produce a prolonged (1 h) activation of ...the cells. This chemical noxious stimulus produced a first peak of firing which lasted 10 min followed by a second peak of prolonged activity which was monitored for 50 min. gamma-D-glutamylglycine (DGG), a non-selective N-methyl-D-aspartate (NMDA) and quisqualate/kainate (non-NMDA) receptor antagonist was applied intrathecally both as a pretreatment and after the formalin. A complete abolition of both peaks of the formalin response was produced by DGG pretreatment (1000 micrograms) (n = 4). This dose produced profound inhibition of the acute C-fibre evoked responses of the same cells. However, no inhibitions were produced when the antagonist was applied once the formalin response had developed (n = 4). The selective NMDA receptor antagonist 5-amino-phosphonovaleric acid (AP5) was administered intrathecally (250 and 500 micrograms) as a 40 min pretreatment and caused a small inhibition of the first peak but a marked dose-related reduction in the second prolonged phase (n =7). AP5 did not influence the C-fibre inputs onto the cells. The non-competitive NMDA receptor channel blockers, ketamine and MK801, were administered i.v. during the second phase of firing. Ketamine (1-8 mg/kg) caused a short-lasting but marked and dose-related inhibition of the neuronal responses to formalin (n = 11). MK801 (0.5-1 mg/kg) resulted in a prolonged inhibition of cell firing during the second phase of the response (n = 11).
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