Effects of premedication with tiletamine/zolazepam/medetomidine during general anesthesia using sevoflurane/fentanyl in swine undergoing pancreas transplantation.

OBJECTIVE: To assess cardiac and hemodynamic responses and body temperature during long-term general anesthesia using sevoflurane/fentanyl after premedication with a tiletamine/zolazepam/medetomidine combination in swine undergoing experimental pancreas transplantation. MATERIALS AND METHODS: Twelve Landrace female pigs of means weight 46.4 +/- 5.1 kg were premedicated by intramuscular administration of tiletamine/zolazepam (3.5 mg/kg), medetomidine (0.03 mg/kg), and atropine (0.02 mg/kg), before anesthesia with 0.75 minimum alveolar concentration sevoflurane and continuous intravenous fentanyl infusion (5.7 +/- 0.7 microg/kg/h). Assessment of heart rate, arterial blood pressure, and temperature in pigs undergoing allogenic pancreas transplant surgery were registered at the start of anesthesia (T0), as well as at 60 (T60), 120 (T120), and 180 (T180) minutes after T0, and finally at the end of anesthesia (T anesthesia end), when we switched off the sevoflurane vaporizer. Analysis of variance was used to determine differences between times with P < .05 considered significant. Results are given as mean values +/- standard deviations. RESULTS: Arterial blood pressure significantly decreased from T120 to the end of anesthesia, while a significantly decreased heart rate was only evident at T60. Body temperature decreased significantly from T60 to the end of anesthesia. These decreases, however, lacked clinical relevance; all parameters were within normal range. No major anesthetic complications were observed in this study. CONCLUSIONS: The administration of a tiletamine/zolazepam/medetomidine combination as premedication in swine subjected to pancreas transplantation allowed for a safe reduction of sevoflurane/fentanyl requirements during long-term general anesthesia. Despite arterial blood pressure and body temperature evidencing a decrease during anesthetic maintenance, all parameters remained within normal range values.

Insulin-like growth factor 1 is required for survival of transit-amplifying neuroblasts and differentiation of otic neurons.

Neurons that connect mechanosensory hair cell receptors to the central nervous system derive from the otic vesicle from where otic neuroblasts delaminate and form the cochleovestibular ganglion (CVG). Local signals interact to promote this process, which is autonomous and intrinsic to the otic vesicle. We have studied the expression and activity of insulin-like growth factor-1 (IGF-1) during the formation of the chick CVG, focusing attention on its role in neurogenesis. IGF-1 and its receptor (IGFR) were detected at the mRNA and protein levels in the otic epithelium and the CVG. The function of IGF-1 was explored in explants of otic vesicle by assessing the formation of the CVG in the presence of anti-IGF-1 antibodies or the receptor competitive antagonist JB1. Interference with IGF-1 activity inhibited CVG formation in growth factor-free media, revealing that endogenous IGF-1 activity is essential for ganglion generation. Analysis of cell proliferation cell death, and expression of the early neuronal antigens Tuj-1, Islet-1/2, and G4 indicated that IGF-1 was required for survival, proliferation, and differentiation of an actively expanding population of otic neuroblasts. IGF-1 blockade, however, did not affect NeuroD within the otic epithelium. Experiments carried out on isolated CVG showed that exogenous IGF-1 induced cell proliferation, neurite outgrowth, and G4 expression. These effects of IGF-1 were blocked by JB1. These findings suggest that IGF-1 is essential for neurogenesis by allowing the expansion of a transit-amplifying neuroblast population and its differentiation into postmitotic neurons. IGF-1 is one of the signals underlying autonomous development of the otic vesicle.

Delayed inner ear maturation and neuronal loss in postnatal Igf-1-deficient mice.

Insulin-like growth factor-1 (IGF-1) has been shown to play a key role during embryonic and postnatal development of the CNS, but its effect on a sensory organ has not been studied in vivo. Therefore, we examined cochlear growth, differentiation, and maturation in Igf-1 gene knock-out mice at postnatal days 5 (P5), P8, and P20 by using stereological methods and immunohistochemistry. Mutant mice showed reduction in size of the cochlea and cochlear ganglion. An immature tectorial membrane and a significant decrease in the number and size of auditory neurons were also evident at P20. IGF-1-deficient cochlear neurons showed increased caspase-3-mediated apoptosis, along with aberrant expression of the early neural markers nestin and Islet 1/2. Cochlear ganglion and fibers innervating the sensory cells of the organ of Corti presented decreased levels of neurofilament and myelin P(0) in P20 mouse mutants. In addition, an abnormal synaptophysin expression in the somata of cochlear ganglion neurons and sensory hair cells suggested the persistence of an immature pattern of synapses distribution in the organ of Corti of these animals. These results demonstrate that lack of IGF-1 in mice severely affects postnatal survival, differentiation, and maturation of the cochlear ganglion cells and causes abnormal innervation of the sensory cells in the organ of Corti.

Involvement of insulin-like growth factor-I in inner ear organogenesis and regeneration.

The verterbrate inner ear is an excellent model system to study signalling mechanisms in embryonic development. During the last years, insulin-like growth factor-I (IGF-I) has attracted attention in relation to the regulation of inner ear ontogenesis. IGF-I and its high-affinity tyrosine-kinase receptor are expressed during early stages of inner ear development. IGF-I is a powerful mitogen for the otic vesicle, where it stimulates cell-division and mitogenic signalling cascades. Later in development, IGF-I also promotes survival and neurogenesis of the otic neurones in the cochleovestibular ganglion (CVG). The actions of IGF-I are associated with the generation of lipidic messengers and the activation of Raf kinase, which results in the rapid induction of the expression of the proliferative cell nuclear antigen (PCNA) and the nuclear proto-oncogenes c-fos and c-jun. Regulation of organogenesis involves a dynamic balance of the mechanisms regulating cell division, differentiation and death. A model is proposed where this balance is the consequence of the action of IGF-I and NGF, which converge in Raf activation or suppression. The combinatorial expression of jun and Fos family members in particular domains of the otic vesicle would be the final result of such cascade. Some of these mechanisms may be also implicated in otic regeneration.