Structure-function Relationships Using the Cirrus Spectral Domain Optical Coherence Tomograph and Standard Automated Perimetry

Purpose: To evaluate the relationship between glaucomatous structural damage assessed by the Cirrus Spectral Domain OCT (SDOCT) and functional loss as measured by standard automated perimetry (SAP). Methods: Four hundred twenty-two eyes (78 healthy, 210 suspects, 134 glaucomatous) of 250 patients were recruited from the longitudinal Diagnostic Innovations in Glaucoma Study and from the African Descent and Glaucoma Evaluation Study. All eyes underwent testing with the Cirrus SDOCT and SAP within a 6-month period. The relationship between parapapillary retinal nerve fiber layer thickness (RNFL) sectors and corresponding topographic SAP locations was evaluated using locally weighted scatterplot smoothing and regression analysis. SAP sensitivity values were evaluated using both linear as well as logarithmic scales. We also tested the fit of a model (Hood) for structure-function relationship in glaucoma. Results: Structure was significantly related to function for all but the nasal thickness sector. The relationship was strongest for superotemporal RNFL thickness and inferonasal sensitivity (R(2) = 0.314, P < 0.001). The Hood model fitted the data relatively well with 88% of the eyes inside the 95% confidence interval predicted by the model. Conclusions: RNFL thinning measured by the Cirrus SDOCT was associated with correspondent visual field loss in glaucoma.

Baroreceptor-mediated activation of sympathetic nerve activity to salivary glands

Salivary gland function is regulated by both the sympathetic and parasympathetic nervous systems. Previously we showed that the basal sympathetic outflow to the salivary glands (SNA(SG)) was higher in hypertensive compared to normotensive rats and that diabetes reduced SNA(SG) discharge at both strains. In the present study we sought to investigate how SNA(SG) might be modulated by acute changes in the arterial pressure and whether baroreceptors play a functional role upon this modulation. To this end, we measured blood pressure and SNA(SG) discharge in Wistar-Kyoto rats (WRY-intact) and in WRY submitted to sinoaortic denervation (WRY-SAD). We made the following three major observations: (i) in WRY-intact rats, baroreceptor loading in response to intravenous infusion of the phenylephrine evoked an increase in SNA(SG) spike frequency (81%, p<0.01) accompanying the increase mean arterial pressure ((sic)MAP: +77 +/- 14 mmHg); (ii) baroreceptor unloading with sodium nitroprusside infusion elicited a decrease in SNA(SG) spike frequency (17%, p<0.01) in parallel with the fall in arterial blood pressure ((sic)MAP: 30 3 mmHg) in WRY-intact rats; iii) in the WRY-SAD rats, phenylephrine-evoked rises in the arterial pressure ((sic)MAP: +56 +/- 6 mmHg) failed to produce significant changes in the SNA(SG) spike frequency. Taken together, these data show that SNA(SG) increases in parallel with pharmacological-induced pressor response in a baroreceptor dependent way in anaesthetised rats. Considering the key role of SNA(SG) in salivary secretion, this mechanism, which differs from the classic cardiac baroreflex feedback loop, strongly suggests that baroreceptor signalling plays a decisive role in the regulation of salivary gland function. (C) 2012 Elsevier Inc. All rights reserved.

Computational analyses on the structure-function relation in ion channels

Ion channels are protein molecules, embedded in the lipid bilayer of the cell membranes. They act as powerful sensing elements switching chemicalphysical stimuli into ion-fluxes. At a glance, ion channels are water-filled pores, which can open and close in response to different stimuli (gating), and one once open select the permeating ion species (selectivity). They play a crucial role in several physiological functions, like nerve transmission, muscular contraction, and secretion. Besides, ion channels can be used in technological applications for different purpose (sensing of organic molecules, DNA sequencing). As a result, there is remarkable interest in understanding the molecular determinants of the channel functioning. Nowadays, both the functional and the structural characteristics of ion channels can be experimentally solved. The purpose of this thesis was to investigate the structure-function relation in ion channels, by computational techniques. Most of the analyses focused on the mechanisms of ion conduction, and the numerical methodologies to compute the channel conductance. The standard techniques for atomistic simulation of complex molecular systems (Molecular Dynamics) cannot be routinely used to calculate ion fluxes in membrane channels, because of the high computational resources needed. The main step forward of the PhD research activity was the development of a computational algorithm for the calculation of ion fluxes in protein channels. The algorithm - based on the electrodiffusion theory - is computational inexpensive, and was used for an extensive analysis on the molecular determinants of the channel conductance. The first record of ion-fluxes through a single protein channel dates back to 1976, and since then measuring the single channel conductance has become a standard experimental procedure. Chapter 1 introduces ion channels, and the experimental techniques used to measure the channel currents. The abundance of functional data (channel currents) does not match with an equal abundance of structural data. The bacterial potassium channel KcsA was the first selective ion channels to be experimentally solved (1998), and after KcsA the structures of four different potassium channels were revealed. These experimental data inspired a new era in ion channel modeling. Once the atomic structures of channels are known, it is possible to define mathematical models based on physical descriptions of the molecular systems. These physically based models can provide an atomic description of ion channel functioning, and predict the effect of structural changes. Chapter 2 introduces the computation methods used throughout the thesis to model ion channels functioning at the atomic level. In Chapter 3 and Chapter 4 the ion conduction through potassium channels is analyzed, by an approach based on the Poisson-Nernst-Planck electrodiffusion theory. In the electrodiffusion theory ion conduction is modeled by the drift-diffusion equations, thus describing the ion distributions by continuum functions. The numerical solver of the Poisson- Nernst-Planck equations was tested in the KcsA potassium channel (Chapter 3), and then used to analyze how the atomic structure of the intracellular vestibule of potassium channels affects the conductance (Chapter 4). As a major result, a correlation between the channel conductance and the potassium concentration in the intracellular vestibule emerged. The atomic structure of the channel modulates the potassium concentration in the vestibule, thus its conductance. This mechanism explains the phenotype of the BK potassium channels, a sub-family of potassium channels with high single channel conductance. The functional role of the intracellular vestibule is also the subject of Chapter 5, where the affinity of the potassium channels hEag1 (involved in tumour-cell proliferation) and hErg (important in the cardiac cycle) for several pharmaceutical drugs was compared. Both experimental measurements and molecular modeling were used in order to identify differences in the blocking mechanism of the two channels, which could be exploited in the synthesis of selective blockers. The experimental data pointed out the different role of residue mutations in the blockage of hEag1 and hErg, and the molecular modeling provided a possible explanation based on different binding sites in the intracellular vestibule. Modeling ion channels at the molecular levels relates the functioning of a channel to its atomic structure (Chapters 3-5), and can also be useful to predict the structure of ion channels (Chapter 6-7). In Chapter 6 the structure of the KcsA potassium channel depleted from potassium ions is analyzed by molecular dynamics simulations. Recently, a surprisingly high osmotic permeability of the KcsA channel was experimentally measured. All the available crystallographic structure of KcsA refers to a channel occupied by potassium ions. To conduct water molecules potassium ions must be expelled from KcsA. The structure of the potassium-depleted KcsA channel and the mechanism of water permeation are still unknown, and have been investigated by numerical simulations. Molecular dynamics of KcsA identified a possible atomic structure of the potassium-depleted KcsA channel, and a mechanism for water permeation. The depletion from potassium ions is an extreme situation for potassium channels, unlikely in physiological conditions. However, the simulation of such an extreme condition could help to identify the structural conformations, so the functional states, accessible to potassium ion channels. The last chapter of the thesis deals with the atomic structure of the !- Hemolysin channel. !-Hemolysin is the major determinant of the Staphylococcus Aureus toxicity, and is also the prototype channel for a possible usage in technological applications. The atomic structure of !- Hemolysin was revealed by X-Ray crystallography, but several experimental evidences suggest the presence of an alternative atomic structure. This alternative structure was predicted, combining experimental measurements of single channel currents and numerical simulations. This thesis is organized in two parts, in the first part an overview on ion channels and on the numerical methods adopted throughout the thesis is provided, while the second part describes the research projects tackled in the course of the PhD programme. The aim of the research activity was to relate the functional characteristics of ion channels to their atomic structure. In presenting the different research projects, the role of numerical simulations to analyze the structure-function relation in ion channels is highlighted.

A mouse model of Schwartz-Jampel syndrome reveals myelinating Schwann cell dysfunction with persistent axonal depolarization in vitro and distal peripheral nerve hyperexcitability when perlecan is lacking

Congenital peripheral nerve hyperexcitability (PNH) is usually associated with impaired function of voltage-gated K(+) channels (VGKCs) in neuromyotonia and demyelination in peripheral neuropathies. Schwartz-Jampel syndrome (SJS) is a form of PNH that is due to hypomorphic mutations of perlecan, the major proteoglycan of basement membranes. Schwann cell basement membrane and its cell receptors are critical for the myelination and organization of the nodes of Ranvier. We therefore studied a mouse model of SJS to determine whether a role for perlecan in these functions could account for PNH when perlecan is lacking. We revealed a role for perlecan in the longitudinal elongation and organization of myelinating Schwann cells because perlecan-deficient mice had shorter internodes, more numerous Schmidt-Lanterman incisures, and increased amounts of internodal fast VGKCs. Perlecan-deficient mice did not display demyelination events along the nerve trunk but developed dysmyelination of the preterminal segment associated with denervation processes at the neuromuscular junction. Investigating the excitability properties of the peripheral nerve suggested a persistent axonal depolarization during nerve firing in vitro, most likely due to defective K(+) homeostasis, and excluded the nerve trunk as the original site for PNH. Altogether, our data shed light on perlecan function by revealing critical roles in Schwann cell physiology and suggest that PNH in SJS originates distally from synergistic actions of peripheral nerve and neuromuscular junction changes.

Maternal and Postweaning High-Fat Diets Disturb Hippocampal Gene Expression, Learning, and Memory Function

We tested the hypothesis that excess saturated fat consumption during pregnancy, lactation, and/or postweaning alters the expression of genes mediating hippocampal synaptic efficacy and impairs spatial learning and memory in adulthood. Dams were fed control chow or a diet high in saturated fat before mating, during pregnancy, and into lactation. Offspring were weaned to either standard chow or a diet high in saturated fat. The Morris Water Maze was used to evaluate spatial learning and memory. Open field testing was used to evaluate motor activity. Hippocampal gene expression in adult males was measured using RT-PCR and ELISA. Offspring from high fat-fed dams took longer, swam farther, and faster to try and find the hidden platform during the 5-day learning period. Control offspring consuming standard chow spent the most time in memory quadrant during the probe test. Offspring from high fat-fed dams consuming excess saturated fat spent the least. The levels of mRNA and protein for brain-derived neurotrophic factor and activity-regulated cytoskeletal-associated protein were significantly decreased by maternal diet effects. Nerve growth factor mRNA and protein levels were significantly reduced in response to both maternal and postweaning high-fat diets. Expression levels for the N-methyl-D-aspartate receptor (NMDA) receptor subunit NR2B as well as synaptophysin were significantly decreased in response to both maternal and postweaning diets. Synaptotagmin was significantly increased in offspring from high fat-fed dams. These data support the hypothesis that exposure to excess saturated fat during hippocampal development is associated with complex patterns of gene expression and deficits in learning and memory.

Nerve-sparing open radical retropubic prostatectomy

INTRODUCTION: In recent years, the surgical technique for open radical prostatectomy has evolved and increasing attention is paid to preserving anatomic structures and the impact on outcome and quality of life. METHODS: Technical aspects of nerve-sparing open radical retropubic prostatectomy (RRP) are described. Patient selection criteria and functional results are discussed, focusing on postoperative urinary continence. RESULTS: The video demonstrates the nerve-sparing open RRP and important steps are elucidated with schematic drawings. The value of nerve sparing, not only for preserving erectile function, but also for preserving urinary continence is discussed and results from our institution are presented. In our series, urinary incontinence was present in 1 of 71 patients (1%) with attempted bilateral nerve-sparing, 11 of 322 (3%) with attempted unilateral nerve-sparing, or 19 of 139 (14%) without attempted nerve-sparing surgery. In multiple logistic regression analysis, the only statistically significant factor influencing urinary continence after open RRP was attempted nerve sparing (odds ratio, 4.77; 95% confidence interval, 2.18-10.44; p=0.0001). CONCLUSIONS: Nerve-sparing surgery has a significant impact on erectile function and urinary continence and should be performed in all patients provided radical tumour resection is not compromised. For successful nerve preservation we advocate a lateral approach to the prostate to improve visualisation and simplify separation of the neurovascular bundles from the dorsolateral prostatic capsule. Bunching, ligating, and incising Santorini's plexus over the prostate and not over the sphincter ensures a bloodless surgical field. Mucosa-to-mucosa adaptation of the reconstructed bladder neck and the urethra is another important factor to be observed.

Enhancing rehabilitation of motor deficits with peripheral nerve stimulation

A number of different neurorehabilitation strategies include manipulation of the somatosensory system, e.g. in the form of training by passive movement. Recently, peripheral electrical nerve stimulation has been proposed as a simple, painless method of enhancing rehabilitation of motor deficits. Several physiological studies both in animals and in humans indicate that a prolonged period of patterned peripheral electrical stimulation induces short-term plasticity at multiple levels of the motor system. Small-scale studies in humans indicate that these plastic changes are linked with improvement in motor function, particularly in patients with chronic motor deficits after stroke. Somatosensory-mediated disinhibition of motor pathways is a possible underlying mechanism and might explain why peripheral electrical stimulation is more effective when combined with active training. Further large-scale studies are needed to identify the optimal stimulation protocol and the patient groups that stand to benefit the most from this technique.

Differential effects of captopril and nitrates on muscle sympathetic nerve activity in volunteers

BACKGROUND The sympathetic nervous system (SNS) is an important regulator of cardiovascular function. Activation of SNS plays an important role in the pathophysiology and the prognosis of cardiovascular diseases such as heart failure, acute coronary syndromes, arrhythmia, and possibly hypertension. Vasodilators such as adenosine and sodium nitroprusside are known to activate SNS via baroreflex mechanisms. Because vasodilators are widely used in the treatment of patients with cardiovascular diseases, the aim of the present study was to assess the influence of clinically used dosages of isosorbide dinitrate and captopril on sympathetic nerve activity at rest and during stimulatory maneuvers. METHODS AND RESULTS Twenty-eight healthy volunteers were included in this double-blind placebo-controlled study, and muscle sympathetic nerve activity (MSA; with microelectrodes in the peroneal nerve), blood pressure, heart rate, and neurohumoral parameters were measured before and 90 minutes after the oral administration of 40 mg isosorbide dinitrate or 6.25 mg captopril. Furthermore, a 3-minute mental stress test and a cold pressor test were performed before and 90 minutes after drug administration. Resting MSA did not change after captopril and decreased compared with placebo (P < .05 versus placebo), whereas isosorbide dinitrate led to a marked increase in MSA (P < .05). Systolic blood pressure was reduced by isosorbide dinitrate (P < .05), whereas captopril decreased diastolic blood pressure (P < .05). The increases in MSA, blood pressure, and heart rate during mental stress were comparable before and after drug administration regardless of the medication. During cold pressor test, MSA and systolic and diastolic blood pressures increased to the same degree independent of treatment, but after isosorbide dinitrate, the increase in MSA seemed to be less pronounced. Heart rate did not change during cold stimulation. Plasma renin activity increased after captopril and isosorbide dinitrate (P < .05), whereas placebo had no effect. Endothelin-1 increased after placebo and isosorbide dinitrate (P < .05) but not after captopril. CONCLUSIONS Thus, captopril suppressed MSA despite lowering of diastolic blood pressure but allowed normal adaptation of the SNS during mental or physical stress. In contrast, the nitrate strongly activated the SNS under baseline conditions. These findings demonstrate that vasodilators differentially interact with the SNS, which could be of importance in therapeutic strategies for the treatment of patients with cardiovascular diseases.

Eomesodermin, a target gene of Pou4f2, is required for retinal ganglion cell and optic nerve development in the mouse.

The mechanisms regulating retinal ganglion cell (RGC) development are crucial for retinogenesis and for the establishment of normal vision. However, these mechanisms are only vaguely understood. RGCs are the first neuronal lineage to segregate from pluripotent progenitors in the developing retina. As output neurons, RGCs display developmental features very distinct from those of the other retinal cell types. To better understand RGC development, we have previously constructed a gene regulatory network featuring a hierarchical cascade of transcription factors that ultimately controls the expression of downstream effector genes. This has revealed the existence of a Pou domain transcription factor, Pou4f2, that occupies a key node in the RGC gene regulatory network and that is essential for RGC differentiation. However, little is known about the genes that connect upstream regulatory genes, such as Pou4f2 with downstream effector genes responsible for RGC differentiation. The purpose of this study was to characterize the retinal function of eomesodermin (Eomes), a T-box transcription factor with previously unsuspected roles in retinogenesis. We show that Eomes is expressed in developing RGCs and is a mediator of Pou4f2 function. Pou4f2 directly regulates Eomes expression through a cis-regulatory element within a conserved retinal enhancer. Deleting Eomes in the developing retina causes defects reminiscent of those in Pou4f2(-/-) retinas. Moreover, myelin ensheathment in the optic nerves of Eomes(-/-) embryos is severely impaired, suggesting that Eomes regulates this process. We conclude that Eomes is a crucial regulator positioned immediately downstream of Pou4f2 and is required for RGC differentiation and optic nerve development.

Nerve Injury-Induced Neuropathic Pain Causes Disinhibition of the Anterior Cingulate Cortex

Neuropathic pain caused by peripheral nerve injury is a debilitating neurological condition of high clinical relevance. On the cellular level, the elevated pain sensitivity is induced by plasticity of neuronal function along the pain pathway. Changes in cortical areas involved in pain processing contribute to the development of neuropathic pain. Yet, it remains elusive which plasticity mechanisms occur in cortical circuits. We investigated the properties of neural networks in the anterior cingulate cortex (ACC), a brain region mediating affective responses to noxious stimuli. We performed multiple whole-cell recordings from neurons in layer 5 (L5) of the ACC of adult mice after chronic constriction injury of the sciatic nerve of the left hindpaw and observed a striking loss of connections between excitatory and inhibitory neurons in both directions. In contrast, no significant changes in synaptic efficacy in the remaining connected pairs were found. These changes were reflected on the network level by a decrease in the mEPSC and mIPSC frequency. Additionally, nerve injury resulted in a potentiation of the intrinsic excitability of pyramidal neurons, whereas the cellular properties of interneurons were unchanged. Our set of experimental parameters allowed constructing a neuronal network model of L5 in the ACC, revealing that the modification of inhibitory connectivity had the most profound effect on increased network activity. Thus, our combined experimental and modeling approach suggests that cortical disinhibition is a fundamental pathological modification associated with peripheral nerve damage. These changes at the cortical network level might therefore contribute to the neuropathic pain condition.

Nerve Transfers for Persistent Traumatic Peroneal Nerve Palsy: The Inselspital Bern Experience

BACKGROUND Patients in whom conventional peroneal nerve repair surgery failed to reconstitute useful foot lift need to be evaluated for their suitability to undergo a concomitant tendon transfer procedure or nerve transfers. OBJECTIVE To report our first clinical experience with nerve transfers for persistent traumatic peroneal nerve palsy. METHODS Between 2007 and 2013, 8 patients were operated on for foot drop after unsuccessful nerve surgery. Six patients without fatty degeneration of the anterior tibial muscle and proximal lesion of the peroneal nerve were oriented for tibial to peroneal nerve transfer. In the other 2 cases where the anterior and lateral compartments were destructed, the anterior tibial muscle function was reconstructed with a neurotized lateral gastrocnemius transfer. For each patient, we graded postoperative results using the Bureau of Meteorology Research Centre scheme and the Ninkovic assessment scale. RESULTS Of the 6 patients who underwent nerve transfer of the anterior tibial muscle, 2 patients had excellent results, 1 patient had good results, 1 patient had fair results, and 2 patients had poor results. Of the 2 patients that underwent neurotized lateral gastrocnemius transfer, 1 patient achieved excellent results after tenolysis, whereas 1 patient achieved poor results. After the nerve transfer, 5 patients did not wear an ankle-foot orthosis. Four patients did not limp. Four patients were able to walk barefoot, navigate stairs, and participate in activities. CONCLUSION Early clinical results after tibial to peroneal nerve transfer and neurotized lateral gastrocnemius transfer appear mixed. The results of nerve transfer seem, on the whole, less reliable than the literature reports on tendon transfer. ABBREVIATIONS EMG, electromyographyNAP, nerve action potential.

Partial lateralization of the nasopalatine nerve at the incisive foramen for ridge augmentation in the anterior maxilla prior to placement of dental implants: a retrospective case series evaluating self-reported data and neurosensory testing

The objective of this study was to assess implant therapy after a staged guided bone regeneration procedure in the anterior maxilla by lateralization of the nasopalatine nerve and vessel bundle. Neurosensory function following augmentative procedures and implant placement, assessed using a standardized questionnaire and clinical examination, were the primary outcome variables measured. This retrospective study included patients with a bone defect in the anterior maxilla in need of horizontal and/or vertical ridge augmentation prior to dental implant placement. The surgical sites were allowed to heal for at least 6 months before placement of dental implants. All patients received fixed implant-supported restorations and entered into a tightly scheduled maintenance program. In addition to the maintenance program, patients were recalled for a clinical examination and to fill out a questionnaire to assess any changes in the neurosensory function of the nasopalatine nerve at least 6 months after function. Twenty patients were included in the study from February 2001 to December 2010. They received a total of 51 implants after augmentation of the alveolar crest and lateralization of the nasopalatine nerve. The follow-up examination for questionnaire and neurosensory assessment was scheduled after a mean period of 4.18 years of function. None of the patients examined reported any pain, they did not have less or an altered sensation, and they did not experience a "foreign body" feeling in the area of surgery. Overall, 6 patients out of 20 (30%) showed palatal sensibility alterations of the soft tissues in the region of the maxillary canines and incisors resulting in a risk for a neurosensory change of 0.45 mucosal teeth regions per patient after ridge augmentation with lateralization of the nasopalatine nerve. Regeneration of bone defects in the anterior maxilla by horizontal and/or vertical ridge augmentation and lateralization of the nasopalatine nerve prior to dental implant placement is a predictable surgical technique. Whether or not there were clinically measurable impairments of neurosensory function, the patients did not report them or were not bothered by them.

Pancreatic β cells synthesize and secrete nerve growth factor

Differentiation and function of pancreatic β cells are regulated by a variety of hormones and growth factors, including nerve growth factor (NGF). Whether this is an endocrine or autocrine/paracrine role for NGF is not known. We demonstrate that NGF is produced and secreted by adult rat pancreatic β cells. NGF secretion is increased in response to elevated glucose or potassium, but decreased in response to dibutyryl cAMP. Moreover, steady-state levels of NGF mRNA are down-regulated by dibutyryl cAMP, which is opposite to the effect of cAMP on insulin release. NGF-stimulated changes in morphology and function are mediated by high-affinity Trk A receptors in other mammalian cells. Trk A receptors are present in β cells and steady-state levels of Trk A mRNA are modulated by NGF and dibutyryl cAMP. Taken together, these findings suggest endocrine and autocrine roles for pancreatic β-cell NGF, which, in turn, could be related to the pathogenesis of diabetes mellitus where serum NGF levels are diminished.

Radixin Is Involved in Lamellipodial Stability during Nerve Growth Cone Motility

Immunocytochemistry and in vitro studies have suggested that the ERM (ezrin-radixin-moesin) protein, radixin, may have a role in nerve growth cone motility. We tested the in situ role of radixin in chick dorsal root ganglion growth cones by observing the effects of its localized and acute inactivation. Microscale chromophore-assisted laser inactivation (micro-CALI) of radixin in growth cones causes a 30% reduction of lamellipodial area within the irradiated region whereas all control treatments did not affect lamellipodia. Micro-CALI of radixin targeted to the middle of the leading edge often split growth cones to form two smaller growth cones during continued forward movement (>80%). These findings suggest a critical role for radixin in growth cone lamellipodia that is similar to ezrin function in pseudopodia of transformed fibroblasts. They are consistent with radixin linking actin filaments to each other or to the membrane during motility.

The visual response of retinal ganglion cells is not altered by optic nerve transection in transgenic mice overexpressing Bcl-2

Attempts to rescue retinal ganglion cells from retrograde degeneration have had limited success, and the residual function of surviving neurons is not known. Recently, it has been found that axotomized retinal ganglion cells die by apoptotic mechanisms. We have used adult transgenic mice overexpressing the Bcl-2 protein, a powerful inhibitor of apoptosis, as a model for preventing injury-induced cell death in vivo. Several months after axotomy, the majority of retinal ganglion cells survived and exhibited normal visual responses. In control wild-type mice, the vast majority of axotomized retinal ganglion cells degenerated, and the physiological responses were abolished. These results suggest that strategies aimed at increasing Bcl-2 expression, or mimicking its function, might effectively counteract trauma-induced cell death in the central nervous system. Neuronal survival is a necessary condition in the challenge for promoting regeneration and eventually restoring neuronal function.