Biomedical subjects

Xavier Navarro

Publications and source records attributed to Xavier Navarro.

At least 19 recordsLinked to original sources

PubMed2007

Chronic transplantation of olfactory ensheathing cells promotes partial recovery after complete spinal cord transection in the rat.

The goal of this study was to ascertain whether olfactory ensheathing cells (OECs) were able to promote axonal regeneration and functional recovery when transplanted 45 days after complete transection of the thoracic spinal cord in adult rats. OECs promoted partial restitution of supraspinal pathways evaluated by motor evoked potentials and modest recovery of hindlimb movements. In addition, OEC grafts reduced lumbar reflex hyperexcitability from the first month after transplantation. Histological results revealed that OECs facilitated corticospinal and raphespinal axons regrowth through the injury site and into the caudal spinal cord segments. Interestingly, raphespinal but not corticospinal fibers regenerated long distances through the gray matter and reached the lower lumbar segments (L5) of the spinal cord. However, delayed OEC grafts failed to reduce posttraumatic astrogliosis. In conclusion, the beneficial effects found in the present study further support the use of OECs for treating chronic spinal cord injuries.

Animals↗

PubMed2006

Velocity recovery cycles of single C fibres innervating rat skin.

To improve knowledge about axonal membrane properties in nociceptive and non-nociceptive C fibres, we studied impulse-dependent velocity changes by in vivo microneurography in the rat sciatic nerve. Cutaneous C fibres were classified, based primarily on their activity-dependent slowing profile, as Type 1A (mechano-responsive nociceptors; CMR; n = 23), Type 1B (mechano-insensitive nociceptors; CMI; n = 24), Type 2 (cold units; n = 2), Type 3 units (unknown function; n = 4) or Type 4 (presumed sympathetics; n = 23) units. They were excited by single, double and triple electrical stimuli to the skin at mean rates of 0.25, 0.5, 1 and 2 Hz and with interstimulus intervals ranging from 2 to 1000 ms. All CMRs exhibited only postspike subnormality at 0.25 and 0.5 Hz. They gradually developed supernormality with higher stimulation rates, and 12/19 CMRs were supernormal at 1 Hz. The CMIs showed a greater tendency towards supernormality, with 10/21 already supernormal at 0.25 Hz, 17/24 at 0.5 Hz and all were supernormal at 1 Hz. In some CMIs but in none of the CMRs, the supernormal period was directly followed by a peak in late subnormality. Among non-nociceptive fibres, all Type 4 units exhibited long-lasting supernormality independent of the stimulation rate, whereas the cold units showed short-lived supernormality. In both, supernormality increased with higher stimulation rates. Regardless of fibre function or stimulation rate, a second conditioning stimulus always induced additional slowing, providing evidence for a passive origin of supernormality in all rat C fibre subtypes. However, the degree and time-course of extra slowing due to a preconditioning stimulus was highly dependent on fibre function and stimulation rate. These data indicate axonal membrane differences between different functional classes of C fibres, which resemble those previously described in human C fibres.

Animals↗

PubMed2006

Olfactory ensheathing glia graft in combination with FK506 administration promote repair after spinal cord injury.

The aim of this study was to determine whether a combination of olfactory ensheathing cell (OEC) graft with the administration of FK506, two experimental approaches that have been previously reported to exert protective/regenerative effects after spinal cord injury, promotes synergic restorative effects after complete or partial spinal cord injuries. In partial spinal cord injury, combination of an OEC graft and FK506 reduced functional deficits evaluated by the BBB score, motor-evoked potentials (MEPs) and H reflex tests, diminished cavitation, astrogliosis and increased sparing/regeneration of raphespinal fibers compared to untreated and single-treatment groups of rats. After complete spinal cord transection, the combined treatment significantly improved functional outcomes, promoted axonal regeneration caudal to the lesion, and diminished astrogliosis compared only to non-transplanted animals. Slightly, but non-significant, better functional and histological results were found in OEC-grafted animals treated with FK506 than in those given saline after spinal cord transection. Nevertheless, the combined treatment increased the percentage of rats that recovered MEPs and promoted a significant reduction in astrogliosis. In conclusion, this study demonstrates that OEC grafts combined with FK506 promote additive repair of spinal cord injuries to those exerted by single treatments, the effect being more remarkable when the spinal cord is partially lesioned.

Analysis of Variance↗

PubMed2006

Differential motor and electrophysiological outcome in rats with mid-thoracic or high lumbar incomplete spinal cord injuries.

We have investigated the motor changes in rats subjected to a moderate photochemical injury on mid-thoracic (T8) or high lumbar (L2) spinal cord segments. Fourteen days after surgery, L2 injured animals presented gross locomotor deficits (scored 10+/-2.8 in the BBB scale), decreased amplitude of motor-evoked potentials (MEPs) recorded on tibialis anterior (TA) and plantar (PL) muscles (24% and 6% of the preoperative mean values, respectively), reduced M wave amplitudes (75%, 62%), and also facilitated monosynaptic reflexes evidenced by an increase of the H/M amplitude ratio (158% and 563%). On the other hand, T8 injured animals had only slight deficits in locomotion (18+/-0.6 in the BBB scale), a minimal reduction in MEP amplitudes (78% and 71% in TA and PL muscles), normal M wave amplitudes, and a milder increase of the H/M ratio in the TA muscle (191%) but less pronounced in the PL muscle (172%). The percentage of spared tissue at the site of injury was similar in both experimental groups (L2: 79% and T8: 82%). Taken together, these results indicate that lumbar spinal injuries have more severe consequences on hindlimb motor output than injuries exerted on thoracic segments. The causes of this anatomical difference may be attributed to damage inflicted on the central pattern generator of locomotion resulting in dysfunction of lumbar motoneurons and altered spinal reflexes modulation.

Animals↗

PubMed2006

Effects of COX-2 and iNOS inhibitors alone or in combination with olfactory ensheathing cell grafts after spinal cord injury.

STUDY DESIGN: We studied the effects of inhibitors of COX-2 (NS398) and iNOS (aminoguanidine) alone or in combination with olfactory ensheathing cell (OEC) grafts after spinal cord injury in the rat. OBJECTIVE: To assess the role exerted by COX-2 and iNOS after spinal cord injury and an OEC transplant. SUMMARY OF BACKGROUND DATA: COX-2 and iNOS exert a detrimental effect after spinal cord injury. In contrast, OECs grafted into the injured spinal cord mediate neuroprotection and also promote the up-regulation of COX-2 and iNOS. METHODS: Photochemical injury was induced at T8 spinal cord segment. Rats received local injection of OECs (n = 15) or vehicle (DMEM; n = 15). Six subgroups of rats (n = 5 rats each) were given NS398 (DM-NS; OEC-NS), aminoguanidine (DM-AG; OEC-AG), or saline (DM-SS; OEC-SS). Locomotor ability, pain sensibility, tissue sparing, and density of blood vessels were evaluated. RESULTS: Two weeks following injury, motor skills and nociceptive response were significantly higher in DM-NS and DM-AG than in DM-SS rats. The area of preserved spinal cord parenchyma was higher in treated animals than in those given saline. In contrast, functional outcome, tissue sparing, and density of blood vessels were lower in OEC-NS and OEC-AG than in OEC-SS animals. CONCLUSIONS: These results suggest that, although COX-2 and iNOS exert a detrimental role after spinal cord injury, they may play an important role in the neuroprotective mechanisms induced by OEC grafts after spinal cord injury.

Animals↗

PubMed2006

Design, in vitro and in vivo assessment of a multi-channel sieve electrode with integrated multiplexer.

This paper reports on the design, in vitro and in vivo investigation of a flexible, lightweight, polyimide based implantable sieve electrode with a hybrid assembly of multiplexers and polymer encapsulation. The integration of multiplexers enables us to connect a large number of electrodes on the sieve using few input connections. The implant assembly of the sieve electrode with the electronic circuitry was verified by impedance measurement. The 27 platinum electrodes of the sieve were coated with platinum black to reduce the electrode impedance. The impedance magnitude of the electrode sites on the sieve (geometric surface area 2,200 microm(2)) was |Z(f=1kHz)| = 5.7 kOmega. The sieve electrodes, encased in silicone, have been implanted in the transected sciatic nerve of rats. Initial experiments showed that axons regenerated through the holes of the sieve and reinnervated distal target organs. Nerve signals were recorded in preliminary tests after 3-7 months post-implantation.

Action Potentials↗

PubMed2006

Correlation between target reinnervation and distribution of motor axons in the injured rat sciatic nerve.

Peripheral nerve injuries are rarely followed by complete return of function. Deficits are particularly important for motor function, resulting in paralysis and muscle atrophy. In different groups, the sciatic nerve was either crushed or transected and repaired by direct suture or by tube repair using silicone or collagen tubes. After 60 days, nerve regeneration was assessed by electrophysiological and functional tests, nerve morphology and immunohistochemistry against choline acetyltransferase (ChAT) for labeling motor axons. Suture and tube repair resulted in similar levels of muscle reinnervation, but significantly lower than after nerve crush. Recovery of walking track pattern was poor in all groups after nerve section. The numbers of regenerated myelinated fibers and of ChAT+ fibers were similar to control values after nerve crush, but increased after section and repair. The normal fascicular architecture and grouping of ChAT+ fibers were maintained after nerve crush, but lost after section and repair, where motor fibers were scattered within small regenerated fascicles throughout the nerve. The loss of fascicular organization was related to the deficient recovery of locomotor function. Thus, labeling of motor axons by ChAT immunohistochemistry provides useful information for the study of the degree and specificity of nerve regeneration.

Animals↗

PubMed2006

Improvement of quality of life by means of antitachy pacing: from PainFREE to the ADVANCE-D Trial.

BACKGROUND: Implantable cardioverter-defibrillators (ICD) can terminate ventricular tachyarrhythmias with shocks (painful) or antitachycardia pacing (painless). According to the results of the Pacing Fast VT Reduces Shock ThErapies Trials, antitachycardia pacing (ATP) can avoid painful shocks and also increase device longevity. The purpose of the ADVANCE-D (Atp DeliVery for PAiNless ICD ThErapy) study is to determine the most appropriate ventricular tachycardia (VT) therapy, so as to optimize painless therapy for life-threatening arrhythmias. METHODS AND RESULTS: The ADVANCE-D is a prospective, multicenter, parallel, two-arm randomized study designed to evaluate the efficacy of two different sequences of ATP therapies (burst 15 pulses, 88%, vs burst 8 pulses, 88%), during an episode of spontaneous arrhythmia classified as fast VT (FVT) in patients with a Class I or IIA indication for ICD implantation (single and dual chamber devices). The primary endpoint is to compare the efficacy of two ATP therapies for FVT episodes. The study will enroll a minimum of 900 patients within 2 years, followed-up for 12 months. The investigation is expected to be completed in 2007. CONCLUSIONS: The ADVANCE-D trial is the first large randomized clinical investigation aimed to evaluate optimal programming and efficacy of ATP.

Cardiac Pacing, Artificial↗

PubMed2005

FK 506 reduces tissue damage and prevents functional deficit after spinal cord injury in the rat.

We examined the efficacy of FK 506 in reducing tissue damage after spinal cord injury in comparison to methylprednisolone (MP) treatment. Rats were subjected to a photochemical injury (T8) and were given a bolus of MP (30 mg/kg), FK 506 (2 mg/kg), or saline. An additional group received an initial bolus of FK 506 (2 mg/kg) followed by daily injections (0.2 mg/kg intraperitoneally). Functional recovery was evaluated using open-field walking, inclined plane tests, motor evoked potentials (MEPs), and the H-reflex response during 14 days postoperation (dpo). Tissue sparing and glial fibrillary acidic protein (GFAP), biotinylated tomato lectin LEC, cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and interleukin 1 beta (IL-1 beta) immunoreactivity were quantified in the injured spinal cord. FK 506-treated animals demonstrated significantly better neurologic outcome, higher MEP amplitudes, and lower H-wave amplitude compared to that of saline-treated rats. In contrast, administration of MP did not result in significant differences with respect to the saline-treated group. Histologic examination revealed that tissue sparing was largest in FK 506-treated compared to saline and MP-treated animals. GFAP and COX-2 reactivity was decreased in animals treated with FK 506 compared to that in animals given MP or saline, whereas IL-1 beta expression was similarly reduced in both FK 506- and MP-treated groups. Microglia/macrophage response was reduced in FK 506 and MP-injected animals at 3 dpo, but only in MP-treated animals at 7 dpo with respect to saline-injected rats. Repeated administrations of FK 506 improved functional and histologic results to a greater degree than did a single bolus of FK 506. The results indicate that FK 506 administration protects the damaged spinal cord and should be considered as potential therapy for treating spinal cord injuries.

Animals↗

PubMed2005

Acute and delayed transplantation of olfactory ensheathing cells promote partial recovery after complete transection of the spinal cord.

The present study was undertaken to determine whether olfactory ensheathing cells (OECs) from the olfactory bulb were capable to promote axonal regeneration and functional recovery when transplanted either acutely or 1 week delayed into the T8 transected rat spinal cord. OEC transplants increased recovery of functional outcomes, as shown electrophysiologically by return of motor evoked potentials and by reduction of hindlimb hyperreflexia, and behaviorally by recovery of movements of hindlimb joints. Axonal regeneration was proven histologically by demonstrating long axonal outgrowth of raphespinal, coerulospinal, and corticospinal tracts within the caudal cord stump. Expression of GFAP and NG2 was down-regulated in perilesional cord segments in transplanted animals, indicating a more suitable environment for axonal regeneration. Overall, earlier recovery and better functional and histological results were observed in rats receiving acute than delayed OEC transplants. The beneficial effects obtained with transplantation after transection are encouraging for the application of OECs in the human injured spinal cord.

Acute Disease↗

PubMed2005

Long term assessment of axonal regeneration through polyimide regenerative electrodes to interface the peripheral nerve.

Polyimide sieve electrodes were implanted between the severed ends of the sciatic nerve in rats. The degree of axonal regeneration through the electrode was examined by physiological and histological methods from 2 to 12 months postimplantation. Regeneration was successful in the 30 animals implanted. Functional reinnervation of hindlimb targets progressed to reach maximal levels at 6 months. Comparatively, the reinnervation of distal plantar muscles was lower than that of proximal muscles and of digital nerves. The number of regenerated myelinated fibers increased from 2 to 6 months, when it was similar to control values. The majority of myelinated fibers crossing the via holes and regenerated through the distal nerve had a normal appearance. However, in a few cases decline of target reinnervation and loss of regenerated nerve fibers was found from 6 to 12 months postimplantation. Motor axons labeled by ChAT immunoreactivity regenerated scattered within minifascicles, although they were found at higher density at the periphery of the regenerated nerve. The number of ChAT-positive axons was markedly lower distally than proximally to the sieve electrode.

Action Potentials↗

PubMed2005

A critical review of interfaces with the peripheral nervous system for the control of neuroprostheses and hybrid bionic systems.

Considerable scientific and technological efforts have been devoted to develop neuroprostheses and hybrid bionic systems that link the human nervous system with electronic or robotic prostheses, with the main aim of restoring motor and sensory functions in disabled patients. A number of neuroprostheses use interfaces with peripheral nerves or muscles for neuromuscular stimulation and signal recording. Herein, we provide a critical overview of the peripheral interfaces available and trace their use from research to clinical application in controlling artificial and robotic prostheses. The first section reviews the different types of non-invasive and invasive electrodes, which include surface and muscular electrodes that can record EMG signals from and stimulate the underlying or implanted muscles. Extraneural electrodes, such as cuff and epineurial electrodes, provide simultaneous interface with many axons in the nerve, whereas intrafascicular, penetrating, and regenerative electrodes may contact small groups of axons within a nerve fascicle. Biological, technological, and material science issues are also reviewed relative to the problems of electrode design and tissue injury. The last section reviews different strategies for the use of information recorded from peripheral interfaces and the current state of control neuroprostheses and hybrid bionic systems.

Animals↗

PubMed2004

FK506 enhances regeneration of axons across long peripheral nerve gaps repaired with collagen guides seeded with allogeneic Schwann cells.

We assessed the effects of FK506 administration on regeneration after a 6-mm gap repair with a collagen guide seeded with allogeneic Schwann cells (SCs) in the mouse sciatic nerve. SCs were isolated from predegenerated adult sciatic nerves and expanded in culture using a defined medium, before being seeded in the collagen guide embedded in Matrigel. Functional reinnervation was evaluated by noninvasive methods to determine recovery of motor, sensory, and autonomic functions in the hindpaw over 4 months postoperation. Histological analysis of the regenerated nerves was performed at the end of the study. Using simple collagen guides for tubulization repair, treatment with an immunosuppressant dose of FK506 (5 mg/kg/day) resulted in significant improvement of the onset and the degree of reinnervation. While the introduction of allogeneic SCs did not improve regeneration versus a collagen guide filled only with Matrigel, treatment with FK506 allowed for successful regeneration in all the mice and for significant improvement in the levels of functional recovery. Compared with the untreated group, there was greater survival of transplanted pre-labeled SCs in the FK506-treated animals. Morphologically, the best nerve regeneration (in terms of nerve caliber and numbers of myelinated axons) was obtained with SC-seeded guides from FK506-treated animals. Thus, FK506 should be considered as adjunct therapy for various types of tubulization repair.

Absorbable Implants↗

PubMed2004

Effects of the immunophilin ligand FK506 on nerve regeneration in collagen guides seeded with Schwann cells in rats.

We assessed the effects of FK506 administration on regeneration after 5-mm gap repair with a collagen guide seeded with syngeneic Schwann cells in the rat sciatic nerve. Functional reinnervation was evaluated by non-invasive methods to determine recovery of motor and sensory functions in the hindpaw over 4 months postoperation. Histological analysis of the regenerated nerves was performed at the end of follow-up. Treatment with FK506 (1 mg/kg for the first 2 months) resulted in significant improvement of the onset and the degree of reinnervation. The numbers of myelinated fibers in the distal regenerated nerve were similar between treated and control groups. In conclusion, FK506 improves functional recovery after repair with collagen guides seeded with syngeneic Schwann cells.

Animals↗

PubMed2004

Acute transplantation of olfactory ensheathing cells or Schwann cells promotes recovery after spinal cord injury in the rat.

We compared the neurological and electrophysiological outcome, glial reactivity, and spared spinal cord connectivity promoted by acute transplantation of olfactory ensheathing cells (group OEC) or Schwann cells (group SC) after a mild injury to the rat spinal cord. Animals were subjected to a photochemical injury of 2.5 min irradiation at the T8 spinal cord segment. After lesion, a suspension containing 180,000 OECs or SCs was injected. A control group (group DM) received the vehicle alone. During 3 months postsurgery, behavioral skills were assessed with open field-BBB scale, inclined plane, and thermal algesimetry tests. Motor (MEPs) and somatosensory evoked potentials (SSEPs) were performed to evaluate the integrity of spinal cord pathways, whereas lumbar spinal reflexes were evaluated by the H reflex responses. Glial fibrillary acidic protein and proteoglycan expressions were quantified immunohistochemically at the injured spinal segments, and the preservation of corticospinal and raphespinal tracts caudal to the lesion was evaluated. Both OEC- and SC-transplanted groups showed significantly better results in all the behavioral tests than the DM group. Furthermore, the OEC group had higher MEP amplitudes and lower H responses than the other two groups. At the injury site, the area of spared parenchyma was greater in transplanted than in control injured rats. OEC-transplanted animals had reduced astrocytic reactivity and proteoglycan expression in comparison with SC-transplanted and DM rats. Taken together, these results indicate that transplantation of both OEC and SC has potential for restoration of injured spinal cords. OEC grafts showed superior ability to reduce glial reactivity and to improve functional recovery.

Animals↗

PubMed2004

Reorganization of reflex responses mediated by different afferent sensory fibers after spinal cord transection.

Adult rats were submitted to a complete spinal cord transection at T9 level to address peripheral and spinal reflex changes in the caudal lumbar segments. Compound muscle and nerve action potentials decreased in amplitude and increased their duration between 14 and 30 days but recovered to near to normal values thereafter. The H wave amplitude increased during follow-up, resulting in significantly higher H/M ratio in tibialis anterior (223%), gastrocnemius (160%), and plantar (304%) muscles with respect to preoperatory values (P < 0.01). Sixty minutes after spinal cord transection, component C1 (conveyed by Aalphabeta afferents) disappeared in the crossed but not in the ipsilateral withdrawal reflex. Components C2 (Adelta) and C3 (C afferents) were abolished on both. C1 and C3 reappeared for both reflexes in all injured animals, while C2 reappeared in a few cases. C1 ipsilateral component became highly facilitated (209% of presurgery values, P < 0.01), whereas C3 (82%) and C2 (24%) recovered partially. Crossed reflex component C1 attained in all animals similar to normal values (85%) but with longer duration. C3 increased with time although it remained significantly lower than the original (67%) whereas C2 reappeared in only 2/8 animals. In conclusion, spinal cord injury induces a transient disability of caudal spinal cord segments that progressively reverts along time. Ipsilateral reflex components mediated by thick Aalphabeta fibers (H reflex and C1) but not those mediated by thin fibers (C2 and C3) remained present after injury showing long-lasting facilitation whereas contralateral reflex components were abolished after injury and showed limited recovery.

Afferent Pathways↗

PubMed2004

Comparison of continuous and discontinuous FK506 administration on autograft or allograft repair of sciatic nerve resection.

An immunosuppressant drug that also possesses neuroregenerative properties, FK506 enhances the rate of axonal regeneration and improves recovery after nerve lesions. Nevertheless, prolonged immunosuppression may not be justified to assure the success of nerve regeneration. In this study, we compare the effects of continuous and discontinuous FK506 treatment on regeneration and reinnervation after sciatic nerve resection repaired with autologous or allogenic grafts in the mouse. For each type of repair, one group received FK506 (5 mg/kg) for 4 months, whereas a second group was treated with FK506 at 5 mg/kg for 5 weeks followed by 3 mg/kg for 4 weeks; a control group received saline only. Functional reinnervation was assessed by noninvasive methods to determine recovery of motor, sensory, and autonomic functions in the hind paw over 4 months after operation. Morphological analysis of the regenerated nerves was performed at the termination of the study. Autografts and allografts treated with sustained FK506 (5 mg/kg) reached high levels of reinnervation and followed a course of recovery faster than controls. The numbers of myelinated fibers also were similar. Allografts without immunosuppression demonstrated a slower rate of regeneration, exhibiting lower final levels of recovery compared with other groups and containing fewer numbers of regenerating myelinated fibers. Withdrawal of immunosuppressant therapy resulted in a decline in the degree of reinnervation in all functions tested during the third month, with stabilization between the third and fourth months. The number of regenerated myelinated fibers in the group was significantly lower than in autografts. Thus, continuous or discontinuous FK506 administration slightly accelerated the rate of reinnervation in autografts. In allograft repair, FK506 significantly enhanced both the rate and degree of regeneration and recovery, but its withdrawal resulted in graft rejection, a marked deterioration in function, and loss of regenerating fibers.

Animals↗

PubMed2004

The DATAS rationale and design: a controlled, randomized trial to assess the clinical benefit of dual chamber (DDED) defibrillator.

Single chamber (SC) implantable cardioverter defibrillators (ICDs) have several limitations that might be relevant during follow-up, like atrial pacing requirements, inadequate therapies, sustained atrial tachyarrhythmias and difficulties to achieve an accurate diagnosis of the arrhythmia. Dual chamber (DC) ICDs offer an attractive and rational solution, although controversy remains if the costs and complexity of these devices offer a real clinical advantage. The Dual Chamber & Atrial Tachyarrhythmias Adverse Events Study (DATAS) was designed to analyze the ability of DC ICD, DDED, to reduce clinically significant adverse events compared with SC ICD in a non-selected population with conventional indications for ICD implantation. This is a prospective, multicentre, randomized, open labelled study, with three arms: two of them (simulated SC ICD and true DC ICD) cross-over, and the third (true SC ICD) parallels the other two. The composite primary end point comprises four Clinically Significant Adverse Events (CSAE): (1) all-cause mortality, (2) invasive intervention, hospitalization or prolongation of hospitalization due to cardiovascular cause, (3) inappropriate shocks, and (4) sustained symptomatic atrial tachyarrhythmias that (a) require urgent termination or (b) last more than 48h leading to therapeutic intervention. Secondary end points constitute each of the individual components of CSAE, cardiovascular status, quality of life and a detailed analysis of atrial and ventricular arrhythmias. To date (June 2003) there have been 343 patients enroled from 947 screened patients. The projected enrollment includes 360 patients and the conclusion of the study is expected at the beginning of 2005.

Arrhythmia, Sinus↗