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.     

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.     

Nerve guides seeded with autologous schwann cells improve nerve regeneration

This study evaluates the ability of Schwann cells (SCs) transplanted into a nerve guide to improve regeneration and reinnervation after sciatic nerve resection and repair, leaving a 6-mm gap, in the mouse. SCs were isolated from predegenerated adult sciatic nerves and expanded in culture using a chemically defined medium. Syngeneic, isogeneic, and autologous SCs were suspended in Matrigel and seeded in resorbable, permeable poly(l-lactide-co-epsilon-caprolactone) guides at 150,000 cells/tube. Guides containing SCs were compared to guides filled with Matrigel alone and with peroneal nerve autografts. Functional reinnervation was assessed by noninvasive methods to determine recovery of sweating, nociceptive, sensory, and motor functions in the hindpaw during 4 months postoperation. Morphological analysis of the regenerated nerves was performed at the end of follow-up. The group with an autograft achieved faster and higher levels of reinnervation and higher number of regenerated myelinated fibers than groups repaired by tubulization. The immunogenicity of transplanted SCs influenced the outcome of nerve regeneration. Transplants of autologous SCs resulted in slightly lower levels of reinnervation than autografts, but higher recovery and number of regenerated fibers reaching the distal nerve than transplants of isologous and syngeneic SCs, although most of the differences were not statistically significant. Syngeneic SCs did not improve regeneration with respect to acellular guides. Prelabeled transplanted SCs were found to survive into the guide 1-3 months after implantation, to a larger number when they were autologous than syngeneic. Cellular prostheses composed of a resorbable guide seeded with autologous SCs appear as an alternative for repairing long gaps in injured nerves, approaching the success of autografts.     

Improvement of regeneration with predegenerated nerve transplants in silicone chambers

We compared regeneration and reinnervation of target organs after sciatic nerve resection and repair with silicone tubes filled with saline solution or with a peroneal nerve segment as a nerve transplant versus an autologous sciatic nerve graft leaving either 4 mm or 6 mm gaps. The aims of this study were to evaluate the effects of predegeneration and donor immunogenicity of nerve transplants. Functional reinnervation was assessed by noninvasive methods to determine recovery of sweating, sensory and motor functions in the hindpaw after three months postoperation for 4 mm and four months postoperation for 6 mm gap groups. Morphometrical analysis of the regenerated nerve were performed at the end of the follow-up. The group with an autograft achieved faster and higher levels of reinnervation for the four functions tested than any of the groups repaired by tubulization. The introduction of a small nerve transplant improved regeneration and reinnervation with respect to a saline solution filled tube slightly with a 4 mm gap, but significantly with a 6 mm long gap. The beneficial effects of the nerve transplant were significantly increased when it was predegenerated, while disappearing when its cellular component was eliminated by repeated freezing. The immunogenicity of the nerve transplant dramatically affected nerve regeneration, as it was impeded by an heterologous transplant in the tube. In summary, the use of silicone chambers with an autologous predegenerated nerve transplant may be an alternative for repairing long gaps in injured nerves, approaching the level of success of an ideal autologous nerve graft.     

Effects of FK506 on regeneration and macrophages in injured rat sciatic nerve

Effects of FK506 [5.0 mg/kg body weight (BW), subcutaneous, daily] on nerve regeneration and presence of macrophages in lesioned rat sciatic nerves were studied. Models of autologous nerve graft or a nerve crush lesion were used and regeneration was evaluated by immunocytochemistry (also used to detect ED1/ED2 macrophages) and sensory pinch reflex test, respectively. Treatment with FK506 did not increase regeneration distance or regeneration rate in the autologous nerve grafts. However, regeneration distances after nerve crush were significantly longer following treatment with FK506. The number of macrophages (ED1/ED2) in nerve grafts increased over time, but treatment with FK506 had limited effects only in the presence of ED2 macrophages. Present and previously published studies may imply that there is a time-related and type-of-injury-related profile of FK506's pro-regenerative effect.     

Inaccurate projection of rat soleus motoneurons: A comparison of nerve repair techniques

The objectives of this study were 1) to determine the degree to which soleus motoneurons find their appropriate target following crush and transection injuries to the sciatic nerve, and 2) to determine whether repair of a transected nerve with a silicone tube leads to greater specificity of reinnervation and recovery of muscle function than the standard epineurial suture repair method. Sixty adult female Sprague-Dawley rats were randomly assigned to one of three sciatic nerve injury groups: crush injury, transection with epineurial suture repair, or transection with a silicone tube repair. The degree to which soleus motoneurons were able to find their appropriate target following a sciatic nerve injury was examined using a double labeling dye technique in which the original soleus motor pool was labeled with fast blue and reinnervating motoneurons were labeled with Dil. Soleus motoneurons were able to find their appropriate target following a crush injury. The accuracy of reinnervation following a transection injury and repair, however, was relatively poor. Only 14% of the original soleus motoneurons found the correct target following a transection injury. Repair of a lesioned nerve with a silicone tube and a 5-mm gap as opposed to epineurial sutures did not increase the specificity of reinnervation or the degree of muscle recovery. © 1997 John Wiley & Sons, Inc.     

Peripheral nerve regeneration through bioresorbable and durable nerve guides

We compared reinnervation of target organs after sciatic nerve resection and repair by tubulization with biodurable tubes of silicone and teflon, or bioresorbable nerve guides of collagen and poly(L-lactide-co-6-caprolactone) (PLC) leaving a 6 mm gap in different groups of mice. All tubes were of 1 mm inside diameter and thin-walled (50 to 250 microm). Functional reinnervation was assessed by noninvasive methods to determine recovery of sweating, sensory and motor functions in the hindpaw repeatedly during 5 months postoperation. PLC guides allowed faster and higher levels of reinnervation for the four functions tested than collagen and silicone tubes, while teflon tubes gave the lowest levels of recovery. Regenerative reinnervation by thin nociceptive and sudomotor fibers was higher than by large sensory and alphamotor fibers in all groups. Resorbable tubes promoted regeneration in a higher proportion of mice than durable tubes. In cases with effective regeneration the nerve cable was multifascicular, with mild to moderate mononuclear cell infiltrates and a thin newly formed perineurium. The number of myelinated fibers was higher in PLC and silicone tubes than in collagen and teflon tubes. There was only minimal inflammatory reaction within the remnants of collagen tubes, but not in the other materials. PLC tubes of slow reabsorption rate seem useful for repairing long gaps in injured nerves.     

Thyroid hormone enhances transected axonal regeneration and muscle reinnervation following rat sciatic nerve injury

Improvement of nerve regeneration and functional recovery following nerve injury is a challenging problem in clinical research. We have already shown that following rat sciatic nerve transection, the local administration of triiodothyronine (T3) significantly increased the number and the myelination of regenerated axons. Functional recovery is a sum of the number of regenerated axons and reinnervation of denervated peripheral targets. In the present study, we investigated whether the increased number of regenerated axons by T3‐treatment is linked to improved reinnervation of hind limb muscles. After transection of rat sciatic nerves, silicone or biodegradable nerve guides were implanted and filled with either T3 or phosphate buffer solution (PBS). Neuromuscular junctions (NMJs) were analyzed on gastrocnemius and plantar muscle sections stained with rhodamine α‐bungarotoxin and neurofilament antibody. Four weeks after surgery, most end‐plates (EPs) of operated limbs were still denervated and no effect of T3 on muscle reinnervation was detected at this stage of nerve repair. In contrast, after 14 weeks of nerve regeneration, T3 clearly enhanced the reinnervation of gastrocnemius and plantar EPs, demonstrated by significantly higher recovery of size and shape complexity of reinnervated EPs and also by increased acetylcholine receptor (AChRs) density on post synaptic membranes compared to PBS‐treated EPs. The stimulating effect of T3 on EP reinnervation is confirmed by a higher index of compound muscle action potentials recorded in gastrocnemius muscles. In conclusion, our results provide for the first time strong evidence that T3 enhances the restoration of NMJ structure and improves synaptic transmission. © 2010 Wiley‐Liss, Inc.     

Reorganization and orientation of regenerating nerve fibres,perineurium, and epineurium in preformed mesothelial tubes – an experimental study on the sciatic nerve of rats

Regeneration of severed peripheral nerves is unfortunately often incomplete, due to loss of nerve fibers and neuroma formation. A new approach is presented with the intention of improving the conditions for nerve repair. In the first of the two stages, a pseudosynovial tube is formed around a silicone rubber rod, surrounded by a stainless steel spiral, which was placed in the backs of rats. This tube, in the second stage, is used as a free “tube graft” to bridge gaps of about 10–12-mm lengths in the severed sciatic nerve. The tube was kept open by the metal spiral. Regenerating nerve fibers with their sprouts grew into the initially open space in the tube. A new nerve trunk was formed, comprised of closely packed myelinated and unmyelinated axons, organized into fascicles. Demonstration by electron microscopy and by EMG recording of reinnervation of foot muscles supported successful long-term results. The fascicles were delimited by perineurial and epineurial sheaths and, furthermore, showed signs of maturation. It was also demonstrated that the nerve-fiber regeneration ceased after a few weeks if there was no distal nerve inserted into the tube. The importance of optimizing the interaction between local factors and regenerating nerve fibers for reestablishment of functionally valuable motor units is discussed.     

Nanofibrous nerve conduits for repair of 30-mm-long sciatic nerve defects*

It has been confirmed that nanofibrous poly(3-hydroxybutyrate-co-3-hydroxyvalerate) nerve conduit can promote peripheral nerve regeneration in rats. However, its efficiency in repair of over 30-mm-long sciatic nerve defects needs to be assessed. In this study, we used a nanofibrous poly(3-hydroxybutyrate-co-3-hydroxyvalerate) nerve conduit to bridge a 30-mm-long gap in the rat sciatic nerve. At 4 months after nerve conduit implantation, regenerated nerves were macroscopically observed and histologically assessed. In the nanofibrous graft, the rat sciatic nerve trunk had been reconstructed by restoration of nerve continuity and formation of myelinated nerve fiber. There were Schwann cells and glial cells in the regenerated nerves. Masson’s trichrome staining showed that there were no pathological changes in the size and structure of gastrocnemius muscle cells on the operated side of rats. These findings suggest that nanofibrous poly(3-hydroxybutyrate-co-3-hydroxyvalerate) nerve conduit is suitable for repair of long-segment sciatic nerve defects.     

Chondroitinase treatment increases the effective length of acellular nerve grafts

Acellular nerve allografts have been explored as an alternative to nerve autografting. It has long been recognized that there is a distinct limit to the effective length of conventional acellular nerve grafts, which must be overcome for many grafting applications. In rodent models nerve regeneration fails in acellular nerve grafts greater than 2 cm in length. In previous studies we found that nerve regeneration is markedly enhanced with acellular nerve grafts in which growth-inhibiting chondroitin sulfate proteoglycan was degraded by pretreatment with chondroitinase ABC (ChABC). Here, we tested if nerve regeneration can be achieved through 4-cm acellular nerve grafts pretreated with ChABC. Adult rats received bilateral sciatic nerve segmental resection and repair with a 4 cm, thermally acellularized, nerve graft treated with ChABC (ChABC graft) or vehicle-treated acellularized graft (Control graft). Nerve regeneration was examined 12 weeks after implantation. Our findings confirm that functional axonal regeneration fails in conventional long acellular grafts. In this condition we found very few axons in the distal host nerve, and there were marginal signs of sciatic nerve reinnervation in few (2/9) rats. This was accompanied by extensive structural disintegration of the distal graft and abundant retrograde axonal regeneration in the proximal nerve. In contrast, most (8/9) animals receiving nerve repair with ChABC grafts showed sciatic nerve reinnervation by direct nerve pinch testing. Histological examination revealed much better structural preservation and axonal growth throughout the ChABC grafts. Numerous axons were found in all but one (8/9) of the host distal nerves and many of these regenerated axons were myelinated. In addition, the amount of aberrant retrograde axonal growth (originating near the proximal suture line) was markedly reduced by repair with ChABC grafts. Based on these results we conclude that ChABC treatment substantially increases the effective length of acellular nerve grafts.     

Comparative dose-dependence study of FK506 on transected mouse sciatic nerve repaired by allograft or xenograft

We evaluated the effects of FK506, at doses of 0.2, 2, and 5 mg/kg/day, on the response to nerve grafts implanted in outbred mice. A 6 mm long segment of the sciatic nerve was transected and repaired by autograft (the same segment resected), allograft (from another mouse), or xenograft (from a rat nerve). The regenerating nerves were harvested after 3 weeks and studied under light and electron microscope. Allografts of animals treated with the 5 mg/kg/day dose of FK506 appeared similar to those from autografts, demonstrating an equivalent number of myelinated fibers. In mice treated with the 2 mg/kg/day dose, regeneration was slightly hindered, as indicated by the reduced number of myelinated fibers. In contrast, in mice given a 0.2 mg/kg/day dose of FK506, allografts were not different from untreated allografts; both groups showed a marked rejection response with only few unmyelinated axons and no myelinated fibers. Xenografts showed a more severe rejection than allografts, with a marked inflammatory cell reaction throughout the graft. In contrast, in mice treated with the 5 mg/kg/day dose, xenografts exhibited a mild cell reaction and a greater number of regenerated myelinated fibers. In conclusion, effective axonal regeneration is achieved with FK506 administration at doses of 5 mg/kg/day through allografts and, partially, through xenografts.     

Effects of motor and sensory nerve transplants on amount and specificity of sciatic nerve regeneration

Nerve regeneration after complete transection does not allow for adequate functional recovery mainly because of lack of selectivity of target reinnervation. We assessed if transplanting a nerve segment from either motor or sensory origin may improve specifically the accuracy of sensory and motor reinnervation. For this purpose, the rat sciatic nerve was transected and repaired with a silicone guide containing a predegenerated segment of ventral root (VR) or dorsal root (DR), compared to a silicone guide filled with saline. Nerve regeneration and reinnervation was assessed during 3 months by electrophysiologic and functional tests, and by nerve morphology and immunohistochemistry against choline acetyltransferase (ChAT) for labeling motor axons. Functional tests showed that reinnervation was successful in all the rats. However, the two groups with a root allotransplant reached higher degrees of reinnervation in comparison with the control group. Group VR showed the highest reinnervation of muscle targets, whereas Group DR had higher levels of sensory reinnervation than VR and saline groups. The total number of regenerated myelinated fibers was similar in the three groups, but the number of ChAT+ fibers was slightly lower in the VR group in comparison with DR and saline groups. These results indicate that a predegenerated root nerve allotransplant enhances axonal regeneration, leading to faster and higher levels of functional recovery. Although there is not clear preferential reinnervation, regeneration of motor axons is promoted at early times by a motor graft, whereas reinnervation of sensory pathways is increased by a sensory graft.     

Histologic assessment of sciatic nerve regeneration following resection and graft or tube repair in the mouse

The present study determines the number and morphology of myelinated fibers that regenerate after resection of the mouse sciatic nerve. In different groups of mice, a resection of 4 or 6 mm of the sciatic nerve was left unrepaired, repaired with silicone or collagen guides or by an autologous nerve graft of the same or smaller calibre. Regeneration was examined, under light microscopy, 3 months after operation and quantified by morphometric analysis of light micrographs of cross-sectional nerve fibers. The results show that, without repair, few nerve fibers reach the distal nerve stump, while tubulization or autografts allowed better regeneration. Tube repair allowed a comparable degree of regeneration to that of an autograft with 4 mm gaps, but lower with 6 mm gaps. Regeneration was limited with a gap of 6 mm in silicone tubes, but was successful in half the mice with collagen tubes. The size and myelination of regenerated fibers were below normal values in all experimental groups, although they were closer to normal with sciatic autografts than after smaller grafts and tubulization. There were no signs of secondary degeneration in the nerve regenerates within silicone and collagen tubes. ? 1996 Elsevier Science Ireland Ltd. All rights reserved.     

Extent of fiber regeneration after peripheral nerve repair: silicone splint vs. suture, gap repair vs. graft

The degree of regeneration in surgically repaired sciatic nerves in rats was measured using a simple new electrophysiologic method: comparison of the size of nerve responses evoked by stimulation distal and proximal to the anastomosis. Five different repair procedures were evaluated. After simple end-to-end suture anastomosis, about 40% of the severed parent fibers regenerated past the suture line. The result was substantially improved when the anastomosis was covered with a newly designed thinwall silicone sheath which incorporated a narrow longitudinal slit. The presence of suture material at the point of anastomosis had no effect. Finally, regeneration across a 5-mm gap ensheathed in silicone (67%) was better than regeneration through a 5-mm autograft (45%).     

Sciatic nerve regeneration across gaps within silicone chambers: long-term effects of NGF and consideration of axonal branching

We examined whether the short-term beneficial effects of nerve growth factor (NGF) upon regeneration are sustained over a prolonged period of time across 8-mm gaps within silicone chambers. Rat sciatic nerve regeneration both with and without NGF was examined after 10 weeks. Myelinated counts from the regenerated sciatic and distal tributary nerves were correlated to the numbers of motor and sensory neurons retrogradely labeled with horseradish peroxidase (HRP) applied distal to the regenerated segment. Regenerated sciatic and sural nerves were examined ultrastructurally for morphological analysis. Both regenerated groups by 10 weeks achieved essentially complete counts of myelinated axons in the distal tributary nerves and the regenerated segment of the sciatic nerve compared to the uninjured controls. There were similar numbers of retrogradely labeled sensory and motor neurons in the dorsal root ganglia (DRG) and lumbar spinal cord of both groups and, surprisingly, of the uninjured normal control group. Ultrastructural analysis demonstrated no difference in the distribution of axonal diameters or myelin thickness between the regenerated groups. In evaluating regeneration in experimental silicone chamber models, it is important to determine such parameters as the percentage of neurons that grow across the gap and the incidence of axonal sprouting. One can then make accurate assessments of experimental perturbations and predict whether they improve the naturally occurring regeneration through chambers. These results must ultimately be compared with equivalent determinations in the uninjured nerve. At 10 weeks there was essentially complete regeneration of both the NGF and control regenerative groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

FK506 increases peripheral nerve regeneration after chronic axotomy but not after chronic schwann cell denervation

Poor functional recovery after peripheral nerve injury is attributable, at least in part, to chronic motoneuron axotomy and chronic Schwann cell (SC) denervation. While FK506 has been shown to accelerate the rate of nerve regeneration following a sciatic nerve crush or immediate nerve repair, for clinical application, it is important to determine whether the drug is effective after chronic nerve injuries. Two models were employed in the same adult rats using cross-sutures: chronic axotomy and chronic denervation of SCs. For chronic axotomy, a chronically (2 months) injured proximal tibial (TIB) was sutured to a freshly cut common peroneal (CP) nerve. For chronic denervation, a chronically (2 months) injured distal CP nerve was sutured to a freshly cut TIB nerve. Rats were given subcutaneous injections of FK506 or saline (5 mg/kg/day) for 3 weeks. In the chronic axotomy model, FK506 doubled the number of regenerated motoneurons identified by retrograde labeling (from 205 to 414 TIB motoneurons) and increased the numbers of myelinated axons (from 57 to 93 per 1000 microm2) and their myelin sheath thicknesses (from 0.42 to 0.78 microm) in the distal nerve stump. In contrast, after chronic denervation, FK506 did not improve the reduced capacity of SCs to support axonal regeneration. Taken together, the results suggest that FK506 acts directly on the neuron (as opposed to the denervated distal nerve stump) to accelerate and promote axonal regeneration of neurons whose regenerative capacity is significantly reduced by chronic axotomy.     

Evaluation of the long-term regenerative potential in an experimental nerve amputee model

In this study, we evaluated the long-term maintenance of regenerated axons in an experimental nerve amputee model. The sciatic nerve of adult rats was transected and repaired with a silicone tube leaving a short gap; the distal nerve segment was again transected 10 mm distally and the distal stump either introduced in a capped silicone chamber (amputee group) or connected to denervated targets (tibial branch into the gastrocnemius muscle and peroneal nerve apposed to skin) (reinnervation group). Morphological studies were performed at 2.5, 6, and 9 months after surgery. In all cases, axons regenerated across the silicone tube and grew in the distal nerve segment. In the amputee group, the morphological results show the expected features of a neuroma that is formed when regenerating axons are prevented from reaching the end organs, with a large number of axonal profiles indicative of regenerative sprouting. The number of myelinated axons counted at the distal nerve was sustained over 9 months follow-up, indicating that regenerated axons are maintained chronically. Immunohistochemical labeling showed maintained expression of choline acetyltransferase, calcitonin gene-related peptide, and growth-related peptides 43 in the distal neuroma at 6 and 9 months. Reconnection of the distal nerve to foreign targets mildly improved the pattern of nerve regeneration, decreasing the number of excessive sprouts. These results indicate that axons regenerated may be eventually interfaced with external input-output systems over long time, even if ending in the absence of distal targets as will occur in amputee limbs.     

H reflex restitution and facilitation after different types of peripheral nerve injury and repair

This study addresses the restitution of monosynaptic H reflex after nerve injuries and their role in the recovery of walking. Adult rats were submitted to sciatic crush, complete section repaired by aligned or crossed fascicular suture, or an 8-mm resection repaired by autograft or tube repair. The sciatic nerve was stimulated proximal to the injury site and the M and H waves were recorded from gastrocnemius (GCm) and plantar (PLm) muscles at monthly intervals during 3 months postoperation. Walking track tests were also carried out and the sciatic functional index (SFI) calculated to assess gait recovery. The M and H waves reappeared in all the animals at the end of the follow-up. The H/M amplitude ratio increased during the first stages of regeneration and tended to decrease to control values as muscle reinnervation progressed. However, final values of the H/M ratio for the PLm remained significantly higher in all the groups except that with a nerve crush. The walking track pattern showed an appreciable recovery only after crush injury. Final SFI values correlated positively with the M wave amplitude and negatively with the H/M ratio. In conclusion, H reflex is facilitated after peripheral nerve injury and regeneration and tends to return to normal excitability with time. Changes in the H reflex circuitry and excitability correlated positively with the deficient recovery of walking pattern after severe nerve injury.     

Delayed nerve regeneration in streptozotocin diabetic rats

Nerve regeneration across a 10-mm gap was delayed in streptozotocin diabetic rats 3 and 4 weeks after transecting the sciatic nerve. Opposite ends of each cut nerve were introduced into a silicone tube, leaving a 10-mm gap. Electron microscopy was used to evaluate the progress of regeneration in sections at 2-mm intervals across the 10-mm gap. After 3 weeks, control axons had bridged the 10-mm gap, and myelin sheaths extended for 6-8 mm. By contrast, axons and their myelin sheaths were seen no further than 2 mm from the proximal stump in diabetic animals. By 4 weeks, axons had bridged the gap in diabetics; however, they appeared immature and showed dystrophic changes. The findings suggest that although regeneration does occur in diabetic nerves, it is significantly delayed and qualitatively impaired.