In spite of an enormous amount of new experimental laboratory data based on evolving neuroscientific concepts during the last 25 years peripheral nerve injuries still belong to the most challenging and difficult surgical reconstructive problems. Our understanding of biological mechanisms regulating posttraumatic nerve regeneration has increased substantially with respect to the role of neurotrophic and neurite-outgrowth promoting substances, but new molecular biological knowledge has so far gained very limited clinical applications. Techniques for clinical approximation of severed nerve ends have reached an optimal technical refinement and new concepts are needed to further increase the results from nerve repair. For bridging gaps in nerve continuity little has changed during the last 25 years. However, evolving principles for immunosuppression may open new perspectives regarding the use of nerve allografts, and various types of tissue engineering combined by bioartificial conduits may also be important. Posttraumatic functional reorganizations occurring in brain cortex are key phenomena explaining much of the inferior functional outcome following nerve repair, and increased knowledge regarding factors involved in brain plasticity may help to further improve the results. Implantation of microchips in the nervous system may provide a new interface between biology and technology and developing gene technology may introduce new possibilities in the manipulation of nerve degeneration and regeneration.
We have investigated the effect of long-term strict glycaemic control on peripheral and autonomic nerve function in 45 IDDM patients (age 18-42 years, diabetes duration 7-23 years) without clinical signs of neuropathy or other neurological disease. They were randomly assigned to treatment either with continuous insulin infusion, multiple injections (4-6 times daily), or conventional treatment (twice daily) for 4 years and followed prospectively for 8 years. Motor and sensory nerve conduction velocities were measured at the start and after 8 years. Autonomic nerve function tests were performed only once, after 8 years. A significant reduction of nerve conduction velocity was observed during 8 years in patients with mean HbA1 more than 10% (n = 12, group mean 10.9%, range 10.1-13.2%) compared to patients with HbA1 less than 10% (n = 33, group mean 9.0%, range 7.5-9.9%). Change of motor nerve conduction velocity in the peroneal nerve was: -4.8 +/- 4.9 (SD) vs -2.2 +/- 5.3 m/s (p
Oulu Center for Cell-Matrix Research, Biocenter Oulu, Department of Medical Biochemistry and Molecular Biology, University of Oulu, and Department of Clinical Neurophysiology, Oulu University Hospital, FIN-90221 Oulu, Finland.
Although the Schwann cell basement membrane (BM) is required for normal Schwann cell terminal differentiation, the role of BM-associated collagens in peripheral nerve maturation is poorly understood. Collagen XV is a BM zone component strongly expressed in peripheral nerves, and we show that its absence in mice leads to loosely packed axons in C-fibers and polyaxonal myelination. The simultaneous lack of collagen XV and another peripheral nerve component affecting myelination, laminin a4, leads to severely impaired radial sorting and myelination, and the maturation of the nerve is permanently compromised, contrasting with the slow repair observed in Lama4-/- single knock-out mice. Moreover, the Col15a1-/-;Lama4-/- double knock-out (DKO) mice initially lack C-fibers and, even over 1 year of age have only a few, abnormal C-fibers. The Lama4-/- knock-out results in motor and tactile sensory impairment, which is exacerbated by a simultaneous Col15a1-/- knock-out, whereas sensitivity to heat-induced pain is increased in the DKO mice. Lack of collagen XV results in slower sensory nerve conduction, whereas the Lama4-/- and DKO mice exhibit increased sensory nerve action potentials and decreased compound muscle action potentials; x-ray diffraction revealed less mature myelin in the sciatic nerves of the latter than in controls. Ultrastructural analyses revealed changes in the Schwann cell BM in all three mutants, ranging from severe (DKO) to nearly normal (Col15a1-/-). Collagen XV thus contributes to peripheral nerve maturation and C-fiber formation, and its simultaneous deletion from neural BM zones with laminin a4 leads to a DKO phenotype distinct from those of both single knock-outs.