Considerations in evaluating new treatment alternatives following peripheral nerve injuries: a prospective clinical study of methods used to investigate sensory, motor and functional recovery.

The current problem finding reliable and objective methods for evaluating results after peripheral nerve repair is a challenge when introducing new clinical techniques. The aim of this study was to obtain reference material and to evaluate the applicability of different tests used for clinical assessment after peripheral nerve injuries. Fifteen patients with a history of complete median nerve transsection and repair, and 15 healthy volunteers were included. Each subject was investigated using a battery of conventional and new tests for functional, sensory and motor recovery including questionnaires, clinical evaluations, neurophysiological and physiological findings. The results were statistically analysed and comparisons were made within the patient group and between patients and healthy volunteers using a 'per protocol' and an 'intention to treat' approach. Criteria for success were stipulated in order to be able to judge the usefulness of each method. The results showed that 19 of 34 variables, representing six of 16 methods, were not able to fulfil the criteria and were thus questionable for the evaluations of nerve repair in a clinical trial setting. However, 2pd, sensory recovery according to the non-modified British Medical Research Council, sensory neurography, manual muscle test, electromyography, questionnaires (i.e. DASH and the 4 question form) and performance tests (i.e. AMPS and Sollerman's subtests 4 and 8) did fulfil the criteria defined for being useful.

End-to-side nerve coaptation: a qualitative and quantitative assessment in the primate.

There are several reasons why end-to-side nerve coaptation has not been widely adopted clinically. Among these are the putative damage inflicted on the donor nerve and the variable quality of the regeneration in the recipient nerve. So far experiments on end-to-side nerve repair have been short term and mostly carried out on rats. This long-term study of end-to-side nerve repair of ulnar to median and median to ulnar nerve was performed using adult nonhuman primates. Eleven nerve repairs were studied at different time points. Eighteen, 22, 33 and 57 months after surgery a qualitative and quantitative analysis of the donor nerve and regenerating nerve revealed variable levels of percentage axonal regeneration compared with matched controls (1.4%-136%). Morphological evidence of donor nerve damage was identified distal to the coaptation site in four of the 11 cases, and in these cases the best axonal regeneration in the corresponding recipient nerves was observed. This donor nerve damage could neither be demonstrated in terms of a decrease in axon counts distal to the coaptation nor as donor target organ denervation. Recipient target organ regeneration like the axonal regeneration varied, with evidence of motor regeneration in eight out of 11 cases and sensory regeneration, as measured by percentage innervation density compared with matched controls, varied from 12.5% to 49%. Results from the present study demonstrate that the end-to-side coaptation technique in the nonhuman primate does not give predictable results. In general the motor recovery appeared better than the sensory and in those cases where donor nerve damage was observed there was better motor and sensory regeneration overall than in the remaining cases.

Apolipoprotein E gene and Alzheimer's disease: is tau the link?

The finding that APOE (the gene encoding apolipoprotein E) polymorphic variation was associated with an altered risk of developing Alzheimer's disease (AD) was a significant advance and immediately prompted a search for the mechanisms responsible for this alteration. Some 6 years later, a number of different hypotheses remain that might account for this influence on pathogenesis with no single mechanism being unequivocally accepted. The different approaches to understanding these mechanisms can be broadly categorized as: those suggesting a remote effect, such as different rates of vascular risk factors in those with the different APOE alleles; those proposing altered neuronal vulnerability, perhaps due to apolipoprotein E (ApoE)-isoform-specific differences in local cholesterol transport; and those hypotheses postulating an ApoE interaction with the two key lesions of AD, plaques and tangles. In this chapter we will review the evidence for and against an interaction between ApoE and the neuronal cytoskeleton, in particular with the microtubule-associated protein tau.

Primary sensory neuron survival following targeted administration of nerve growth factor to an injured nerve.

Nerve injuries induce neurochemical changes within primary sensory neurons, including expression of neuropeptides, and a loss of a substantial proportion of the neurons may possibly be caused by a lack of neurotrophic support. In the present study the role of nerve growth factor (NGF) in preventing these changes was investigated in monkeys by giving NGF peripherally through a fibronectin (Fn) conduit. A sensory nerve (superficial radial) was transected and a gap of 5 mm was bridged with either autologous sural nerve graft (SNG), Fn, or Fn impregnated with NGF (Fn-NGF). After four months the dorsal root ganglia, that received the cutaneous afferents of the nerve, were removed and analysed by quantitative immunohistochemistry using antibodies to calcitonin gene related polypeptide (CGRP) and substance P. The percentage of immunostained cells was taken as an indication of neuronal survival. The results showed that SNG and Fn-NGF reduced the loss of CGRP positive sensory neurons compared with Fn alone. For substance P-positive neurons the differences were small with only a tendency towards reduction of neuronal death after NGF had been given, suggesting that NGF might act preferentially on a subpopulation of CGRP immunoreactive sensory neurons that do not coexist with substance P.

Nerve growth factor enhances peripheral nerve regeneration in non-human primates.

Fibronectin mat implants impregnated with NGF have been successfully used in rat nerve regeneration model. The aim of this study was to assess their action in a primate model. Mats were implanted into a 5 mm gap in a peripheral nerve in Macaca fascicularis monkeys, either alone (Fn) or in the presence of nerve growth factor (Fn + NGF). Four months postoperatively, the regenerated nerve was analysed by light microscopy, and target skin reinnervation was assessed by quantification of cutaneous nerve terminals immunostained with protein gene product (PGP) antibodies. The diameter of the regenerated nerve was similar in Fn + NGF grafts and nerve autografts, but significantly larger for plain Fn grafts with evidence of more connective tissue surrounding the axons. Myelinated fibres counts showed similarities in normal control nerve, nerve autograft and Fn + NGF graft groups. However, in nerve grafted with plain Fn mats the regenerating fibres were lower in number and showed a wider variability in diameter and myelination, resulting in a significantly smaller G-ratio (axonal diameter/myelinated fibre diameter). The amount of cutaneous reinnervation was lowest in Fn graft group, while comparable amounts of skin reinnervation were observed in the Fn + NGF and autograft groups. These results suggest that Fn-mats are a suitable conduit to promote peripheral nerve regeneration also in primate, and supplying NGF locally at the lesion site can further enhance nerve regrowth.

Neuronal survival using a resorbable synthetic conduit as an alternative to primary nerve repair.

Clinically optimal situations for primary nerve repair are rarely observed. Crushed nerve ends result in either suboptimal repair or a need for nerve grafting. Functional results after nerve surgery are relatively poor, including major sensory deficits, which may be due to the death of primary sensory neurons that follows the nerve injury. The aim of this study was to determine if using polyhydroxybutyrate (PHB), a resorbable nerve conduit, could be an alternative to primary nerve repair in reducing loss of neurons. The superficial radial nerves in 20 cats were sectioned bilaterally and primarily repaired microsurgically by the use of two different strategies; either wrapping the nerve ends in sheets of PHB or epineurally suturing of the nerve. After 6 or 12 months, the surviving neurons within the dorsal root ganglia [C5-T1] were counted. No statistically significant differences were found between the two methods. This may imply a future possibility of using PHB as a synthetic nerve graft in situations where suboptimal primary repair or nerve grafts are the alternatives.

A new resorbable wrap-around implant as an alternative nerve repair technique.

Poly-3-hydroxybutyrate (PHB), a bacterial storage product, is available as bioabsorbable sheets and has been used in this study for primary nerve repair. The aim was to assess axonal regeneration following such repair and determine the inflammatory response to PHB. In 20 adult cats, the transected superficial radial nerve was wrapped in PHB sheets, while primary epineural repair was carried out in the contralateral limb. At 6 and 12 months, the repair sites were assessed immunohistochemically for macrophage infiltration and myelinated axons were counted in the distal nerve. Mean macrophage counts across the whole width of the nerve in both groups at 6 and 12 months showed no statistically significant difference. Nor was there any significant difference between the two groups at both time-points in axon counts, axon diameter, myelin thickness and g-ratio. There was a statistically significant increase in fibre diameters at 12 months, indicating that fibres were undergoing continuous maturation.

The neurotrophins NGF and NT-3 reduce sensory neuronal loss in adult rat after peripheral nerve lesion.

The effect of three different neurotrophins on axotomy-induced death of adult rat sensory neurons was examined. The ventral branch of the 13th spinal nerve was transected and the corresponding neurons in the 13th thoracic (T13) dorsal root ganglion (DRG) were pre-labelled with Fast Blue (FB). For a period of 4 weeks, animals received either no treatment, continuous intrathecal infusion of phosphate buffer, nerve growth factor (NGF), neurotrophin-3 (NT-3), or brain-derived neurotrophic factor (BDNF). Labelled neurons remaining after this period were counted. Inert, or no treatment, resulted in extensive loss of the DRG neurons. BDNF application was virtually non-effective, while NGF or NT-3 resulted in a greater number of FB-labelled neurons compared to normal controls. This suggests that NGF and NT-3 are survival factors for adult sensory neurons with a therapeutic potential in peripheral nerve injuries.

[Who is ready for clinical discharge? Empirical study on concepts of clinical discharge treatment and clinical readiness]. / Vem är klinikfärdig? Empirisk studie om begreppen medicinskt färdigbehandlad och klinikfärdig.

The purpose of this study was to find criteria characteristic for patients in need of care and social services. The criteria should serve as a guideline for patients and staff to facilitate care planning before discharge. The sample consisted of 49 patients, born before 1925, in need of emergency inpatient treatment, admitted to medical- or orthopaedic wards. Data of the patient's self care needs were collected by interviews, assessment of self care status and need of treatment. The patients could be divided into three groups depending on type of discharge. Group A (n = 27) discharged home, group B (n = 7) discharged to geriatric clinic and group C (n = 15) discharged and in need of further care and social services. Criteria indicating the patients further assistance from the community were in group C (medical- and orthopaedic wards) deficit in daily living activities and locomotion. Group B had an increased need of support from the physiotherapist and the occupational therapist, in locomotion as well as daily living activities The physician's assessment showed that the criteria behind the decision "no further medical treatment appropriate" and "ready for discharge" were not related to medical impairment but to lack of self care, need of care, rehabilitation and social services.