The role of neurotrophic factors in disorders of peripheral nerves and motor neurons.

Recent, exciting research in neurotrophic factors has significantly enhanced our understanding of their actions. Neurotrophic factors have been shown to have robust effects on neuronal survival and differentiation in vitro and in vivo and have been tested in animal models of human neurologic disorders. These studies have encouraged initiation of clinical trials of several neurotrophic factors for diseases of peripheral nerves and motor neurons. In this article, the author reviews the data for the actions of neurotrophic factors on peripheral nerves and motor neurons, the rationale for their use in clinical trails. The results of clinical trials of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and insulin-like growth factor type 1 (IGF-1), three neurotrophic factors that have been tested in phase III studies, are also reviewed.

Nitric oxide activation of TrkB through peroxynitrite.

NIH-3T3 cells stably transfected with TrkB, the receptor for brain-derived neurotrophic factor (BDNF), were used to study the effects of NO and peroxynitrite on TrkB. 3-Morpholinosydnonimine (SIN-1), a donor of NO and O2- which immediately react to form peroxynitrite, induced TrkB tyrosine phosphorylation in a dose-dependent relationship from 2 to 40 mM. TrkB phosphorylation by SIN-1 was blocked by superoxide dismutase, which converts O2 to H2O2 and prevents its reaction with NO to form peroxynitrite, and by K252a, an inhibitor of TrkB phosphorylation by BDNF. Treatment with NO or O2- alone did not activate TrkB. Treatment directly with 1-4 mM peroxynitrite resulted in a dose-dependent increase in tyrosine phosphorylation of TrkB. SIN-1 treatment induced tyrosine phosphorylation of phospholipase C-gamma1 (PLC-gamma1) and induced its binding with activated TrkB, similar to that seen with BDNF downstream signaling pathways. These studies demonstrate activation of TrkB through peroxynitrite.

Mice deficient in Six5 develop cataracts: implications for myotonic dystrophy.

Expansion of a CTG trinucleotide repeat in the 3' UTR of the gene DMPK at the DM1 locus on chromosome 19 causes myotonic dystrophy, a dominantly inherited disease characterized by skeletal muscle dystrophy and myotonia, cataracts and cardiac conduction defects. Targeted deletion of Dm15, the mouse orthologue of human DMPK, produced mice with a mild myopathy and cardiac conduction abnormalities, but without other features of myotonic dystrophy, such as myotonia and cataracts. We, and others, have demonstrated that repeat expansion decreases expression of the adjacent gene SIX5 (refs 7,8), which encodes a homeodomain transcription factor. To determine whether SIX5 deficiency contributes to the myotonic dystrophy phenotype, we disrupted mouse Six5 by replacing the first exon with a beta-galactosidase reporter. Six5-mutant mice showed reporter expression in multiple tissues, including the developing lens. Homozygous mutant mice had no apparent abnormalities of skeletal muscle function, but developed lenticular opacities at a higher rate than controls. Our results suggest that SIX5 deficiency contributes to the cataract phenotype in myotonic dystrophy, and that myotonic dystrophy represents a multigenic disorder.

Statistical motor unit number estimation: reproducibility and sources of error in patients with amyotrophic lateral sclerosis.

The reliability of motor unit number estimation (MUNE) for assessment of the long-term course of ALS is dependent on the reproducibility of the technique. We report our results with the statistical method of MUNE on the ulnar nerve/hypothenar muscle in 16 ALS patients who were studied on 52 occasions. On each occasion, MUNE was performed twice with one electrode placement and once with a different placement. For each MUNE, mean surface motor unit potential amplitude was determined within three different recording ranges or windows at different stimulus intensities. The MUNE results had excellent reproducibility with coefficients of variation of 19% and test-retest correlation coefficients from 0.75 to 0.86. With examination of sources for variability, the reproducibility of statistical MUNE is not affected by minor variation in stimulation and recording electrode placement but may be improved by modifying methods for recording window selection. The high reproducibility of statistical MUNE supports its reliability for estimating the rate of motor unit loss in ALS.

Early BDNF, NT-3, and NT-4 signaling events.

Much more is known about nerve growth factor (NGF) signaling than that initiated by brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), or NT-4. We sought to study early BDNF, NT-3, and NT-4 signaling events. Using TrkB-expressing cells, we found that BDNF and NT-4 individually induced tyrosine phosphorylation of TrkB in a dose-dependent fashion. At maximally effective concentrations, BDNF or NT-4 induced robust TrkB tyrosine phosphorylation at 5 min; this progressively declined at 15, 30, and 60 min. Using immunoprecipitation, PI3-kinase and tyrosine phosphorylated PLC-gamma1 and SHC were shown to be associated with tyrosine phosphorylated TrkB in response to both BDNF and NT-4. BDNF and NT-4 induced similar intensities of phosphorylation of TrkB and signaling intermediates at equivalent doses. NT-3 treatment of TrkC-expressing cells induced very similar patterns for induction of TrkC tyrosine phosphorylation and recruitment of signaling intermediates. BDNF, NT-3, and NT-4 caused rapid tyrosine phosphorylation of ERK and SNT. These data suggest that the earliest signaling events for BDNF, NT-3, and NT-4 are very similar to those for NGF.

Sciatic neuropathy.

Injuries to the sciatic nerve cause neurologic deficits in the peroneal and tibial nerve distributions. Interestingly, most injuries result in more severe deficits to the peroneal division compared to the tibial division. Thus, it can sometimes be difficult to distinguish sciatic neuropathy from peroneal neuropathy. The long course of the sciatic nerve leaves it vulnerable to nerve injury from a variety of causes. Most sciatic neuropathies are acute in onset, such as from hip arthroplasty and hip fracture or dislocation, but some occur from prolonged compression, such as during coma. Entrapment of the sciatic nerve by mass lesions or by the piriformis muscle is relatively rare.

Recurrent multifocal demyelinating neuropathy with febrile illness and IgG subset deficiency.

We describe a unique syndrome of recurrent multifocal demyelinating motor greater than sensory deficits in cranial and peripheral nerve distributions with rapid, spontaneous improvement. Three patients presented with episodes over a period of 7 to 24 years, largely accompanied by febrile illness. Variably decreased IgG1 and IgG3 subclass levels were found. We postulate an immune-mediated process based upon the clinical presentation and presence of decreased IgG subclass levels.

Doctors, patients, and perceived job image: an empirical study of stress and nurses in Singapore.

This study examined the relationships among three potential sources of stress, namely, demands from patients/relatives, demands from doctors, and perceived job image, and several work-related outcomes, namely, job satisfaction, organizational commitment, intention to quit, and job-induced tension. Respondents consist of nurses from two tertiary-care hospitals in Singapore. Findings of this study suggest that demands from patients/relatives, doctors, and perceived job image were significantly associated with nurses' job satisfaction, organizational commitment and job-induced tension. While demands from patients/relatives and perceived job image were significantly associated with intention to quit, the relationship between demands from doctors and nurses' intention to quit failed to reach statistical significance. Implications of the findings are discussed.

Longitudinal study of fiber density and motor unit number estimate in patients with amyotrophic lateral sclerosis.

We examined fiber density, compound muscle action potential (CMAP) amplitude, and motor unit number estimate (MUNE) of the abductor digiti minimi and grip strength longitudinally. We sought to determine the effects of ALS on these measurements and to evaluate which of these tests may be more sensitive in evaluating progression of ALS and possibly predicting survival. Ten patients were examined at months 0, 3, and 6. A significant decrease in MUNE and increase in fiber density were observed at months 3 and 6 (p < 0.02) compared with baseline (month 0). Mean CMAP and grip strength declined, but not significantly. The decrease in MUNE over 6 months was significantly greater than that of CMAP and grip strength (p < 0.025). The significant changes in MUNE and fiber density over time suggest that they are more sensitive in measuring the rate of progression of ALS. To evaluate further the utility of these tests, we arbitrarily divided the patients into equal groups based on length of survival. MUNE declined significantly in the group with shorter survival (p < 0.01). Conversely, fiber density increased significantly in patients with longer survival (p < 0.01). With similar statistical analysis there were no significant differences in decline of CMAP or grip strength in either subgroup over 6 months. Our study suggests that MUNE and fiber density are more sensitive than CMAP and grip strength in detecting progression of ALS. Furthermore, we raise the hypotheses that a greater increase in fiber density identifies a group of patients with ALS who will have longer survival, and that a greater decline in MUNE identifies a group with a worse prognosis.

Endocytosis of activated TrkA: evidence that nerve growth factor induces formation of signaling endosomes.

The survival, differentiation, and maintenance of responsive neurons are regulated by nerve growth factor (NGF), which is secreted by the target and interacts with receptors on the axon tip. It is uncertain how the NGF signal is communicated retrogradely from distal axons to neuron cell bodies. Retrograde transport of activated receptors in endocytic vesicles could convey the signal. However, little is known about endocytosis of NGF receptors, and there is no evidence that NGF receptors continue to signal after endocytosis. We have examined early events in the membrane traffic of NGF and its receptor, gp140(TrkA) (TrkA), in PC12 cells. NGF induced rapid and extensive endocytosis of TrkA in these cells, and the receptor subsequently moved into small organelles located near the plasma membrane. Some of these organelles contained clathrin and alpha-adaptin, which implies that TrkA is internalized by clathrin-mediated endocytosis. Using mechanical permeabilization and fractionation, intracellular organelles derived from endocytosis were separated from the plasma membrane. After NGF treatment, NGF was bound to TrkA in endocytic organelles, and TrkA was tyrosine-phosphorylated and bound to PLC-gamma1, suggesting that these receptors were competent to initiate signal transduction. These studies raise the possibility that NGF induces formation of signaling endosomes containing activated TrkA. They are an important first step in elucidating the molecular mechanism of NGF retrograde signaling.

Nerve growth factor and the neurotrophic factor hypothesis.

The discovery of nerve growth factor (NGF) over 40 years ago led to the formulation of the "Neurotrophic Factor Hypothesis". This hypothesis states that developing neurons compete with each other for a limited supply of a neurotrophic factor (NTF) provided by the target tissue. Successful competitors survive; unsuccessful ones die. Subsequent research on NTFs has shown that NTF expression and actions are considerably more complex and diverse than initially predicted. Even for NGF, different regulatory patterns are seen for different neuronal populations. As would be predicted by the "Neurotrophic Factor Hypothesis", NGF levels critically regulate basal forebrain cholinergic neuron size and neurochemical differentiation. In contrast, the level of trkA, the NGF receptor, regulates these properties in caudate-putamen cholinergic neurons. Understanding NTF regulation and actions on neurons has led to their use in clinical trials of human neurological diseases. NTFs may emerge as important therapies to prevent neuronal dysfunction and death.

Neurologic complications of lumbar epidural anesthesia and analgesia.

We reviewed the clinical features of 12 patients with neurologic complications following lumbar epidural anesthesia or analgesia. Eleven patients experienced lumbosacral radiculopathy or polyradiculopathy and, of these, 10 received epidural anesthesia or analgesia and one received subarachnoid injection of medication after intended epidural anesthesia. One patient suffered a moderately severe thoracic myelopathy in the setting of unintended spinal anesthesia. The two patients with more severe polyradiculopathy had severe lumbar spinal stenosis on MRI. The other patients experienced mild to moderate neurologic deficits most often involving the L-2 root, and MRIs, when performed, were unremarkable. EMG on three patients helped to localize the lesions to the lumbosacral roots and to quantify the extent of axonal loss. Ten patients were ambulatory upon discharge from the hospital and had good neurologic outcome. One patient with severe polyradiculopathy did not improve after 4 years and had severe motor axonal loss based upon electrodiagnostic studies. The patient with a thoracic myelopathy was ambulatory 4 months after onset. Although generally a safe procedure with low frequency of complications, lumbar epidural anesthesia or analgesia occasionally causes neurologic sequelae such as radiculopathy or myelopathy. Neurologic complications may be more severe in the presence of spinal stenosis or after inadvertent subarachnoid injection of anesthetic or analgesic agent.

Therapeutic applications of neurotrophic factors in disorders of motor neurons and peripheral nerves.

Research in the past few years has produced exciting progress in our understanding of neurotrophic factors. Robust effects of neurotrophic factors on neuronal survival and differentiation in animal studies have encouraged initiation of clinical trials for diseases of the human nervous system. In this article, the data for the actions of neurotrophic factors and the rationale for their use in clinical trials are reviewed. Recent data demonstrating efficacy of insulin-like growth factor 1 in amyotrophic lateral sclerosis suggest that neurotrophic factors can be used to treat neurological disease.

The electrophysiologic features of sciatic neuropathy in 100 patients.

We reviewed the electrophysiologic data of 100 consecutive patients with sciatic neuropathy in order to better understand this disorder. Most patients (93%) had electrodiagnostic signs of significant axonal loss. Seven patients had predominantly signs of demyelination; 6 were due to compression and 1 was idiopathic. The peroneal division was more severely affected than the tibial division in 64% of patients. Tibialis anterior EMGs were abnormal in 92%, and the EDB CMAP was low in amplitude or absent in 80%. CMAP and SNAP amplitudes and EMGs were all normal in the tibial division in 12%. In contrast, the tibial division was more severely affected in only 8 patients. Of those, 5 were due to thigh trauma (gunshot wounds or femur fracture), 2 from gunshot wounds to the hip, and the other was chronic and idiopathic. Sciatic neuropathies are commonly, but not always, axonal loss lesions that affect the peroneal greater than tibial division.

Sciatic neuropathy: clinical and prognostic features in 73 patients.

We examined the clinical features of patients with sciatic neuropathy and the factors that influence prognosis. Of 92 consecutive patients referred for EMG evaluation of sciatic neuropathy, 73 fulfilled strict inclusion and exclusion criteria and had adequate clinical and electrophysiologic information. The etiologies included hip arthroplasty (21.9%), acute external compression (13.7%), infarction (9.6%), gunshot wound (9.6%), hip fracture/dislocation (9.6%), femur fracture (4.1%), contusion (4.1%), and uncertain (16.4%). We used life table analysis to determine outcome and to identify prognostic factors in patients with acute or subacute onset. Moderate or better recovery (improvement to grade 2 or by two of six clinical grades) occurred in most patients (30% by 1 year, 50% by 2 years, 75% by 3 years). A subgroup experienced excellent improvement (by three of six grades, or to grade 2) less frequently (33% by 2 and 3 years). Of the nine factors tested, two predicted an earlier or better recovery: a recordable compound muscle action potential of the extensor digitorum brevis (p < 0.025), and an initial absence of paralysis of muscles controlling ankle plantar flexion and dorsiflexion (p < 0.05). Thus, good but incomplete recovery occurs over 2 to 3 years in most patients with sciatic neuropathy, particularly in those without severe motor axonal loss.