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Biomedical subjects

John W Griffin

Publications and source records attributed to John W Griffin.

At least 19 recordsLinked to original sources
PubMed2006

Activity-dependent slowing of conduction velocity in uninjured L4 C fibers increases after an L5 spinal nerve injury in the rat.

Growing evidence suggests that uninjured afferents may play an important role in neuropathic pain following nerve injury. The excitability of nociceptive neurons in the L4 spinal nerve appears to be enhanced following an injury to the adjacent L5 spinal nerve. In this study, we investigated whether the action-potential conduction properties of unlesioned, unmyelinated fibers are also altered. A teased-fiber technique was used to record from single C fibers from the L4 spinal nerve of the rat in vitro. Repeated electrical stimulation of the tibial nerve was used to investigate activity-dependent slowing of conduction velocity. Twin pulse stimulation at a 50 ms interpulse interval allowed investigation of supranormal conduction velocity. Blinded experiments were performed 8-10 days after sham surgery and after an L5 spinal nerve ligation (L5 SNL). Activity-dependent slowing revealed two populations of C fibers, a "nociceptor" population with a large degree of activity-dependent slowing and a "non-nociceptor" population with a smaller degree of activity-dependent slowing. Both populations showed enhanced activity-dependent slowing of conduction velocity and enhanced supranormal conduction velocities in lesioned animals compared to sham animals. Activity-dependent slowing was also enhanced after an L5 SNL in the mouse. These alterations in conduction velocity may reflect changes in expression of ion channels responsible for the membrane excitability. These data provide additional evidence that a nerve injury leads to persistent alterations in the properties of adjacent uninjured, unmyelinated fibers.

Action Potentials↗
PubMed2005

Degeneration of myelinated efferent fibers prompts mitosis in Remak Schwann cells of uninjured C-fiber afferents.

The factors inducing normally innervated Schwann cells in peripheral nerve to divide are poorly understood. Transection of the fourth and fifth lumbar ventral roots (L4/5 ventral rhizotomy) of the rat is highly selective, sparing unmyelinated axons and myelinated sensory axons; Wallerian degeneration is restricted to myelinated efferent fibers. We found that L4/5 ventral rhizotomy prompted many normally innervated nonmyelinating (Remak) Schwann cells to enter cell cycle; myelinating Schwann cells of intact (sensory) axons did not. Three days after L4/5 ventral rhizotomy, [3H]thymidine incorporation into Remak Schwann cells increased 30-fold. Schwann cells of degenerating efferents and endoneurial cells also incorporated label. Increased [3H]thymidine incorporation persisted at least 10 d after ventral rhizotomy. Despite Remak Schwann cell proliferation, the morphology of unmyelinated nerve (Remak) bundles was static. Seven days after L5 ventral rhizotomy, Remak Schwann cells in the L5-predominant lateral plantar nerve increased slightly; endoneurial cells doubled. Terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling-positive nuclei increased dramatically in peripheral nerve after L5 ventral rhizotomy; many of these were macrophage nuclei. In summary, we find that the degeneration of myelinated motor axons produced signals that were mitogenic for nonmyelinating Schwann cells with intact axons but not for myelinating Schwann cells with intact axons.

Afferent Pathways↗
PubMed2005

Overlap of pathology in paralytic rabies and axonal Guillain-Barre syndrome.

We describe clinical and pathological features of a case of paralytic rabies with acute axonal neuropathy that closely resembled axonal Guillain-Barre syndrome. This case emphasizes that there is overlap of both clinical and pathological features in paralytic rabies and axonal Guillain-Barre syndrome. These findings raise the possibility that infectious and autoimmune etiologies can lead to similar morphological changes in the nerves.

Campylobacter jejuni↗
PubMed2005

Myelin-associated glycoprotein and complementary axonal ligands, gangliosides, mediate axon stability in the CNS and PNS: neuropathology and behavioral deficits in single- and double-null mice.

Complementary interacting molecules on myelin and axons are required for long-term axon-myelin stability. Their disruption results in axon degeneration, contributing to the pathogenesis of demyelinating diseases. Myelin-associated glycoprotein (MAG), a minor constituent of central and peripheral nervous system myelin, is a member of the Siglec family of sialic acid-binding lectins and binds to gangliosides GD1a and GT1b, prominent molecules on the axon surface. Mice lacking the ganglioside biosynthetic gene Galgt1 fail to express complex gangliosides, including GD1a and GT1b. In the current studies, CNS and PNS histopathology and behavior of Mag-null, Galgt1-null, and double-null mice were compared on the same mouse strain background. When back-crossed to >99% C57BL/6 strain purity, Mag-null mice demonstrated marked CNS, as well as PNS, axon degeneration, in contrast to prior findings using mice of mixed strain background. On the same background, Mag- and Galgt1-null mice exhibited quantitatively and qualitatively similar CNS and PNS axon degeneration and nearly identical decreases in axon diameter and neurofilament spacing. Double-null mice had qualitatively similar changes. Consistent with these findings, Mag- and Galgt1-null mice had similar motor behavioral deficits, with double-null mice only modestly more impaired. Despite their motor deficits, Mag- and Galgt1-null mice demonstrated hyperactivity, with spontaneous locomotor activity significantly above that of wild type mice. These data demonstrate that MAG and complex gangliosides contribute to axon stability in both the CNS and PNS. Similar neuropathological and behavioral deficits in Galgt1-, Mag-, and double-null mice support the hypothesis that MAG binding to gangliosides contributes to long-term axon-myelin stability.

Animals↗
PubMed2004

The time course of epidermal nerve fibre regeneration: studies in normal controls and in people with diabetes, with and without neuropathy.

We sought to develop and validate a standardized cutaneous nerve regeneration model and to define the rate of epidermal nerve fibre (ENF) regeneration first in healthy control subjects and then in neuropathic and neuropathy-free subjects with diabetes. Next, we assessed the effect of different factors on the rate of nerve fibre regeneration and investigated whether such an approach might offer insight into novel trial designs and outcome measures. All subjects had a standardized topical capsaicin dressing applied to the distal lateral thigh. ENF densities derived from skin biopsies were determined at baseline, after capsaicin treatment and at reinnervation time points. For each subject, the best fit line from post-denervation data was determined and the slope was used as the rate of regeneration. In healthy control subjects, regeneration was correlated with psychophysical sensory testing, electron microscopy studies and immunohistochemistry with alternative axonal membrane markers. Topical capsaicin application produced complete or nearly complete denervation of the epidermis in both control subjects and people with diabetes. The rate of regeneration was associated with the baseline ENF density (P < 0.001), but not age (P = 0.75), gender (P = 0.18), epidermal thickness (P = 0.4) or post-capsaicin treatment density (P = 0.7). ENF regeneration, as determined by recovery of ENF density, occurred at a rate of 0.177 +/- 0.075 fibres/mm/day in healthy control subjects and was significantly reduced in subjects with diabetes (0.074 +/- 0.064, P < 0.001) after adjusting for changes in baseline ENF density. Among subjects with diabetes, the presence of neuropathy was associated with a further reduction in regenerative rate (0.10 +/- 0.07 versus 0.04 +/- 0.03, P = 0.03), though diabetes type (P = 0.7), duration of diabetes (P = 0.3) or baseline glycated haemoglobin (P = 0.6) were not significant. These results have several implications. First, topical capsaicin application can produce a uniform epidermal nerve fibre injury that is safe and well tolerated, and offers an efficient strategy to measure and study nerve regeneration in man. Secondly, using our techniques, reduced rates of nerve regeneration were found in people with diabetes without evidence of neuropathy and indicate that abnormalities in peripheral nerve function are present early in diabetes, before signs or symptoms develop. These results suggest that regenerative neuropathy trials could include non-neuropathic subjects and that trial duration can be dramatically shortened.

Adult↗
PubMed2004

DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4).

Juvenile amyotrophic lateral sclerosis (ALS4) is a rare autosomal dominant form of juvenile amyotrophic lateral sclerosis (ALS) characterized by distal muscle weakness and atrophy, normal sensation, and pyramidal signs. Individuals affected with ALS4 usually have an onset of symptoms at age <25 years, a slow rate of progression, and a normal life span. The ALS4 locus maps to a 1.7-Mb interval on chromosome 9q34 flanked by D9S64 and D9S1198. To identify the molecular basis of ALS4, we tested 19 genes within the ALS4 interval and detected missense mutations (T3I, L389S, and R2136H) in the Senataxin gene (SETX). The SETX gene encodes a novel 302.8-kD protein. Although its function remains unknown, SETX contains a DNA/RNA helicase domain with strong homology to human RENT1 and IGHMBP2, two genes encoding proteins known to have roles in RNA processing. These observations of ALS4 suggest that mutations in SETX may cause neuronal degeneration through dysfunction of the helicase activity or other steps in RNA processing.

Adolescent↗
PubMed2004

An anti-ganglioside antibody-secreting hybridoma induces neuropathy in mice.

Immune responses against gangliosides are strongly implicated in the pathogenesis of some variants of Guillain-Barré syndrome (GBS). For example, IgG antibodies against GM1, GD1a, and related gangliosides are frequently present in patients with post-Campylobacter acute motor axonal neuropathy (AMAN) variant of GBS, and immunization of rabbits with GM1 has produced a model of AMAN. However, the role of anti-ganglioside antibodies in GBS continues to be debated because of lack of a passive transfer model. We recently have raised several monoclonal IgG anti-ganglioside antibodies. We passively transfer these antibodies by intraperitoneal hybridoma implantation and by systemic administration of purified anti-ganglioside antibodies in mice. Approximately half the animals implanted with an intraperitoneal clone of anti-ganglioside antibody-secreting hybridoma developed a patchy, predominantly axonal neuropathy affecting a small proportion of nerve fibers. In contrast to hybridoma implantation, passive transfer with systemically administered anti-ganglioside antibodies did not cause nerve fiber degeneration despite high titre circulating antibodies. Blood-nerve barrier studies indicate that animals implanted with hybridoma had leaky blood-nerve barrier compared to mice that received systemically administered anti-ganglioside antibodies. Our findings suggest that in addition to circulating antibodies, factors such as antibody accessibility and nerve fiber resistance to antibody-mediated injury play a role in the development of neuropathy.

Animals↗
PubMed2004

Transplanted neural stem cells promote axonal regeneration through chronically denervated peripheral nerves.

Regeneration in the peripheral nervous system is impaired after prolonged periods of denervation. Currently, no interventions exist to alter the outcome after prolonged denervation. To examine the role of transplanted neural stem cells (NSC), we prepared chronically denervated distal tibial nerve segments. After 6 months of chronic denervation, we transplanted vehicle, C17.2 mouse NSCs, or C17.2 mouse NSCs engineered to overexpress GDNF to the distal tibial nerve and performed a peroneal nerve cross-suture. In animals transplanted with the NSCs, there was better regeneration of the peroneal axons into the tibial nerve as measured by counting the number of axons and by the emergence of compound motor action potentials in the tibial innervated foot muscles. Improved regeneration correlated with a reduction of chondroitin sulphate proteoglycan (CSPG) immunoreactivity in the extracellular matrix (ECM). In vitro, supernatant from C17.2 NSCs contained large quantities of secreted matrix metalloprotease-2 (MMP-2), degraded the CSPGs on chronically denervated tibial nerve sections, and reversed the CSPG-induced inhibition of neuritic outgrowth of DRG neurons. This reversal was inhibited by selective MMP-2 inhibitors. This is the first successful demonstration of regeneration through a chronically denervated nerve. These findings suggest that improved regeneration in the PNS can be accomplished by combining neurotrophic factor support and removal of axon growth inhibitory components in the extracellular matrix.

Action Potentials↗
PubMed2003

New insights into diabetic polyneuropathy.

Patients with complaints of numbness, tingling, and dysesthesias in the toes and feet are frequently referred to neurologists. Often, the only objective evidence for peripheral nerve dysfunction in these patients is limited to small-caliber sensory nerve fibers. On examination these patients may have reduced distal pinprick sensation, and distal leg skin biopsies show loss of small-caliber nerve fibers. Studies focusing on small-caliber nerve fibers have led to a growing impression that neuropathy can be associated with early diabetes or impaired glucose tolerance (IGT). Often, neuropathy can be the presenting symptom of either diabetes or IGT. Furthermore, the oral glucose tolerance test appears to be a more sensitive measure of glucose dysmetabolism in these patients than levels of fasting blood glucose or glycated hemoglobin. Patients with IGT-associated neuropathy may represent an attractive target population for future regenerative studies given that their neuropathy is less severe and presumably more easily reversed than neuropathy occurring in patients with diabetes.Historically, small-caliber fibers have not been extensively evaluated due to a lack of objective measures. Several measures to evaluate these fibers are emerging, including skin biopsy with visualization of epidermal nerve fibers. The accessibility of epidermal nerve fibers makes them an attractive target for nerve injury models, which have potential for development as novel outcome measures. Such approaches may address some of the challenges of past diabetic polyneuropathy trials.

Biopsy↗
PubMed2003

Differential distribution of HLA-DQ beta/DR beta epitopes in the two forms of Guillain-Barré syndrome, acute motor axonal neuropathy and acute inflammatory demyelinating polyneuropathy (AIDP): identification of DQ beta epitopes associated with susceptibility to and protection from AIDP.

Guillain-Barré syndrome (GBS), an acute, immune-mediated paralytic disorder affecting the peripheral nervous system, is the most common cause of acute flaccid paralysis in the post-polio era. GBS is classified into several subtypes based on clinical and pathologic criteria, with acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy (AMAN) being the most common forms observed. To better understand the pathogenesis of GBS and host susceptibility to developing the disease, the distribution of HLA class II Ags along with the seroreactivity to Campylobacter jejuni were investigated in a population of GBS patients from northern China. Using DNA-based typing methods, 47 patients with AMAN, 25 patients with AIDP, and 97 healthy controls were studied for the distribution of class II alleles. We found that the DQ beta RLD(55-57)/ED(70-71) and DR beta E(9)V(11)H(13) epitopes were associated with susceptibility to AIDP (p = 0.009 and p = 0.004, respectively), and the DQ beta RPD(55-57) epitope was associated with protection (p = 0.05) from AIDP. These DQ beta/DR beta positional residues are a part of pockets 4 (DQ beta 70, 71, DR beta 13), 6 (DR beta 11), and 9 (DQ beta 56, 57, DR beta 9); have been demonstrated to be important in peptide binding and T cell recognition; and are associated with other diseases that have a pathoimmunological basis. Class II HLA associations were not identified with AMAN, suggesting a different immunological mechanism of disease induction in the two forms of GBS. These findings provide immunogenetic evidence for differentiating the two disease entities (AMAN and AIDP) and focuses our attention on particular DR beta/DQ beta residues that may be instrumental in understanding the pathophysiology of AIDP.

Acute Disease↗
PubMed2003

Epidermal reinnervation after intracutaneous axotomy in man.

Two distinct patterns of reinnervation occur after injury to the cutaneous nerves: regenerative growth of the injured nerve and "collateral sprouting" of neighboring intact nerves. We describe two complementary models of regrowth of transected small sensory fibers in human skin. The "incision" model uses a circular incision that transects the subepidermal plexus, resulting in Wallerian degeneration of the nerve fibers that enter the incised cylinder, leaving a defined zone of denervated dermis and epidermis. The "excision" model utilizes an identical incision, followed by removal of the incised cylinder of skin, leaving a denervated area in which Schwann cells are absent. In the incision model, the earliest reinervation of denervated epidermis occurred by collateral sprouting from the terminals of epidermal axons from just outside the incision line. These axon terminals extended horizontally across the incision line and through the superficial layers of the epidermis, beneath the stratum corneum. By 13 days, numerous regenerating axons appeared in the deeper dermis derived from transected axons. These regenerating axons grew toward and ultimately into the epidermis, so that epidermal axonal density had normalized by 30-75 days. The invasion of these axons was associated with regression of the horizontally growing collateral sprouts. In the excision model, new fibers arose by terminal elongation of the epidermal axons outside the incision line, as in the incision model, and especially by collateral branching of epidermal fibers at the incision margins. These collaterals reached the epidermal surface of the basal lamina at the dermal-epidermal junction and then grew slowly toward the center of the denervated circle. In contrast to the incision model, however, complete reinnervation was not achieved even after 23 months. These models can be used to study reinnervation of denervated skin in man in different injury models and have relevance for exploring the stimuli for axonal growth and remodeling.

Adult↗
PubMed2003

Glial cell line-derived neurotrophic factor alters axon schwann cell units and promotes myelination in unmyelinated nerve fibers.

Glial cell line-derived neurotrophic factor (GDNF) plays an important role in the development and maintenance of a subset of dorsal root ganglion sensory neurons. We administered high-dose exogenous recombinant human GDNF (rhGDNF) daily to adult rats to examine its effect on unmyelinated axon-Schwann cell units in intact peripheral nerves. In rhGDNF-treated animals, there was a dramatic proliferation in the Schwann cells of unmyelinated fibers, which resulted in the segregation of many unmyelinated axons into a 1:1 relationship with Schwann cells and myelination of normally unmyelinated small axons. This study demonstrates that the administration of high doses of a growth factor to adult rats can change the phenotype of nerve fibers from unmyelinated to myelinated.

Animals↗
PubMed2003

FK506 is neuroprotective in a model of antiretroviral toxic neuropathy.

Antiretroviral toxic neuropathy is the most common neurological complication of human immunodeficiency virus infection. This painful neuropathy not only affects the quality of life of human immunodeficiency virus-infected patients but also severely limits viral suppression strategies. We have developed an in vitro model of this toxic neuropathy to better understand the mechanism of neurotoxicity and to test potential neuroprotective compounds. We show that among the dideoxynucleosides, ddC appears to be the most neurotoxic, followed by ddI and then d4T. This reflects their potency in causing neuropathy. AZT, which does not cause a peripheral neuropathy in patients, does not cause significant neurotoxicity in our model. Furthermore, in this model, we show that the immunophilin ligand FK506 but not cyclosporin A prevents the development of neurotoxicity by ddC, as judged by amelioration of ddC-induced "neuritic pruning," neuronal mitochondrial depolarization, and neuronal necrotic death. This finding suggests a calcineurin-independent mechanism of neuroprotection. As calcineurin inhibition underlies the immunosuppressive properties of these clinically used immunophilin ligands, this holds promise for the neuroprotective efficacy of nonimmunosuppressive analogs of FK506 in the prevention or treatment of antiretroviral toxic neuropathy.

Animals↗