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J W Griffin

Publications and source records attributed to J W Griffin.

At least 19 recordsLinked to original sources
PubMed1995

Unifying hypothesis for the pathogenesis of HIV-associated dementia complex, vacuolar myelopathy, and sensory neuropathy.

Neurological diseases associated with HIV infection include dementia, vacuolar myelopathy, and sensory neuropathy. Although in vitro studies suggest that other nervous system cell types could harbor HIV, immunohistochemical and in situ hybridization studies have indicated that only macrophages/microglia are significantly infected in the central nervous system. In the peripheral nervous system, even HIV-infected macrophages are rare. Therefore, theories regarding the pathogenesis of HIV-associated neurologic disorders have centered around the elaboration of substances that may be toxic to neurons, oligodendrocytes or myelin. These potential toxins include HIV proteins, cellular metabolites, and cytokines. In this review we present evidence that there are large numbers of macrophages/microglia present in the nervous system of patients with these diseases and that they produce tumor necrosis factor (TNF)-alpha. The large increase in macrophage activity late in HIV infection may be due to the diminution in production by CD4-positive T cells of cytokines such as interleukin (IL)-4 and IL-10 which are inhibitors of macrophage activities. We hypothesize that HIV-associated dementia complex, vacuolar myelopathy, and sensory neuropathy are directly or indirectly related to the increased numbers of macrophages found in brain, spinal cord, and peripheral nerve. Future therapies may be directed towards inhibition of macrophage functions.

AIDS Dementia Complex↗
PubMed1995

Increasing neurofilament subunit NF-M expression reduces axonal NF-H, inhibits radial growth, and results in neurofilamentous accumulation in motor neurons.

The carboxy-terminal tail domains of neurofilament subunits neurofilament NF-M and NF-H have been postulated to be responsible for the modulation of axonal caliber. To test how subunit composition affects caliber, transgenic mice were generated to increase axonal NF-M. Total neurofilament subunit content in motor and sensory axons remained essentially unchanged, but increases in NF-M were offset by proportionate decreases in both NF-H and axonal cross-sectional area. Increase in NF-M did not affect the level of phosphorylation of NF-H. This indicates that (a) in vivo NF-H and NF-M compete either for coassembly with a limiting amount of NF-L or as substrates for axonal transport, and (b) NF-H abundance is a primary determinant of axonal caliber. Despite inhibition of radial growth, increase in NF-M and reduction in axonal NF-H did not affect nearest neighbor spacing between neurofilaments, indicating that cross-bridging between nearest neighbors does not play a crucial role in radial growth. Increase in NF-M did not result in an overt phenotype or neuronal loss, although filamentous swellings in perikarya and proximal axons of motor neurons were frequently found.

Amino Acid Sequence↗
PubMed1995

Guillain-Barré syndrome in northern China. The spectrum of neuropathological changes in clinically defined cases.

The pathology of the Guillain-Barré syndrome remains controversial, and autopsied cases available for study by contemporary techniques are uncommon. Large numbers of cases clinically diagnosed as Guillain-Barré syndrome occur in northern China. In this study we examined the neuropathological changes in 12 autopsied cases from Hebei Province, China. Eleven died early in the course of their disease. In all cases tissue was specially handled and fixed for electron microscopy and for immunocytochemistry. Three of these 12 cases had typical acute inflammatory demyelinating polyneuropathy (AIDP) with lymphocytic infiltration and macrophage-mediated demyelination, reproducing the pathological picture most often reported in Guillain-Barré syndrome in North America, Europe, and Australia. Six cases had predominantly axonal involvement, characterized by Wallerian-like degeneration of nerve fibres, with only minimal demyelination and with minimal inflammation in five. Three cases, even though paralysed at the time of death, had only very mild changes in the spinal roots and sciatic nerves. Within the group of six predominantly axonal cases, there were important differences both in the severity of the abnormalities and in the classes of fibres involved. Three cases had extensive Wallerian-like degeneration of sensory as well as motor fibres [acute motor-sensory axonal neuropathy (AMSAN)], while in the other three cases the fibre degeneration affected the motor nerve fibres almost exclusively. These latter cases establish a structural basis for the clinical and electrophysiological picture termed the acute motor axonal neuropathy (AMAN) pattern. In both the AMAN and the AMSAN patterns, a prominent feature was the presence of macrophages within the periaxonal space, surrounding or displacing the axon, and surrounded by an intact myelin sheath. These studies show that the early pathological changes in cases clinically diagnosed as the Guillain-Barré syndrome are diverse and not restricted to the well-known pattern of AIDP, and that the predominant pathological patterns may differ in different parts of the world. The differences in pathological findings between acute inflammatory demyelinating polyneuropathy and the axonal patterns are likely to reflect differences in the pathogenetic mechanisms. The periaxonal macrophages in the axonal patterns suggest that an important epitope may be localized to the axolemma or periaxonal space. The mild cases indicate that severe paralysis can occur early in Guillain-Barré syndrome without prominent structural changes along the nerve, suggesting that physiological block or nerve terminal changes may be implicated.

Acute Disease↗
PubMed1995

Guillain-Barré syndrome in northern China. Relationship to Campylobacter jejuni infection and anti-glycolipid antibodies.

Guillain-Barré syndrome has been considered to be primarily an acute inflammatory demyelinating polyneuropathy (AIDP). Our experience with Guillain-Barré syndrome in northern China differs from the traditional concept. Electrophysiologically and pathologically, most of our patients have motor axonal degeneration with minimal cellular inflammation, which we have termed 'acute motor axonal neuropathy' (AMAN). The current studies were undertaken to characterize prospectively the clinical, electrophysiological, and serological features of Guillain-Barré syndrome, defined clinically, in northern China. In 1991 and 1992, we characterized by electrodiagnostic criteria 129 Chinese patients with Guillain-Barré syndrome. The AMAN form was present in 65% of patients, the AIDP form in 24% and 11% were unclassifiable. For the 38 patients who presented from January to October, 1992, we performed serological assays for antibodies to Campylobacter jejuni and to glycolipids. Of these 38 patients, 55% had AMAN, 32% had AIDP and 13% were unclassifiable. Sixty-six percent of the 38 had serological evidence of recent C. jejuni infection as compared with 16% of village controls (P = 0.001). Seventy-six percent of AMAN patients and 42% of AIDP patients were seropositive. IgG anti-GM1 antibodies were more frequent in Guillain-Barré syndrome patients compared with village controls (42% versus 6%; P < 0.01). However, no statistically significant correlations were found between the pattern of disease, AMAN or AIDP, anti-glycolipid antibodies, or C. jejuni antibodies. Based on electrophysiological criteria, Guillain-Barré syndrome in northern China can be divided into two predominant forms: AIDP and AMAN. The AMAN form is more common and predominates in the yearly summer outbreaks of Guillain-Barré syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

Octreotide enhances positive calcium balance in Duchenne muscular dystrophy.

Although receptors for somatostatin are found in bone cells, the effect of somatostatin analogs on calcium metabolism is unknown. The authors studied, in a metabolic ward, the effect of octreotide (a long-acting somatostatin analog) and a placebo in two 6-day calcium balance periods in 8 children with Duchenne muscular dystrophy. As expected, octreotide (2 micrograms/kg, subcutaneously, every 8 hours) reduced serum growth hormone and somatomedin (IGF-1) to levels found in growth hormone deficiency. Octreotide enhanced calcium retention by 30% (96 mg daily [P < 0.04]) in 7 boys for whom complete data (diet, urine, and fecal calcium) were available. In 6 children with urinary calcium excretion (Uca) greater than 50 mg daily, octreotide markedly lowered Uca, from 114 +/- 23 mg daily to 61 +/- 9 mg daily (P < 0.03). Calcium retention occurred in patients with or without initial hypercalciuria, but the higher the basal Uca, the greater was the inhibition by octreotide (r = 0.79; P < 0.03). Inactive, nonambulatory patients had a more pronounced response of Uca to octreotide (P < 0.02). Octreotide caused a mild, nonsignificant reduction in fecal calcium, with no major changes in serum calcium, phosphorus, parathyroid hormone, urinary excretion of sodium and potassium, or in creatinine clearance. Based on the current observations and the presence of receptors for somatostatin in bone cells, this hormone may have, at least on a short-term basis, an anabolic effect on calcium, perhaps favoring its deposition in bone.

Adolescent↗
PubMed1995

Effects of anti-E2 monoclonal antibody on sindbis virus replication in AT3 cells expressing bcl-2.

Antibodies directed to Sindbis virus (SV) envelope protein E2 are able to control virus replication in vivo and in persistently infected cultures of neurons in vitro. We investigated the mechanisms by which anti-E2 monoclonal antibody (MAb) alters virus replication by using AT3 rat prostatic carcinoma cells expressing the inhibitor of apoptosis bcl-2. Treatment of SV-infected AT3-bcl-2 cells with anti-E2 MAb G5 for 2 h decreased the rate of virus release for 6 to 8 h after removal of the antibody. Electron microscopic analysis of MAb-treated cells revealed that failure of virus release was linked to a defect in the budding process. The decrease in extracellular virus particles occurred despite continued formation of nucleocapsids and synthesis of envelope glycoproteins. MAb treatment delayed the inhibition of K+ influx and shutoff of host cell protein synthesis by SV infection in a dose-dependent manner. Synthesis of host cell factors and of nonstructural polyprotein precursors required for the formation of initial replication complexes was also prolonged, causing a slower shutdown of overall viral RNA synthesis. We conclude that one mechanism by which anti-E2 MAb treatment down-regulates SV replication is by reestablishing certain critical host cell functions in infected cells.

Animals↗
PubMed1995

Antiviral activity of alpha interferon in Sindbis virus-infected cells is restored by anti-E2 monoclonal antibody treatment.

Pretreatment of AT3 rat prostatic carcinoma cells expressing the inhibitor of apoptosis bcl-2 (AT3-bcl-2 cells) with alpha interferon (IFN-alpha) affected replication of a virulent strain of Sindbis virus (SV) but did not protect against virus-induced cell death. Treatment of cells with IFN-alpha late during infection affected ongoing SV replication very little. Previous studies have shown that cross-linking of the viral glycoprotein E2 with antibody delays the inhibition of K+ influx by improving the function of Na+K+ATPase and the Na(+)-K(+)-2Cl-cotransport system in SV-infected cells (P. Després, J. W. Griffin, and D. E. Griffin, J. Virol. 69:7006-7014, 1995). In these studies, we have shown that treatment of infected cells with anti-E2 monoclonal antibody also restored the ability of IFN-alpha to induce antiviral activity in infected cells late during infection. The very low rate of virus release in SV-infected cells treated simultaneously with anti-E2 monoclonal antibody and IFN-alpha was postulated to be linked to inhibition of virus maturation. Synergistic effects of antibody and IFN-alpha are likely to be important for control of SV replication in vivo.

Animals↗
PubMed1995

Cutaneous innervation in sensory neuropathies: evaluation by skin biopsy.

OBJECTIVE: To use punch skin biopsies to evaluate the loss of intra-epidermal nerve fibers in sensory neuropathies. BACKGROUND: Previous assessments of epidermal nerve fibers have been constrained by relatively insensitive staining techniques and variability in quantification. METHODS: Punch skin biopsies were performed on the heel and leg of HIV-seronegative controls, HIV-seropositive individuals without neuropathy, and patients with sensory neuropathies, including HIV-seronegative and HIV-positive individuals. After formalin fixation, 50-microns free-floating sections were stained with a monoclonal antibody to neuron-specific ubiquitin hydrolase, PGP9.5. The number of intraepidermal fibers/mm in at least three sections from each patient was counted by one observer blinded to site and clinical status. RESULTS: Dermal and epidermal nerve fibers were readily identified and quantified. The immunostaining technique reliably demonstrated a dermal plexus of myelinated and unmyelinated fibers parallel to the surface of the skin. In the epidermis, unmyelinated fibers ascended vertically between the keratinocytes to reach the stratum corneum. The number of intra-epidermal fibers/mm in the distal leg (mean +/- SEM) was 17.84 +/- 3.03 in seven HIV-seronegative controls. Epidermal fiber number was significantly reduced (p = 0.01) in five HIV-infected patients with sensory neuropathies associated with didanosine or zalcitabine therapy (1.07 +/- 0.40) and in eight HIV-seronegative patients with sensory neuropathies (3.1 +/- 3.1). Four of five neurologically normal HIV-seropositive subjects had reduced numbers of epidermal fibers, suggesting a subclinical neuropathy. Serial biopsies in one individual demonstrated the evolution of degenerating epidermal fibers after development of zalcitabine-induced sensory neuropathy. CONCLUSION: Skin biopsies stained with the sensitive panaxonal marker anti-PGP9.5 demonstrated significant reduction in intraepidermal fibers in sensory neuropathies. This simple and repeatable technique is a reliable method for quantitation of small cutaneous sensory fibers. In addition, skin biopsies may be useful in assessing the course and spatial distribution of involvement in peripheral nerve disease.

Adult↗
PubMed1995

Axotomy-induced axonal degeneration is mediated by calcium influx through ion-specific channels.

We examined the role of extracellular calcium entry, the possible involvement of axonal calcium channels, and the potential protective effect of calcium channel and calpain antagonists in axotomy-induced axonal degeneration using murine dorsal root ganglia in cell culture. We found that calcium entry is both necessary and sufficient to induce axonal degeneration after axotomy, and may be inhibited by cobalt, manganese, dihydropyridines, and bepridil. Tetrodotoxin and omega-conotoxin are ineffective in preventing axonal degeneration. The activation of calpains also appears to be necessary and sufficient for axonal degeneration to proceed, and can be blocked with membrane-permeant leupeptin analogs and the oxirane aloxistatin. Although other calcium-activated events may occur, it appears that inhibition of calpain is sufficient to preserve the axon at the light microscope level, and to prevent axonal cytoskeleton degradation as detected by immunofluorescent staining. Our results suggest that axonal degeneration after axotomy involves the following sequence of events: (1) a lag-period after axotomy prior to the onset of axonal degeneration, (2) entry of calcium into the axon through an intact axolemma via a calcium-specific ion transport mechanism, (3) activation of calcium-dependent effector molecules such as calpains, (4) degradation of the axonal cytoskeleton. The details of the second step require further elucidation, and are of particular interest because this step is a potential target for therapies directed towards peripheral neuropathies.

Animals↗
PubMed1992

Ophthalmic involvement in myo-neuro-gastrointestinal encephalopathy syndrome.

We studied the clinical, histopathologic, neuroradiologic, biochemical, and genetic profile of a patient with the myo-neuro-gastrointestinal encephalopathy syndrome, a recently described multisystem mitochondriopathy characterized by blepharoptosis and ophthalmoparesis. The patient had severe intestinal pseudo-obstruction and a mixed demyelinating and axonal neuropathy. Abnormal collections of mitochondria in nerve and muscle as well as diffuse white matter disease were present. Cytochrome oxidase activity in muscle mitochondria was reduced. No mitochondrial DNA deletions were detected.

Adult↗
PubMed1992

Cytokine expression in the brain during the acquired immunodeficiency syndrome.

The pathogenesis of central nervous system (CNS) disease in acquired immunodeficiency syndrome (AIDS) is poorly understood but may be related to specific effects of the immune system. Cytokines such as tumor necrosis factor and interleukin-1 may have toxic effects on CNS cells and have been postulated to contribute to the pathogenesis of the neurological complications of human immunodeficiency virus (HIV) infection. To characterize viral and immunological activity in the CNS, frozen specimens taken at autopsy from the cerebral cortex and white matter of HIV-seropositive and -seronegative individuals were stained immunocytochemically for mononuclear cells, major histocompatibility complex (MHC) antigens, HIV, astrocytes, and the cytokines interleukin-1 and -6, tumor necrosis factor-alpha and -beta, and interferon gamma. Levels of soluble CD4, CD8, and interleukin-2 receptor, as well as interferon gamma, tumor necrosis factor-alpha, beta 2-microglobulin, neopterin, and interleukin-6 and -1 beta were assayed in the cerebrospinal fluid and plasma of many of these individuals during life. The HIV-seropositive group included individuals without neurological disease, those with CNS opportunistic infections, and those with HIV encephalopathy. Perivascular cells, consisting primarily of macrophages with some CD4+ and CD8+ T cells and rare B cells, were consistently MHC class II positive. MHC class II antigen was also present on microglial cells, which were frequently positive for tumor necrosis factor-alpha. HIV p24 antigen, when present, was found on macrophages and microglia. Endothelial cells were frequently positive for interleukin-1 and interferon gamma and less frequently for tumor necrosis factor and interleukin-6. There were gliosis and significant increases in MHC class II antigen, interleukin-1, and tumor necrosis factor-alpha in HIV-positive patients compared to HIV-negative brains. Cerebrospinal fluid from most of the patients tested had increased levels of tumor necrosis factor, beta 2-microglobulin, and neopterin. There was no correlation in HIV-positive individuals between levels of cytokines and the presence or absence of CNS disease. These data indicate that there is a relative state of "immune activation" in the brains of HIV-positive compared to HIV-negative individuals, and suggest a potential role for the immune system in the pathogenesis of HIV encephalopathy.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Somatofugal axonal atrophy precedes development of axonal degeneration in acrylamide neuropathy.

Somatofugal axonal atrophy is part of the neuronal perikaryal response to axonal injury (axon reaction). Chronic administration of acrylamide (AC) produces proximal atrophy in virtually all sensory fibers in lumbar dorsal root ganglion (DRG) despite the presence of many intact axons in the distal portion of the sciatic nerve. This suggests that the development of axonal atrophy in AC-intoxicated animals is not solely due to a toxic chemical-induced axonal degeneration (axotomy). In this study, we asked whether axonal atrophy arises before onset of axonal degeneration. Rats were given a single intraperitoneal (i.p.) high dose of AC (75 mg/kg), which blocks retrograde axonal transport, followed by daily intraperitoneal injections (30 mg/kg, for 4 days). At 5 days, sensory fibers in the L4 and L5 DRG appeared smaller in caliber and less circular in shape compared to fibers from age-matched normal animals. Axonal diameters of sensory fibers in the L5 dorsal root were significantly (p less than 0.05) reduced at distances up to 2 mm from the DRG. Quantitative electron microscopy demonstrated that the reduction in caliber was due to a decreased neurofilament (NF) content. Axonal degeneration was not present in the distal portion of both centrally (dorsal root) and peripherally (sciatic nerve) projecting sensory fibers at this time, although primary afferent terminals in muscles of the hindfeet were packed with NFs. The somatofugal progression of the atrophy was evident following more prolonged exposures (10-28 days). It is suggested that AC produces somatofugal axonal atrophy by inhibiting the delivery of a retrogradely transported target-derived "trophic" signal to the neuronal perikaryon.

Acrylamide↗
PubMed1992

Macrophage responses and myelin clearance during Wallerian degeneration: relevance to immune-mediated demyelination.

Macrophages are important effector cells in immune-mediated demyelination. Current concepts regarding their entry and activation focus on the effects of T-cell-derived cytokines. This presentation describes the responses of macrophages and microglia to a non-inflammatory, non-immune injury, Wallerian degeneration. During Wallerian degeneration in the peripheral nervous system (PNS), macrophages are promptly and abundantly recruited from the circulation, and myelin clearance is prompt. In the central nervous system (CNS), the appearance of macrophages is markedly slower, and entry from the circulation is modest or absent. Myelin clearance is similarly delayed. The nature of the factors promoting macrophage entry and activation in Wallerian degeneration, and the bases for the differences between PNS and CNS, are relevant to current issues in immune-mediated demyelination.

Animals↗
PubMed1992

Chronic demyelinating polyneuropathy associated with eosinophilia-myalgia syndrome.

Eosinophilia-myalgia syndrome (EMS) is a newly described syndrome associated with use of L-tryptophan. A neuropathy with features of axonal degeneration has also been described in conjunction with EMS. Demyelinating polyneuropathy is not a well recognised association of the syndrome. The two patients with EMS reported presented with profound weakness and sensory loss and were found to have clinical, electrophysiological and pathological evidence of a chronic demyelinating polyneuropathy. The concurrence of this neuropathy with EMS, as well as several other features of their illness, is suggestive of an immune mediated mechanism in the pathophysiology of EMS.

Aged↗
PubMed1992

Wallerian degeneration in peripheral nerve disease.

This article first reviews the different classes of nerve injury. The temporal evolution of electrophysiologic changes occurring during Wallerian degeneration in humans is then described, followed by a description of sequential structural changes and cellular responses that occur after nerve transection. The final section focuses on the basis for resurgent research interest in Wallerian degeneration and the different research approaches being taken to answer basic science and clinical questions.

Animals↗
PubMed1992

Aluminum-induced neurofilamentous changes in cultured rat dorsal root ganglia explants.

Intrathecal administration of aluminum (AI) salts to susceptible species causes prominent accumulations of neurofilaments (NFs) in neurons of the CNS. Involved nerve cells display abnormal phosphorylation of perikaryal NFs, impaired axonal transport of NFs, and reduced levels of mRNA for NF proteins. Further understanding of the pathogenesis of AI toxicity has been limited by difficulties inherent in the available in vivo systems. For this reason, we have developed a model to study the effects of AI on cultured sensory neurons. Explant cultures of rat dorsal root ganglia (DRG) were exposed to 1 mM aluminum lactate for 1 d, 3 d, or 7 d and then examined morphologically. Accumulations of NFs were noted as early as 1 d after exposure, and prominent masses of NFs were seen at 3 and 7 d. Northern analysis of mRNA extracted from the cultured ganglia showed that high, medium, and low molecular weight NF protein mRNA levels were markedly reduced compared to control values by 1 d of exposure. Class II beta-tubulin mRNA was also moderately decreased. Reversibility of toxicity was assessed by removing the aluminum lactate from the medium after a 3 d exposure and examining the cultures 1 week later. The perikaryal masses of NFs dispersed and the levels of mRNA coding for the NF proteins and class II beta-tubulin increased. The neurotoxic effects of AI on cultured DRG recapitulates the effects of intrathecal administration of AI on animals; this model produces similar changes in neuronal morphology with neurofilamentous masses and similar modifications of NF gene expression.(ABSTRACT TRUNCATED AT 250 WORDS)

Aluminum↗