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Biomedical subjects

C A Wiley

Publications and source records attributed to C A Wiley.

At least 91 records · Page 5Linked to original sources
PubMed1993

Peripheral nerve lesions in HTLV-I associated myelopathy (HAM/TSP).

Peripheral nerve dysfunction (PND) was found in as many as 43% of our patients with human T-cell lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM/TSP). To evaluate the PND further we biopsied the sural nerve in 6 patients. The histological features were varying degrees of demyelination, remyelination, axonal atrophy and degeneration, and perineurial fibrosis. "Globule" or "sausage" formation was prominent in two of the specimens. Inflammatory infiltrates were absent. No deposits of IgG, IgM, IgA, or complement were detected in the biopsies. No viral antigen or proviral DNA was detected. It is proposed that the PND and the histological findings noted are part of HTLV-I-associated disease and not an unrelated disorder. The pathogenesis of the PND remains unclear. There was no evidence of direct viral infection. The histological findings could represent primary changes induced by viral-triggered release of soluble factors, such as cytokines or secondary changes to more proximal disease, e.g., root involvement.

Adult↗
PubMed1993

HTLV-1 in acquired adult myopathy.

We report a 53-year-old Jamaican man with 20 years of progressing weakness involving proximal limb muscles and neck flexors. Serum CK was 1100 IU/L. EMG demonstrated spontaneous activity, myopathic motor units, and full recruitment patterns in weak muscles. Muscle biopsy revealed marked myofiber degeneration with extensive fibrosis, suggesting a chronic myopathic process. HTLV-1 antibody was present in serum in high titers by ELISA and Western blot. Immunohistochemistry with rabbit polyclonal antisera to HTLV-1 showed rare staining myocytes. PCR demonstrated HTLV-1 DNA in frozen muscle tissue. This myopathy, associated with HTLV-1 infection, has clinical and pathological features similar to a dystrophy. We recommend serological screening for HTLV-1 in cryptogenic adult myopathies.

HTLV-I Infections↗
PubMed1993

Synaptic and dendritic pathology in murine retroviral encephalitis.

Central nervous system (CNS) damage occurs during retroviral infection in both man and animals. As a model of human disease, we studied the distribution and extent of CNS damage during retroviral infection with two molecularly cloned, neurotropic murine leukemia viruses. Both viruses mediate a spongiform encephalopathy involving predominantly the brainstem and spinal cord. During the course of disease, immune reactivity for synaptophysin (SYN) (to identify presynaptic elements) and microtubule-associated protein-2 (MAP-2) (to identify postsynaptic elements) were quantified using confocal laser microscopy. Immunostaining of SYN in the cerebral cortex (an area not exhibiting spongiform lesions) was similar in viral infected and age-matched control mice. However, compared to age matched controls, SYN staining in the brainstem (an area exhibiting spongiform lesions) of viral infected mice progressively declined during the course of disease. Quantitative analysis showed greater reduction of MAP-2 immunostaining in viral-infected mice compared to age-matched controls. In infected mice, both regions with and without spongiform lesions showed diminished MAP-2 staining. Widely distributed microscopic vacuolation of dendritic processes was observed in confocal preparations. These findings suggest primary dendritic damage in murine retroviral infection of the CNS similar to what has been described in human immunodeficiency virus-1 encephalitis.

Animals↗
PubMed1993

Herpesviruses in chronic encephalitis associated with intractable childhood epilepsy.

Herpesviruses (especially cytomegalovirus [CMV] and Epstein-Barr virus [EBV]) have been implicated in the pathogenesis of chronic (Rasmussen) encephalitis associated with epilepsy. To assess the presence of herpesvirus genes in brain tissue from epileptic children with chronic (usually Rasmussen type) encephalitis, DNA was extracted from surgically resected brain tissue and studied by the polymerase chain reaction using primers specific for CMV, varicella zoster virus, herpes simplex virus, EBV, and human herpesvirus 6 genes. By this technique evidence for the presence of low levels of CMV and EBV genes was detected in most brain specimens from encephalitis patients and in several brain specimens from patients without encephalitis (eg, cortical dysplasia, gliosis, or encephalomalacia) who also had intractable epilepsy. Occasionally, both EBV and CMV genes were found in the same brain. Signal strength for both CMV and EBV was much lower in epileptic brains than in the brains of acquired immunodeficiency syndrome patients with CMV encephalitis or brain lymphoma. We found evidence for infection of the brain by human herpesvirus 6 in only one patient with encephalitis. Polymerase chain reaction technology applied to resected brain tissue from epileptic patients may provide evidence for or against viral-mediated pathogenesis of Rasmussen encephalitis or other types of encephalitis. The small amounts of EBV and CMV genes found suggest that herpesvirus infection of the brain does not directly cause Rasmussen encephalitis.

Autoradiography↗
PubMed1993

Expression of major histocompatibility complex antigens and serum neutralizing antibody in murine retroviral encephalitis.

Murine leukemia virus infection serves as a model for noninflammatory degeneration of the central nervous system (CNS). During the course of infection with either of the molecularly cloned viruses pNE-8 or ts-1, we observed that ts-1 spread twice as rapidly as pNE-8, and ascended higher in the neuraxis. Endothelial cells were infected first, followed by oligodendrocytes and neurons, while astrocytes containing glial fibrillary acidic protein were not infected. Additionally, ts-1 also infected macrophages/microglia. Major histocompatibility complex (MHC) class I beta 2-microglobulin expression was minimal in pNE-8 infected mice, while it was elevated in endothelial cells of early ts-1 lesions, and in macrophages/microglia during later stages. Occasional infected cells expressed beta 2-microglobulin while rare endothelial and parenchymal cells expressed MHC class II in both viral infections. Limited intra-CNS MHC expression may be one of the mechanisms of viral persistence and will present a barrier to developing immunotherapy for CNS retroviral infections. The few mice that escaped lethal infection had higher serum titers of neutralizing antibodies and showed no neuropathologic changes or detectable virus in the CNS. Higher titers of neutralizing antibodies may protect the CNS from infection.

Animals↗
PubMed1993

Retinal calcifications in cytomegalovirus retinitis.

Cytomegalovirus (CMV) retinitis has been well documented in the literature, both in patients with acquired immune deficiency syndrome (AIDS) and in other immunocompromised hosts. The clinical and histopathologic findings in three patients with AIDS and CMV retinitis are presented. In areas of healed retinitis, focal, yellow-white, plaque-like lesions and small refractile retinal lesions were noted clinically. Histopathologic studies confirmed the plaque-like lesions to be intraretinal calcifications. Detailed clinical pathologic correlation between fundus photographs and histologic material is made and its clinical importance discussed.

AIDS-Related Opportunistic Infections↗
PubMed1993

An animal model of focal, subacute, viral retinitis.

To study local intravitreal therapies for retinitis due to herpes viruses, an animal model of focal, subacute, relatively nonlethal herpes family retinitis is needed. Herpes simplex virus type 1 (HSV-1) was injected into the subretinal space of 33 Dutch pigmented rabbit eyes. The animals were observed for up to 42 days after the inoculation. All inoculated eyes developed a focal, enlarging area of retinitis in a predictable manner, showing focal enlarging areas of retinal opacification and necrosis with variable retinal hemorrhage. In the inoculated eyes, retinal detachment developed in all animals within 21 days; 33% of the animals developed focal retinitis in the uninoculated eye. Histologic examination showed encephalitis to be present in 11 (73%) of the 15 animals studied after 1 week. This model may be used to evaluate the therapeutic efficacy of new antiviral agents and modalities in the treatment of herpes family viral retinitis. The model is most similar to herpes simplex or zoster retinitis in humans, but also shares some similarities (and differences) with cytomegalovirus (CMV) retinitis in humans.

Acute Disease↗
PubMed1993

The pathogenesis of murine retroviral infection of the central nervous system.

Several decades have lapsed since the original description of retroviral infection of the central nervous system (CNS) appeared. With the recent arrival of the autoimmune deficiency syndrome (AIDS) epidemic and the associated human retroviral encephalitis, interest in murine models has been rekindled. In most of the published studies, susceptible mouse strains are infected as neonates with molecularly cloned type-C retroviruses. In most models, a spongiform encephalopathy follows an early CNS endothelial cell infection. The subsequent pathogenesis of this encephalopathy is unknown. In some models neuronal and glial infection is seen, while in others only non-neuroglial elements are infected. This variation can be traced to differences in strains of mice and viruses in addition to differences in assays. The different models offer fertile experimental ground to decipher the role of direct versus indirect neuroglial damage. Reconciliation of these various models where the final neuropathology appears so similar, may be the key to understanding their pathogenesis.

Animals↗
PubMed1993

Mechanisms of immune activation of human immunodeficiency virus in monocytes/macrophages.

Monocytes/macrophages (M/M) are the major host of human immunodeficiency virus (HIV) in solid tissues. However, blood monocytes are nonpermissive for HIV infection, indicating that M/M activation or differentiation is necessary for HIV replication. Since M/M are activated during immune responses, we investigated the effect of T-cell activation on HIV expression in M/M derived from peripheral blood of HIV-infected individuals. Previously, we reported that coculture of monocytes from HIV-infected donors with T cells and mitogens resulted in M/M differentiation and HIV expression. Production of HIV by M/M from infected donors required direct contact between monocytes and T cells (for the first 24 h), and the response to alloantigens, but not mitogens, was restricted to HLA-DR. In this study, we found that HIV was more readily recovered from M/M of asymptomatic HIV seropositive donors (69%) than from M/M of symptomatic donors (57%). Viral antigens (e.g., inactivated herpes simplex virus) could initiate the immune response and HIV expression. The ability of noninfected T cells to activate HIV expression in M/M and observations that treatments of M/M with antibodies to deplete T cells did not reduce HIV expression suggested that the monocytes were endogenously infected. To define the aspects of immune activation specifically involved in initiating HIV expression in M/M, interactions of M/M and T cells and participation of cytokines were investigated. The T cell which activated M/M was CD4+ CD8-. Fixed allogeneic cells are known to induce T-cell activation but were not able to serve as antigen for M/M differentiation, suggesting that M/M may need to function as antigen-presenting cells to receive the signal to differentiate and express HIV. Blocking of M/M-T-cell interaction with antibodies directed against LFA-1 or interleukin-1 prevented HIV expression. However, inhibition of later stages of T-cell activation, such as blocking of interleukin-2 receptors, did not diminish HIV expression in M/M. Consistent with the requirement for cell-cell contact between M/M and T cells, a variety of cytokines were unable to initiate HIV replication in M/M. The ability of T cells to induce cellular differentiation and HIV replication in M/M in vitro suggests that initiation of an immune response to an antigen, such as an opportunistic pathogen, could be a mechanism by which HIV disseminates to tissues in vivo.

Antigens, CD↗
PubMed1993

In vivo model of HIV infection of the human brain.

Approximately one quarter of the AIDS patients have severe HIV encephalitis with diffuse neuronal damage that may be mediated by immune factors secreted by CNS macrophages. Based on an in vitro brain microsphere model, we developed an in vivo system in which human embryonic brain tissue survives for several months in the interscapular fat pad of SCID mice. Coculture of human brain tissue with macrophages prior to transplantation resulted in infiltration of the microspheres by activated macrophages. When the macrophages were infected in vitro with a neurotropic HIV strain, viral particles were detected in vivo up to 3 months after transplantation. HIV-infected transplants contained multinucleated giant cells similar to those seen in HIV encephalitis. However, the neuroglial component degenerated in the fat pad of SCID mice. The absence of synaptogenesis in the human transplants suggests that the murine fat pad lacks adequate stimuli or support for human neuronal differentiation. To study neurologic damage associated with HIV infection, sites of implantation that stimulate synaptogenesis (e.g. murine CNS) will need to be explored. Based on these findings we conclude that transplantation of brain microspheres with HIV-infected macrophages into SCID mice may be an achievable model of HIV encephalitis.

AIDS Dementia Complex↗
PubMed1993

Quantitation of human immunodeficiency virus, immune activation factors, and quinolinic acid in AIDS brains.

HIV encephalitis is unusual in that neurologic damage occurs in the absence of significant infection of neuronal or glial cells. Because the predominant infected cell in the brain is the macrophage, it has been proposed that release of viral or immune activation factors from macrophages may mediate neurologic damage. Numerous studies have examined the concentration of immune activation factors in the cerebrospinal fluid (CSF), however, there has been no correlation between these CSF measurements and severity of HIV encephalitis (Wiley, C.A., C.L. Achim, R.D. Schrier, M.P. Heyes, J.A. McCutchen, and I. Grant. 1992. AIDS (Phila.). 6:1299-1307. Because CSF measurements may not represent tissue concentrations of these factors, we examined the concentrations of HIV p24, quinolinic acid (QUIN), IL-1, IL-3, IL-6, TNF-alpha, and GMCSF within the brains of 10 AIDS autopsies. Homogenization and extraction of cortical gray, cortical white and deep gray matter showed a good correlation between the amount of HIV gp41 immunostaining and extracted HIV gag protein p24. The concentrations of cytokines were low in the tissue extracts and showed no correlation with severity of HIV encephalitis. Brain extracts from mild cases of HIV encephalitis showed elevated levels of TNF-alpha in deep gray matter, while in more severe cases, elevated TNF-alpha levels were also found within cortical white and cortical gray matter. Brain tissue and CSF QUIN concentrations were substantially increased compared to control values. QUIN concentrations were not correlated with the severity of HIV encephalitis. We conclude that increased tissue levels of TNF-alpha and QUIN may have a role in the etiology of HIV-related neurologic dysfunction.

AIDS Dementia Complex↗
PubMed1993

Evaluation of retinal toxicity and liposome encapsulation of the anti-CMV drug 2'-nor-cyclic GMP.

PURPOSE: Human cytomegalovirus (HCMV) is an important pathogen in the immunocompromised patient. CMV retinitis is a leading cause of blindness in patients with AIDS. Ganciclovir and foscarnet are currently the treatments being used for this retinitis, but they both have major toxicities when used systemically. Intravitreal therapy with ganciclovir has been used in some patients who cannot tolerate systemic treatment. The major problem with this modality is the necessity for administration of between 1 and 3 intravitreal injections per eye per week. 2'-nor-cyclic GMP is a nucleotide analog, a cyclic phosphate derivative of ganciclovir. Neutral salts of the compound are extremely water soluble, and the charged phosphate group at neutral pH make it an ideal candidate for encapsulation into a multivesicular liposome system. METHODS: The authors evaluated the retinal toxicity of the diethanolammonium salt 2'-nor-cyclic GMP by using electroretinographic, morphologic, and ophthalmoscopic techniques after intravitreal injections in rabbit eye. RESULTS: The intraocular therapeutic index for 2'-nor-cyclic GMP is 20. At the 10 micrograms dose, electroretinogram, ophthalmoscopic examination, and both light and electron microscopy revealed no abnormalities. Toxicity was evident at 50 micrograms and higher doses with ERG changes (loss of amplitude) and retinal pathology that varied from vacuolization of the retinal pigment epithelium and loss of height of the outer photoreceptor segment to loss of the entire outer retina. In addition, an in vitro drug release half-life of 1,000 hours (more than 75 times that of ganciclovir) was found for 2'-nor-cyclic GMP in liposome, which may be able to be exploited in the therapy of patients with CMV retinitis unable to tolerate toxic systemic therapy. CONCLUSION: The anti-CMV drug, 2'-nor-cyclic GMP, may be promising for intravitreal injection, particularly if encapsulated into liposomes.

Animals↗
PubMed1992

The prethreaded pupillary dilating (torpedo) suture for phakic and aphakic eyes.

A variety of methods for maintaining pupillary dilation for intraocular surgery have been advocated because pharmacologic agents may fail to maintain or adequately dilate the pupil. We have used a threaded needle to rapidly dilate the pupils of 19 aphakic, pseudophakic, or phakic eyes without damaging the lens or pseudophakos. This dilating suture can be constructed from available materials at low cost. We discuss the preparation of the suture and the techniques that allow rapid and reliable dilation during posterior vitrectomy or anterior segment surgery. Histologic studies were performed on rabbit eyes and demonstrated the position of the suture after performing pupillary dilation in phakic eyes. The technique has been used to dilate the pupils of phakic, aphakic, and pseudophakic patients without evidence of clinically significant complications.

Animals↗
PubMed1992

Management of dysphagia in inclusion body myositis.

Inclusion body myositis is an inflammatory myopathy in which dysphagia has been considered a rare finding. However, recent literature finds dysphagia an increasingly common symptom as more cases of inclusion body myositis are identified. Unlike some inflammatory myopathic disorders, inclusion body myositis is resistant to treatment with corticosteroids, and therefore, the otolaryngologist may be consulted regarding surgical options for relief of dysphagia. A patient is described in whom severe progressive dysphagia associated with inclusion body myositis developed. Impaired pharyngeal wall motion and cricopharyngeal achalasia were demonstrated by videofluoroscopic evaluation, and the patient was successfully treated by cricopharyngeal myotomy. The pathophysiologic nature of inclusion body myositis and the mechanisms of cervical dysphagia in the inflammatory myopathies are reviewed.

Aged↗
PubMed1992

Spectrum of human immunodeficiency virus-associated neocortical damage.

A spectrum of neurocognitive defects, termed human immunodeficiency virus type 1 (HIV-1)-associated cognitive/motor complex, has been described in patients with acquired immunodeficiency syndrome (AIDS). AIDS dementia complex (ADC) is a severe form of this disease seen in 20 to 30% of terminally ill patients. The etiology of this complex is distinct from commonly observed opportunistic infections seen in brains of patients with AIDS and has been attributed to HIV infection within the brain. At autopsy, the brains of patients with ADC contain numerous HIV-infected macrophages/microglia with prominent subcortical damage, together termed HIV encephalitis. We retrospectively analyzed all 107 brains from a three-year period (1988-1990) of AIDS autopsies using immunocytochemistry to detect HIV. Rather than breaking into distinct groups of HIV encephalitis versus non-HIV encephalitis, the specimens revealed a spectrum of severity of HIV infection. Although only 16% of the brains showed the histological hallmarks of HIV encephalitis, more than 50% of the autopsies showed moderate to severe HIV infection. In a subset of 23 AIDS autopsies during which short postmortem times and absence of significant opportunistic infection permitted quantitative analysis of dendritic and synaptic complexities, we identified a strong correlation between neocortical dendritic and presynaptic damage and abundance of HIV envelope protein in the neocortical gray and deep white matter. This correlation suggests that the presence of HIV-1 in the neocortex may be responsible by direct or indirect mechanisms for dendritic and synaptic damage.

AIDS Dementia Complex↗
PubMed1992

Neurological consequences of immune dysfunction: lessons from HIV infection and multiple sclerosis.

In a recent workshop held on Sanibel Island, Florida (18-21 January 1992), the two most common neuroimmunologic diseases of young adults, multiple sclerosis (MS) and HIV encephalopathy, were jointly discussed. The logic of assembling investigators from these two fields was based not on an assumed etiologic connection between MS and retroviral infection of the central nervous system (CNS), but rather in the hope of uncovering potential common pathogenic mechanisms, particularly as might relate to trafficking of mononuclear cells into the central nervous system, the distribution and function of macrophages and microglia, the structure and function of the blood-brain barrier, and the role of cytokines released by activated cells. Multiple sclerosis is a disease without a known etiologic agent or pathogenesis. While the causative agent for HIV leukoencephalopathy is known, the pathogenesis of the disease remains entirely enigmatic (a topic covered by R. Johnson). This meeting brought together two different groups of investigators to compare and contrast the diseases and to share perspectives, paradigms, and data with the aim of cross-fertilizing the disciplines and generating healthy hybrids.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Atypical healing of cytomegalovirus retinitis. Significance of persistent border opacification.

PURPOSE: To analyze a phenomenon seen in patients with acquired immune deficiency syndrome (AIDS) with cytomegalovirus (CMV) retinitis undergoing systemic antiviral treatment: a persistent white border opacification on the edge of healed CMV retinitis. PATIENTS AND METHODS: The authors prospectively evaluated a population of 137 patients with AIDS and CMV retinitis during a 44-month period. Eleven patients (12 eyes) who were undergoing maintenance antiviral treatment were identified with an atypical healing response--the persistence of a white flat border opacification that did not advance for many weeks to months. Patient records and photographs were reviewed. Results of one autopsy were analyzed with histopathology and special stains. RESULTS: The persistent white edge maintained (without advancement or smoldering) for an average of 11.6 weeks (range, 4 to 41 weeks). This border opacification was not affected by reinduction treatment in the six patients to whom reinduction was given. Results from histopathologic examination of one patient with a persistent white border are presented: these results show that dead cytomegalic cells formed stable structures within the retina, causing white opacification that could be confused with active lesions. Immunoperoxidase stains identified CMV antigens. CONCLUSION: This persistent white border opacification, which does not advance or smolder, represents an important clinical entity that should be recognized during antiviral treatment for CMV retinitis. It can often be observed. If it is not recognized as a stable configuration, patients may undergo unnecessary reinductions with potentially toxic doses of antiviral medications.

AIDS-Related Opportunistic Infections↗