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Biomedical subjects

S Jacobson

Publications and source records attributed to S Jacobson.

At least 73 records · Page 4Linked to original sources
PubMed1998

ELI-spot of Th-1 cytokine secreting PBMC's in multiple sclerosis: correlation with MRI lesions.

The Th1-like cytokines, interleukin 2 (IL-2), interferon gamma (IFN-gamma), and lymphotoxin alpha (LT-alpha) have been implicated in the immunopathogenesis of multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE), an animal model of immune mediated demyelination. These cytokines have been associated with opening of the blood brain barrier (BBB) in EAE and in vitro, but not in MS. We used an enzyme-linked immunospot (ELI-spot) assay to measure relative numbers of cytokine-secreting peripheral blood mononuclear cells (PBMC) from eight MS patients who were followed with serial monthly contrast-enhanced head magnetic resonance imagings (MRI) and phlebotomy. We found a significant positive correlation between changes in IL-2 secreting cells and MRI lesions over a 6-month time period. There was a weaker association between contrast-enhancing MRI lesions and IFN-gamma or LT-alpha secreting cells. These data are the first to show a significant positive correlation between any cytokine and serial gadolinium (Gd-) MRI disease activity in MS patients. The association between IFN-gamma and LT-alpha secretion and MRI lesions is less clear.

Adult↗
PubMed1998

Neuronal molecular mimicry in immune-mediated neurologic disease.

Molecular mimicry is implicated in the pathogenesis of autoimmune diseases such as diabetes mellitus, rheumatoid arthritis, and multiple sclerosis (MS). Cellular and antibody-mediated immune responses to shared viral-host antigens have been associated with the development of disease in these patients. Patients infected with human T-lymphotropic virus type I (HTLV-I) develop HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), an immune-mediated disorder of the central nervous system (CNS) that resembles some forms of MS. Damage to neuronal processes in the CNS of HAM/TSP patients is associated with an activated cellular and antibody-mediated immune response. In this study, IgG isolated from HAM/TSP patients was immunoreactive with uninfected neurons and this reactivity was HTLV-I specific. HAM/TSP IgG stained uninfected neurons in human CNS and cell lines but not nonneuronal cells. Neuronal western blots showed IgG reactivity with a single 33-kd band in all HAM/TSP patients tested. By contrast, no neuron-specific IgG reactivity could be demonstrated from HTLV-I seronegative controls and, more important, from HTLV-I seropositive, neurologically asymptomatic individuals. Both immunocytochemical staining and western blot reactivity were abolished by preincubating HAM/TSP IgG with HTLV-I protein lysate but not by control proteins. Staining of CNS tissue by a monoclonal antibody to HTLV-I tax (an immunodominant HTLV-I antigen) mimicked HAM/TSP IgG immunoreactivity. There was no staining by control antibodies. Absorption of HAM/TSP IgG with recombinant HTLV-I tax protein or preincubation of CNS tissue with the monoclonal antibody to HTLV-I tax abrogated the immunocytochemical and western blot reactivity of HAM/TSP IgG. Furthermore, in situ human IgG localized to neurons in HAM/TSP brain but not in normal brain. These data indicate that HAM/TSP patients develop an antibody response that targets uninfected neurons, yet reactivity is blocked by HTLV-I, suggesting viral-specific autoimmune reactivity to the CNS, the damaged target organ in HAM/TSP.

Autoimmune Diseases↗
PubMed1998

Reduction in HTLV-I proviral load and spontaneous lymphoproliferation in HTLV-I-associated myelopathy/tropical spastic paraparesis patients treated with humanized anti-Tac.

Human T-lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurological disease that results from an interaction of retroviral infection and immune activation. In this study, five doses (1 mg/kg) of humanized anti-Tac antibody were administered to 9 HAM/TSP patients at weeks 0, 2, 6, 10, and 14. Preliminary immunological studies on HAM/TSP patients treated with humanized anti-Tac indicate that there is a selective down-regulation of activated T cells and a decrease in the HTLV-I viral load in peripheral blood lymphocytes, most likely through the selective removal of HTLV-I-infected, activated CD4+ lymphocytes.

Antibodies↗
PubMed1998

Effects of Dispersant Treatment on the Acute Aquatic Toxicity of Petroleum Hydrocarbons

The acute effects of both untreated and dispersant-treated Prudhoe Bay crude oil on the early life-stages of three marine species were investigated. Identification of which water-accommodated fraction (undispersed or chemically dispersed) was considered "more toxic" was dependent on species, time, and endpoint (and by inference, test protocol). Generally, the data showed that at roughly equivalent hydrocarbon concentrations untreated oil solutions resulted in higher initial effects (< 1 h) in mysid and topsmelt tests, whereas dispersed oil solutions elicited higher levels of larval abnormality in abalone tests and higher levels of mortality in mysid tests. While differences in test protocols existed among the species tested, topsmelt were the most sensitive species to untreated oil solutions, with mysids being most sensitive to dispersed oil solutions.

Journal Article↗
PubMed1998

The effects of anesthesia and gender on intraocular pressure in lions (Panthera leo).

Intraocular pressure (IOP) was measured in a pride of 22 (11 males, 11 females) lions (Panthera leo) using a Schiotz tonometer. Two anesthetic protocols were used in the study. Lions in group I (n = 14) were anesthetized using xylazine, atropine sulfate, and ketamine. Lions in group II (n = 8) were anesthetized using ketamine and diazepam. Five sequential readings were taken from each eye of every lion. There were no significant differences in IOP between the two anesthetic groups, between left and right eyes, or over the five readings. The IOP was significantly higher in males than in females, controlling for age and weight. The mean (+/-SD) tonometer reading in 22 eyes of 11 male lions was 2.9 (+/-0.5) mm; with a 95% confidence interval (CI) of 1.6-4.5 mm. The mean tonometer reading in 22 eyes of 11 female lions was 4.0 (+/-0.7) mm, with a 95% CI of 1.8-6.3 mm. Using the 1955 Friedenwald human calibration table, the estimated mean IOP in 22 eyes of 11 male lions was 24.9 (+/-2.0) mm Hg, with a 95% CI of 20.4-29.4 mm Hg. The estimated mean IOP in 22 eyes of 11 female lions was 20.9 (+/-2.4) mm Hg, with a 95% CI of 15.6-26.3 mm Hg.

Adjuvants, Anesthesia↗
PubMed1997

Behavioral and pharmacologic treatment of delirium.

Delirium is an acute confusional state with a fluctuating course. Since the syndrome of delirium is associated with derangements of cognition, attention and level of consciousness, it can cause behaviors that are difficult to manage. Hallucinations, agitation, insomnia and anxiety are common in the delirious patient. Behavioral and pharmacologic interventions can be used while the underlying etiology of delirium is sought. Nonpharmacologic measures include frequent reassurance, environmental cues to reorient the patient and the judicious use of physical restraints. Haloperidol, which has negligible anticholinergic effects, is the drug most often used to treat the symptoms of delirium. Short-acting benzodiazepines may be useful in patients with delirium caused by alcohol withdrawal, but these agents may cause increased agitation in elderly patients and patients with hepatic dysfunction.

Cognitive Behavioral Therapy↗
PubMed1997

Human T cell leukemia virus type I (HTLV-I)-specific CD8+ CTL clones from patients with HTLV-I-associated neurologic disease secrete proinflammatory cytokines, chemokines, and matrix metalloproteinase.

Human T cell leukemia virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic, progressive neurologic disease characterized by marked degeneration of the spinal cord and the presence of infiltrating CD8+ T cells and macrophages. HAM/TSP patients have very high frequencies of HTLV-I-specific CD8+ CTL in peripheral blood and in cerebrospinal fluid. In this study, we show that HAM/TSP patients also have elevated levels of peripheral blood CD8+ T cells that produce intracellular IFN-gamma. To address the potential role of soluble mediators secreted by CD8+ T cells in the pathogenesis of HAM/TSP, we have analyzed the capacity of a panel of nine HTLV-I-specific CD8+ CTL clones derived from three HAM/TSP patients to secrete cytokines, chemokines, and matrix metalloproteinases. The results demonstrate that the majority of these CTL clones secrete IFN-gamma, TNF-alpha, macrophage-inflammatory protein-1alpha and -1beta, IL-16, and matrix metalloproteinase-9. These findings indicate that HTLV-I-specific CD8+ CTL are an important source of proinflammatory soluble mediators that may contribute significantly to the pathogenesis of HAM/TSP.

Chemokines↗
PubMed1997

Accumulation of human T lymphotropic virus (HTLV)-I-specific T cell clones in HTLV-I-associated myelopathy/tropical spastic paraparesis patients.

Human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraperesis (HAM/TSP) is a slowly progressive neurologic disorder following infection with HTLV-I. It is characterized by spasticity and hyper-reflexia of the lower extremities, urinary bladder disturbance, lower extremity muscle weakness, and sensory disturbances. HTLV-I, as an inducer of a strong humoral and cytotoxic response, is a well-known pathogenic factor for the progression of HAM/TSP. Peptides derived from proviral tax and env genes provide epitopes recognized by T cells. We herein report an accumulation of distinct clonotypes of alpha/beta TCR+ peripheral blood T lymphocytes from HAM/TSP patients in comparison with that observed in both asymptomatic carriers and healthy controls, using the reverse-transcriptase PCR/single-strand conformation polymorphism method. We also found that some of the accumulated T cell clones in the peripheral blood and cerebrospinal fluid are HTLV-I Tax(11-19) peptide specific. Such clones were found to expand strongly after being cultured with an HTLV-I Tax(11-19) peptide. Moreover, the cultured samples exhibited a strong MHC class I-restricted cytotoxic activity against HTLV-I Tax(11-19) peptide-expressing targets, and therefore most likely also include the disease-associated T cell clones observed in the patients. This is the first report of a direct assessment of Ag-specific T cell responses in fresh PBL and cerebrospinal fluid.

Clone Cells↗
PubMed1997

Approach to generalized weakness and peripheral neuromuscular disease.

A large number of intellectually engaging and potentially serious neuromuscular diseases have been presented. The emergency medicine physician must be able to recognize those entities that have the potential to clinically deterioration. The evaluation of weakness requires a comprehensive, broad-based differential that is driven by the history and physical. Diagnostic testing is determined by the clinical suspicion as is the urgency for further work-up. The following are the final diagnoses of the eight illustrative cases that were presented at the beginning of this article. Case 1. This unfortunate woman had a metabolic myopathy that was only diagnosed after enzymatic analysis of a muscle biopsy. Her genetic defect, carnitine palmitoyltransferase deficiency, is unusual as it does not present until late in adolescence or slightly later in life. It is a defect in lipid metabolism in which long-chain fatty acids are unable to gain entrance into the mitochondrion for oxidative degradation. The defect is apparent only after prolonged exercise or fasting. In this patient, rhabddomyolysis led to acute renal failure that resolved without requiring temporary dialysis. Case 2. This patient had an elevated CPK-MM. Her EMG showed myopathic changes and her nerve conduction studies were normal. She had a positive test for antinuclear antibodies. A biopsy of her quadriceps muscle revealed lymphocytic infiltration of the muscle fibers that showed some focal myocyte degeneration. The diagnosis of dermatomyositis was made based on the findings noted previously and the heliotrope hue of her periorbital skin. A search for an occult neoplasm was negative. She responded moderately to a course of high-dose prednisone. Case 3. The laboratory test that confirmed this diagnosis was the potassium of 2.4 mEq/L. The remainder of the electrolytes were normal. Infusion of 20 mEq of potassium over 2 hours led to a prompt return of normal muscle strength. The final diagnosis was hypokalemic periodic paralysis. In this disease there is an inherited defect in the ability of the myocyte to maintain a normal transmembrane potential. The defect is latent until there is a precipitating factor, such as an high carbohydrate meal or prolonged immobility. There is also a form seen with thyrotoxicosis and is essentially cured when the patient becomes euthyroid. The disease is seen most frequently in Asian males, although it is reported in most ethnic groups. Prophylaxis in these patients is with acetazolamide which raises the serum potassium indirectly by causing a metabolic acidosis. Triamterene and spironolactone have also been successfully used on occasion. This patient turned out to have thyrotoxicosis as well. Case 4. This man had both cranial motor and peripheral muscular dysfunction. There was no evidence of nonmotor cranial nerve dysfunction, nor was there evidence of any peripheral sensory deficits. The diagnosis of myasthenia gravis was established by the rapid and transient response of this patient to 2 mg of edrophonium. He was found to have antiacetylcholine receptor antibodies and was also thyrotoxic. He had a stormy course requiring intubation and prolonged ventilation. Eventually, he underwent thymectomy and is stable on pyridostigmine. Case 5. Initially suspected to be hysteria, this patient and his relatives had botulism from home-canned peppers. The index case required prolonged intubation and ventilation. The patients were treated with polyvalent antiserum and gastric lavage to remove the residual contaminated food which was still in their stomachs due to the gastric atony seen with this disease. The botulinus toxin prevents the release of acetylcholine molecules from their storage vesicles in nerve terminals. Thus, this disease is the opposite of the cholinergic syndrome seen with organophosphate insecticide poisonings except that cognitive functioning is not impaired in botulism. Case 6. This is a celebrated case that took a great deal of sleuthing

Adult↗
PubMed1997

Association of human herpes virus 6 (HHV-6) with multiple sclerosis: increased IgM response to HHV-6 early antigen and detection of serum HHV-6 DNA.

Viruses have long been suggested to be involved in the etiology of multiple sclerosis (MS). This suggestion is based on (1) epidemiological evidence of childhood exposure to infectious agents and increase in disease exacerbations with viral infection; (2) geographic association of disease susceptibility with evidence of MS clustering; (3) evidence that migration to and from high-risk areas influences the likelihood of developing MS; (4) abnormal immune responses to a variety of viruses; and (5) analogy with animal models and other human diseases in which viruses can cause diseases with long incubation periods, a relapsing-remitting course, and demyelination. Many of these studies involve the demonstration of increased antibody titers to a particular virus, whereas some describe isolation of virus from MS material. However, no virus to date has been definitively associated with this disease. Recently, human herpesvirus 6 (HHV-6), a newly described beta-herpes virus that shares homology with cytomegalovirus (CMV), has been reported to be present in active MS plaques. In order to extend these observations, we have demonstrated increased IgM serum antibody responses to HHV-6 early antigen (p41/38) in patients with relapsing-remitting MS (RRMS), compared with patients with chronic progressive MS (CPMS), patients with other neurologic disease (OND), patients with other autoimmune disease (OID), and normal controls. Given the ubiquitous nature of this virus and the challenging precedent of correlating antiviral antibodies with disease association, these antibody studies have been supported by the detection of HHV-6 DNA from samples of MS serum as a marker of active viral infection.

Antigens, Viral↗
PubMed1997

Correlation of morphine sulfate in blood plasma and saliva in pediatric patients.

This study sought to determine whether saliva concentrations of morphine correlate with plasma levels of morphine in pediatric patients receiving morphine analgesia for severe pain, and to evaluate whether the measurement of saliva morphine concentrations would be a useful, noninvasive, clinical tool to diagnose systemic exposure to morphine. Fifteen pediatric patients were enrolled; for the control group, 18 adult volunteers were recruited. Patients received continuous morphine drips to ameliorate pain caused by a sickle cell vasoocclusive crisis (range, 10-40 micrograms/kg.h). Control subjects were randomized into those receiving acetaminophen with either 8 mg (n = 13) or 30 mg (n = 5) of codeine. All participants fasted at least 2 hours before sample collection. Blood and saliva samples were collected simultaneously. All samples were analyzed by radioimmunoassay for morphine. There was no correlation between saliva and plasma morphine concentrations in either the patients receiving intravenous morphine (r = 0.04, P = 0.89) or in the controls receiving codeine (r = 0.43, P = 0.08). There was no observed difference in the mean counts per minute (CPM) for saliva samples in the pH range 3.96 to 8.06. Saliva concentrations of morphine cannot be used to predict the plasma concentration of morphine in children or adults. However, the concentration of morphine in saliva may be used as a qualitative indicator of systemic exposure to morphine in a subject.

Adolescent↗
PubMed1997

Astrocyte-specific expression of human T-cell lymphotropic virus type 1 (HTLV-1) Tax: induction of tumor necrosis factor alpha and susceptibility to lysis by CD8+ HTLV-1-specific cytotoxic T cells.

Human T-cell lymphotropic virus type 1 (HTLV-1) is associated with a chronic neurological disease termed HTLV-1-associated myelopathy/tropical spastic paraperesis (HAM/TSP). Although the pathogenesis of this disease remains to be elucidated, the evidence suggests that immunopathological mechanisms are involved. Since HTLV-1 tax mRNA was colocalized with glial acidic fibrillary protein, a marker for astrocytes, we developed an in vitro model to assess whether HTLV-1 infection activates astrocytes to secrete cytokines or present viral immunodominant epitopes to virus-specific T cells. Two human astrocytic glioma cell lines, U251 and U373, were transfected with the 3' portion of the HTLV-1 genome and with the HTLV-1 tax gene under astrocyte-specific promoter control. In this study, we report that Tax-expressing astrocytic glioma transfectants activate the expression of tumor necrosis factor alpha mRNA in vitro. Furthermore, these Tax-expressing glioma transfectants can serve as immunological targets for HTLV-1-specific cytotoxic T lymphocytes (CTL). We propose that these events could contribute to the neuropathology of HAM/TSP, since infected astrocytes can become a source for inflammatory cytokines upon HTLV-1 infection and serve as targets for HTLV-1-specific CTL, resulting in parenchymal damage by direct lysis and/or cytokine release.

Astrocytes↗
PubMed1997

HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP): a chronic progressive neurologic disease associated with immunologically mediated damage to the central nervous system.

This review examines information on clinical, pathological and immunological events in the slowly progressive neurologic disorder associated with the human T lymphotropic virus type-I (HTLV-I) termed HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP). The role of cellular immune responses to HTLV-I in patients with HAM/TSP and how these responses may be associated with the pathogenesis of this disorder will be discussed. While a number of immunologic responses have been shown to be abnormal in HAM/TSP patients, studies on HTLV-I specific cytotoxic T cell responses (CTL) will be specifically examined. By defining such antigen specific functional cellular host responses to HTLV-I we hope to better understand the underlying mechanisms that may be involved in the neuropathology of HTLV-I associated neurologic disease. This has led to a number of HTLV-I associated immunopathogenic models that may be operative in HAM/TSP patients. Importantly, based on these models, potential immunotherapeutic strategies for disease intervention can be devised. Moreover, such an analysis may have significant implications for our understanding of other HTLV-I associated clinical disorders and other neurological diseases in which viral etiologies have been suggested.

Adolescent↗
PubMed1997

Cortical neuronal cytoskeletal changes associated with FIV infection.

HIV-1 infection is often complicated by central nervous system (CNS) dysfunction. Degenerative neuronal changes as well as neuronal loss have been documented in individuals with AIDS. Feline immunodeficiency virus (FIV) infection of cats provides a model for both the immune and the central nervous system manifestations of HIV infection of humans. In this study we have examined neurons in the frontal cortex of feline immunodeficiency virus-infected cats and controls for immunoreactivity with SMI 32, an antibody recognizing a non-phosphorylated epitope on neurofilaments. We noted a significant increase in the number of immunoreactive pyramidal cells in infected animals compared to controls. The changes seen in the neuronal cytoskeleton as a consequence of the inoculation with FIV were similar to those seen in humans undergoing the normal aging process as well as those suffering from neurological diseases, including Alzheimer's and dementia pugilistica. The changes we noted in the feline brain were also similar to that reported in animals with traumatic injuries or with spontaneously occurring or induced motor neuron diseases, suggesting that the increase in reactivity represents a deleterious effect of FIV on the central nervous system.

Animals↗