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Biomedical subjects

S Jacobson

Publications and source records attributed to S Jacobson.

At least 91 records · Page 5Linked to original sources
PubMed1997

C2H2-546: a zinc finger protein differentially expressed in HTLV-1 infected T cells.

We report the cloning and characterization of a novel cDNA termed C2H2-546 which encodes a C2H2-type zinc finger protein. C2H2-546 RNA is expressed in the HTLV-1 infected T cells examined which were derived from HAM-TSP patients, but not in T cells derived from ATL patients. The C2H2-546 gene is conserved in humans and primates and maps to chromosome 10q11.2, a site associated with a variety of cancers. Thus, C2H2-546 is a candidate regulatory molecule important in the formation of these tumors, and may serve as an important marker to distinguish HTLV-1 infected ATL versus HAM-TSP T cell lineages.

Amino Acid Sequence↗
PubMed1997

Immunopathogenesis of HTLV-I associated neurologic disease: massive latent HTLV-I infection in bone marrow of HAM/TSP patients.

The localization of mammalian retroviruses to specified immune organs has significant implications on the pathophysiology of retroviral associated diseases. Human T-cell Lymphotropic Virus Type I (HTLV-I) is considered a CD4+ lymphotropic virus although the virus has been shown to infect a large variety of cells in vitro. Similarly, the human immunodeficiency virus (HIV), once thought to be harbored only in CD4+ peripheral blood lymphocytes (PBL) has been shown to be present in latent form in lymph nodes of HIV infected patients. HTLV-I Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) is a chronic progressive neurologic disorder of the central nervous system and is believed to result from infection of HTLV-I in association with an immunopathogenic or autoimmune mechanism. Here we describe experiments which utilize the in situ hybridization/polymerase chain reaction technology to demonstrate extensive HTLV-I infection of bone marrow in HAM/TSP patients. We discuss these results in the context of HTLV-I associated neurologic disease and extend these observations to other disorders of potential retroviral etiology and autoimmune involvement.

Bone Marrow↗
PubMed1997

Review of a home-based palliative care program for children with malignant and non-malignant diseases.

This retrospective chart review presents the patient characteristics and utilization of the home-based palliative care program at The Hospital for Sick Children in Toronto. A total of 126 children dying from a broad spectrum of diseases was admitted during the period 1986-1994, referred from neurosurgery, genetic/metabolic, neurology, neonatology, nephrology, cardiology, general pediatrics, general surgery, and pulmonology. At the time of review, 15 patients remained alive and 18 had been discharged from the program. Mean age at the time of referral was 4.8 +/- 0.51 years and mean age at death was 5.3 +/- 0.55 years. The mean number of days in hospital was 26.5 +/- 14.6 while days spent at home averaged 98.4 +/- 15.2; thus 80% of the children's remaining time was spent at home. The average number of parent-team contacts was 3.5 +/- 0.9 by pager and 24.0 +/- 2.9 by telephone. Of the 93 patients who died in the program, 53% died at home, 18% died in community hospitals, and 29% died in a tertiary care facility. Analgesic medications were administered to 54% of the patients; 56% of these then required opioid analgesia for pain and symptom management. Home-based palliative care appeared to be an effective program for many children with a variety of terminal illnesses after adequate supports for the child and family had been established.

Adolescent↗
PubMed1996

Correction in trans for Fabry disease: expression, secretion and uptake of alpha-galactosidase A in patient-derived cells driven by a high-titer recombinant retroviral vector.

Fabry disease is an X-linked metabolic disorder due to a deficiency of alpha-galactosidase A (alpha-gal A; EC 3.2.1.22). Patients accumulate glycosphingolipids with terminal alpha-galactosyl residues that come from intracellular synthesis, circulating metabolites, or from the biodegradation Of senescent cells. Patients eventually succumb to renal, cardio-, or cerebrovascular disease. No specific therapy exists. One possible approach to ameliorating this disorder is to target corrective gene transfer therapy to circulating hematopoietic cells. Toward this end, an amphotropic virus-producer cell line has been developed that produces a high titer (>10(6) i.p. per ml) recombinant retrovirus constructed to transduce and correct target cells. Virus-producer cells also demonstrate expression of large amounts of both intracellular and secreted alpha-gal A. To examine the utility of this therapeutic vector, skin fibroblasts from Fabry patients were corrected for the metabolic defect by infection with this recombinant virus and secreted enzyme was observed. Furthermore, the secreted enzyme was found to be taken up by uncorrected cells in a mannose-6-phosphate receptor-dependent manner. In related experiments, immortalized B cell lines from Fabry patients, created as a hematologic delivery test system, were transduced. As with the fibroblasts, transduced patient B cell lines demonstrated both endogenous enzyme correction and a small amount of secretion together with uptake by uncorrected cells. These studies demonstrate that endogenous metabolic correction in transduced cells, combined with secretion, may provide a continuous source of corrective material in trans to unmodified patient bystander cells (metabolic cooperativity).

3T3 Cells↗
PubMed1996

A bicistronic therapeutic retroviral vector enables sorting of transduced CD34+ cells and corrects the enzyme deficiency in cells from Gaucher patients.

Corrective gene transfer for therapeutic intervention in metabolic and hematopoietic disorders has been hampered by the relatively inefficient transduction of human hematopoietic stem cells. To overcome this, a bicistronic recombinant retrovirus has been generated that delivers both a therapeutic glucocerebrosidase (GC) cDNA for the treatment of Gaucher disease, and a small murine cell surface antigen (heat-stable antigen [HSA]) as a selectable marker. An amphotropic retroviral-producing cell clone was created, and filtered supernatant was used to transduce NIH 3T3 cells. Sorting of transduced cells by flow cytometry enabled separation into populations based on cell surface fluorescence intensity derived from the expressed HSA. Significant increases in GC enzyme activity were seen for the transduced and especially the transduced and sorted cells. Similarly, increases in GC specific activity were seen in transduced and sorted skin fibroblasts from a patient with Gaucher disease. To streamline future transfer and sorting protocols for hematopoietic cells, transformed B-cell lines from Gaucher patients were created. Type I B cells were transduced and sorted, and large increases in GC specific activity occurred with concomitant increases in integrated retroviral copy numbers. In addition, toward the goal of using this selectable approach for corrective gene transfer to bone marrow stem cells, CD34+ cells were isolated from normal BM donors, transduced, and sorted based on cell surface expression of HSA. Proviral DNA was detected in approximately 40% of clonogenic progenitor colonies derived from unsorted, transduced CD34+ cells, demonstrating the high titer of the vector. However, after sorting, 100% of the colonies had the corrective GC cDNA, demonstrating the efficiency of this selective system for human hematopoietic progenitors. It is expected that strategies based on this approach will allow sorting of transduced cells of many types before implantation of transduced cells to animals or patients. This vector system may also be used to simplify manipulations and studies on retroviral-mediated gene delivery in vitro and for in vivo models.

3T3 Cells↗
PubMed1996

Longitudinal studies of the duplication form of Charcot-Marie-Tooth polyneuropathy.

This study presents a longitudinal comparison of motor nerve conduction velocities (MCVs) in patients with Charcot-Marie-Tooth type 1A with proven duplication of a segment of chromosome 17p11.2p12. Results were compared for 8 CMT1A duplication patients from one family whose MCV measurements were taken 22 years apart (1967 and 1989). Measurements from a total of seven median motor and five peroneal motor MCVs were compared. Median MCVs showed a slight reduction that averaged 2.2 m/s, and peroneal MCVs showed an average decrease of 3.0 m/s. In addition, mild objective increase in limb weakness was seen in only 1 of 8 patients and subjective symptoms of gradual worsening of leg strength were noted in half the patients over the same period. In this study of a small group of CMT1A patients with proven segmental duplication of chromosome 17p11.2p12, the motor conduction velocities and clinical motor exam did not change significantly over 22 years.

Adolescent↗
PubMed1996

Human T-cell lymphotropic virus type II-associated myelopathy: clinical and immunologic profiles.

Human T-cell lymphotropic virus type II (HTLV-II) is endemic in several ethnic tribes and among intravenous drug users in metropolitan areas. Despite the presence of HTLV-II in these various populations, the association of HTLV-II with disease is sparse and mainly limited to isolated case reports. This study is an extension of an earlier description of an HTLV-II-infected patient with neurologic disease and presents the clinical and immunologic findings of 4 patients with HTLV-II seropositivity and spastic paraparesis. The patients are of African-American origin with 3 of the patients being of Amerindian descent. All of the patients are seronegative for the human immunodeficiency virus (HIV). The patients progressed to a nonambulatory state in less than 5 years. Magnetic resonance imaging studies obtained from 3 of the patients demonstrated white matter disease in the cerebrum and spinal cord. The cerebrospinal fluid and serum contained antibodies to HTLV-II. The presence of proviral HTLV-II was confirmed by polymerase chain reaction analysis of peripheral blood lymphocytes (PBLs). A spinal cord biopsy from 1 patient demonstrated HTLV RNA within a lesion. Immunologic studies on 2 patients demonstrated that spontaneous lymphoproliferation of PBLs was present but decreased relative to HTLV-I-infected patients. The clinical and immunologic findings from these HTLV-II-infected patient resemble those found in HTLV-I-associated myelopathy/tropical spastic paraparesis.

Adult↗
PubMed1996

Comparison of acute aquatic effects of the oil dispersant Corexit 9500 with those of other Corexit series dispersants.

The acute aquatic toxicity of a new Corexit series dispersant, Corexit 9500, was evaluated and compared with that of others in the series using early life stages of two common nearshore marine organisms: the red abalone (Haliotis rufescens) and a kelp forest mysid (Holmesimysis costata). Spiked-concentration testing was performed under closed, flowthrough conditions, with dispersant concentrations measured in real time using UV spectrophotometry. Median-effect concentrations ranged from 12.8 to 19.7 initial ppm for Haliotis and from 158.0 to 245.4 initial ppm for Holmesimysis. The difference in sensitivity of the two types of tests was consistent with patterns seen with other oil dispersants. Also, these data indicate Corexit 9500 to be of similar toxicity to Corexit 9527 and 9554. Corexit 9500 represents a reformulation of a long-time industry "standard," Corexit 9527, to allow use on higher viscosity oils and emulsions. The present data suggest that acute aquatic toxicity concerns surrounding the use of this newer dispersant should not be significantly different from those associated with the use of Corexit 9527.

Animals↗
PubMed1996

Cellular immune responses to HTLV-I: immunopathogenic role in HTLV-I-associated neurologic disease.

This review examines current information on cellular immune responses to the human T lymphotropic virus type I (HTLV-I). HTLV-I has been associated with a number of diseases, but this review focuses primarily on the relationship of HTLV-I with a slowly progressive neurologic disorder termed HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). In particular, this review discusses 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. 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 (cytotoxic T lymphocytes) are specifically examined. By defining such antigen-specific functional cellular host responses to HTLV-I, we hope to understand better 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 immuno-pathogenic 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.

Cytotoxicity, Immunologic↗
PubMed1996

Analysis of the T-cell receptor repertoire of human T-cell leukemia virus type 1 (HTLV-1) Tax-specific CD8+ cytotoxic T lymphocytes from patients with HTLV-1-associated disease: evidence for oligoclonal expansion.

Human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic, progressive neurological disease characterized by marked degeneration of the spinal cord and the presence of antibodies against HTLV-1. Patients with HAM/TSP, but not asymptomatic carriers, show very high precursor frequencies of HTLV-1-specific CD8+ T cells in peripheral blood and cerebrospinal fluid, suggestive of a role of these T cells in the pathogenesis of the disease. In HLA-A2+ HAM/TSP patients, HTLV-1-specific T cells were demonstrated to be directed predominantly against one HTLV-1 epitope, namely, Tax11-19. In the present study, we analyzed HLA-A2-restricted HTLV-1 Tax11-19-specific cytotoxic T cells from three patients with HAM/TSP. An analysis of the T-cell receptor (TCR) repertoire of these cells revealed an absence of restricted variable (V) region usage. Different combinations of TCR V alpha and V beta genes were utilized between, but also within, the individual patients for the recognition of Tax11-19. Sequence analysis of the TCR showed evidence for an oligoclonal expansion of few founder T cells in each patient. Apparent structural motifs were identified for the CDR3 regions of the TCR beta chains. One T-cell clone could be detected within the same patient over a period of 3 years. We suggest that these in vivo clonally expanded T cells might play a role in the pathogenesis of HAM/TSP and provide information on HTLV-1-specific TCR which may elucidate the nature of the T cells that infiltrate the central nervous system in HAM/TSP patients.

Amino Acid Sequence↗
PubMed1996

PCR-in situ hybridization detection of human T-cell lymphotropic virus type 1 (HTLV-1) tax proviral DNA in peripheral blood lymphocytes of patients with HTLV-1-associated neurologic disease.

PCR-in situ hybridization (PCR-ISH) was developed and utilized to determine the distribution of human T-cell lymphotropic virus type 1 (HTLV-1) tax proviral DNA in peripheral blood lymphocytes (PBL) from patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). PCR-ISH of HTLV-1 tax DNA in PBL from patients with HAM/TSP revealed that 1 in 5,000 to 1 in 10,000 PBL contained virus. PCR-ISH was sensitive, because a positive signal was consistently demonstrated from the HTLV-1-infected cell lines HUT-102 (which contains four to six copies of HTLV-1 proviral DNA per cell) and MT-1 (which contains one to three copies of HTLV-1 proviral DNA per cell). Also, intracellular amplification by PCR-ISH significantly increased sensitivity compared with conventional ISH and was shown to be specific for HTLV-1 tax DNA. These results are in contrast to solution-phase PCR amplification in which greater than 1% of cells were estimated to be infected. The discordance between these results is discussed and may indicate that more than one copy of HTLV-1 tax proviral DNA is present in an individual PBL.

Base Sequence↗
PubMed1996

Detecting risk drinking during pregnancy: a comparison of four screening questionnaires.

OBJECTIVES: This study investigated the efficacy of screening for risk drinking during pregnancy with two brief questionnaires, TWEAK and T-ACE. Both include an assessment of tolerance based on the number of drinks women report they can hold. METHODS: Subjects were disadvantaged African-American obstetric patients in Detroit, Mich. Traditional alcoholism screens (Michigan Alcohol Screening Test [MAST], CAGE) and the tolerance question were administered (n = 2717); TWEAK and T-ACE were constructed from tolerance and embedded MAST and CAGE items. In a separate sample (n = 1420), only the T-ACE was administered. Periconceptional risk drinking was the gold standard. Screen evaluations were based on receiver-operating characteristic analyses. RESULTS: At the cutpoint of 2, sensitivity/specificity for embedded screens were 91/77 for TWEAK and 88/79 for T-ACE; comparable values for T-ACE alone were 67/86. TWEAK and T-ACE screened more effectively than CAGE or MAST. CONCLUSIONS: Embedded versions of TWEAK and T-ACE were both highly sensitive to periconceptional risk drinking in this population. Administering T-ACE alone reduced its sensitivity; this suggests that MAST and CAGE administration improves its performance.

Adult↗
PubMed1996

Tumor necrosis factor alpha expression in the spinal cord of human T-cell lymphotrophic virus type I associated myelopathy/tropical spastic paraparesis patients.

HTLV-I Associated Myelopathy Tropical Spastic Paraparesis (HAM/TSP) is a chronic degenerative disease mainly affecting the spinal cord. The pathogenesis of HAM/TSP is unknown, but is thought to involve immunopathogenic mechanisms. Several reports have detected inflammatory cytokines such as tumor necrosis factor alpha (TNF alpha) in HAM/TSP patients. In this study, we used in situ hybridization (ISH) to examine the expression of TNF alpha RNA in spinal cord autopsy specimens from three chronic HAM/TSP patients with long-term disease (10-20 years duration). ISH identified many TNF alpha-expressing cells throughout all three patient's spinal cord tissues. Two patient's spinal cord tissue showed inflammatory cells, however double labeling by ISH for TNF alpha RNA with immunohisto-chemistry for CD45RO (a marker for memory T-cells) or CD-68 (a marker for microglia/macrophages) did not colocalize TNF alpha RNA with either CD45RO or CD-68 positive cells. Therefore, TNF alpha is expressed in the spinal cord of chronic HAM/TSP patients compared to normal controls and TNF alpha-expressing cells do not appear to be memory T-cells, microglia or macrophages.

Antigens, CD↗
PubMed1996

Prevalence of malocclusion and awareness of dental appearance in young adults.

The aims of this study were to determine the remaining subjective and objective need for orthodontic treatment, symptoms of CMD, and headache. 120 boys and 121 girls at 19 years of age participated. They were registered with casts and were sent a questionnaire about chewing ability, headache, subjective symptoms of CMD and experience of orthodontic treatment. They were also asked to give their opinion of their own teeth by putting a mark on a line. The results showed that 89.6% of the adolescents had a normal sagittal molar relationship and 9.6% a postnormal molar relationship. Space conditions of the upper and lower incisors displayed a large range. Most of the adolescents were satisfied with their dentition even though a large range was obvious. Factors of significance for the subjects' subjective opinion of their dentition were space conditions, overjet and inclination of upper incisors. It was concluded that the remaining need of treatment was low, girls being more interested in treatment than boys. The boys' and girls' subjective opinions of their own teeth after treatment were similar. Orthodontic treatment clearly increased the subjects' subjective appreciation of their own teeth.

Adult↗
PubMed1996

Human T lymphotropic virus type I (HTLV-I)-specific T helper cell responses from HTLV-I seronegative patients with chronic myelopathy and MS in Japan.

Human T lymphotropic virus type I (HTLV-I) is a human retrovirus etiologically linked to Adult T cell leukemia (ATL) and HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP). Although most HAM/TSP patients have high anti-HTLV-I antibody titers in their sera, HTLV-I infected but seronegative patients with neurological diseases have been reported. To clarify whether seronegative, HTLV-I related neurological disease may exist, we have developed a method that measures the production of interleukin-2 (IL-2) from HTLV-I synthetic peptide-stimulated peripheral blood lymphocytes (PBL) of HTLV-I infected persons. This method is sensitive enough to detect exposure to HTLV-I before seroconversion or even before detection by PCR. We examined 12 patients with chronic progressive myelopathy and eight patients with multiple sclerosis (MS) in central Japan, where the prevalence rate of HTLV-I is between one and four percent among asymptomatic blood donors, using the IL-2 production assay. None of them were positive by the assay, suggesting seronegative HTLV-I myelopathy is very rare among patients with chronic progressive myelopathy and MS in Japan.

Adult↗
PubMed1995

Selection of transduced CD34+ progenitors and enzymatic correction of cells from Gaucher patients, with bicistronic vectors.

The gene transfer efficiency of human hematopoietic stem cells is still inadequate for efficient gene therapy of most disorders. To overcome this problem, a selectable retroviral vector system for gene therapy has been developed for gene therapy of Gaucher disease. We constructed a bicistronic retroviral vector containing the human glucocerebrosidase (GC) cDNA and the human small cell surface antigen CD24 (243 bp). Expression of both cDNAs was controlled by the long terminal repeat enhancer/promoter of the Molony murine leukemia virus. The CD24 selectable marker was placed downstream of the GC cDNA and its translation was enhanced by inclusion of the long 5' untranslated region of encephalomyocarditis virus internal ribosomal entry site. Virus-producing GP+envAM12 cells were created by multiple supernatant transductions to create vector producer cells. The vector LGEC has a high titer and can drive expression of GC and the cell surface antigen CD24 simultaneously in transduced NIH 3T3 cells and Gaucher skin fibroblasts. These transduced cells have been successfully separated from untransduced cells by fluorescence-activated cell sorting, based on cell surface expression of CD24. Transduced and sorted NIH 3T3 cells showed higher GC enzyme activity than the unsorted population, demonstrating coordinated expression of both genes. Fibroblasts from Gaucher patients were transduced and sorted for CD24 expression, and GC enzyme activity was measured. The transduced sorted Gaucher fibroblasts had a marked increase in enzyme activity (149%) compared with virgin Gaucher fibroblasts (17% of normal GC enzyme activity). Efficient transduction of CD34+ hematopoietic progenitors (20-40%) was accomplished and fluorescence-activated cell sorted CD24(+)-expressing progenitors generated colonies, all of which (100%) were vector positive. The sorted, CD24-expressing progenitors generated erythroid burst-forming units, colony-forming units (CFU)-granulocyte, CFU-macrophage, CFU-granulocyte/macrophage, and CFU-mix hematopoietic colonies, demonstrating their ability to differentiate into these myeloid lineages in vitro. The transduced, sorted progenitors raised the GC enzyme levels in their progeny cells manyfold compared with untransduced CD34+ progenitors. Collectively, this demonstrates the development of high titer, selectable bicistronic vectors that allow isolation of transduced hematopoietic progenitors and cells that have been metabolically corrected.

3T3 Cells↗
PubMed1995

Detection of human T-lymphotropic virus type I (HTLV-I) tax RNA in the central nervous system of HTLV-I-associated myelopathy/tropical spastic paraparesis patients by in situ hybridization.

Autopsy specimens from 3 patients with human T-lymphotropic virus (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) were examined for the presence of HTLV-I in the central nervous system (CNS). In situ hybridization using an HTLV-I tax RNA probe detected cells containing HTLV-I RNA in spinal cord and cerebellar sections. HTLV-I infected cells were located within the white matter and, in particular, within the anterior and lateral funiculi of the spinal cord. Consistent with previously described HAM/TSP pathology, there were perivascular infiltrates in these CNS specimens. Significantly, HTLV-I RNA was not localized to these infiltrates but was detected deeper within the neural tissue. Furthermore, phenotypic analysis demonstrated that at least some of the infected cells were astrocytes. While previous polymerase chain reaction studies have demonstrated the presence of proviral HTLV-I in CNS specimens, here we provide evidence for the in situ expression of HTLV-I RNA in the CNS of HAM/TSP patients.

Aged↗