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R S Smith

Publications and source records attributed to R S Smith.

At least 145 records · Page 8Linked to original sources
PubMed1991

Production of a pokeweed antiviral protein (PAP)-containing immunotoxin, B43-PAP, directed against the CD19 human B lineage lymphoid differentiation antigen in highly purified form for human clinical trials.

We describe a standardized method for the preparation and purification of a potent immunotoxin against B-lineage leukemia/lymphoma cells, constructed with the ribosome inhibitory single chain plant toxin pokeweed antiviral protein (PAP) and a murine IgG1 monoclonal antibody (MoAb) specific for the human B lineage differentiation antigen CD19 for human clinical trials. PAP was prepared from spring leaves of Phytolacca americana plants by ammonium sulfate precipitation and purified to homogeneity by successive steps of ion exchange chromatography. B43 MoAb was produced in vitro by hollow fiber technology and purified to homogeneity by affinity chromatography. PAP toxin and B43 MoAb were modified via their free amino groups prior to their intermolecular conjugation. 2-iminothiolane was used to introduce reactive sulfhydryl groups into PAP and N-succinimidyl 3-(2-pyridyldithio) propionate was used to introduce 2-pyridyl disulfide bonds into B43 MoAb. Modified PAP was reacted with modified B43 MoAb resulting in a sulfhydryl-disulfide exchange reaction and yielding disulfide linked PAP-B43 MoAb conjugates, which we refer to as B43-PAP immunotoxin. B43-PAP immunotoxin was subjected to preparative gel filtration chromatography and cation exchange chromatography to obtain a highly purified, sterile, and pyrogen-free immunotoxin preparation with less than 5% free antibody contamination and less than 0.5% free PAP contamination. The final product displayed a high affinity for and a very potent anti-leukemic activity against B lineage leukemia cells. With slight modifications, the procedures detailed in this report should be generally applicable to preparation of other PAP-MoAb conjugates for treatment of cancer or AIDS.

Amino Acid Sequence↗
PubMed1991

The immune system is a key factor in the etiology of psychosocial disease.

The immune system is proposed as the key to understanding the etiology and treatment of psychosocial disease. There is a dense communication network between the immune system and the central nervous system (CNS). Immune cell cytokines, via direct action on the CNS, induce fever, alter sleep, pain perception and pituitary hormone release and reduce appetite and activity in animals. Interleukin-2 and interferon given to humans result in global behavioral and cognitive pathology. Activation of the immune system by pathogens produces global cognitive and behavioral pathology also. Recently, controlled trials have demonstrated that diet can cause psychosocial disease, presumably by an immune mechanism. Immune system abnormalities have been identified in manic-depressive psychosis, schizophrenia and alcoholism. Lithium carbonate is not only prophylactic for all three of these diseases, but it also powerfully stimulates the immune system. This is proposed as the mechanism of lithium's therapeutic effect. The antipsychotics, haloperidol and the phenothiazines, affect the immune system also. The rapid development of AIDS dementia complex can be explained by the remarkable influence the immune system has on the CNS.

AIDS Dementia Complex↗
PubMed1991

Is schizophrenia caused by excessive production of interleukin-2 and interleukin-2 receptors by gastrointestinal lymphocytes?

Excessive production of interleukin-2 (IL-2) and IL-2 receptors (IL-2R) by gastrointestinal (GI) T-lymphocytes is hypothesized as the cause of schizophrenia. It is based on: 1) IL-2 given to human volunteers can cause all the symptoms of schizophrenia; 2) GI lymphocytes in nonhuman primates produce much more IL-2 and IL-2R when stimulated than peripheral blood lymphocytes; 3) the GI tract is the largest lymphoid 'organ' in the body. The hypothesis appears to: 1) explain the protective effect of rheumatoid arthritis on schizophrenia; 2) make mechanistically plausible the findings on wheat and schizophrenia; 3) be consistent with and explain many of the known immunological abnormalities in schizophrenia.

Arthritis, Rheumatoid↗
PubMed1991

The macrophage theory of depression.

Excessive secretion of macrophage monokines is proposed as the cause of depression. Monokines when given to volunteers can produce the symptoms necessary for the Diagnostic and Statistical Manual of Mental Disorders, Third Edition Revised (DSM-III-R) diagnosis of major depressive episode. Interleukin-1 (IL-1) can provoke the hormone abnormalities linked with depression. This theory provides an explanation for the significant association of depression with coronary heart disease, rheumatoid arthritis, stroke and other diseases where macrophage activation occurs. The 3:1 female/male incidence of depression ratio is accounted for by estrogen's ability to activate macrophages. The extraordinary low rate of depression in Japan is consistent with the suppressive effect of eicosapentanoic acid on macrophages. Fish oil is proposed as a prophylaxis against depression and omega-6 fat as a promoter. Infection, tissue damage, respiratory allergies and antigens found in food are some of the possible causes of macrophage activation triggering depression.

Arteriosclerosis↗
PubMed1991

The evolution of lymphadenopathy and hypergammaglobulinemia are evidence for early and sustained polyclonal B lymphocyte activation during human immunodeficiency virus infection.

To examine whether polyclonal activation of B lymphocytes as measured by hypergammaglobulinemia contributes to lymphadenopathy in human immunodeficiency virus (HIV) infection, correlates of adenopathy were examined in 240 homosexual men. Lymph node size was measured in 12 sites semiannually over 4 years. Both adenopathy and hyperglobulinemia developed within 1 year after seroconversion and persisted at high levels. Adenopathy declined near diagnosis of AIDS whereas serum IgG decreased 8-16 months after diagnosis. Adenopathy attributable to HIV occurred in all palpable node groups. By logistic regression, HIV-positive men were best discriminated from HIV-negative men by size of posterior cervical nodes and the number of sites with enlarged nodes. In a repeated measures model of covariance, adenopathy in HIV-positive men was associated with more CD4+ cells (P less than .002), elevated serum globulins (P less than .01), and lower platelet counts (P less than .05). Adenopathy declined over time (P less than .001) and with diagnosis of AIDS or AIDS-related complex (P less than .03). Thus, adenopathy and hypergammaglobulinemia are correlated and follow a similar course through various stages of HIV infection, suggesting that both are caused by polyclonal B cell activation.

AIDS-Related Complex↗
PubMed1991

Nonoperative management of hepatic trauma.

In an attempt to determine whether selective, nonoperative management of hepatic trauma might be efficacious, a retrospective review of liver injuries was undertaken. Of the 48 patients with liver injuries identified, there were 34 men and 14 women with an average age of 28.5 years. Mechanism of injury consisted of blunt trauma in 23 patients, stab wounds in 14 patients, and 11 patients had gunshot wounds. There were 12 grade I injuries, 15 grade II injuries, 17 grade III injuries, 2 grade IV injuries, and 1 grade V injury. Diagnosis of liver trauma was made at the time of exploratory laparotomy in 15 patients and suggested by abdominal computed tomography (CT) scan in 18 patients; the remaining 15 patients had a positive peritoneal lavage which led to exploratory laparotomy. Following blunt trauma, 14 patients, all of whom underwent diagnostic abdominal CT scans which confirmed hepatic injury, had nonoperative treatment. All patients who received nonoperative management maintained stable vital signs and only five required transfusion. None of the patients who were treated nonoperatively developed complications or required delayed laparotomy. There were no deaths in this group. Of the 34 patients undergoing exploratory laparotomy, 19 required either no treatment or minor hepatorrhaphy. However, 17 of 25 patients with penetrating wounds had associated abdominal injuries which required operative treatment. Based on the information obtained in this review, it is recommended that stable patients with isolated hepatic injuries, secondary to blunt trauma confirmed by CT scan, may be managed nonoperatively. Due to the high frequency of associated injuries found in patients with penetrating trauma, nonoperative therapy is not advised.

Abdominal Injuries↗
PubMed1990

Identical IgM antibodies recognizing a glycine-alanine epitope are induced during acute infection with Epstein-Barr virus and cytomegalovirus.

We studied antibody production in serial serum samples from patients with acute Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infections. Sera were analyzed both by enzyme-linked immunosorbent assay (ELISA) using a synthetic peptide (P62) derived from the glycine-alanine repeating region of the Epstein-Barr nuclear antigen (EBNA-1) and by immunoblotting. In prior studies, we have shown that patients with acute EBV infection make IgM antibodies that react with this peptide, that recognize a viral-specific protein (EBNA-1), and that bind with a number of proteins present in uninfected cells; however, antibody binding to these autoantigens was inhibited by the peptide. IgG antibodies reactive with the peptide did not appear until months after the disease and were specific for the EBNA-1 protein. We now find that patients with acute CMV infection but not those with acute infections from a variety of other nonherpes organisms also produce IgM antibodies that recognize the EBV-derived peptide P62. These antibodies also appear to recognize the same cellular proteins as the EBV-induced IgM antibodies. The IgM antibodies appeared in all acutely infected CMV patients studied and occurred both in patients with previous EBV infections and in one patient studied who had not previously been exposed to EBV. It appears that infection with EBV or CMV can induce the synthesis of a very similar or identical set of IgM antibodies.

Amino Acid Sequence↗
PubMed1990

Familial hypobetalipoproteinemia caused by a mutation in the apolipoprotein B gene that results in a truncated species of apolipoprotein B (B-31). A unique mutation that helps to define the portion of the apolipoprotein B molecule required for the formation of buoyant, triglyceride-rich lipoproteins.

Apolipoprotein B-100 has a crucial structural role in the formation of VLDL and LDL. Familial hypobetalipoproteinemia, a syndrome in which the concentration of LDL cholesterol in plasma is abnormally low, can be caused by mutations in the apo B gene that prevent the translation of a full-length apo B-100 molecule. Prior studies have revealed that truncated species of apo B [e.g., apo B-37 (1728 amino acids), apo B-46 (2057 amino acids)] can occasionally be identified in the plasma of subjects with familial hypobetalipoproteinemia; in each of these cases, the truncated apo B species has been a prominent protein component of VLDL. In this report, we describe a kindred with hypobetalipoproteinemia in which the plasma of four affected heterozygotes contained a unique truncated apo B species, apo B-31. Apolipoprotein B-31 is caused by the deletion of a single nucleotide in the apo B gene, and it is predicted to contain 1425 amino acids. Apolipoprotein B-31 is the shortest of the mutant apo B species to be identified in the plasma of a subject with hypobetalipoproteinemia. In contrast to longer truncated apo B species, apo B-31 was undetectable in the VLDL and the LDL; however, it was present in the HDL fraction and the lipoprotein-deficient fraction of plasma. The density distribution of apo B-31 in the plasma suggests the possibility that the amino-terminal 1425 amino acids of apo B-100 are sufficient to permit the formation and secretion of small, dense lipoproteins but are inadequate to support the formation of the more lipid-rich VLDL and LDL particles.

Adult↗
PubMed1990

Water contamination in North Cornwall: a retrospective cohort study into the acute and short-term effects of the aluminum sulphate incident in July 1988.

IN JULY 1988 the drinking water supply of part of Cornwall was contaminated with 20 tons of aluminum sulphate solution. Emergency measures ensured that aluminum sulphate levels in most parts of the water distribution system were rapidly reduced, but residents were supplied with water containing raised concentrations of aluminum and other metals for at least a few days. A retrospective cohort study compared 480 individuals in the exposed area with 532 individuals resident in an area served by a different water supply. The exposed group were more likely to complain of all 18 symptoms in the questionnaire enquiry. They had a significantly higher relative risk of experiencing painful joints. These symptoms were reported by less than a quarter of the respondents exposed to contaminated water. This may represent a previously unrecognised acute effect of water contamination with aluminum sulphate, but the study does not exclude the possibility that the threshold for symptom reporting was lowered by anxiety and by the publicity associated with the incident. The overall response rate of the study was low (45%) and reflects the difficulties in both carrying out and interpreting environmental epidemiological studies of acute incidents.

Accidents, Occupational↗
PubMed1990

Child abuse.

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Child↗
PubMed1990

Synthetic peptide assays to detect human immunodeficiency virus types 1 and 2 in seropositive individuals.

Detection of antibodies to human immunodeficiency virus type 1 by enzyme-linked immunosorbent assay is the standard method to screen blood products. With the description of human immunodeficiency virus type 2 as a second retrovirus involved in the pathogenesis of acquired immunodeficiency syndrome, additional laboratory testing is required to screen blood products. However, owing to the serological cross-reactivity of human immunodeficiency virus types 1 and 2 at the molecular level, it is impossible to distinguish human immunodeficiency virus type 2-infected blood with enzyme-linked immunosorbent assays formatted with human immunodeficiency virus type 1 viral lysates. Synthetic peptides from the conserved envelope region of the human immunodeficiency virus transmembrane protein offer a new approach to develop site-specific diagnostic assays that will identify and discriminate between human immunodeficiency virus types 1 and 2.

Amino Acid Sequence↗
PubMed1989

G-protein involvement in matrix-mediated motility and invasion of high and low experimental metastatic B16 melanoma clones.

Membranes from a B16 murine melanoma clone of high experimental metastatic capacity show increased amounts of pertussis toxin (PT) substrate when compared to a low metastatic counterpart. Using specific antibodies, we identified Gi2 as the PT-sensitive G-protein uniquely abundant in highly metastatic cells. ADP ribosylation of a G-protein alpha subunit by PT decreased both the migration of tumor cells through Matrigel (Collaborative Research, Bedford, MA) and the fibronectin-, laminin-, and collagen type IV-mediated motility of a high metastatic clone. Treatment of cells from a low metastatic clone with PT did not alter either the relatively low invasive capacity or lower motility of these cells. While cholera toxin treatment of cells resulted in decreased invasion and motility of both high and low metastatic clones, there were significant qualitative and quantitative differences, when compared to the PT effects, which indicated that the two toxins were acting on different second messenger systems. PT treatment of B16 clones of high or low experimental metastatic capacity does not result in any alteration in cellular cyclic AMP accumulation suggesting that the PT substrate is not linked with the adenylyl cyclase enzyme complex. The data suggest that a PT-sensitive G-protein, possibly Gi2, regulates second messenger pathways that contribute to the metastatic capacity of B16 melanoma cells.

1-Methyl-3-isobutylxanthine↗
PubMed1989

Junction between parent and daughter axons in regenerating myelinated nerve: properties of structure and rapid axonal transport.

The primary aim of this work was to investigate the properties of rapid axonal transport in regenerating myelinated axons in the sciatic nerve of Xenopus laevis, with particular attention to events at the junction between the proximal, intact axon (the "parent") and the distal, newly formed axon (the "daughter"). Morphological studies indicated that all myelinated axons initiated regeneration and that at least 80% of these axons regenerated at a rate of 1 mm/day or greater (20 degrees C). The ultrastructure of the junctional region was examined at regeneration times between 3 days and 20 weeks. The main qualitative change in the junctional axoplasm over this period was in its content of particulate organelles. At times up to 2 weeks regeneration, the junction contained abnormal numbers of 50 nm diameter vesicles and 10 nm granules. Between 2 and 5 weeks the junction showed in addition a peripheral rim of large membrane-bounded organelles around a central core of microtubules and neurofilaments. At longer times the numbers of large membrane-bounded organelles diminished and all junctions contained prominent accumulations of 10 nm granules. The rate of rapid axonal transport of protein was similar in parent and daughter axons. Compared to the parent axons, a 2-5 times greater amount of protein was deposited to a stationary phase in daughter axons. Specimens of nerve that were subjected to mechanical stress during the removal of the perineurium showed a large accumulation of rapidly transported protein in the region of the crush at regeneration times up to 40 days; some of the accumulated protein was subsequently transported retrogradely. Video microscopy of isolated axons supplied evidence that the transport deficit in mechanically stressed nerve was a partial block of anterograde vesicle transport, plus a reversal of anterograde transport, at the junction of parent with daughter axons. No structural changes were detected in mechanically stressed nerve. The results show that the junction between parent and daughter myelinated axons is a region with distinct morphology at which the dynamics of anterograde axonal transport may change dramatically.

Animals↗
PubMed1989

Real-time imaging of axonally transported subresolution organelles in vertebrate myelinated axons.

A procedure is described for the real-time imaging of organelles of sub-resolution dimensions that undergo rapid axonal transport in myelinated axons. The procedure uses commercially available processors to enhance images that are obtained with a video microscope. Image detail is enhanced by spatial high-pass filtering. Small moving organelles are detected by subtracting a dynamically updated image of stationary cellular detail from one that contains the same stationary features plus images of the moving organelles.

Animals↗
PubMed1989

Antibodies to an Epstein-Barr virus nuclear antigen synthetic peptide in infectious mononucleosis. Report of two cases.

The Epstein-Barr virus nuclear antigen (EBNA-1) contains a region of repeating glycine and alanine amino acids. It has been shown that this region contains a major epitope of EBNA-1. With well-characterized sequential sera from two cases of acute infectious mononucleosis, a specific IgM response was detected to the EBNA-1 synthetic peptide by enzyme-linked immunosorbent assay (ELISA). Conversely, an IgG response was observed in the convalescent phase of the illness with a progressive decline of the IgM antibodies. This response was observed with heterophil-positive and heterophil-negative EBV/IM. The peptide-specific serologic response was confirmed by immunoblotting, the serial serum samples on extracts of EBV transformed B-cells. There was excellent correlation between the antipeptide ELISA and blotting techniques.

Acute-Phase Reaction↗
PubMed1989

Adult periorbital fibromatosis.

Three patients aged 15 to 40 years with fibromatosis of the periorbital region were studied. A history of acute onset, preceding trauma, and pain associated with a palpable mass were typical features. Rapid recurrence followed surgical excision. Misdiagnosis is common in this benign disease and may lead to unnecessary examinations for malignancy. Surgical excision or debulking of these masses is indicated for diagnosis and pain relief, but long-term follow-up indicates that these lesions will often spontaneously resolve with time.

Adolescent↗