Biomedical subjects
J Walker
Publications and source records attributed to J Walker.
Expression of EGFR, HER-2/neu, P53, and PCNA in endometrioid, serous papillary, and clear cell endometrial adenocarcinomas.
Expression of four biologic markers was studied in 69 cases of endometrial cancer to identify their association with cell type, decreased survival, and increased tumor metastasis. Cell types included endometrioid (n = 45), serous papillary (n = 16), and clear cell (n = 8). Immunohistochemical stains were employed to detect the presence of epidermal growth factor receptor (EGFR), HER-2/neu, p53, and proliferating cell nuclear antigen (PCNA). Analysis revealed that EGFR was expressed in 49%, HER-2/neu in 59%, p53 in 9%, and PCNA in 16% of tumor specimens. HER-2/neu overexpression was significantly associated with depth of myometrial invasion. p53 and PCNA immunoreactivity significantly correlated with nonendometrioid histology, although PCNA was less specific in labeling these less favorable cell types. EGFR immunoreactivity also significantly correlated with nonendometrioid cell types and tumor metastases at time of diagnosis. Seventy-seven percent of patients with metastatic disease were EGFR-positive versus 36% positivity in patients with no evidence of metastases (P < 0.002). For patients with endometrioid adenocarcinoma, evidence of EGFR overexpression decreased survival from 89 to 69% (P < 0.04). In the serous papillary and clear cell category, EGFR positivity decreased survival from 86 to 27% (P < 0.03). EGFR strongly correlates with tumor metastasis and patient survival in endometrial cancer. Altered expression of this oncoprotein may serve as a guide to prognosis and treatment in these patients.
Molecular biology: the forensic applications.
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Acquisition of cytomegalovirus infection by premature neonates.
In order to evaluate the risk of premature infants acquiring cytomegalovirus (CMV) infection, a prospective study was made of infants of 32 weeks gestation or less admitted to a neonatal unit. Infants were assessed at birth to exclude congenital CMV infection and followed to the age of 1 month post-term. A total of 16/131 (12.2%) infants acquired CMV infection; 6 of CMV antibody-negative and 10 of CMV antibody-positive mothers. Six of 65 (9.23%) infants of CMV antibody-negative mothers who had been transfused with blood acquired CMV infection compared with 0 of 18 infants of CMV antibody-negative mothers, and who had not been transfused with blood. Acquired CMV infection was also more common in infants of CMV antibody-positive mothers and who had been transfused with blood, i.e. 9 of 34 (26.47%) compared with 1 of 14 (7.14%). The relative risk was 3.7 (95% confidence interval 1.53-5.87). This study suggests that all premature infants requiring blood transfusion should be transfused with CMV antibody-negative blood regardless of the CMV immune status of their mothers.
Review: the frequency and severity of adverse drug reactions in elderly people.
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The expression of carbohydrate antigens in activated T cells and in autoimmune diseases.
Cell surface carbohydrate antigens have been implicated in cell differentiation and maturation and may play a role in immunoregulation. The expression of carbohydrates in peripheral blood lymphocytes (PBL) was studied by double immunofluorescence flow cytometry, using MoAbs CT1 and CT2 but only a small proportion of cells bound these MoAbs. MoAbs CT1, CT2 and the lectin vicia villosa (VV) which share specificity for Gal NAc were then used to examine lymphocytes from patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Behcet's disease (BD) and IgA nephropathy. A significant increase in MoAbs CT1 CT2 and VV binding CD4 or CD8 cells was found only with lymphocytes from patients with SLE. However, MoAbs CT or VV binding lymphocytes from healthy subjects were significantly up-regulated by activation with a mitogen (PHA), cross-linked anti-CD3 MoAb or a common antigen (65kDa heat shock protein), suggesting that an increased proportion of T cells expressing these carbohydrates results from any of the three types of lymphocyte activating agents. Inhibition studies were then carried out to determine the relationship between the MoAbs CT1 and CT2, VV and GalNAc. Indeed, VV binding to T cells was significantly inhibited by either MoAbs CT1 or CT2, or GalNAc but not GlucNAc, suggesting that VV shares a common binding site with MoAb CT and that GalNAc may constitute one of the sugar receptors. Investigations of lymphocytes from adult peripheral blood in health and disease suggest that carbohydrate antigens may play a role in activation and immunoregulation.
Identification of a novel antigen from Corynebacterium pseudotuberculosis that protects sheep against caseous lymphadenitis.
A 40-kDa protein antigen from Corynebacterium pseudotuberculosis has been identified by application of a strategy that employs locally derived antibody-secreting cells (ASC). ASC probes generated by culture of ASC obtained from the lymph node draining the site of infection showed a specificity restricted to a 40-kDa antigen. Analysis of immunoblots with sequential serum samples taken from sheep during the course of experimental primary infection with C. pseudotuberculosis also revealed the 40-kDa antigen as an early immunodominant antigen. Sheep vaccinated with two 100-micrograms doses of a 40-kDa antigen preparation in aluminium hydroxide adjuvant were protected against infection with C. pseudotuberculosis, with an 82% reduction in the proportion of infected sheep and a 98% reduction in lung lesions. Sera from vaccinated sheep exhibited a strong response only to the 40-kDa antigen on immunoblots. These results strongly suggest that the 40-kDa antigen plays a major role in immunity to caseous lymphadenitis.
Observations of hypophosphatemia and its management in nutrition support.
Severe hypophosphatemia is associated with significant morbidity in hospitalized patients. Specialized nutrition support is an important factor that contributes to the development of this metabolic disorder. Current treatment regimens for hypophosphatemia are empiric and often fail to normalize serum phosphorus concentrations in these patients. Patients who develop hypophosphatemia during the administration of specialized nutrition support exhibit increased phosphorus demands and require aggressive replacement therapy.
Dynamic external fixation of unstable fractures of the distal part of the radius. A prospective, randomized comparison with static external fixation.
A prospective, randomized study was done to compare the results of dynamic external fixation (the Clyburn device) with those of static external fixation (the AO/ASIF device) in the treatment of fifty unstable fractures of the distal part of the radius. Mobilization of the wrist from neutral to 30 degrees of flexion was begun in the dynamic-fixator group at approximately two weeks, and full motion, allowing 30 degrees of extension, was started at approximately four weeks. The external fixation frames in both groups were kept in place for approximately ten weeks. Mobilization of the wrist in the dynamic-fixator group provided little gain in the mean motion of the wrist at the time of the removal of the fixator or at the one, six, or twelve-month evaluation. The static-fixator group had greater flexion of the wrist and radial deviation at the early and late follow-up examinations, while the dynamic-fixator group demonstrated only greater ulnar deviation one month after the fixator had been removed. Motion of the wrist in the dynamic-fixator group resulted in a statistically significant loss of radial length compared with that in the static-fixator group (four millimeters compared with one millimeter, p < 0.001). Complications were more frequent in the dynamic-fixator group. As evaluated with a modification of the scoring system of Gartland and Werley, 92 percent of the results at one year were excellent or good in the static-fixator group and 76 percent, in the dynamic-fixator group. The results of this study cannot support the concept of early mobilization with a dynamic external fixator for the treatment of unstable fractures of the distal part of the radius.
Sleep management. Evaluating advice booklets for parents.
Health professionals are increasingly using information booklets to disseminate important health messages to a wider population. However, such booklets are rarely evaluated from the consumer's point of view. Robert Deller and Jo Walker describe an evaluation by parents of a series of booklets giving parents advice about dealing with sleep problems in young children.
Antibodies to human and non-human primate cellular and culture medium components in macaques vaccinated with the simian immunodeficiency virus.
Inactivated simian immunodeficiency virus (SIV) grown in a human T-cell line induces protection from infection by the virus in macaques. However, observations that immunization with uninfected human T cells or with SIV-1 prepared in human T cells can also induce protection, has raised the possibility that protective antigens could be of human cellular origin. Sera from animals immunized with fixed infected and uninfected human T cells, as well as from animals immunized with partially purified cell-free SIV have been examined for their ability to bind to human and macaque peripheral blood mononuclear cells (PBMC) and to-components present in fetal calf serum (FCS) in which the cells were grown. Analysis by flow cytometry suggests that antibodies to human cell surface antigens can be elicited with both inactivated SIV grown in human T cells and by uninfected T cells. There was a significant association between the presence of anti-cell antibodies and protection from infection. However, anti-cell surface antibodies were not detected with macaque mononuclear cells by flow cytometry or by immunoprecipitation, unless these cells were first treated with FCS or activated by a mitogen. Immunoprecipitation of resting human PBMC with sera from immunized animals suggests the presence of antibodies to class I heavy and light chains [beta 2-microglobulin (beta 2 m)] and to bovine beta 2m, which may originate in FCS used to grow the cell line. Antibodies to CD4 were also found in sera from animals immunized with SIV grown in human T cells. We suggest that human cellular components augmented by FCS elicit anti-class I heavy chain, beta 2m, CD4 and FCS antibodies which may be responsible for protection against SIV infection in macaques.
The adenosine 5',5"',P1,P4-tetraphosphate receptor is at the cell surface of heart cells.
We have previously demonstrated the existence of an adenosine 5',5"',P1,P4-tetraphosphate (Ap4A) receptor in mouse hart membrane fractions [Hilderman, R. H., Martin, M., Zimmerman, J. K., & Pivorun, E. P. (1991) J. Biol. Chem. 266, 6915-6918]. However, we did not determine the cellular localization or distribution of the receptor. In this report, the Ap4A receptor is shown to be on the cell surface of individual mouse heart cells by the following four methods: (1) intact cells show specific, saturable, and reversible binding of Ap4A; (2) monoclonal antibodies (Mabs) raised against the Ap4A receptor inhibit Ap4A binding to its receptor on intact heart cells; (3) bound Mabs are shown to be at the outer cell surface via reaction with a alkaline phosphatase conjugated goat anti-rat IgG; (4) when intact cells are labeled with the impermeable cell surface labeling reagent, (sulfosuccinimido) biotin, labeled receptor is immunoprecipitated with Mabs. Furthermore, subcellular fractionation of mouse hearts demonstrates that virtually all of the Ap4A receptor is associated with a membrane fraction with at least 77% of the active receptor on plasma membranes.
T- and B-cell functions and epitope expression in nonhuman primates immunized with simian immunodeficiency virus antigen by the rectal route.
Transmission of human immunodeficiency virus (HIV) in North America and Europe occurs most commonly through the rectal mucosa during homosexual intercourse. The simian immunodeficiency virus (SIV) macaque model has been used to investigate rectal immunization. The vaccine used was a recombinant SIV gag p27 expressed as hybrid Ty virus-like particles (Ty-VLP). Sequential ororectal (OR) mucosal immunization was compared with i.m. immunization. Whereas both routes of immunization induced serum IgA and IgG p27 antibodies, only OR immunization induced rectal secretory IgA antibodies. Specific CD4+ T-cell proliferative responses to stimulation with p27 were found after i.m. immunization only in the blood and spleen, but after OR immunization they were found in the internal iliac and inferior mesenteric lymph nodes in addition to the blood and spleen. T-cell epitope mapping of the proliferative responses of short-term cell lines (STCLs) grown from peripheral blood or lymphoid cells revealed a major epitope within the polypeptide 121-150 after either route of immunization. Two minor T-cell epitopes were found within peptide 41-80 in STCLs from splenic and circulating cells. B-cell epitope mapping of serum or biliary IgA and IgG antibodies revealed two overlapping or adjacent immunodominant epitopes to the T-cell epitopes within the polypeptides 121-170 and 51-90. The results suggest that rectal augmented by oral immunization with a recombinant particulate antigen in nonhuman primates elicits secretory IgA and to a lesser extent IgG responses in the draining lymph nodes and the rectal mucosa, whereas systemic immunization targets predominantly splenic and circulating T- and B-cell responses. These findings may have important implications in the strategy of designing vaccines in prevention of homosexual transmission of HIV infection.
Benylin (dextromethorphan) abuse and mania.
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Identification of a serine protease which activates the mouse heart adenosine 5',5"',P1,P4-tetraphosphate receptor.
We have previously demonstrated that a serine protease dependent processing step is required for activation of the 30-kDa adenosine 5',5"',P1,P4-tetraphosphate (Ap4A) receptor. However, monoclonal antibodies (Mabs) against a 212-kDa polypeptide inhibit Ap4A binding to its receptor [Walker et al. (1993) Biochemistry 32, 1264-1269]. SDS-PAGE followed by autoradiography of [3H]diisopropylfluorophosphate (DIPF) covalently attached to membrane fractions reveals that the serine protease is the 212-kDa polypeptide or a proenzyme. Mabs against the 30-kDa Ap4A receptor are identified that inhibit Ap4A binding to its membrane receptor. These Mabs do not recognize the 212-kDa membrane protein but recognize four membrane proteins with molecular masses of 67, 55, 42, and 30 kDa. These data suggest that the precursor for the Ap4A receptor is a 67-kDa polypeptide which undergoes multiple cleavage events, at least one by the 212-kDa protein.
Activation of the mouse heart adenosine 5',5"'-P1-P4-tetraphosphate receptor.
We have previously demonstrated that mouse brain membrane fractions have a specific, saturable receptor for diadenylated nucleotides. Binding is specific for two adenosines, and the length of the phosphate bridge is critical, with four phosphates being optimal [Hilderman et al. (1991) J. Biol. Chem. 266, 6915-6918]. In this report, we demonstrate that adenosine 5',5"'-P1,P4-tetraphosphate (Ap4A) binding to its receptor is dependent upon an activation step that requires divalent cations and a serine protease. Monoclonal antibodies (Mabs) are identified that inhibit Ap4A binding to its membrane receptor. These antibodies recognize a 212-kDa membrane protein. However, SDS-PAGE analysis of Ap4A cross-linked to membrane fractions reveals that Ap4A is not attached to the 212-kDa peptide but to a 30-kDa polypeptide. Appearance of the 30-kDa polypeptide is dependent on the activation step, and one of the inhibitory antibodies blocks its appearance. We suggest that the protease-dependent processing step involves cleavage of the 212-kDa component with the appearance of an active 30-kDa receptor.
Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor alpha.
OBJECTIVE: To evaluate the safety and efficacy of a chimeric monoclonal antibody to tumor necrosis factor alpha (TNF alpha) in the treatment of patients with rheumatoid arthritis (RA). METHODS: Twenty patients with active RA were treated with 20 mg/kg of anti-TNF alpha in an open phase I/II trial lasting 8 weeks. RESULTS: The treatment was well tolerated, with no serious adverse events. Significant improvements were seen in the Ritchie Articular Index, which fell from a median of 28 at study entry to a median of 6 by week 6 (P < 0.001), the swollen joint count, which fell from 18 to 5 (P < 0.001) over the same period, and in the other major clinical assessments. Serum C-reactive protein levels fell from a median of 39.5 mg/liter at study entry to 8 mg/liter at week 6 (P < 0.001), and significant decreases were also seen in serum amyloid A and interleukin-6 levels. CONCLUSION: Treatment with anti-TNF alpha was safe and well tolerated and resulted in significant clinical and laboratory improvements. These preliminary results support the hypothesis that TNF alpha is an important regulator in RA, and suggest that it may be a useful new therapeutic target in this disease.