Providing Olympic-class care aim of Canadian medical team.
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Canada↗
Biomedical subjects
J Brooks
Publications and source records attributed to J Brooks.
Genetic modulation of antigen presentation by HLA-B27 molecules.
In studies of antigenic peptide presentation, we have found a healthy volunteer whose lymphoblastoid cells were unable to present three different virus-derived epitopes to cytotoxic T lymphocytes (CTL) despite expressing the correct restricting HLA-B27 molecules on the cell surface. B cell lines were established from other members of the donor's family, including individuals suffering from ankylosing spondylitis and related diseases, and were tested for their ability to function as target cells in the same assay. None of the eight B cell lines that expressed HLA-B27 presented a known peptide epitope to CTL. However, cells from a family member that expressed HLA-B8 could present an epitope peptide restricted by that molecule. The B27 molecule in this family proved to be the B2702 subtype on isoelectric focusing gels, appearing in exactly the same position as B2702 from other cell lines that did present the peptide. To exclude mutations resulting in noncharged amino acid substitutions, cDNA coding for B2702 was cloned from the proband's cell line and sequenced. No coding changes were found. The cloned cDNA was transfected into HLA-A- and B-negative HMy/C1R cells, and the B2702 molecules generated in this environment rendered these cells, after incubation with peptide, susceptible to lysis by peptide-specific CTL. These data are compatible with the presence of a factor(s), possibly HLA linked, interfering with antigen presentation by otherwise normal B2702 molecules in this family.
Antigen-Presenting Cells↗
Restoration of the LFA-3 adhesion pathway in Burkitt's lymphoma cells using an LFA-3 recombinant vaccinia virus: consequences for T cell recognition.
Conjugate formation between cytotoxic T lymphocytes (CTL) and target B cells, as observed in vitro, is mediated by interactions between adhesion molecules on the two cell surfaces rather than involving immune recognition through the T cell receptor. It is still not clear to what extent such adhesive contacts facilitate the process of immune recognition and target cell lysis. However, work on the Epstein-Barr virus (EBV)-associated malignancy Burkitt's lymphoma (BL) has suggested that down-regulation of one particular adhesion molecule, the lymphocyte function-associated antigen LFA-3, on the tumor cell surface is a key factor in allowing these target cells to escape EBV-specific T cell surveillance. To examine this directly, we used a cDNA for the full-length transmembrane form of LFA-3 to construct a recombinant vaccinia virus (Vacc-LFA 3), which is capable of restoring surface LFA-3 in adhesion molecule-negative BL cell lines to levels as high as seen in EBV-transformed lymphoblastoid cell lines (LCL); biochemical studies confirmed expression of the authentic N-glycosylated protein. The recombinant vaccinia-encoded LFA-3 was functional as an adhesion molecule since BL cells acutely infected with Vacc-LFA-3 then acquired the ability to form conjugates with activated T cells in vitro. However, there was no clear dependence upon LFA-3 when such BL cell lines were tested as targets for cytotoxic T lymphocytes (CTL). Firstly, LFA-3- BL cells could be killed by allospecific CTL recognizing HLA class I alloantigens, in some cases as efficiently as the corresponding LCL. In other cases where lysis was slightly below that of the LCL, Vacc-LFA-3 infection of the BL cells increased lysis up to, but never beyond, LCL values. Secondly, we studied the sensitivity of BL to EBV-specific HLA class I-restricted CTL using a BL target line which was LFA-3- but which expressed the same spectrum of EBV target proteins as an LCL. This line was not recognized by appropriately HLA-matched effectors, even after restoration of LFA-3 expression. We conclude that the LFA-3 status of BL cells influences their conjugate forming ability in in vitro assays but not necessarily their sensitivity to immune T cell-mediated cytolysis.
Antigens, Surface↗
Failure of ritodrine to prevent preterm labor in the sheep.
OBJECTIVES: The purpose of this study was to determine whether continuous infusion of ritodrine could prevent preterm delivery in sheep. STUDY DESIGN: Sheep in preterm labor induced by RU 486 (mifepristone) received infusions of either ritodrine (n = 5) or saline solution (n = 5), and the progress of labor was monitored. beta 2-Adrenergic receptor density and function (agonist-induced cyclic adenosine monophosphate production) was measured in myometrial samples from both groups. RESULTS: Ritodrine initially inhibited labor contractions. This inhibition was only maintained for 16 hours, after which both the amplitude and frequency of electromyographic bursts and contractions returned. The failure of the myometrium to respond to ritodrine (desensitization) was associated with significant reductions in agonist-induced cyclic adenosine monophosphate production and beta 2-adrenergic receptor concentration in myometrial tissue collected from these animals compared with the saline solution-treated controls. CONCLUSIONS: Continuous infusion of ritodrine to sheep in preterm labor produces only a transient inhibition of contractions. This desensitization is caused by a down-regulation of myometrial beta 2-adrenergic receptors.
Animals↗
Immune escape by Epstein-Barr virus (EBV) carrying Burkitt's lymphoma: in vitro reconstitution of sensitivity to EBV-specific cytotoxic T cells.
Epstein-Barr virus (EBV) positive Burkitt's lymphoma (BL) cells are markedly less sensitive to EBV-specific cytotoxic T cell (CTL) recognition than EBV-transformed lymphoblastoid cell lines of normal B cell origin. Three features of the BL cell phenotype might contribute to this reduced susceptibility: (i) low expression of cell adhesion molecules, (ii) low expression of HLA class I and selective down-regulation of particular alleles, and (iii) down-regulation of all transformation-associated EBV antigens except EBV-encoded nuclear antigen (EBNA)-1. This study assesses the individual importance of each of these features for immune escape. For this purpose the WW1-BL cell line was used which expresses all the known transformation-associated EBV antigens (EBNA-1 to -6 and latent membrane protein-1 and -2) but which is negative for HLA A11 and for the adhesion molecule leukocyte function associated antigen-3 (LFA-3). Using recombinant vectors, these deficiencies have been sequentially corrected and the cells have been tested for sensitivity to EBV (B95.8 strain)-induced CTL preparations recognizing epitope(s) of EBNA-4 in the context of HLA A11. Expression of HLA A11 alone or in combination with LFA-3 did not sensitize WW1-BL cells to these effectors. Lysis was only achieved when HLA A11 was co-expressed with the B95.8 virus-encoded EBNA-4 protein, and in these circumstances sensitization did not require LFA-3. These results indicate that reconstitution of the relevant HLA-EBV epitope target complex on the cell membrane is sufficient to render BL cells sensitive to virus-specific cytolysis. The requirement for EBNA-4 reconstitution to achieve lysis of the WW1-BL/A11 transfectant suggested that the resident WW1 virus-encoded EBNA-4 protein did not contain the relevant target epitope for HLA A11-restricted recognition. This was confirmed by transferring the WW1 virus isolate into another A11-positive B cell background.
Antigens, CD↗
Prevention of diabetes in nonobese diabetic mice by dendritic cell transfer.
The purpose of this study was to determine the effect of dendritic cell (DC) transfers on the incidence of diabetes in female nonobese diabetic (NOD) mice. Groups of 4-wk-old NOD female mice were given a single foot pad of DCs (70-90% purity) isolated from the draining lymph nodes (LN) of the pancreas (PLN), the cervical LNs, or the axillary/inguinal LNs. In addition, other groups of NOD mice received purified spleen DCs, purified PLN T cells (the major contaminating population in DC preparations), or the injection vehicle PBS. All groups were monitored for diabetes for one year. Significant protection from diabetes was observed in NOD mice receiving greater than 1 x 10(4) PLN DCs in comparison to mice receiving other DCs populations, PLN T cells, or PBS (P less than 0.05). The pancreata of NOD mice that received PLN DCs demonstrated significantly lower levels of lymphocytic infiltration in the islets that age-sex matched nondiabetic female NOD control mice (P less than 0.05). LN cells from nondiabetic NOD mice that received PLN DC protected irradiated female recipients from the adoptive transfer of diabetes to a greater degree than LN cells from age and sex matched nondiabetic female NOD mice that did not receive PLN DC transfers at 36 d (P = 0.014) and at 1 yr (P = 0.0015) after transfer. These data suggest that the PLN DC transfers are able to modulate autoimmunity and limit diabetes expression in the NOD mouse. PLN DCs transfers may regulate autoimmunity by the induction of regulatory cells.
Animals↗
Relationship between gonadotrophin subunit gene expression, gonadotrophin-releasing hormone receptor content and pituitary and plasma gonadotrophin concentrations during the rebound release of FSH after treatment of ewes with bovine follicular fluid during the luteal phase of the cycle.
The modulation of FSH secretion at the beginning and middle of the follicular phase of the cycle represents the key event in the growth and selection of the preovulatory follicle. However, the mechanisms that operate within the pituitary gland to control the increased release of FSH and its subsequent inhibition in vivo remain unclear. Treatment of ewes with bovine follicular fluid (bFF) during the luteal phase has been previously shown to suppress the plasma concentrations of FSH and, following cessation of treatment on day 11, a rebound release of FSH occurs on days 12 and 13. When luteal regression is induced on day 12, this hypersecretion of FSH results in an increase in follicle growth and ovulation rate. To investigate the mechanisms involved in the control of FSH secretion, ewes were treated with twice daily s.c. injections of 5 ml bFF on days 3-11 of the oestrous cycle and luteal regression was induced on day 12 with prostaglandin (PG). The treated ewes and their controls were then killed on day 11 (luteal), or 16 or 32 h after PG and their pituitaries removed and halved. One half was analysed for gonadotrophin and gonadotrophin-releasing hormone (GnRH) receptor content. Total pituitary RNA was extracted from the other half and subjected to Northern analysis using probes for FSH-beta, LH-beta and common alpha subunit. Frequent blood samples were taken and assayed for gonadotrophins. FSH secretion was significantly (P less than 0.01) reduced during bFF treatment throughout the luteal phase and then significantly (P less than 0.01) increased after cessation of treatment, with maximum secretion being reached 18-22h after PG, and then declining towards control values by 32h after PG. A similar pattern of LH secretion was seen after bFF treatment. Pituitary FSH content was significantly (P less than 0.05) reduced by bFF treatment at all stages of the cycle. No difference in the pituitary LH content was seen. The increase in GnRH receptor content after PG in the controls was delayed in the treated animals. Analysis of pituitary mRNA levels revealed that bFF treatment significantly (P less than 0.01) reduced FSH-beta mRNA levels in the luteal phase. Increased levels of FSH-beta, LH-beta and alpha subunit mRNA were seen 16h after PG in the bFF-treated animals, at the time when FSH and LH secretion from the pituitary was near maximum.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Luteinizing hormone pulses, follicle-stimulating hormone and control of follicle selection in sheep.
The growth of large oestrogenic follicles that have the potential to ovulate if given an appropriate luteinizing hormone (LH) signal is dictated by the plasma concentration of follicle-stimulating hormone (FSH). Basal amounts of LH are essential for this FSH-induced follicle growth, but pulses of LH do not appear to be essential. The fall in FSH concentration during the follicular phase of the oestrous cycle in sheep, and the subsequent withdrawal of FSH from other developing follicles may not be sufficient to explain follicle selection. There is little evidence to support an active suppression of the growth of other follicles by a factor(s) produced by the dominant, or selected follicle. It is possible that LH pulses cause active atresia of non-selected follicles. The selected follicle is the one that can survive the fall in plasma FSH and the large increase in LH pulses during the follicular phase and selection may simply be a case of being the follicle(s) that is present at the correct time to receive adequate FSH and develop sufficiently to survive the inhibitory effects of LH pulses. Several mechanisms whereby LH pulses may inhibit follicle growth are suggested, and avenues for future research, particularly related to the expression of the LH receptor on granulosa cells of the developing follicle, are outlined.
Animals↗
T cell recognition of Epstein-Barr virus associated lymphomas.
Epstein-Barr virus, a lymphotropic herpesvirus of humans, has potent B cell growth transforming activity yet persists in the lymphoid tissues of most individuals as a lifelong asymptomatic infection. Virus induced B cell growth transformation in vitro is associated with the expression of a limited set of viral genes encoding six nuclear antigens (EBNA 1, 2, 3A, 3B, 3C and LP) and two latent membrane proteins (LMP 1, 2). Healthy virus carriers possess strong EBV specific CTL memory that can be reactivated in vitro. Here, we summarize experiments in which the antigenic specificities of these HLA class I restricted memory CTL responses have been mapped in a range of individuals with different HLA backgrounds. Of the known EBV latent proteins, EBNA 3A, 3B and 3C are frequently the dominant targets for such responses, but examples of responses directed against epitopes of EBNA 2, EBNA-LP or the LMP have been identified; by contrast, CTL responses against epitopes of EBNA 1 have not been observed. Epstein-Barr virus is associated with at least three malignancies of lymphoid origin--immunoblastic lymphomas of the immunosuppressed, endemic Burkitt's lymphoma and a subset of Hodgkin's disease. The immunoblastic lymphomas express the complete spectrum of EBV coded latent proteins and a cellular phenotype similar to that of in vitro transformed B lymphoblastoid cell lines; accordingly, they remain sensitive to EBV specific CTL recognition. Endemic BL cells are not recognized by such CTL, and at least three consistent features of this tumour could contribute to immune escape: (a) allele specific downregulation of HLA class I antigen expression, (b) absence/low expression of cellular adhesion molecules and (c) restriction of EBV latent protein expression to EBNA 1 only. The relative importance of these three features of the BL cell phenotype with regard to sensitivity to CTL recognition is re-interpreted in the light of recent results. Finally, the pattern of virus latent protein expression in EBV positive Hodgkin's disease is described, and the possibility of EBV specific CTL control against this tumour is discussed.
Antigens, Viral↗
Frequency of G-985 mutation in medium chain acyl-coenzyme A dehydrogenase (MCAD) deficiency in sudden infant death syndrome (SIDS).
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Acyl-CoA Dehydrogenase↗
Use of nonlinear, mixed-effects modeling for population analysis of ofloxacin: effects of age on oral drug pharmacokinetics.
To compare the effect of age on pharmacokinetics of orally administered ofloxacin, two separate studies were reanalyzed using mixed-effect modeling with the program NONMEM. Subjects were male volunteers, 36 age 65 years or greater and 24 age 18-40 years. The younger group received three 100-mg tablets and the older group received two 200-mg tablets of ofloxacin. Serial blood samples obtained throughout dosing were assayed for drug concentrations using high-performance liquid chromatography. A pharmacostatistical model was developed for the data using mixed-effect modeling with NONMEM. A one-compartment open model with first-order absorption, which included the covariables weight and age, best fit the data. Mean (SE) population values were clearance/F 0.219 (0.009) L/hr/kg, volume of distribution/F 1.50 (0.071) L/kg, and absorption rate constant 2.26 (0.048) hr-1. Older subjects had a 29% lower clearance and 13% lower volume of distribution then the younger subjects.
Administration, Oral↗
Using neural networks to diagnose cancer.
While artificial brains are in the realm of science fiction, artificial neural networks (ANNs) are scientific facts. An artificial neural network is a computational structure modeled somewhat on the neural structure of the brain; both have many highly interconnected processing elements. These biologically inspired processing elements are taught by feeding examples until the results are acceptable. In the past 5 years, neural networks have become successful in providing meaningful second opinions in clinical diagnosis. In our research, a prototype artificial neural network was trained on numeral ultrasound data of 52 actual cases and then correctly identified renal cell carcinoma from renal cysts and other conditions without diagnostic errors. Our nonlinear artificial neural network was trained on software using the standard backpropagation paradigm on a 80386 microcomputer. Our ANN learned from ultrasound data in 52 cases (17 malignant, 30 cysts, and 5 other) at a Memphis hospital. The trained prototype performed without error on 47 cases which were not in the data used for training. This prototype must be validated by extending this study to more cases.
Carcinoma, Renal Cell↗
Localization of the sites of synthesis and action of prolactin by immunocytochemistry and in-situ hybridization within the human utero-placental unit.
While the fetal pituitary synthesizes and releases prolactin, it is also produced within the utero-placental unit during pregnancy in women and has been localized in the amnion, chorion and decidua. However, it is not clear whether prolactin is synthesized within all these non-fetal pituitary tissues. We have investigated prolactin production and its gene expression using tissue culture, immunocytochemistry and in-situ hybridization techniques. Prolactin was immunolocalized not only in the decidua but also in amnion and trophoblast cells. In contrast, the in-situ hybridization results showed that silver grains, formed by specific hybridization of a prolactin cDNA probe to prolactin mRNA, were confined to decidual cells of early and term pregnancy. The results from tissue cultures correlated well with those of in-situ hybridization, that is that only the decidua made detectable prolactin, while it was undetectable in the culture medium from trophoblast tissue, irrespective of the stage of pregnancy. This study, for the first time, establishes that only decidualized cells are involved in biosynthesis of prolactin; other prolactin-containing cells in the amnion and trophoblast appear to sequester prolactin, possibly via receptors, suggesting that prolactin may play an important paracrine role within the amnion and syncitio- and cytotrophoblast of the utero-placental unit.
Blotting, Northern↗
Computed tomography changes in neurosarcoidosis clearing with steroid treatment.
Contrast enhancement computed tomography (CT) in a patient with central nervous system (CNS) sarcoidosis revealed increased densities particularly in the frontal and temporal areas. Treatment with prednisone improved the condition, and the CT abnormality disappeared. These previously undescribed findings can be of help in establishing the diagnosis and in following the patient's response to treatment.
Adult↗
Randomized phase II clinical trial of adriamycin, methotrexate, and actinomycin-D in advanced measurable pancreatic carcinoma: a Gastrointestinal Tumor Study Group Report.
Sixty-six patients with advanced pancreatic carcinoma were randomized to receive single agent chemotherapy with either adriamycin, methotrexate, or actinomycin-D using conventional dose, route and schedule of administration. All patients had measurable lesions which were used to objective assessment of response. For adriamycin, 2 of 25 patients (8%) evidenced a partial response (2 of 15 (13%) previously untreated patients). One of 25 patients treated with methotrexate and one of 28 received actinomycin-D responded. The duration of responses ranged from 43-64 days for those patients with no chemotherapy prior to study entry. The median survival of patients who received adriamycin as initial treatment was 12 weeks compared to 8 weeks for methotrexate and 6 weeks for actinomycin-D therapy.
Adult↗
Method for measuring blood flows and volumes using indicator-dilution techniques in patients with transposition of the great vessels.
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Blood Volume↗
Experimental internuclear ophthalmoplegia.
A midline experimental lesion separating the medial longitudinal fasciculi at and below the level of the abducens nuclei without damaging either fasciculus at the level of the nuclei has produced defects of ocular motility resembling those of clinical internuclear ophthalmoplegia. Electromyographic recordings during lateral gaze demonstrate: (1) lack of inhibition of the lateral rectus muscle in the adducting eye, (2) delayed inhibition of the medial rectus muscle in the abducting eye, and (3) occasional evidence of excitation of the medial rectus muscle of the abducting eye probably associated with pupillary constriction. The presumed physiologic mechanisms involved in conjugate gaze movements are discussed in the light of the experimental findings.
Animals↗
Noise as a health hazard in the boilermaking industry.
An investigation was made into noise hazard aspects of three boilermaking firms. This consisted of noise measurement of both background and impact noises, of field audiometry of the workforce and a questionnaire. Environmental findings so far show the noise to be hazardous to hearing. Audiometric testing revealed a high rate of hearing impairment. A general lack of knowledge of noise hazard was shown, and the need for a hearing conservation programme demonstrated.
Adolescent↗