The heart of the matter: Dalton Camp and his controversial transplant.
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Canada↗
Biomedical subjects
J Brooks
Publications and source records attributed to J Brooks.
Regional DNA hypermethylation at D17S5 precedes 17p structural changes in the progression of renal tumors.
In a preceding paper for brain tumors, we demonstrate a tight association between regional hypermethylation at locus D17S5 of chromosome 17p and allelic loss of this chromosome. Because 17p allelic losses occur at the earliest stages of brain tumors, the exact temporal relationship between this event and the hypermethylation could not be elucidated. In renal cancers, two linked structural changes on chromosome 17p, allelic loss and p53 gene mutations, generally occur late in progression. We now show that D17S5 hypermethylation is tightly coupled to both of these genetic changes in late stage renal tumors. However, the methylation change is the only one of the 17p abnormalities which occurs at a high incidence in early-stage renal cancers (hypermethylation, 50%; 17p allelic loss, 13%; p53 mutations, 0%). Our results firmly suggest that D17S5 regional hypermethylation precedes the appearance of the consistent 17p genetic changes in renal cancers, suggesting that this event either marks, or may even cause, chromatin changes which predispose to genetic instability.
Alleles↗
Threat of skin cancer changing the way Australians live.
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Australia↗
Museum a perfect memorial to the Lady of the Lamp.
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History of Nursing↗
A new variant of serosubtype P1.16 in Neisseria meningitidis from Norway, associated with increased resistance to bactericidal antibodies induced by a serogroup B outer membrane protein vaccine.
Based on differences in reaction pattern with monoclonal antibodies against the P1.16 epitope, a new variant of the class 1 protein in Neisseria meningitidis serogroup B was identified in Norway. A single amino acid deletion was revealed when the part of the gene region encoding the second variable region of the protein was sequenced. This new variant was designated P1.16c. About 5% of the B:15:P1.7,16 strains in Norway from the time period 1987-1991 were P1.16c. In a localized area in Southern Norway, 5/8 (62%) of the P1.7,16 strains were P1.16c. The P1.16b mutant, recently described in England, was not found among the Norwegian meningococcal isolates. Strains carrying the P1.16c mutation showed increased resistance to bactericidal killing, not only by P1.16-specific monoclonal antibodies, but also by the sera from individuals immunized with a vaccine based on outer membranes from a B:15:P1.7,16 strain.
Amino Acid Sequence↗
Unusual behavior of clear cell chondrosarcoma.
We report two unusual cases of clear cell chondrosarcoma. Both emphasize the slow-growing nature of the lesion and the need for long-term follow-up. Additionally, the clinical, radiologic and histologic characteristics of this neoplasm are discussed.
Bone Neoplasms↗
Cloning and sequencing of the sheep pituitary gonadotropin-releasing hormone receptor and changes in expression of its mRNA during the estrous cycle.
We have isolated a full length cDNA clone coding for the sheep GnRH receptor (GnRH-R). The amino acid sequence shows greater homology to the human GnRH-R sequence than the two rodent receptors published so far. We have also carried out physiological studies investigating the pattern of expression of the GnRH-R mRNA throughout the estrous cycle. GnRH receptor mRNA and GnRH binding levels were both significantly (P < 0.05) increased over luteal levels up until the time of the preovulatory LH surge, whilst post-surge, a significant (P < 0.05) decline was seen. These changes were related to increased follicle estradiol production in the follicular phase. In contrast, no changes in the abundance of LH beta mRNA were seen throughout the estrous cycle, but the pituitary content of LH significantly (P < 0.05) decreased after the preovulatory LH surge. These results suggest that there is a close relationship between the abundance of GnRH-R mRNA and translation of the GnRH-R in sheep.
Amino Acid Sequence↗
Immunolocalization of oestrogen and progesterone receptors in the human decidua in relation to prolactin production.
The distribution of oestrogen and progesterone receptors within the decidualized stroma of the uterus was examined in early and term human pregnancy and the results related to the effect of oestradiol and progesterone on prolactin production by decidua in vitro. In early pregnancy progesterone receptors were present in the nucleus of decidualized cells of both the capsularis and parietalis but not in glandular cells. In contrast at term progesterone receptors were located within the cytoplasm of decidual cells. Oestrogen receptors were detected only in the nucleus and were present in greater amounts in decidua capsularis than parietalis in early pregnancy, but were not detectable in term decidua. Both oestrogen and progesterone receptors were present in the nuclei of cells of arterioles within the decidua. In early pregnancy prolactin production decreased during in-vitro culture of decidua parietalis but was maintained in decidua capsularis, associated with an increase in progesterone production by the decidua capsularis. In term decidua, prolactin production in vitro was only stimulated by a combination of oestradiol and progesterone. These results suggest, firstly, that maintained decidualization and prolactin production by decidua capsularis during treatment of women in early pregnancy with the anti-progestin mifepristone is not due to an absence of progesterone receptor; secondly, there is a shift in immunoreactive progesterone receptor in decidual cells from the nucleus in early pregnancy to the cytoplasm in term pregnancy. This may indicate an alteration in the action of progesterone around the time of parturition; and thirdly, in term decidua, progesterone, apparently acting through the cytoplasmic receptor, is active in increasing prolactin production in vitro only when combined with oestradiol.
Cells, Cultured↗
GnRH-dependent and -independent components of FSH secretion after acute treatment of anoestrous ewes with ovine follicular fluid and a GnRH antagonist.
Gonadotrophin and inhibin concentrations were measured in anoestrous ewes after acute treatment with either saline, ovine follicular fluid (oFF), GnRH antagonist, or oFF and GnRH antagonist in combination. The increase in mean LH concentrations observed in ewes treated with oFF alone, was not seen in either of the groups treated with GnRH antagonist, in which LH pulsatility was completely inhibited. This result suggests that the LH rebound that follows follicular fluid treatment is GnRH dependent. Blockade of GnRH had no effect on the suppression of FSH seen after follicular fluid injection, indicating that this component of FSH secretion is independent of short-term GnRH input. After this initial suppression, a rebound release of FSH was seen in the group treated with oFF alone. The addition of GnRH antagonist appeared to decrease the rebound, suggesting that this rebound release of FSH may have a GnRH-dependent component. Inhibin concentrations in both oFF-treated groups increased after oFF injection and then declined to pretreatment values. However, a second rise in inhibin concentration, concomitant with the FSH rebound in ewes receiving oFF alone, was seen in the group treated with oFF and GnRH antagonist. As this rise in endogenous inhibin concentration could also act to suppress the rebound release of FSH, it cannot be conclusively proved from this study that GnRH input is required for the generation of the rebound release of FSH after treatment with oFF.
Anestrus↗
Providing Olympic-class care aim of Canadian medical team.
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Canada↗
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↗
Compliance with medication orders among the elderly after hospital discharge.
Patient compliance with medication prescriptions in the period immediately following hospital discharge should be of concern to all hospital personnel responsible for the appropriate use of medications, notably Pharmacy and Therapeutics and Quality Assurance Committees. We reviewed the medical records of patients over age 65 discharged from one acute-care hospital. Two days after discharge, we contacted subjects by phone and determined which medications they were taking and at what frequency. We compared discharge orders for medication use with actual use, as determined by self-reports. Of the 44 patients for whom we had complete data, 64% used at least one medication that was not ordered by the physician at discharge, and 73% failed to use at least one medication according to the way it was ordered. Of all drugs ordered at discharge, 32% were not taken at all. Hospital personnel should evaluate their discharge procedures and test techniques to improve compliance in discharged elderly patients.
Aged↗
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↗