PubMed Health⌕ Search

Biomedical subjects

J Bray

Publications and source records attributed to J Bray.

At least 19 recordsLinked to original sources
PubMed2000

Plasmid/liposome transfer of the human manganese superoxide dismutase transgene prevents ionizing irradiation-induced apoptosis in human esophagus organ explant culture.

Esophagitis is a major limiting factor in the treatment of lung cancer by radiation alone or in combination with chemotherapy. We have previously demonstrated that intraesophageal injection of manganese superoxide dismutase-plasmid/liposome (MnSOD-PL) complex into C3H/HeNsd mice blocks irradiation-induced esophagitis. To determine whether the human esophagus can be similarly transfected, normal human esophageal sections obtained from the margins of esophagectomy specimens from esophageal cancer patients were transfected in vitro with alkaline phosphatase (AlkP)-PL complex and stained for AlkP activity, and the percent of cells expressing AlkP was calculated. At 24 hr after transfection with 20 or 200 microgram of AlkP-PL complex, 55.0% and 85.8% of esophageal epithelial cells expressed detectable AlkP, respectively. Other sections transfected with MnSOD-PL complex showed transgene mRNA by nested reverse transcriptase-polymerase chain reaction (RT-PCR) assay and increased MnSOD biochemical activity for at least 96 hr after transfection. Irradiated MnSOD-PL complex-transfected sections demonstrated a significantly decreased percentage of apoptotic cells when compared to irradiated control sections. Following 1,000 cGy, MnSOD-PL-treated samples showed 7.5 +/- 2.8% and 33.3 +/- 7.3% apoptotic cells at 24 and 48 hr compared to 53.6 +/- 6.9% and 59.0 +/- 13.8% for nontransfected controls (P < 0.0001 and P < 0.1175). After 2,000 cGy, results at 24 and 48 hr were 25.0 +/- 7.6% and 66.9 +/- 4.9% for MnSOD-transfected sections compared to 65.6 +/- 4.3% and 90.0 +/- 4.1% for control sections (P < 0.0001 and P = 0.0353), respectively. Thus, human esophageal sections can be transfected with MnSOD-PL complex in vitro and thereby protected against ionizing irradiation-induced apoptosis. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 128-137 (2000).

Alkaline Phosphatase↗
PubMed1999

An ethnographic study of psychiatric nursing.

There is a well documented continuing anomaly between what is expected of a psychiatric nurse and observations of practice. This paper presents an ethnographic study carried out in three acute psychiatric in-patient units over one year. Methods used were participant observation and semistructured interviews of 15 trained nurses. Three themes were isolated during and following data analysis: the difficulty of working closely with mentally disturbed individuals; maintaining distance and congruent care. There was a notable dichotomy, that of wanting to work with the patients but constantly feeling that what they intuitively wanted to do was not right.

Anthropology, Cultural↗
PubMed1998

Identification of stathmin as a novel substrate for p38 delta.

p38 mitogen-activated protein kinases (MAPK) are a family of kinases that are activated by cellular stresses and inflammatory cytokines. Although there are many similarities shared by the isoforms of p38 (alpha, beta, gamma, and delta), p38 delta differs from the others in some respects such as inhibitor sensitivity and substrate specificity. Utilizing in a solution kinase assay, we identified a novel p38 delta substrate as stathmin. Stathmin is a cytoplasmic protein that was previously reported to be a substrate of several intracellular signaling kinases and has recently been linked to regulation of microtubule dynamics. p38 delta has significantly higher in vitro phosphorylating activity against stathmin than other p38 isoforms or related MAPKs. In transient expression studies, we found that in addition to different stimuli osmotic stress activates p38 delta to phosphorylate stathmin. The sites of phosphorylation were mapped to Ser-25 and Ser-38, both in vitro and in cells.

Base Sequence↗
PubMed1998

A double-blind comparison of the efficacy and safely of paroxetine and imipramine in the treatment of depression with dementia.

OBJECTIVES: To compare the efficacy of paroxetine and imipramine prospectively in patients with coexisting depression and dementia. METHODS: An 8-week, double-blind, parallel group trial comparing paroxetine 20-40 mg/day with imipramine 50-100 mg/day in 198 patients aged 60 years or over with a Montgomery-Asberg Depression Rating Scale (MADRS) score > or = 20 and a Folstein mini-mental state evaluation score of 17-23 points after a 3- to 7-day placebo run-in period. RESULTS: Both paroxetine and imipramine reduced the MADRS and the Clinical Global Impression (CGI) severity-of-illness and global improvement scores at weeks 2, 4, 8 and at endpoint, with no significant differences between treatment groups at any timepoint (MADRS, p > or = 0.368; cgi, p > or = 0.286). There was a statistically significant difference in favour of paroxetine at both the week 4 and week 8 timepoints (analysis of variance, p < or = 0.049) in the Cornell scale for depression in dementia: at endpoint there was no significant difference between treatments (p = 0.103). Treatment-emergent adverse experiences were reported by 51.5% (51/99) of patients treated with paroxetine and 50.5% (50/99) of patients treated with imipramine. Anticholinergic adverse experiences (paroxetine 6.1%; imipramine 13.1%) and serious non-fatal adverse experiences (paroxetine 4.0%; imipramine 8.1%) were reported by more patients in the imipramine group than in the paroxetine group. CONCLUSIONS: Paroxetine and imipramine were both effective in the treatment of depression in elderly subjects with co-existing dementia, and no significant differences were detected between the groups. There were trends suggesting that paroxetine was better tolerated than imipramine in terms of anticholinergic adverse experiences and serious non-fatal adverse experiences.

Aged↗
PubMed1998

Purification and activation of recombinant p38 isoforms alpha, beta, gamma, and delta.

p38 is a proline-directed serine/threonine kinase that is activated by inflammatory cytokines and cellular stress. At present, four isoforms of p38 have been identified and termed alpha, beta, gamma, and delta. We expressed each p38 homolog in Escherichia coli and purified the recombinant isoforms. p38alpha and C-terminal Flag-tagged p38beta were purified by Q-Sepharose fast flow, hydroxyapatite, and Q-Sepharose high-performance chromatography. His-tagged p38gamma was purified using Ni2+-NTA resin followed by Mono Q chromatography. Glutathione S-transferase-Flag p38delta was purified using M2 affinity agarose and gel-filtration chromatography. Upstream activators of p38, constitutively active (ca) MKK3 and MKK6, were also cloned, purified, and used to activate each p38 isoform. p38 alpha, gamma, and delta were phosphorylated by both MKK6 and caMKK3. p38beta was phosphorylated only by MKK6. Mass spectrometry analysis and kinase assays showed that MKK6 was the superior reagent for phosphorylating and activating all p38 isoforms.

Activating Transcription Factor 2↗
PubMed1998

Prevention of late effects of irradiation lung damage by manganese superoxide dismutase gene therapy.

Organ and tissue damage caused by ionizing irradiation is directly related to volume irradiated, total dose and dose rate. The acute effects are in part mediated by cellular activation of early response genes, including those for transcriptional activators of genes for humoral cytokines. In the lung, as in other organs, recovery from the acute effects of ionizing irradiation does not always correlate with prevention of the critical late effects, including fibrosis, which contribute to organ failure. An interventional technique by which to protect normal organs from the late effects of irradiation has remained elusive. We now demonstrate that overexpression of a transgene for human manganese superoxide dismutase (MnSOD) delivered by plasmid-liposome, or adenovirus to the lungs of C57BL/6J or Nu/J mice, respectively, before irradiation exposure, decreases the late effects of whole lung irradiation (organizing alveolitis/fibrosis). These data provide a rational basis for the design of gene therapy approaches to organ protection from irradiation damage.

Adenoviridae↗
PubMed1998

Patient-centred performance monitoring systems and multi-agency care provision: a case study using a stakeholder participative approach.

We describe the processes involved in the development of an information system which can assess how care given by a number of agencies could be monitored by those agencies. In particular, it addresses the problem of sharing information as the boundaries of each agency are crossed. It focuses on the care of one specific patient group--the rehabilitation of elderly patients in the community, which provided an ideal multi-agency setting. It also describes: how a stakeholder participative approach to information system development was undertaken, based in part on the Soft Systems Methodology (SSM) approach (Checkland, 1981, 1990); some of the difficulties encountered in using such an approach; and the ways in which these were addressed. The paper goes on to describe an assessment tool called SCARS (the Southampton Community Ability Rating Scale). It concludes by reflecting on the management lessons arising from this project. It also observes, inter alia, how stakeholders have a strong preference for simpler, non-IT based systems, and comments on the difficulties encountered by stakeholders in attempting to reconcile their perceptions of the needs of their discipline or specialty with a more patient-centred approach of an integrated system.

Aged↗
PubMed1997

Molecular cloning and characterization of a novel p38 mitogen-activated protein kinase.

The p38 mitogen-activated protein kinases (MAPK) are activated by cellular stresses and play an important role in regulating gene expression. We have isolated a cDNA encoding a novel protein kinase that has significant homology (57% amino acid identity) to human p38alpha/CSBP. The novel kinase, p38delta, has a nucleotide sequence encoding a protein of 365 amino acids with a putative TGY dual phosphorylation motif. Dot-blot analysis of p38delta mRNA in 50 human tissues revealed a distribution profile of p38delta that differs from p38alpha. p38delta is highly expressed in salivary gland, pituitary gland, and adrenal gland, whereas p38alpha is highly expressed in placenta, cerebellum, bone marrow, thyroid gland, peripheral leukocytes, liver, and spleen. Like p38alpha, p38delta is activated by cellular stress and proinflammatory cytokines. p38delta phosphorylates ATF-2 and PHAS-I, but not MAPK-activated protein kinase-2 and -3, known in vivo and in vitro substrates of p38alpha. We also observed that p38delta was strongly activated by MKK3 and MKK6, while p38alpha was preferentially activated by MKK6. Other experiments showed that a potent p38alpha kinase inhibitor AMG 2372 minimally inhibited the kinase activity of p38delta. Taken together, these data indicate that p38delta is a new member of the p38 MAPK family and that p38delta likely has functions distinct from that of p38alpha.

Amino Acid Sequence↗
PubMed1997

Modeling the proliferative response of T cells to IL-2 and IL-4.

Interleukin (IL) -2 and IL-4 are growth factors for both T and B cells. When both cytokines are present, synergy is observed in some cases and antagonism in others. The studies presented here describe the use of a detailed mathematical model for the proliferative response of the T cell line, HT-2. This cell line responds to IL-2 and to IL-4 and shows a synergistic response when both cytokines are present. This model incorporates the observed synergy between these two cytokines while at the same time incorporating the known down-regulatory effect of IL-4 on the number of IL-2 receptors (IL-2R) at the cell surface, and it is able to reproduce a variety of experimental data. The major results from these studies include the following: the observation that the binding of IL-4 to its receptor is 1/10 as effective in delivering a proliferative signal as IL-2 binding to its receptor, the determination of the threshold number of bindings required to signal proliferation stimulated by IL-2 and IL-4, the demonstration that many different sets of experimental data can be accurately modeled, and the use of simple parameter terms to model the synergy between IL-2 and IL-4.

Cell Division↗
PubMed1997

Effect of rhBMP-2 on the osteogenic potential of bone marrow stromal cells from an osteogenesis imperfecta mouse (oim).

To understand whether osteogenesis imperfecta (OI) could result from defective differentiation of osteoprogenitor cells, we investigated the osteogenic potential of bone marrow stromal cells from a mouse model of human OI (oim). Bone marrow was flushed from the femurs and tibias of oim and normal littermates using a syringe with Dulbecco's modified Eagle's medium, and cells were allowed to adhere to flasks. Adherent cells were trypsinized and passaged weekly at a 1:4 split. The established stromal cells were assessed for collagen synthesis, alkaline phosphatase, and osteocalcin production in the presence or absence of rhBMP-2. The stromal cells were also assessed for mineralization by Von-Kossa staining and for exogenous gene transfer using adeno-lacZ and a retroviral vector. The bone marrow stromal cells from oim mice synthesized alpha 1(I) homotrimers as expected, whereas the stromal cells from the normal littermates synthesized alpha 1(I)2 alpha 2(I) heterotrimers. The bone marrow stromal cells exhibited low levels of alkaline phosphatase activity under basal conditions: upon treatment with rhBMP-2, the level of the alkaline phosphatase activity increased approximately 40-fold. Cytochemical staining of the cells confirmed the expression of alkaline phosphatase by the oim stromal cells and its augmentation by rhBMP-2. Osteocalcin production in the stromal cells was also enhanced approximately threefold by rhBMP-2. oim stromal cells grown in the presence of beta-glycerophosphate and ascorbic acid demonstrated Von-Kossa-positive solid deposits after 3 weeks in culture. Ten days after infection with adeno-lacZ, approximately 70% of oim stromal cells expressed the transgene product, and after infection with a retrovirus, approximately 20% of the cells expressed the transgene. These data indicate that bone marrow stromal cells, have osteogenic potential, and also the potential to be transduced with exogenous genes. Under basal conditions, however, the stromal cells from oim mice exhibited significantly lower levels of alkaline phosphatase activity than their normal littermates.

Alkaline Phosphatase↗
PubMed1997

A double-blind, multicenter study in primary care comparing paroxetine and clomipramine in patients with depression and associated anxiety. Paroxetine Study Group.

BACKGROUND: 60%-90% of patients with a primary diagnosis of depression also experience symptoms of anxiety, and such patients have a poorer prognosis than those with uncomplicated depression. The serotonin selective reuptake inhibitors have demonstrated efficacy in the treatment of both depression and certain anxiety states. Furthermore, in a metaanalysis of the paroxetine clinical trial database of 2963 patients in whom depression predominated, there was a concomitant reduction in the Hamilton Rating Scale for Depression anxiety factor. The purpose of the present study was to prospectively compare the efficacy of paroxetine and clomipramine in patients specifically selected for coexisting depression and anxiety. METHOD: This was a 12-week, double-blind, parallel-group trial comparing paroxetine 20-40 mg/day with clomipramine 75-150 mg/day in 1002 patients with a Montgomery-Asberg Depression Rating Scale (MADRS) score > or = 20 and a Clinical Anxiety Score (CAS) > or = 11 after a 3-7 day placebo run-in period. RESULTS: Both paroxetine and clomipramine reduced the MADRS and CAS ratings at 2, 6, and 12 weeks and at endpoint, with no significant differences between treatment groups at any time point. CGI severity of illness and global improvement ratings were also similar throughout the trial; however, there was a statistically significant difference in the CGI efficacy index at 6 weeks and at endpoint, favoring paroxetine (p = .015 and p = .015, respectively). Paroxetine resulted in fewer treatment-emergent adverse experiences and related withdrawals than clomipramine (p = .025 and p = .008, respectively). The number of serious adverse experiences was not significantly different in the paroxetine group compared with the clomipramine group (14 [2.8%] vs. 27 [5.4%]), but did approach statistical significance (p = .056). Anticholinergic-emergent adverse experiences were reported twice as frequently by patients in the clomipramine group as in the paroxetine group (36.1% vs. 18.6%). CONCLUSION: There was no evidence of any significant difference in efficacy between paroxetine and clomipramine in patients with coexisting depression and anxiety. However, paroxetine was better tolerated as shown by total treatment-emergent adverse experiences, anticholinergic adverse experiences, and withdrawals due to adverse experiences.

Adolescent↗
PubMed1996

Public information.

Explore the source record for details and available documents.

Attitude to Health↗
PubMed1996

Role of bone marrow stromal cells in irradiation leukemogenesis.

The role of bone marrow stromal cells of the hematopoietic microenvironment in ionizing-irradiation leukemogenesis is a focus of current investigation. Evidence from recent in vitro and in vivo experiments suggests that damage by slowly proliferating cells of the hematopoietic microenvironment contributes to the sustained survival of irradiation-damaged hematopoietic progenitor cells/stem cells and can contribute to the selection and proliferation of a malignant clone. The molecular mechanism of the interaction of irradiated stromal cells with attached hematopoietic cells has been difficult to evaluate. Irradiated bone marrow stromal cell line D2XRII demonstrated altered patterns of fibronectin splicing and increased expression of several transcriptional splice variants of macrophage-colony-stimulating factor. Differential display has revealed specific radiation-induced gene transcripts which persist after irradiation of stromal cells in vitro or in vivo. In recent experiments, we demonstrated that irradiation of mouse bone marrow stromal cell line D2XRII induces release of significant levels of transforming growth factor (TGF)-beta into the tissue culture medium despite the lack of a detectable increase in TGF-beta mRNA. Since TGF-beta is known to induce reactive oxygen species (ROS), we tested how a target hematopoietic cell line, responsive to ROS by up-regulation of a transgene for an antioxidant protein, responded to cocultivation with irradiated bone marrow stromal cells. Bone marrow stromal cell line GPIa/GBL, derived from long-term bone marrow culture of a C57BL/6J-GPIa mouse, was irradiated in vitro and then cocultured with the interleukin (IL)-3-dependent hematopoietic progenitor cell line 32D cl 3, or with each of several subclonal lines expressing a transgene for human manganese superoxide dismutase (MnSOD). Cobblestone island formation, as a measure of adherence and proliferation by 32D-MnSOD clones in the presence or absence of IL-3, was increased with irradiated compared to control GPIa cells. Furthermore, using a fluorescent dye which detects ROS, hematopoietic cells cocultivated with irradiated stromal cells demonstrated higher levels of intracellular ROS than cells cocultivated and forming cobblestone islands on nonirradiated stromal cells. Since ROS are known to induce mutations in hot spots in the p53 gene, it appears worthwhile to investigate a potential mechanism for irradiated stromal cell induction of hematopoietic stem cell transformation through ROS-induced mutations. The present cell culture and molecular biology techniques provide new methods to analyze the effects of irradiated stromal cells on closely attached hematopoietic stem cells during irradiation leukemogenesis.

Animals↗
PubMed1996

The subtalar angle: a proposed measure of rearfoot structure.

The purpose of this study was to propose a new measure of rearfoot structure to further enhance the understanding of the function of the foot. Landmarks visible on sagittal plane radiographs were used to represent the approximate direction of the subtalar joint axis in the sagittal plane based upon descriptions from the literature of its orientation. Four landmarks were chosen, resulting in four calculated angles. One hundred lateral view radiographs were analyzed. The mean values ranged from 28.7 degrees to 47.7 degrees. These values are within the ranges reported from both cadaver and in vivo studies. Tests of repeatability of the measures resulted in intraclass coefficient values between 0.94 and 0.98, suggesting good reliability. All four angles correlated highly among each other (r = 0.88-0.97). Examination of the validity of any one of these measures is left to those who are able to accurately calculate the orientation of the subtalar joint axis.

Foot↗
PubMed1995

Mapping receptor binding sites in interleukin (IL)-1 receptor antagonist and IL-1 beta by site-directed mutagenesis. Identification of a single site in IL-1ra and two sites in IL-1 beta.

Interleukin-1 receptor antagonist (IL-1ra), an IL-1 family member, binds with high affinity to the type I IL-1 receptor (IL-1RI), blocking IL-1 binding but not inducing an IL-1-like response. Extensive site-directed mutagenesis has been used to identify residues in IL-1ra and IL-1 beta involved in binding to IL-1RI. These analyses have revealed the presence of two discrete receptor binding sites on IL-1 beta. Only one of these sites is present on IL-1ra, consisting of residues Trp-16, Gln-20, Tyr-34, Gln-36, and Tyr-147. Interestingly, the absent second site is at the location of the major structural difference between IL-1ra and IL-1 beta, which are otherwise structurally similar. The two receptor binding sites on IL-1 beta are also present on IL-1 alpha. Thus, it appears that the two IL-1 agonist molecules have two sites for IL-1RI binding, and the homologous antagonist molecule, IL-1ra, has only one. Based on these observations, a hypothesis is presented to account for the difference in activity between the agonist and antagonist proteins. It is proposed that the presence of the two receptor binding sites may be necessary for agonist activity.

Amino Acid Sequence↗