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Biomedical subjects

D Foster

Publications and source records attributed to D Foster.

At least 37 records · Page 2Linked to original sources

The development of nurses as managers: the prevalence of the self-development route.

AIM: This article identifies ways in which hospital sisters and charge nurses (ward managers) are developed as managers in one London teaching hospital. CONTEXT: Ward managers are practising in the context of increasing management responsibility in which decision-making is being driven to occur as close to the patient as possible. Decision-making about the management development opportunities for ward managers rests with senior nurse managers who have espoused their own preferences about the styles of management development open to ward managers. METHODS: For this small-scale exploratory-descriptive study, qualitative research methods were used with a postal self-completed questionnaire followed by a focus group. The target population was a group of 22 senior nurse managers. There was a questionnaire response rate of 68% (n = 15 respondents, four of whom participated in the focus group). FINDINGS: The research exposed and substantiated four styles of management development. The organizational prevalence of these styles and the ward managers' preference for each style were also ascertained. The most prevalent style was the one for which there was the least preference. CONCLUSIONS: The findings indicated that there was a general mismatch between the style of management development prevalent in the organization and the style of management development preferred by the subjects. This left the ward managers generally to follow an unstructured self-development route. The use of a theoretical framework, expressed as a Reluctance-Readiness to Manage Continuum, is suggested to harness the propensity to self-develop and to link it with the organizational need to develop nurses as managers through the paradox of structuring self-development.

Attitude of Health Personnel↗

Use of a screen log to audit patient recruitment into multiple randomized trials in the intensive care unit. Canadian Critical Care Trials Group.

OBJECTIVE: To develop and evaluate a screen log for monitoring enrollment in multiple randomized clinical trials conducted in a single center. SETTING: University-affiliated 20-bed tertiary care medical-surgical intensive care unit (ICU). PATIENTS: Consecutive ICU patients admitted between April 1995 and March 1997. METHODS: We developed a screen log for multicentered studies conducted in our ICU. Using a multiple-project, unicenter perspective, we evaluated the screen log as a tool for monitoring eligibility and enrollment of patients in four multicentered randomized trials focused on stress ulcer prophylaxis, blood transfusion thresholds, immunotherapy for sepsis and mechanical ventilation strategies. RESULTS: The screen log was used as an instrument to monitor trial execution. We recorded all aspects of study enrollment and created a taxonomy of reasons for nonenrollment into each trial. We calculated enrollment efficiency rates and used these data to develop strategies to maximize accrual. The screen log became a communication tool that fostered research-oriented continuous quality improvement initiatives for the management of concurrently conducted randomized trials in our ICU. CONCLUSIONS: Intensivists participating in several clinical trials may be interested in monitoring and maximizing enrollment when conducting multiple studies and understanding the influence of each trial on enrollment into the others. The unicenter, multiple-project screen log is one tool that may help to achieve these goals.

Canada↗

A genetically engineered cell line resistant to subgroup J avian leukosis virus infection (C/J).

A cell line (DF-1¿J) expressing the envelope protein isolated from the ADOL-Hc1 strain of the avian leukosis virus subgroup J (ALV-J) was used to analyze receptor interference to six different isolates of ALV-J as well as ALV subgroups A-D. The traditional gag-specific enzyme-linked immunosorbent assay (ELISA) as well as flow cytometry was used to evaluate viral infection. The parental cell line (DF-1) was susceptible to all ALV subgroups tested while the DF-1¿J cell line was selectively resistant to the subgroup J isolates. The DF-1¿J cell line was resistant to infection by all six ALV-J isolates as determined using the gag-specific ELISA. There was no interference with the other ALV subgroups (A-D) induced by the expression of the ADOL-Hcl envelope. The ALV-J isolates used in this analysis are serologically distinct when analyzed by flow cytometry. Convalescent sera to ADOL-Hcl cross-reacts with all of the ALV-J isolates tested; however, sera to HPRS-103 did not bind to four of the six isolates. Based on the intensity and differential binding of these antisera using flow cytometry, the six ALV-J isolates used can be grouped into four categories. Thus the DF-1¿J cell line is resistant to infection by a serologically and genetically diverse group of ALV-J isolates and should be useful as a diagnostic tool.

Amino Acid Sequence↗

Point mutations in the avian sarcoma/leukosis virus 3' untranslated region result in a packaging defect.

The 3' untranslated region (3' UTR) between the 3' end of env and the long terminal repeat is well conserved among avian retroviruses and is essential for efficient replication. Deletion of the dr1 element within the 3' UTR has been reported to have various effects, including reduced levels of unspliced RNA in the cytoplasm, decreased stability of unspliced RNA, decreased particle production, and decreased genomic RNA packaging. To probe the role of specific sequences within dr1 in virus replication, site-directed mutagenesis was utilized to perturb parts of the predicted secondary structure of dr1. Seven of thirteen mutations had no significant effect; the others resulted in an approximately 10- to 20-fold reduction in replication. These mutants were further characterized and found to impair cytoplasmic accumulation of unspliced RNA only slightly. Furthermore, no decreases were observed in the stability of the unspliced RNA or in the production of virus particles. Genomic RNA packaging, however, was reduced by about 10-fold. Similar amounts of particles were produced by cells containing the mutant and wild-type DNA, and all particles contained similar levels of reverse transcriptase activity. The results suggest that the region of the dr1 disrupted by the mutations plays a role in genomic RNA packaging, although that packaging may not be the only role for dr1.

3' Untranslated Regions↗

Metabolic and genetic determinants of HDL metabolism and hepatic lipase activity in normolipidemic females.

The metabolic and genetic determinants of HDL cholesterol (HDL-C) levels and HDL turnover were studied in 36 normolipidemic female subjects on a whole-food low-fat metabolic diet. Lipid, lipoprotein, and apolipoprotein levels, lipoprotein size, and apolipoprotein turnover parameters were determined, as were genetic variation at one site in the hepatic lipase promoter and six sites in the apolipoprotein AI/CIII/AIV gene cluster. Menopause had no significant effect on HDL-C or turnover. Stepwise multiple regression analysis revealed that HDL-C was most strongly correlated with HDL size, apolipoprotein A-II (apoA-II), and apolipoprotein A-I (apoA-I) levels, which together could account for 90% of the variation in HDL-C. HDL size was inversely correlated with triglycerides, body mass index, and hepatic lipase activity, which together accounted for 82% of the variation in HDL size. The hepatic lipase promoter genotype had a strong effect on hepatic lipase activity and could account for 38% of the variation in hepatic lipase activity. The apoA-I transport rate (AI-TR) was the major determinant of apoA-I levels, but AI-TR was not associated with six common genetic polymorphism in the apoAI/CIII/AIV gene cluster.A simplified model of HDL metabolism is proposed, in which A-I and apoA-II levels combined with triglycerides, and hepatic lipase activity could account for 80% of the variation in HDL-C.

Adult↗

Polyclonal antibodies to domoic acid, and their use in immunoassays for domoic acid in sea water and shellfish.

Ovine antibodies raised against conjugates linked through the secondary amino group of domoic acid (1) were used, together with activated-ester-derived conjugates of domoic acid (DA) as the plate coater, to develop a robust indirect competitive enzyme-linked immunosorbent assay (cELISA) for DA in shellfish and seawater. The ELISA was used to analyze shellfish samples for DA, and was compatible with several extraction procedures. The ELISA had a detection limit below 0.01 ng ml(-1), a limit of quantitation (LOQ) of 0.15 ng ml(-1) and a working range of 0.15-15 ng ml(-1) DA. The LOQ is equivalent to 38 ng g(-1) DA in shellfish flesh, assuming a 250-fold dilution during extraction. This is more than 500 times lower than the maximum permitted level (20 microg g(-1) flesh). The ELISA is designed for use alongside regulatory analyses, and, following formal validation, should be available for pre-screening of regulatory shellfish flesh samples. The ELISA was also shown to be appropriate for analysis of DA in algal cultures and in samples of seawater, and thus has the potential to provide early warning of developing algal blooms.

Animals↗

Dysregulated expression of neutrophil apoptosis in the systemic inflammatory response syndrome.

OBJECTIVE: To study the effect of the systemic inflammatory response syndrome (SIRS) or major elective surgery on the apoptosis of circulating polymorphonuclear neutrophils because an activated inflammatory response is terminated, in part, through the programmed cell death, or apoptosis, of its effector cells. DESIGN: A prospective inception cohort study. SETTING: A mixed surgical and medical intensive care unit of an adult tertiary care hospital. PATIENTS: Sixteen patients with SIRS, 7 uninfected patients who had undergone elective aortic aneurysmectomy, and 8 healthy laboratory control subjects. INTERVENTIONS: Serial blood samples were drawn for evaluation of neutrophil apoptosis, activational state, and surface receptor expression by flow cytometry. MAIN OUTCOME MEASURES: Spontaneous apoptosis was significantly delayed in neutrophils from patients with SIRS (8.6%+/-6.8%) and patients who had undergone elective aortic aneurysmectomy (11.0%+/-5.0%) when compared with controls (34.9%+/-6.8%). These neutrophils were activated as evidenced by enhanced respiratory burst activity and augmented surface expression of CD11b. Apoptosis in response to engagement of cell surface Fas (also known as CD95 or APO-1) with an agonistic antibody was blunted. Plasma from patients with SIRS or patients who had undergone elective aortic aneurysmectomy suppressed the apoptotic responses of control neutrophils (plasma from patients with SIRS, 18.8%+/-10.3%; plasma from patients who had undergone elective aortic aneurysmectomy, 20.0%+/-6.1%; P<.01). Western blot analysis showed normal expression of the key proapoptotic proteases, interleukin 1beta converting enzyme and CPP32 (also known as YAMA, apopain, and caspase 3), indicating that delayed apoptosis was not a consequence of decreased levels of proapoptotic enzymes. CONCLUSIONS: Circulating neutrophils from patients with SIRS or from patients who have undergone major elective surgery show delayed expression of constitutive programmed cell death, and antiapoptotic factors are present in the general circulation. While prolonged neutrophil survival may represent an appropriate adaptive response to injury, the presence of activated and apoptosis-resistant cells in an antiapoptotic environment may contribute to the systemic inflammatory injury characteristic of SIRS and predispose to the development of the multiple organ dysfunction syndrome.

APACHE↗

Thrombopoietin-stimulated ex vivo expansion of human bone marrow megakaryocytes.

The effect of thrombopoietin (TPO) on megakaryocytopoiesis (MKP) has been mainly studied using clonogenic assays in murine systems. In this study, we evaluated MKP in liquid culture using human bone marrow cells. While interleukin 3 (IL-3) and stem cell factor (SCF) are potent activators of TPO-stimulated MKP in the murine system, only IL-3 exhibited synergistic activity with TPO in cultures of human bone marrow. The IL-3 effect on TPO-stimulated megakaryocyte (MK) proliferation, expressed as the absolute number of MKs per seeded CD34+ cell, was more pronounced with purified CD34+ cell (8 +/- 1.6 SE versus 2.8 +/- 0.7 SE in the presence and absence of IL-3, respectively) than with mononuclear cells (MNC) (16 +/- 2.8 SE versus 11 +/- 2.0 SE). This effect of IL-3 on TPO-stimulated MK proliferation was due to a general proliferation of all cell types since the relative frequency of MKs (32.1 +/- 3 SE and 55.8 +/- 3 SE in MNC and CD34+ cells, respectively) was not affected by IL-3. The effect of TPO alone, TPO + IL-3, TPO + SCF, and TPO + IL-3 + SCF on MK proliferation was examined in MNC and CD34+ cultures. Greater numbers of MK per seeded CD34+ were observed in MNC compared to CD34+ cultures under all conditions except when TPO was added with both IL-3 and SCF. The enhancing effect of MNC was also observed on MK ploidy in the presence of TPO and IL-3. While proliferation and ploidy increase with TPO concentration in the murine system, they are inversely related in the human system. A significant 2.5-fold enhancement of TPO-induced MK proliferation was observed when purified CD34+ cells were cultured in inserts separated from human bone marrow stroma, indicating that soluble stimulatory factors are released from the stroma. These observations will be useful for ex vivo expansion of MKs to treat post-transplant or chemotherapy-associated thrombocytopenia.

Animals↗

Biological roles for the second domain of thrombopoietin.

Thrombopoietin (TPO) has been isolated from the plasma of animals in several laboratories as several molecular species which vary in molecular weight from 19 kDa to 35 kDa. Upon biochemical analyses, all of these forms appear to represent proteolytic fragments of TPO which share the same amino-terminal sequences and are therefore truncated at their C-terminal ends. Intact recombinant TPO produced in cell culture is a 70 kDa glycoprotein which contains the full polypeptide backbone encoded by the cDNA sequence. A series of deliberate TPO truncations have been constructed by the introduction of stop codons into the cDNA at various positions. The proteins encoded by the truncated cDNAs have been purified to homogeniety for the purpose of detailed biological and biochemical comparisons of such C-terminally truncated TPO proteins with the full-length intact TPO. These comparisons serve to illuminate the possible biological role(s) of the C-terminal domain, which is so far unique in the family of hematopoietic cytokines. The C-terminal domain appears to regulate the specific activity of TPO, to regulate its circulating half-life, and to promote efficient biosynthesis and secretion of the protein.

Animals↗

Signal transduction through lipid second messengers.

This review emphasizes the generation of glycerolipid and sphingolipid second messengers, and their molecular targets. The role of the phosphatidylinositol transfer protein and phospholipase D in signal transmission, and the structures of the 1, 2-diacylglycerol and calcium-binding sites of protein kinase C are discussed. Further, ceramide signaling through protein kinases and the role of cross-talk in the signaling of apoptosis and inflammation are addressed.

Animals↗

High-level expression of recombinant human fibrinogen in the milk of transgenic mice.

Fibrinogen is a complex plasma protein composed of two each of three different polypeptide chains. We have targeted expression of r-human fibrinogen to the mammary gland of transgenic mice. Three expression cassettes, each containing the genomic sequence for one of the three human fibrinogen chains controlled by sheep whey protein beta-lactoglobulin promoter sequences, were coinjected into fertile mouse eggs. Southern blot analysis demonstrated that more than 80% of the transgenic founders contained all three fibrinogen genes. Reducing sodium dodecyl sulfate polyacrylamide gel electrophoresis of milk from the highest producing founder animal demonstrated the presence of human fibrinogen subunits at concentrations of 2000 micrograms/ml. In several animals with a balanced ratio of the individual fibrinogen subunits, up to 100% of the protein was incorporated into fully assembled fibrinogen hexamers. Incubation of the transgenic milk with thrombin and factor XIII resulted in a cross-linked fibrin clot, indicating that a major portion of the secreted fibrinogen was functional. These studies represent the first report of high-level biosynthesis and secretion of a functional, complex, hexameric protein in the milk of a transgenic animal.

Animals↗

Assessment of knowledge, attitudes, and behaviors relative to cervical cancer and the Pap smear among adolescent girls in West Virginia.

BACKGROUND AND METHODS: Questionnaires assessing knowledge of, attitudes toward, and behaviors relative to cervical cancer and its prevention were administered to 279 tenth-grade girls. RESULTS: Eighty-four percent had heard of cervical cancer, and 83% had heard of the Pap smear. Sexual intercourse with multiple partners and cigarette smoking were risk factors identified by 65% and 40% of these students, respectively. Forty-eight percent reported being sexually active. This group, compared with those not sexually active, was more likely to 1) identify the Pap test as a test involving a vaginal examination, 2) use tobacco products, and 3) be exposed to tobacco smoke. The most common barriers to obtaining a Pap test reported by those sexually active were embarrassment (64%), pain/discomfort (57%), fear of cancer (27%), fear of parents discovering sexual activity (25%), and cost (13%). CONCLUSIONS: Based on the information obtained in this study, the authors recommend changes in school health programs that target adolescent girls: 1) risk factors and behavior should receive more emphasis, and 2) the pelvic examination and Pap test should be described in sufficient detail to address the issues of embarrassment, pain, and discomfort.

Adolescent↗

AIDS-related beliefs, attitudes and intentions among Malawian students in three secondary schools.

This preliminary investigation into factors influencing the intention of Malawian secondary school students to engage in low-risk AIDS-related behaviours was based on the Theory of Reasoned Action (Ajzen & Fishbein, 1980). A total of 191 male and female subjects (mean age 19.32) from three secondary schools in Malawi filled in a questionnaire that sought to elicit their intention to use condoms and to stick to the one same sexual partner. The study lent support to the theory that intention can be predicted from attitudes and subjective norms, F(2,186) = 31.93, p < 0.001 for condom use and F(2, 187) = 15.23, p < 0.001 for sticking to one sexual partner. The results showed that, for the subjects, the intention to comply with these two behavioural regimens was predominantly under attitudinal control though one sub-sample's intention was under normative influence. The study also provided quantitative data on the sexual behavioural patterns of the subjects and used these data to furnish explanations of the main findings. Behavioural change intervention strategies in the light of the findings are discussed.

Acquired Immunodeficiency Syndrome↗

Expression and release of the a and b subunits for human coagulation factor XIII in baby hamster kidney (BHK) cells.

The a subunit of coagulation factor XIII lacks a hydrophobic signal sequence for secretion from cells, while the b subunit has a typical signal sequence. To determine whether the a subunit can be synthesized and released, expression vectors containing the cDNA for either subunit were transfected into baby hamster kidney (BHK) cells. Western blotting analysis and gel filtration chromatography demonstrated that the recombinant a and b subunits (rXIIIa and rXIIIb) had the same molecular weights and subunit structures (a2, b2, and a2b2) as the native molecules. rXIIIa was enzymatically active when activated by thrombin. Most rXIIIb was secreted as measured by ELISA, while most rXIIIa was detected in the cytosol by subcellular fractionation. Co-expression with rXIIIb in the same cells did not promote the release of rXIIIa. Treatment of the cells with brefeldin A, a potent inhibitor of protein transportation, blocked the secretion of rXIIIb, although it had no effect on the release of rXIIIa. Several drugs and heat stress induced the release of rXIIIa, which correlated directly with that of cytoplasmic lactate dehydrogenase. These results suggest that the a subunit is released from cells as a consequence of cell injury, which is independent of the classical secretory pathway.

2,4-Dinitrophenol↗

Mice lacking tartrate-resistant acid phosphatase (Acp 5) have disrupted endochondral ossification and mild osteopetrosis.

Mature osteoclasts specifically express the purple, band 5 isozyme (Acp 5) of tartrate-resistant acid phosphatase, a binuclear metalloenzyme that can generate reactive oxygen species. The function of Acp 5 was investigated by targeted disruption of the gene in mice. Animals homozygous for the null Acp 5 allele had progressive foreshortening and deformity of the long bones and axial skeleton but apparently normal tooth eruption and skull plate development, indicating a rôle for Acp 5 in endochondral ossification. Histomorphometry and mineralization density analysis of backscattered electron imaging revealed widened and disorganized epiphyseal growth plates with delayed mineralization of cartilage in 6- to 8-week-old mutant mice. The membrane bones of the skull showed increased density at all ages examined, indicating defective osteoclastic bone turnover. Increased mineralization density was observed in the long bones of older animals which showed modelling deformities at their extremities: heterozygotes and homozygous Acp 5 mutant mice had tissue that was more mineralized and occupied a greater proportion of the bone in all regions. Thus the findings reflect a mild osteopetrosis due to an intrinsic defect of osteoclastic modelling activity that was confirmed in the resorption pit assay in vitro. We conclude that this bifunctional metalloprotein of the osteoclast is required for normal mineralization of cartilage in developing bones; it also maintains integrity and turnover of the adult skeleton by a critical contribution to bone matrix resorption.

Acid Phosphatase↗

Specificity of leptin action on elevated blood glucose levels and hypothalamic neuropeptide Y gene expression in ob/ob mice.

Correction of the obese state induced by genetic leptin deficiency reduces elevated levels of both blood glucose and hypothalamic neuropeptide Y (NPY) mRNA in ob/ob mice. To determine whether these responses are due to a specific action of leptin or to the reversal of the obese state, we investigated the specificity of the effect of systemic leptin administration to ob/ob mice (n = 8) on levels of plasma glucose and insulin and on hypothalamic expression of NPY mRNA. Saline-treated controls were either fed ad libitum (n = 8) or pair-fed to the intake of the leptin-treated group (n = 8) to control for changes of food intake induced by leptin. The specificity of the effect of leptin was further assessed by 1) measuring NPY gene expression in db/db mice (n = 6) that are resistant to leptin, 2) measuring NPY gene expression in brain areas outside the hypothalamus, and 3) measuring the effect of leptin administration on hypothalamic expression of corticotropin-releasing hormone (CRH) mRNA. Five daily intraperitoneal injections of recombinant mouse leptin (150 micrograms) in ob/ob mice lowered food intake by 56% (P < 0.05), body weight by 4.1% (P < 0.05), and levels of NPY mRNA in the hypothalamic arcuate nucleus by 42.3% (P < 0.05) as compared with saline-treated controls. Pair-feeding of ob/ob mice to the intake of leptin-treated animals produced equivalent weight loss, but did not alter expression of NPY mRNA in the arcuate nucleus. Leptin administration was also without effect on food intake, body weight, or NPY mRNA levels in the arcuate nucleus of db/db mice. In ob/ob mice, leptin did not alter NPY mRNA levels in cerebral cortex or hippocampus or the expression of CRH mRNA in the hypothalamic paraventricular nucleus (PVN). Leptin administration to ob/ob mice also markedly reduced serum glucose (8.3 +/- 1.2 vs. 24.5 +/- 3.8 mmol/l; P < 0.01) and insulin levels (7,263 +/- 1,309 vs. 3,150 +/- 780 pmol/l), but was ineffective in db/db mice. Pair-fed mice experienced reductions of glucose and insulin levels that were < 60% of the reduction induced by leptin. The results suggest that in ob/ob mice, systemic administration of leptin inhibits NPY gene overexpression through a specific action in the arcuate nucleus and exerts a hypoglycemic action that is partly independent of its weight-reducing effects. Furthermore, both effects occur before reversal of the obesity syndrome. Defective leptin signaling due to either leptin deficiency (in ob/ob mice) or leptin resistance (in db/db mice) therefore leads directly to hyperglycemia and the overexpression of hypothalamic NPY that is implicated in the pathogenesis of the obesity syndrome.

Animals↗

Accelerated reconstitution of platelets and erythrocytes after syngeneic transplantation of bone marrow cells derived from thrombopoietin pretreated donor mice.

The recent cloning of the ligand of the c-Mpl hematopoietin receptor has indicated a major role for this cytokine in the development of megakaryocytes. In this study we have applied c-Mpl ligand (thrombopoietin [TPO]) in the setting of syngeneic transplantation in an attempt to accelerate the reconstitution of platelets. Donor mice were treated with 20 kilounits (kU)/d TPO intraperitoneally (ip) for 5 days. This resulted in a 2.5-fold increment in platelet counts from 1,119 x 10(9)/L to 2,582 x 10(9)/L (mean, n = 7). Total numbers of hematopoietic progenitor cells in bone marrow (BM) and spleen, as assessed in a colony-forming unit-granulocyte erythroid monocyte macrophage (CFU-GEMM) colony assay (55.3 v 38.6 x 10(3) CFU/femur; 27.3 v 16.3 x 10(3) CFU/spleen, mean, n = 7) as well as total numbers of burst-forming unit-erythroid (BFU-E) (24.0 v 16.4 x 10(3)/femur; 10.2 v 1.9 x 10(3)/spleen, mean, n = 7), were significantly higher in TPO-treated donors than in saline-treated controls. Female Balb-C mice were lethally (8.5 Gy) irradiated and transplanted with 10(5) BM cells. After transplantation, groups of mice were treated with recombinant murine TPO at a dose of 20 to 30 kU/d ip or subcutaneously (SC) for 5 to 14 days. Using this dose and schedule, TPO did not stimulate the recovery of platelets in comparison with control animals transplanted with equal cell numbers but given vehicle alone. In other experiments, 10(5) BM cells were procured from TPO-treated donor mice and transplanted into lethally irradiated recipient mice. In comparison with animals transplanted with an equal number of BM cells derived from saline-treated controls, recipients of TPO-treated BM cells had significantly faster platelet recovery and higher platelet nadir counts (88 v 30 x 10(9)/L, mean, n = 20). Transplantation of TPO-treated BM cells also resulted in an accelerated recovery of erythrocytes and increased erythrocyte nadir counts (7.2 v 5.0 x 10(12)/L, mean, n = 20). At the day of platelet nadir (day 12 after transplantation) these animals had higher numbers of BFU-Es (770 v 422, mean, n = 5) in the marrow and also had higher reticulocyte counts (44 / 1000 v 8 / 1000 mean, n = 5) in the blood. Therefore, the accelerated recovery of erythrocytes may be a direct effect of TPO on erythropoiesis.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗