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S Hill

Publications and source records attributed to S Hill.

At least 145 records · Page 8Linked to original sources
PubMed1995

Transcriptional activation of the nitrogenase promoter in vitro: adenosine nucleotides are required for inhibition of NIFA activity by NIFL.

The enhancer-binding protein NIFA is required for transcriptional activation of nif promoters by the alternative holoenzyme form of RNA polymerase, which contains the sigma factor sigma 54 (sigma N). NIFA hydrolyzes nucleoside triphosphates to catalyze the isomerization of closed promoter complexes to transcriptionally competent open complexes. The activity of NIFA is antagonized by the regulatory protein NIFL in response to oxygen and fixed nitrogen in vivo. We have investigated the requirement for nucleotides in the formation and stability of open promoter complexes by NIFA and inhibition of its activity by NIFL at the Klebsiella pneumoniae nifH promoter. Open complexes formed by sigma 54-containing RNA polymerase are considerably more stable to heparin challenge in the presence of GTP than in the presence of ATP. This differential stability is most probably a consequence of GTP being the initiating nucleotide at this promoter. Adenosine nucleosides are specifically required for Azotobacter vinelandii NIFL to inhibit open complex formation by native NIFA, and the nucleoside triphosphatase activity of NIFA is strongly inhibited by NIFL under these conditions. We propose a model in which NIFL modulates the activity of NIFA via an adenosine nucleotide switch.

Acid Anhydride Hydrolases↗
PubMed1995

YY1 binds to and regulates cis-acting negative elements in the Epstein-Barr virus BZLF1 promoter.

A 48-bp cis-acting negative element in the Epstein-Barr virus BZLF1 gene P1 promoter has been described previously. By DNase I footprinting experiments, two regions were identified as the protein-binding sites (previously designated site I and site II). In this report, the cellular transcription factor YY1 has been identified as a protein which binds to both of these elements, now designated ZIVA and ZIVB. Both ZIVA and ZIVB conferred cis-acting negative regulation on an enhancerless simian virus 40 promoter. In cotransfection experiments, overexpression of YY1 caused further repression of the enhancerless simian virus 40 promoter containing either the ZIVA or ZIVB element. Cotransfection of a plasmid expressing antisense to YY1 increased the expression of the heterologous promoter containing ZIVA but not ZIVB. In similar experiments carried out with the P1 promoter, overexpression of YY1 caused downregulation of P1 whereas antisense RNA to YY1 caused a slight increase in expression. Analyses of various P1 mutant constructions revealed additional YY1 sites downstream of ZIVB. Overexpression of YY1 also caused downregulation of a P1 mutant with no apparent YY1-binding sites. TPA treatment of Raji cells caused a temporal loss of YY1-binding activity but had no effect on the intracellular levels of YY1 protein. Serum induction of quiescent B cells also caused loss of YY1 binding to the ZIVB site, which was found to be a weak serum response element. In contrast, anti-immunoglobulin G treatment of Akata cells had no effect on either the YY1-binding activity or protein levels. The binding of YY1 to the cis-acting negative elements in infected B cells may play a pivotal role in the maintenance of Epstein-Barr virus latency.

Base Sequence↗
PubMed1995

Survival on dialysis among chronic renal failure patients treated with a supplemented low-protein diet before dialysis.

Concerns have been raised about the possibility of protein restriction resulting in malnutrition and poor subsequent survival on dialysis. However, no studies have examined patients treated with protein restriction to determine their subsequent survival on dialysis. This study prospectively monitored 67 patients with established chronic renal failure (mean initial serum creatinine of 4.3 mg/dL) who were treated with a very low-protein diet (0.3 g/kg per day) supplemented with either essential amino acids or a ketoacid-amino acid mixture and observed closely for clinical complications. Forty-four patients required dialysis. Once dialysis was started, dietary treatment was no longer prescribed. The cumulative mortality rate during the first 2 yr after starting dialysis was 7% (95% confidence interval, 0 to 16%). During this period, only two deaths occurred compared with 11.5 deaths expected on the basis of national mortality rates adjusted for age, sex, race, and cause of renal disease (P = 0.002). However, the protective effect was limited to the first 2 yr on dialysis. Thereafter, mortality rates increased, resulting in a total of 10 deaths during 96.4 person-years of follow-up, which was not significantly lower than the 14.9 deaths expected (P = 0.25). Extrapolation of sequential serum creatinine measurements made before dietary treatment suggests that the improved survival cannot be due to the early initiation of dialysis. Although the lack of an internal control group and data on dialysis lends uncertainty, the large difference in mortality rate between these patients and the nationwide experience indicates that protein restriction and close clinical monitoring predialysis does not worsen and may substantially improve survival during the first 2 yr on dialysis. These findings point out the importance of studying predialysis treatments as a means for lowering mortality on dialysis.

Adult↗
PubMed1995

Advances with phospholipid signalling as a target for anticancer drug development.

The phosphatidylinositol-3-kinases (PtdIns-3-kinase) are a family of enzymes involved in the control of cell replication. One member of the family, the mammalian p110/p85 PtdIns-3-kinase, is a potential target for anticancer drug development because of its role as a component of growth factor and oncogene activated signalling pathways. There are a number of inhibitors of this PtdIns-3-kinase, the most potent being wortmannin (IC50 4 nM). Wortmannin inhibits cancer cell growth and has shown activity against mouse and human tumor xenografts in mice. Other inhibitors of the PtdIns-3-kinase are halogenated quinones which also inhibit cancer cell growth and have some in vivo antitumor activity. Some D-3-deoxy-3-substituted myo-inositol analogues and their corresponding PtdIns analogues have been synthesized. They may act as myo-inositol antimetabolites in the PtdIns-3-kinase pathway and they can inhibit cancer cell growth.

Androstadienes↗
PubMed1994

Mutagenesis of a gene encoding a cytochrome o-like terminal oxidase of Azotobacter vinelandii: a cytochrome o mutant is aero-tolerant during nitrogen fixation.

The amino acid sequence obtained by translating the nucleotide sequence of a 0.55 kb fragment, amplified from Azotobacter vinelandii chromosomal DNA by PCR, was 57% identical to part of the Escherichia coli cyoB gene, encoding subunit I of the cytochrome bo-type quinol oxidase. This fragment was mutated in vitro by insertion of a kanamycin-resistance cassette and introduced into the chromosome of A. vinelandii by homologous recombination. The mutant contained no spectrally detectable cytochrome o. However, in the stationary phase of growth, the level of the alternative oxidase (cytochrome bd) was 11-fold higher than in the wild-type strain. Respiration of the mutant was insensitive to chlorpromazine, an inhibitor thought to act specifically on cytochrome o. Cytochrome o-deficient mutants fixed nitrogen in air, clearly distinguishing the role of this oxidase from that of cytochrome bd, which is required for respiratory protection of oxygen-labile nitrogenase.

Amino Acid Sequence↗
PubMed1994

Is tumor cell radiation resistance correlated with metastatic ability?

Patients who experience local failure following radiation treatment of epithelial malignancies exhibit a substantially higher rate of distant metastasis than those patients who achieve permanent local control. This fact has raised concern that the local failure to control the primary/regional tumor may serve as a marker of a particularly malignant neoplasm, i.e., high metastatic activity and radiation resistance. If this were true, there would be no gains in survival by increasing the efficacy of treating the primary/regional disease because the new local controls would develop distant metastasis. To investigate this concept, the relationship between distant metastasis probability and tumor cell radiation resistance has been studied by examining laboratory and clinical data (in vitro and in vivo assays) from six collaborating centers. TCD50s (radiation dose which inactivates half of the irradiated tumors) and incidence of distant metastasis in mice with local control have been evaluated for 24 murine tumor systems. SF2s (surviving fraction after 2 Gy) were determined in vitro for cell lines from 8 human, 13 mouse, and 15 rat tumors/tumor sublines and the metastatic activity assessed after injection of the cells into syngeneic murine hosts and xenogenic hosts for the human tumors. SF2s of cells from carcinomas of the head/neck, cervix, and endometrium which were controlled locally by radiation +/- surgery from four centers were compared for those which did and those which did not metastasize. The total number of patients studied was 222. The cumulative distributions of SF2s of locally controlled tumors which did and did not metastasize were not different in each of the data sets. Similarly, there was no demonstrable relationship between TCD50s and metastatic frequency in local control mice. Furthermore, the SF2s of murine and human tumor cell lines did not track with metastatic activity. Radiation sensitivity of clinical and laboratory tumors did not correlate with metastatic activity in studies of data from six centers.

Animals↗
PubMed1994

Blood flow measurement in extremity soft tissue sarcoma with technetium-99m hexamethyl-propyleneamineoxime and single photon emission computed tomography.

Blood flow measurements were made in 28 patients with soft tissue sarcoma of the extremities to investigate the prognostic significance of tumour vascularity. Four patients with benign tumours also underwent blood flow measurement. Mean and maximum tumour blood flow was calculated from technetium-99m hexamethyl-propyleneamineoxime uptake measured using single photon emission computed tomography (SPECT), tumour volume measured from SPECT transaxial image reconstructions and cardiac output assessed with Doppler ultrasonography. Twenty-seven malignant lesions and one benign tumour showed increased uptake of isotope relative to surrounding tissues. Mean sarcoma blood flow varied between 1 and 33 ml per 100 ml tumour per min, and maximum flow between 5 and 57 ml per 100 ml per min. Fourteen patients developed progressive disease during the first year of follow-up. Eight of 11 patients with a high isotope uptake ratio, eight of 12 with a high mean blood flow and eight of 14 with a high maximum blood flow relative to the respective medians for the series showed disease progression.

Adult↗
PubMed1994

Sequential insult enhances liver macrophage-signaled hepatocyte dysfunction.

Injury results in altered hepatocyte protein synthesis including the production of acute-phase reactants. Evidence suggests that these hepatocyte products regulate macrophage function; however, their role in liver macrophage-mediated hepatocyte dysfunction following a second insult is poorly characterized. We hypothesize that IL-6-stimulated hepatocyte products alter liver macrophage responses to lipopolysaccharide, contributing to enhanced hepatocyte dysfunction. To test this hypothesis, hepatocytes, obtained by liver collagenase digestion, were treated with rIL-6 (murine, 300 units/ml) for 24 hr, and then liver macrophages, obtained by perfusion and pronase digestion, were added to establish cocultures. Cocultures were then stimulated with endotoxin (LPS, Escherichia coli O111:B4, 10 micrograms/ml) and hepatocyte dysfunction was assessed by determining secretory protein synthesis ([35S]methionine labeling, trichloracetic acid precipitation, and SDS-PAGE) and energy metabolism [mitochondrial respiration using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) dye]. Cultures of hepatocytes alone stimulated with IL-6, LPS, or sequential IL-6 followed by LPS demonstrate no difference in total secretory protein synthesis or mitochondrial respiration. In contrast, hepatocyte-liver macrophage cocultures demonstrate significantly reduced total secretory protein synthesis following sequential IL-6 followed by LPS ([35S]methionine cpm x 10(3): control, 33.8 +/- 8.5; LPS, 25.8 +/- 6.3; IL-6/LPS, 15.7 +/- 6.4; P < 0.05 vs control). This effect is specific to IL-6 since sequential TNF-alpha followed by LPS did not result in significant suppression of secretory protein synthesis. One-dimensional SDS-PAGE of labeled coculture secretory proteins demonstrates qualitative changes following sequential insult in vitro compared to controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Intranasal mupirocin.

Explore the source record for details and available documents.

Administration, Intranasal↗
PubMed1994

Hemophilia growth and development study: baseline neurodevelopmental findings.

Reported baseline findings from the neurological assessment component of the Hemophilia Growth and Development Study (HGDS). HIV-positive (HIV+; n = 207) and HIV-negative (HIV-; n = 126) young males with hemophilia ages 6 to 18 years, were enrolled in a prospective study of their growth and development. At baseline, HIV+ and HIV- subjects were not significantly different in test performance. The number of subjects exhibiting below-average performance in three or more areas assessed was about 25% overall. For both groups, mean test scores were within the average range. Academic and adaptive skills were lower than expected based on mean IQ scores, and more behavioral/emotional problems than expected were reported by parents. Absolute CD4 cell counts per mm3 were not related to neuropsychological performance at baseline. Results suggest that the subjects with HIV were relatively free of HIV-related neuropsychological impairment at baseline and that observed differences from a general population reflect effects of hemophilia as a chronic illness.

Adolescent↗
PubMed1994

Autoregulation of nitrogenase expression in Klebsiella pneumoniae.

An investigation into the influence of N2 on the expression of Klebsiella pneumoniae nitrogenase has led to a reassessment of the role of the nitrogenase MoFe protein in autoregulation. Anaerobic derepression of nitrogenase (C2H2-reducing) activity, of NifD and K polypeptides, and of nifH-lac expression, following the removal of excess NH+4, were greater under N2 than Ar. This enhancement occurred in Nif+ but not in Nif- strains, and in Nif+ strains was prevented by C2H2, an inhibitor of N2 fixation. Thus N2 fixation is important for maintaining derepression. Derepression of nifH-lac under Ar in various Nif+ and Nif- strains (including NifH-, NifD-, NifB- and NifL- mutants) and of wild-type lac under N2 or Ar in a Nif+ strain were measured to investigate the regulation. The mechanism regulating the enhancement under N2 neither involved the MoFe protein of nitrogenase, as proposed by Dixon et al. (1980, Nature 286, 128-132), nor the nifL product, but was probably due to a general upgrading of the N status. Moreover, during batch growth limited by a non-repressing fixed N source, the levels of nifH-lac expression in the Nif+ and Nif- strains suggested that the nifH gene product (or Fe protein) may have a positive autoregulatory function.

Anaerobiosis↗
PubMed1994

Relationships between doctors and managers: the Scottish experience.

Based upon empirical research conducted in 1993, attempts to illustrate the implications of efforts to bring doctors into management. It addresses in particular the role of key appointments such as the medical director and clinical directors and the perceptions of these roles. Doctors continue to demonstrate themselves to be reluctant managers and this continues to pose problems for the aspirations contained in Working for Patients. Crucial questions must be asked about whether management represents a productive use of doctors' time and whether the NHS can afford premium rates for largely inexperienced managers. Identifies changes that have taken place to date and indicates that doctors are, for the most part, still lukewarm about a career in medical management.

Goals↗
PubMed1994

Benign lymph node inclusions mimicking metastatic carcinoma.

AIMS: To draw attention to non-neoplastic inclusions in axillary lymph nodes removed from women with primary breast cancer which may be mistaken for metastases. METHODS: Five examples of non-malignant inclusions were detected in axillary lymph nodes removed from women with mammary carcinoma. Immunohistochemical staining for CAM 5.2 and S100 markers, as well as morphological assessment were performed. RESULTS: Three of the five cases comprised naevus cells and two heterotopic epithelial elements. One of each was initially mistaken for metastatic carcinoma. Naevus cells in the capsule of axillary nodes are often arranged as lines of small, round cells and may readily be misinterpreted as metastatic lobular carcinoma. Heterotopic epithelial elements, in the form of tubules, can easily be mistaken for metastasis from an infiltrating ductal carcinoma. CONCLUSIONS: Awareness of the occasional occurrence of non-neoplastic nodal inclusions will help avoid misdiagnosis. If immunohistochemical markers for epithelial cells are used to screen lymph nodes for metastasis, such lesions could be detected more frequently. It is important to combine immunohistochemistry with morphological assessment and the use of a panel of antibodies in histological diagnosis.

Adult↗
PubMed1994

Differential function of dendritic cells isolated from blood and lymph nodes.

Dendritic cells (DC) isolated from the lymph nodes or spleens of mice and pulsed with contact sensitizers or protein antigens stimulate primary proliferative responses by syngeneic T cells and responses to alloantigens in the mixed leucocyte reaction (MLR). Using enriched human peripheral blood DC, we attempted to stimulate primary immune responses to contact sensitizers by autologous lymphocytes in vitro. No significant proliferation above background levels or CD69 expression (an early activation antigen on lymphocytes) was detected despite using a wide range of donors, chemicals, antigens and cell concentrations. Culture of DC for up to 5 days in vitro in the presence of phytohaemagglutinin (PHA)-conditioned culture supernatants, or recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) also failed to induce primary proliferative responses to contact sensitizers. Comparisons were made between blood and lymph node DC from mice to explore whether the lack of stimulation was the result of differences between mouse and human DC or between DC isolated from different tissues. DC from lymph nodes stimulated primary responses to contact sensitizers in both blood and lymph node lymphocytes whereas blood DC did not stimulate responses. Both lymph node and blood DC stimulated an allogeneic MLR, although blood DC were less efficient than those from lymph node. The data show that DC from different tissues exhibit variable functional activity. DC from blood and lymph nodes were examined to determine whether surface antigen expression is related to functional activity. Murine blood DC expressed similar levels of LFA-1, LECAM-1 and CD44 compared with lymph node DC but lower levels of MHC class II, B7 and ICAM-1. These results may therefore have important implications for antigen processing and presentation in cells from different tissue compartments.

Allergens↗