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Biomedical subjects

G Brown

Publications and source records attributed to G Brown.

At least 217 records · Page 12Linked to original sources
PubMed1995

Treatment of HL60 cells with various combinations of retinoids and 1 alpha,25 dihydroxyvitamin D3 results in differentiation towards neutrophils or monocytes or a failure to differentiate and apoptosis.

It is well documented that treatment of serum-grown HL60 cells with 10(-7) M all-trans retinoic acid (all-trans RA) induces neutrophil differentiation, whereas treatment with 10(-7) M 1 alpha,25 dihydroxyvitamin D3(D3) induces differentiation towards monocytes. In recent investigations, using serum-free grown HL60 cells, we observed that all-trans RA, at 10(-7) M, did not induce neutrophil differentiation and that all-trans RA, at 10(-8) M, reduced the D3 concentration required for monocyte differentiation to 5 x 10(-9) M. In this study, co-operative interactions between all-trans and 9-cis RA and D3 which promote neutrophil and monocyte differentiation of HL60 cells have been analysed in detail. Treatment of serum-free grown HL60 cells with 5 x 10(-7) M all-trans RA or 9-cis RA resulted in sub-optimal neutrophil differentiation (up to 25% mature cells). As shown for all-trans RA, 9-cis RA cooperated with D3 to promote monocyte differentiation. Culture of HL60 cells in 5 x 10(-7) M 9-cis RA together with a wide range of concentrations of D3 resulted in promotion of neutrophil differentiation at 10(-15)-10(-12) D3, a failure to differentiate and apoptosis at 10(-11)-10(-10) M D3, followed by co-operativity between 9-cis RA and 5 x 10(-9) M D3 in inducing monocyte differentiation in the absence of neutrophil differentiation. Similar results were obtained when HL60 cells were treated with 5 x 10(-7) all-trans RA together with a wide range of concentrations of D3. Cross titration analyses of the effects of 9-cis RA and D3 on HL60 cell differentiation were undertaken to determine the boundaries of the concentrations of each agent, alone and in combination, that give rise to optimal neutrophil and monocyte differentiation of HL60 cells. The observed cooperativities between either 9-cis RA or all-trans RA and D3 have important implications for the use of combinations of these agents in differentiation therapy.

Apoptosis↗
PubMed1995

Dynamic wedge factors for a comprehensive range of fields.

Assessing the methods available to model wedge factors as applied to dynamic wedges over a comprehensive range of field elongations is the primary intention of this paper. Wedge factors for dynamically produced wedges were investigated by a series of measurements for square and rectangular fields. A Varian 600C linear accelerator was used for the experimental work. Dynamic wedge angles of 15, 30, 45 and 60 degrees were studied. (The wedge factor was defined as the ratio of the central axis dose reading at 10 cm deep of the wedged field to the reading at 10 cm depth for the same sized open field). The possibility of improving dynamic wedge factors for elongated fields by modelling the rectangular field with the equivalent square (Worthley) and also by the square field of equal area (Arthur) methods was evaluated. Dynamic wedge factors were found to depend on the field size in the wedged direction dominantly. The influence of field elongation in the non-wedged axis was found to be negligible. The experiments indicate that the derivation of a dynamic wedge factor for use with rectangular fields is best based on a square field with a side equal to that in the wedged axis. The application of two square field models (Worthley and Arthur) for elongated fields was found to produce significantly worsened wedge factors for the majority of the fields considered.

Humans↗
PubMed1995

Expression of an adenovirally encoded lymphotoxin-beta inhibitor prevents clearance of Listeria monocytogenes in mice.

The lymphotoxin (LT)-beta heterotrimer was recently identified as a molecule containing LT-alpha subunits, tethered to the cell through non-covalent association with an integral plasma membrane protein, derived from the LT-beta gene. Since knockout mutations of the LT-alpha gene yield animals that lack lymph nodes, whereas animals lacking either or both of the receptors for tumor necrosis factor (TNF) and LT-alpha homotrimers have normal lymph nodes, it has been inferred that the association between the LT-beta heterotrimer and its cognate receptor is required for lymph node ontogeny. Similarly, LT-beta and its receptor are thought to be important for development of the spleen. Since LT-alpha deficient mice lack lymph nodes, it is difficult to assess the extradevelopmental contribution of LT-beta to immune competence. To this end, we employed a strategy for the conditional blockade of LT-beta heteromer activity in normal mice. The interaction between LT-beta and its receptor is essential for the destruction of intracellular Listeria monocytogenes.

Adenoviridae↗
PubMed1994

Intracellular concentrations of inositol, glycerophosphoinositol and inositol pentakisphosphate increase during haemopoietic cell differentiation.

We have analysed the levels of soluble inositol metabolites in HL60 cells as they differentiate towards neutrophils in response to a combination of all-trans-retinoic acid and granulocyte colony-stimulating factor and towards monocytes in response to 1 alpha-25-dihydroxyvitamin D3. In both cases, differentiation was accompanied by increases in intracellular inositol (Ins), glycerophosphoinositol (GroPIns) and inositol pentakisphosphate (InsP5) concentrations. [GroPIns] reached a peak early in the differentiation of both neutrophils and monocytes and subsequently fell to about double the starting level as the cells acquired mature characteristics, and [InsP5] rose later. Similarly, neutrophils derived in culture by the spontaneous differentiation of myeloid blast cells contained increased levels of Ins, GroPIns and InsP5 when compared to their parental blast cells. We have also compared the inositol metabolites present in two pairs of cell lines which are representative of immature and mature B and T lymphocytes. The mature cells again contained the higher levels of GroPIns and InsP5. We have previously demonstrated increases in Ins, GroPIns and Ins(1,3,4,5,6)P5 levels during the differentiation of HL60 cells towards neutrophils in response to DMSO and of GroPIns during the monocytoid differentiation of normal primitive myeloid blast cells in response to PMA. These observations suggest that deacylation of phosphatidylinositol by a phospholipase A/lysophospholipase pathway, forming GroPIns and probably also regulatory arachidonate metabolites, has some role in haemopoietic cell differentiation. The reasons why Ins(1,3,4,5,6)P5 and Ins accumulate during haemopoietic differentiation remain unknown.

Cell Differentiation↗
PubMed1994

Blockade of U50,488H analgesia by antisense oligodeoxynucleotides to a kappa-opioid receptor.

The recently cloned kappa-opioid receptor has binding characteristics consistent with those of a kappa 1-opioid receptor. Repeated intrathecal administration of an antisense oligodeoxynucleotide against the kappa 1-opioid receptor selectively lowers U50,488H (trans-3,4-dichloro-N-methyl-N-[2-(1- pyrrolidinyl)cyclohexyl]benzeneacetemide) analgesia (P < 0.02) without affecting mu or delta analgesia. A mismatched antisense oligodeoxynucleotide in which 4 bases had been switched is inactive against U50,488H analgesia. These studies confirm at the molecular level traditional pharmacological studies implying a distinct receptor mechanisms for kappa 1 analgesia and demonstrate the utility of antisense approaches in studies of opioid pharmacology.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1994

1 alpha,25-Dihydroxyvitamin D3 promotes monocytopoiesis and suppresses granulocytopoiesis in cultures of normal human myeloid blast cells.

Primitive myeloid blast cells (2-10 x 10(6)) were purified from 18-22-week fetal liver-derived mononuclear cell preparations by negative selection followed by counterflow cell elutriation. The cells, when maintained in liquid culture in the presence of 100 U/ml interleukin-3 (IL-3) for the first 5 days and 10 U/ml IL-3 and 30 ng/ml granulocyte colony-stimulating factor thereafter, underwent considerable proliferation resulting in an approximately 30-fold increase in cell number by day 14. Analyses of cell morphology and of the numbers of cells that expressed the neutrophil-associated antigen CD15, the monocyte-associated antigen 61D3, and enzymes alpha-naphthyl acetate esterase (ANAE), human leukocyte elastase, and cathepsin G revealed that proliferation of the cells was associated with their concomitant differentiation toward neutrophils and monocytes. The cultures generated predominantly neutrophils; by day 14, wells seeded with 2 x 10(5) cells produced approximately 5 x 10(6) neutrophils as opposed to only approximately 3.5 x 10(5) cells with a monocytoid morphology. This predominance of granulocytopoiesis over monocytopoiesis was confirmed by the numbers of cells that had acquired expression of the CD15 antigen and ANAE, which were approximately 2 x 10(6) and 1 x 10(5), respectively. By contrast, parallel cultures containing 100 nM 1 alpha,25-dihydroxyvitamin D3 (VitD3) generated more monocytes than neutrophils. At day 14, VitD3-treated cultures contained approximately 2 x 10(6) cells with morphologies consistent with their differentiation toward monocytes and approximately 1 x 10(6) ANAE-positive cells, compared with approximately 9.5 x 10(5) cells having morphologies of granulocyte-series cells and approximately 4.5 x 10(4) CD15-positive cells. In both control and VitD3-treated cultures, the enzymes cathepsin G and human leukocyte elastase were expressed almost exclusively by cells that were differentiating toward neutrophils. These data reveal that VitD3 promotes monocytopoiesis and suppresses granulocytopoiesis of primitive blast cells.

Calcitriol↗
PubMed1994

Expression of a nuclear envelope protein recognized by the monoclonal antibody BU31 in lung tumours: relationship to Ki-67 antigen expression.

The production of the murine monoclonal antibody BU31 is described. This antibody identifies a nuclear envelope protein which is expressed in some but not all cells, and which resembles statin, a protein reported to be expressed by non-proliferating cells. BU31 was applied onto frozen sections of a series of 78 lung tumours and the staining patterns were compared with those obtained with Ki-67. There was an inverse correlation between the proportion of tumour nuclei labelled with the two reagents (r = -0.61, 95 per cent confidence intervals -0.73 to -0.45). However, the four neuroendocrine neoplasms were BU31-negative. Squamous cell carcinomas often showed a peripheral distribution of the cells stained positively with Ki-67, whereas BU31 tended to label centrally situated cells. These observations are consistent with the concept that the antigen recognized by BU31 is expressed by non-proliferating cells in these tumours.

Adult↗
PubMed1994

Simulation of traffic conflicts at unsignalized intersections with TSC-Sim.

This paper describes a traffic conflicts computer simulation model and graphic display for both T and 4-leg unsignalized intersections. The goal of the model is to study traffic conflicts as critical-event traffic situations and the effect of driver and traffic parameters on the occurrence of conflicts. The analysis extends conventional gap acceptance criteria to describe driver's behaviour at unsignalized intersections by combining some aspects of gap acceptance criteria and the effect of several parameters including driver's characteristics such as age, sex, and waiting time. The effect of different traffic parameters such as volume and speed on the number and severity of traffic conflicts is also investigated. The model is unique insofar as it uses a technique of importance sampling and stores the traffic conflicts that occur during the simulation for later study. A graphical animation display is used to show how these conflicts occurred and the values of critical variables at the time. Model results were evaluated against previous work in the literature and validated by using field observations from four unsignalized intersections. The simulation results correlated reasonably well with actual conflict observations and should prove useful for assessing safety performance and feasible solutions for other unsignalized intersections.

Accidents, Traffic↗
PubMed1994

From wishing to intending: differences in salience of positive versus negative consequences.

Goal ratings by 345 subjects in seven data samples supported a functional distinction between two types of positive incentive value, one based on approaching positive affect (positive-based value or PBV), the other on avoiding negative affect (negative-based value or NBV). Ratings of PBV were more related to ratings of earlier action-phases of motivation ("wishing"), whereas ratings of NBV tended to be more related to factors entailed in later action-phases ("urgency/priority" and "intention"). These findings and previous ones are consistent with the proposal that this distinction parallels distinctions in Maslow's motivation theory. If the parallel is accepted, the findings support predictions from Maslow's theory. Results also indicate that purportedly unidimensional rating scales of motivation can reflect more than one underlying attribute.

Affect↗
PubMed1994

Binding and accumulation of hemin in Porphyromonas gingivalis are induced by hemin.

Although hemin is an essential nutrient for the black-pigmented oral bacterium Porphyromonas gingivalis, the mechanisms involved in hemin binding and uptake are poorly defined. In this study, we have examined the binding of hemin and Congo red (CR) to P. gingivalis whole cells and have defined the conditions for maximal binding. Additionally, the accumulation of hemin by P. gingivalis under growing conditions has been characterized. P. gingivalis A7436 was grown under hemin- or iron-deplete conditions (basal medium [BM] or Schaedler broth with dipyridyl [SBD]) or under hemin- or iron-replete conditions (BM with hemin [BMH] or Schaedler broth [SB]), and hemin and CR binding were assessed spectrophotometrically. Binding of hemin by P. gingivalis whole cells was rapid and was observed in samples obtained from cells grown under hemin- and iron-replete and hemin-deplete conditions but was not observed in cells grown under iron limitation. We also found that P. gingivalis whole cells bound more hemin when grown in BMH or SB than cells grown in BM or SBD. Binding of CR by P. gingivalis A7436 was also enhanced when cells were grown in the presence of hemin or when cells were incubated with hemin prior to CR binding. Hemin binding and accumulation were also assessed using [14C]hemin and [59Fe]hemin under growing conditions. Both [14C]hemin and [59Fe]hemin were accumulated by P. gingivalis, indicating that iron and the porphyrin ring were taken into the cell. Binding and accumulation of hemin under growing conditions were also induced by growth of P. gingivalis in hemin-replete media. Hemin accumulation was inhibited by the addition of KCN to P. gingivalis cultures, indicating that active transport was required for hemin uptake. [14C]hemin binding and accumulation were also inhibited by the addition of either cold hemin or protoporphyrin IX. Taken together, these results indicate that P. gingivalis transports the entire hemin moiety into the cell and that the binding and accumulation of hemin are induced by growth of cultures in the presence of hemin.

Binding, Competitive↗
PubMed1994

Dilated cardiomyopathy due to type II X-linked 3-methylglutaconic aciduria: successful treatment with pantothenic acid.

A case of dilated cardiomyopathy in a young boy secondary to type II 3-methylglutaconic aciduria is described. A metabolic cause for his dilated cardiomyopathy was suspected because of the development on the electrocardiogram of an unusual "camel's hump" shape of the T waves, and of progressive thickening with increasing echogenicity of the left ventricular wall. He initially improved on digoxin treatment, but did not maintain the response with conventional dietary treatment for this condition. Supplementation with L-carnitine was associated with rapid deterioration in cardiac state, and may be contraindicated in this condition. At a point when the patient was moribund, large doses of pantothenic acid, a precursor of coenzyme A, produced a dramatic and sustained improvement in myocardial function and in growth, neutrophil cell count, hypocholesterolaemia, and hyperuricaemia, which suggests that limitation of availability of coenzyme A is a fundamental pathological process in this condition. The clinical improvement has been maintained for 13 months, and myocardial function is now nearly normal. Oral pantothenol, unlike pantothenic acid, is not efficacious.

Amino Acid Metabolism, Inborn Errors↗
PubMed1994

Identification of variability of ribosomal DNA spacer from Pseudomonas soil isolates.

The polymerase chain reaction was used to amplify the spacer region located between the 16S and 23S ribosomal RNA genes of strains of Pseudomonas fluorescens and Pseudomonas putida isolated from peat bog, canola field, or arctic plants. Some of spacer region of four of the P. fluorescens strains examined, strains 64-3, 63-28, QP5, and R17-FP2, was about 515 base pairs (bp) in length, and contained the genes for tRNA(Ile) and tRNA(Ala). The DNA sequences of two strains from canola, 64-3 and 63-28, differed at only two positions. The sequences of the peat bog strains QP5 and R17-FP2 were identical. However, differences were noted between the DNA sequence common to the pair of strains 64-3 and 63-28 and the corresponding common sequence for strains QP5 and R17-FP2. These differences were mainly concentrated in two DNA segments of 10 and 19 bp, respectively. A probe for the 19-bp variable segment that occurs in the ribosomal spacer of strains QP5 and R17-FP2 recognized total DNA from these two strains, but not DNA from other bacteria of different origins. These results suggest the existence of a limited degree of variability within the 16S-23S ribosomal DNA spacer region, and that this variability may be useful to the recognition of particular Pseudomonas strains from environmental samples.

Base Sequence↗
PubMed1994

The natural history of familial cavernous malformations: results of an ongoing study.

Cavernous malformations are congenital abnormalities of the cerebral vessels that affect 0.5% to 0.7% of the population. They occur in two forms: a sporadic form characterized by isolated lesions, and a familial form characterized by multiple lesions with an autosomal dominant mode of inheritance. The management of patients with cavernous malformations, particularly those with the familial form of the disease, remains a challenge because little is known regarding the natural history. The authors report the results of an ongoing study in which six families afflicted by familial cavernous malformations have been prospectively followed with serial interviews, physical examinations, and magnetic resonance (MR) imaging at 6- to 12-month intervals. A total of 59 members of these six families were screened for protocol enrollment; 31 (53%) had MR evidence of familial cavernous malformations. Nineteen (61%) of these 31 patients were symptomatic, with seizures in 12 (39%), recurrent headaches in 16 (52%), focal sensory/motor deficits in three (10%), and visual field deficits in two (6%). Twenty-one of these 31 patients underwent at least two serial clinical and MR imaging examinations. A total of 128 individual cavernous malformations (mean 6.5 +/- 3.8 lesions/patient) were identified and followed radiographically. During a mean follow-up period of 2.2 years (range 1 to 5.5 years), serial MR images demonstrated 17 new lesions in six (29%) of the 21 patients; 13 lesions (10%) showed changes in signal characteristics, and five lesions (3.9%) changed significantly in size. The incidence of symptomatic hemorrhage was 1.1% per lesion per year. The results of this study demonstrate that the familial form of cavernous malformations is a dynamic disease; serial MR images revealed changes in the number, size, and imaging characteristics of lesions consistent with acute or resolving hemorrhage. It is believed that the de novo development of new lesions in this disease has not been previously reported. These findings suggest that patients with familial cavernous malformations require careful follow-up monitoring, and that significant changes in neurological symptoms warrant repeat MR imaging. Surgery should be considered only for lesions that produce repetitive or progressive symptoms. Prophylactic resection of asymptomatic lesions does not appear to be indicated.

Adolescent↗