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Biomedical subjects

G Brown

Publications and source records attributed to G Brown.

At least 235 records · Page 13Linked to original sources
PubMed1994

Indomethacin potentiates the induction of HL60 differentiation to neutrophils, by retinoic acid and granulocyte colony-stimulating factor, and to monocytes, by vitamin D3.

We have confirmed previous observations that HL60 cells treated with a combination of 10 nM retinoic acid (RA), and 30 ng/ml granulocyte colony-stimulating factor (G-CSF) differentiate efficiently towards neutrophils, as characterized by their growth arrest and acquisition of phagocytic ability. Such low concentrations of RA alone provoked only a small proportion of HL60 cells to differentiate, and G-CSF alone provoked no differentiation. In the presence of 30 microM indomethacin (an inhibitor of the enzyme cyclooxygenase that catalyses the first step of prostanoid synthesis), the onset of differentiation provoked by RA plus G-CSF was more rapid, but the final proportion of mature cells was unchanged. Indomethacin also potentiated the growth arrest and differentiation of cells in response to 10 nM RA alone. Although the potentiating effect of indomethacin on RA-induced differentiation occurred at several indomethacin and RA concentrations, it was only apparent when the RA concentration used was alone sufficient to induce a small proportion of cells to differentiate. Indomethacin shifted the G-CSF dose-response curve of cells treated with 10 nM RA to lower G-CSF concentrations. 1 alpha,25-dihydroxy vitamin D3 (VitD3) induces HL60 cells to differentiate to monocytes and indomethacin also potentiated the differentiation of HL60 cells in response to low doses of VitD3 5,8,11-eicosatriynoic acid, an inhibitor of 5-lipoxygenase and 12-lipoxygenase, neither potentiated neutrophil differentiation of HL60 cells, nor prevented indomethacin potentiation of the differentiation of RA-primed cells. Treatment of cells with dexamethasone, a steroid whose effects include inhibition of arachidonate mobilization by phospholipase A2, potentiated RA-primed neutrophil differentiation in a manner similar to indomethacin. These observations suggest that an arachidonate metabolite formed downstream of cyclooxygenase suppresses differentiation of HL60 cells both to neutrophils and monocytes, probably by inhibiting some event essential to commitment to differentiation.

Arachidonic Acid↗
PubMed1994

All-trans retinoic acid and 1 alpha,25-dihydroxyvitamin D3 co-operate to promote differentiation of the human promyeloid leukemia cell line HL60 to monocytes.

A basis for differentiation therapy of leukemias is provided by knowledge of agents which induce specific lineage maturation. All-trans retinoic acid (RA) induces differentiation of HL60 cells to neutrophils and is used to treat acute promyelocytic leukemia. We observed that RA did not induced neutrophil differentiation in serum-free grown HL60 cells whereas 50 nM 1 alpha,25-dihydroxyvitamin D3 (D3) induced maximal monocyte differentiation. Increasing RA concentrations reduced the D3 concentration required for monocyte differentiation. Cells treated with 5 nM D3 showed little response, but differentiated maximally with 5 nM D3 and 10 nM RA. The D3 analogs MC903, EB1089 and KH1060 were more potent inducers of monocyte differentiation. The extent to which analog activity was increased after cotreatment with RA was inversely related to potency. Twenty-four hour treatment with 10 nM RA primed cells for response to 5 nM D3; the reverse sequence being ineffective. Priming with 10 nM RA, or subsequent treatment with D3 (5 nM), did not alter expression of mRNAs encoding receptors for D3 (VDR), RA (RAR alpha) or 9-CIS RA (RXR alpha, beta, gamma). That RA promotes both neutrophil and monocyte differentiation has implications for the use of RA and D3 in treatment of leukemias and provides insight into mechanisms whereby RAR, VDR and RXR facilitate monocyte differentiation.

Calcitriol↗
PubMed1993

The use of perfluorophenanthrene in the removal of intravitreal lens fragments.

We used perfluorophenanthrene as an aid during pars plana vitrectomy in removing lens fragments dislocated posteriorly into the vitreous cavity. We reviewed the records of all patients (nine patients, nine eyes) referred with dislocated lenses who underwent pars plana vitrectomy with perfluorophenanthrene for removal of the lens material at Wills Eye Hospital from July 1, 1991, through Nov. 30, 1991. The lens was dislocated during cataract extraction in eight eyes. One eye had a history of nonpenetrating trauma and lens dislocation. In one eye a retinal tear was noted intraoperatively and treated. Six eyes had postoperative visual acuity of 20/50 or better. In all eyes the lens was removed without further complications. Perfluorocarbon liquids such as perfluorophenanthrene may enhance current techniques by allowing easier and safer removal of displaced lens fragments through the pars plana.

Cataract Extraction↗
PubMed1993

Comparison of the levels of inositol metabolites in transformed haemopoietic cells and their normal counterparts.

We have compared the levels of inositol metabolites in three pairs of normal and transformed cells which have been matched with respect to their cell lineage, differentiation and proliferation status: (i) normal human myeloid blast cells and the human promyelocytic leukaemic cell line, HL60; (ii) human umbilical-cord T-helper cells and C8166 cells, a HTLV-1-transformed T-helper cell line; and (iii) an interleukin 3-dependent long-term culture of murine pro-B-cells (BAF3) and BAF3 cells transformed by transfection with the bcr-abl oncogene. Complex patterns of inositol metabolites were present in each of the cell populations. Although there were a number of differences in the levels of certain inositol metabolites between individual cell populations in the paired groups, we did not observe any consistent difference in the levels of inositol metabolites between the proliferating normal and transformed cells. In particular, our data do not support the reported correlation between elevated glycerophosphoinositol (GroPIns) levels and transformation of cells by membrane and cytoplasmic oncogenes which has been reported by other workers. All the cells contained high concentrations of Ins(1,3,4,5,6)P5 (between 12 and 55 microM) and InsP6 (between 37 and 105 microM). The HTLV1-transformed T-helper cells had particularly high levels of total inositol phosphates (predominantly GroPIns, an unidentified inositol bisphosphate and InsP6). The observations are discussed with reference to cell transformation and to the differentiation status of the paired populations.

Animals↗
PubMed1993

The development of short-term memory span: separable effects of speech rate and long-term memory.

We report an experiment investigating the mechanisms responsible for short-term memory span and its development by examining the relationship between memory span and speech rate for words and nonwords of differing spoken lengths. Linear functions related memory span to speech rate for both words and nonwords in children of different ages. The functions for nonwords had equivalent slopes (interpreted as reflecting a contribution from a speech-based process) but lower intercepts (interpreted as reflecting a contribution from a long-term memory component) than the functions for words. Children in both age groups studied showed evidence of a relationship between speech rate and memory span and part of the difference in memory span between age groups appears to reflect a difference in speech rate. However, there is also evidence that the long-term memory component of memory span shows greater efficiency in older children.

Age Factors↗
PubMed1993

Effect of a new nootropic agent, CGS 5649B, on cognition, function, and behavior in dementia.

To determine the efficacy of CGS 5649B, the authors conducted a series of randomized, double-masked, single-subject studies using pairs of treatment periods, each pair including four weeks of active drug administration and four weeks of placebo administration. Thirty-two moderately demented patients completed three treatment pairs, receiving doses of 90, 200, or 600 mg of CGS 5649B during the active periods. Two patients met criteria for individual response in the behavioral measures. In the group analysis none of the differences achieved statistical significance. The authors conclude that CGS 5649B had a favorable impact on behavior for two of 32 patients.

Adult↗
PubMed1993

Protection, pathogenesis and phenotypic plasticity in Plasmodium falciparum malaria.

Why does Plasmodium falciparum cause severe illness in some but not all infections? How is clinical immunity acquired? These questions have intrigued investigators since the clinical epidemiology of malaria was first described. The search for answers to both questions has highlighted the changes that take place at the surface of infected red blood cells during the last half of the erythrocytic cycle. These changes specify the antigenic and adhesive or cytoadherence phenotypes for the infected cell. Now the antigenic and adhesive phenotypes appear to be linked and together undergo clonal variation. In this article David Roberts, Beverley-Ann Biggs, Graham Brown and Christopher Newbold explain how clonal phenotypic variation and the linkage between adhesive and antigenic types contribute to our understanding of naturally acquired immunity and of pathogenesis of severe malaria.

Journal Article↗
PubMed1993

Mediastinal widening--a valuable radiographic sign of superior vena cava thrombosis.

Thrombosis due to indwelling intravenous catheters has become increasingly recognized as an important cause of the benign superior vena cava (SVC) obstruction. We evaluated the PA chest radiographs of nine patients with SVC thrombosis related to Hickman catheter insertion. All nine patients showed mediastinal widening at the time of developing SVC thrombosis and four patients had radiographic signs before the onset of symptoms. Five patients demonstrated lateral displacement of the Hickman catheter with the development of SVC thrombosis. The development of superior mediastinal widening is a valuable sign of SVC thrombosis and its recognition may allow earlier diagnosis and treatment of this condition.

Adult↗
PubMed1993

Cranial computed tomography of elderly patients: an evaluation of its use in acute neurological presentations.

We assessed the use of cranial computed tomography (CT) in elderly patients with acute neurological deficit and its influence on patient management. Clinical notes from 100 consecutive CT referrals from geriatric admissions presenting with acute neurological deficit were reviewed and categorized according to clinical presentation. CT results and subsequent therapy were recorded. Twenty of the patients had treatable lesions (in 6 out of 14 patients with signs atypical of stroke and 7 out of 19 patients with acute confusion). These two groups contained 68% of all treatable lesions found. Forty-four scans yielded no new diagnostic information; these included all scans for transient ischaemic attacks and for progression of stroke. The remaining scans yielded information regarding pathology but did not alter patient management. CT is a valuable first-line investigation in elderly patients presenting with signs atypical of stroke and unexplained confusion but may be less useful in patients with other presentations.

Acute Disease↗
PubMed1993

Families of mtDNA re-arrangements can be detected in patients with mtDNA deletions: duplications may be a transient intermediate form.

In three patients with mitochondrial DNA duplications, there are two additional re-arranged molecules derived from mitochondrial DNA. Two forms of closed circular deletions of mitochondrial DNA have been characterised in all three patients, one being a monomer, and the other a dimer. The junction fragments appear to be the same in the deletion and the duplication, suggesting that both re-arrangements arose from the same initial recombination event, followed by homologous recombination. Sequential muscle biopsy and cell culture studies suggest that the duplication is present only transiently in muscle and cloned fibroblast lines. The duplicated molecule could thus be an intermediate in the formation of the deletion. Evidence is presented for the presence of duplicated mtDNA in 6/11 patients known to have deletions of mitochondrial DNA in muscle, suggesting that this could be a general mechanism for major re-arrangements of mitochondrial DNA. There may be parallels between the families of re-arrangements found in plant mitochondrial DNA, and the three distinct re-arranged molecules described here.

Blotting, Southern↗
PubMed1993

The effect of pregnancy on the response to the TxA2/PGH2 analogue U-46619 in rabbits.

We compared the hemodynamic actions of U-46619, a stable thromboxane A2 (TxA2) prostaglandin H2 (PGH2) analogue, in nonpregnant (NP) rabbits with those observed in late pregnant (P) rabbits. An intravenous injection of U-46619 (10 micrograms) to each of eight NP chronically instrumented rabbits (mean body weight 3.4 kg) induced an immediate (1 min) and reversible fall of cardiac output (CO, 66%) and mean arterial pressure (MAP, 41%, both P < 0.01). P rabbits (n = 6, mean body weight 3.8 kg), however, responded with an elevation of MAP (5%, P < 0.02) upon intravenous injection of the drug (10 micrograms), while CO remained unchanged. The fall of CO in NP rabbits was associated with the temporary disappearance of a fraction of circulating platelets between the superior vena cava and the aortic arch. The number of platelets at 30 and 60 s after U-46619 was reduced (P < 0.05) by 14 and 20% respectively in the aortic blood, whereas caval platelet counts were unchanged until 90 s (-6%, P < 0.05). In contrast, intraaortic administration of this drug (10 micrograms) to NP rabbits resulted in neither thrombocytopenia nor hypotension. U-46619 (10-30 micrograms i.v.) caused no decrease in platelet count in the aorta of P rabbits. In vitro, U-46619-induced aggregation of platelets harvested from P rabbits was also blunted (P < 0.001). This could not be attributed to reduced affinity or number of platelet thromboxane receptors. The data indicate that U-46619 induces a fall of arterial pressure simultaneous with intravascular platelet aggregation.(ABSTRACT TRUNCATED AT 250 WORDS)

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗