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Biomedical subjects

D Brown

Publications and source records attributed to D Brown.

At least 487 records · Page 27Linked to original sources
PubMed1994

Interactions between saturated acyl chains confer detergent resistance on lipids and glycosylphosphatidylinositol (GPI)-anchored proteins: GPI-anchored proteins in liposomes and cells show similar behavior.

Proteins anchored by GPI are poorly solubilized from cell membranes by cold nonionic detergents because they associate with detergent-resistant membranes rich in cholesterol and sphingolipids. In this study, we demonstrated that cholesterol and sphingolipid-rich liposomes were incompletely solubilized by Triton X-100. GPI-anchored placental alkaline phosphatase incorporated in these liposomes was also not solubilized by cold Triton X-100. As sphingolipids have much higher melting temperatures (Tm) than cellular phospholipids, a property correlated with Tm might cause detergent inextractability. In support of this idea, we found that the low-Tm lipid dioleoyl phosphatidylcholine (DOPC) was efficiently extracted from detergent-resistant liposomes by Triton X-100, whereas the high-Tm lipid dipalmitoyl phosphatidylcholine (DPPC) was not. The fluorescence polarization of liposome-incorporated diphenylhexatriene was measured to determine the "fluidity" of the detergent-resistant liposomes. We found that these liposomes were about as fluid as DPPC/cholesterol liposomes, which were present in the liquid-ordered phase, and much less fluid than DOPC or DOPC/cholesterol liposomes. These findings may explain the behavior of GPI-anchored proteins, which often have saturated fatty acyl chains and should prefer a less-fluid membrane. Therefore, we propose that acyl chain interactions can influence the association of GPI-anchored proteins with detergent-resistant membrane lipids. The affinity of GPI-anchored proteins for a sphingolipid-rich membrane phase that is not in the liquid crystalline state may be important in determining their cellular localization.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1994

The epidemiology of measles in England and Wales: rationale for the 1994 national vaccination campaign.

An epidemic of between 100,000 and 200,000 cases of measles during 1995 has been predicted in England and Wales. This prediction was based on epidemiological evidence from several sources. Notifications of measles to the Office of Population Censuses and Surveys have risen in 1994, with a high proportion of cases in children aged over 10 years. An increase in the incidence of measles was seen in data from other sources, including laboratory reports of confirmed infections and consultations with general practitioners for new episodes of measles. Antibody tests were performed on saliva and serum from notified cases in several districts. Over three quarters of the notified cases in 1994 that were confirmed occurred in children of school age. The proportion of children aged 7 to 14 years who were susceptible to measles, obtained from studies of the age specific prevalence of antibody, rose from 6.0% (146/2453) in 1986 and 1987 to 9.2% (144/1565) in 1991. Mathematical modelling has predicted that the level of susceptibility anticipated in the school age population in 1995 would have been sufficient to allow a resurgence of measles. Over half of the cases in the resulting epidemic would have occurred in people aged at least 10 years and, because mortality is higher in this older age group, between 30 and 60 deaths would have occurred. A mass campaign to immunise all children of school age is expected to cause an immediate reduction in disease transmission and prevent a substantial toll of morbidity and mortality.

Adolescent↗
PubMed1994

Rubella surveillance to June 1994: third joint report from the PHLS and the National Congenital Rubella Surveillance Programme.

A downward trend in the incidence of acquired rubella in England and Wales was reversed in 1993 when there were local outbreaks. These affected young adult males in particular, especially those living in college residences. Some spread to local antenatal populations occurred. Twenty-five confirmed infections were reported in pregnant women, most of whom were young and in their first pregnancy; this compares with totals of 12 and two in 1991 and 1992, respectively. Reports of congenital rubella have not risen since the 1993 outbreaks. Diagnosis lags behind birth, however, and further evaluation may be needed. Notifications of 14 infants, including one set of triplets, born with congenital infection since the beginning of 1991 have been received. Nine of the 12 mothers were immigrants, and three of these acquired their infection abroad. Data on antibody prevalence have revealed a large pool of susceptible males aged 10 to 25 years, which indicates that outbreaks in males would continue for some years if no action were taken. The national measles and rubella vaccination campaign in schools this month should abolish the difference in susceptibility between boys and girls up to 16 years of age and hasten progress towards the interruption of rubella transmission in the United Kingdom. Susceptibility in girls aged 13 to 14 years rose to 5.8% in 1993 from an average of 3.6% between 1986 and 1992. This suggests that the vaccination of schoolgirls has recently declined, but this component of the selective rubella vaccination programme will be discontinued after the measles and rubella campaign.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Growth of LLC-PK1 renal cells is mediated by EGR-1 up-regulation of G protein alpha i-2 protooncogene transcription.

The early growth response zinc finger transcription factor (EGR-1) and the heterotrimeric guanine nucleotide binding protein encoded by the protooncogene G alpha i-2 each play pivotal roles in signaling pathways that control cell growth and differentiation. The G alpha i-2 gene 5'-flanking region contains a putative binding site (5'-CGCCCCCGC-3') for EGR-1 that may allow it to be a target gene for EGR-1 mitogenic signaling. We now demonstrate in LLC-PK1 renal cells the temporal expression of EGR-1 protein by immunoblotting and immunocytochemistry coincident with the maximal activation of the G alpha i-2 gene during cell growth. To determine whether G alpha i-2 or EGR-1 influence epithelial cell growth, LLC-PK1 cells were transiently transfected with plasmids encoding cDNAs for G alpha i-2 (pRSV G alpha i-2) or EGR-1 (pRSV EGR-1) driven by a viral Rous sarcoma promoter enhancer to overexpress each protein. Following transfection, cell growth was examined in media containing either 10 or 0.1% fetal bovine serum. Only cells transfected with plasmids encoding G alpha i-2 and EGR-1 had growth rates greater than that of serum replete cohorts. To assess whether EGR-1 was contributing to the transcriptional activation of the G alpha i-2 gene, cells were cotransfected with pRSV EGR-1 and plasmids encoding firefly luciferase reporter genes fused to 5'-flanking areas of the G alpha i-2 gene containing either the EGR-1 binding site or a mutated EGR-1 binding site (5'-AAAAACCGC-3'). A 320% enhancement of G alpha i-2 transcription was found only in LLC-PK1 cells following their transfection with plasmids that contained both the EGR-1 binding site and overexpressed EGR-1 protein. Utilizing mobility shift assays, which compared nuclear extracts from cells before and after cell polarization, a probe containing the EGR-1 motif detected induced nuclear protein complexes during transcriptional activation of the G alpha i-2 gene. An anti-EGR-1 antibody specifically retarded the mobility of the induced nuclear complexes, indicating that the EGR-1 protein was a component of these complexes. These data provide direct evidence for a novel mitogenic signaling pathway coupling proximal signaling events that activate EGR-1 gene expression to a target protooncogene G alpha i-2 that is participatory for growth and differentiation in renal cells.

Animals↗
PubMed1994

Measles in secondary school children: implications for vaccination policy.

The reported incidence of measles in children of secondary school age rose in 1992, after a progressive decline between 1988 and 1991. This rise was maintained in 1993. Several school and community based outbreaks of measles have occurred in the United Kingdom. This paper reports the investigation of an outbreak of measles based in a secondary school, which took place in 1992. Thirty clinical cases were detected among the school's 840 pupils and 10 sporadic cases occurred outside the school. Twenty-one of the school cases provided samples of serum, in 19 of which measles IgM was detected. The overall attack rate was 3.6%, with no significant differences attributable to age and sex. Vaccine efficacy was about 90%. This outbreak is one of the first to be described in the United Kingdom, although other countries (notably the United States) have reported measles in teenagers. The small degree of spread in the community may reflect the current high uptake of measles, mumps, and rubella vaccine and the catch up campaign that took place in 1988. The feasibility and cost effectiveness of various policy options to prevent future outbreaks in secondary schools are now being evaluated.

Adolescent↗
PubMed1994

Platelet membrane fluidity and plasma malondialdehyde levels in Alzheimer's demented patients with and without family history of dementia.

Platelet membrane fluidity (PMF) was measured with three different fluorescent probes, 1,6-diphenyl-1,3,5-hexatriene (DPH), 1-(4-trimethylammoniumphenyl)-6-phenyl-1,3,5-hexatriene (TMA-DPH), 3-(p-phenyl-1,3,5-hexatrienyl)phenyl-propionic acid (DPH-PA), which labeled different parts of the bilayer (the hydrophobic core and the positively and negatively charged regions, respectively) in Alzheimer's disease (AD) patients with and without a family history of dementia, and in a control group. In support of earlier findings in the literature, significantly increased PMF was found by the application of DPH in both groups with AD. The use of the fluorescence probe TMA-DPH, however, revealed no differences between the groups. In contrast, significant rigidification was observed with DPH-PA, but only in the AD group with a positive family history of dementia. The plasma malondialdehyde levels appeared to be similar in each group. Our findings are discussed in light of the controversies regarding the value of PMF measurements in AD.

Aged↗
PubMed1994

The induction of persistence of I-A expression by macrophages from Bcgr mice occurs via a protein kinase C-dependent pathway.

We have described conditions by which MHC class II (I-A) glycoproteins can be induced to be differentially expressed after treatment of macrophages with rIFN-gamma. Treatment of macrophages from BCG-resistant mice with 1 U of rIFN-gamma induced transient I-A expression that decayed in the presence of cycloheximide. Subsequent treatment of these macrophages with 100 U of rIFN-gamma induced the persistence of I-A that was not affected by cycloheximide. The aim of this investigation was to define, by pharmacologic intervention, the second signals that resulted in the induction of persistence of I-A. Treatment of the macrophages that transiently expressed I-A with PMA resulted in the induction of persistence. When we compared the effect of different protein kinase C (PKC) inhibitors with the induction of persistence by rIFN-gamma, we found that H-7 blocked the induction of persistence only when added before or at the same time as the addition of a high dose of rIFN-gamma. In contrast, the addition of staurosporine to macrophages as late as 2 h after treatment with high doses of rIFN-gamma inhibited the induction of I-A persistence. The addition of a high dose of rIFN-gamma to macrophages previously treated with a low dose of rIFN-gamma resulted in the synergistic activation of PKC. The effect of H-7 and of staurosporine on the activation of PKC activity coincided with the effect of these inhibitors on the induction of persistent I-A expression. Tyrosine kinase inhibitors genistein and herbimycin did not affect the induction of I-A persistence nor of PKC activation. Antibody to the IFN-gamma receptor inhibited PKC activation. Finally, the addition of the high dose of rIFN-gamma to macrophages from BALB/c.Bcgs mice, previously treated with the low dose of rIFN-gamma, failed to activate high levels of PKC activity attained after similar treatment of macrophages from BALB/c.Bcgr mice. One effect of the Bcg gene may be to regulate the activation of PKC activity.

Animals↗
PubMed1994

Expression of Bruton's tyrosine kinase protein within the B cell lineage.

Defects in the gene encoding Bruton's tyrosine kinase (Btk), normally expressed in B cells, cause X-linked agammaglobulinemia (XLA). The phenotype of XLA is characterized by a lack of circulating B cells and immunoglobulin. It has been suggested that B cell maturation from the pre-B cell stage to more mature stages is dependent on the appropriate expression of this gene. The Btk mRNA is expressed in B cells and myeloid cells, but protein expression in relation to B cell maturation has not been determined. Moreover, expression of the Btk protein has so far only been investigated in human Epstein-Barr virus-transformed B cell lines, and in murine splenocytes and B cell lines. We have developed an antiserum which recognizes the human Btk protein and shown that normal human tonsillar B cells, peripheral blood monocytes and myeloid cells express the protein, whereas tonsil-derived T cells do not. We also show that the protein is present in early and mature human B cell lines, but is absent in terminally differentiated plasma cell lines. Furthermore, expression is reduced or absent in three B lineage cell lines derived from two patients with defined genetic mutations in Btk and suffering from XLA.

Agammaglobulinaemia Tyrosine Kinase↗