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Biomedical subjects

A Georgiou

Publications and source records attributed to A Georgiou.

At least 19 recordsLinked to original sources
PubMed2001

Binding of Ikaros to the lambda5 promoter silences transcription through a mechanism that does not require heterochromatin formation.

The Ikaros family of proteins are DNA binding factors required for correct development of B and T lymphocytes. Cytogenetic studies have shown that these proteins form complexes with pericentromeric heterochromatin in B cells, and the colocalization of transcriptionally silent genes with these complexes suggests that Ikaros could silence transcription by recruiting genes to heterochromatin. Here we show that a site in the lambda5 promoter that binds Ikaros and Aiolos is required for silencing of lambda5 expression in activated mature B cells. Analysis of methylation and nuclease accessibility indicates that the silenced lambda5 gene is not heterochromatinized in B cells, despite being associated with pericentromeric heterochromatin clusters. We also found that a promoter mutation, which affects Ikaros-mediated silencing of lambda5 expression, is not rescued in a transgenic line that has the gene integrated into pericentromeric heterochromatin. Our results indicate that the Ikaros proteins initiate silencing of lambda5 expression through a direct effect on the promoter with localization to pericentromeric heterochromatin likely to affect the action of Ikaros on regulatory sequences rather than causing heterochromatinization of the gene.

Animals↗
PubMed2001

Influence of context effects on health outcomes: a systematic review.

BACKGROUND: Throughout history, doctor-patient relationships have been acknowledged as having an important therapeutic effect, irrespective of any prescribed drug or treatment. We did a systematic review to determine whether there was any empirical evidence to support this theory. METHODS: A comprehensive search strategy was developed to include 11 medical, psychological, and sociological electronic databases. The quality of eligible trials was objectively assessed by two reviewers, and the type of non-treatment care given in each trial was categorised as cognitive or emotional. Cognitive care aims to influence patients' expectations about the illness or the treatment, whereas emotional care refers to the style of the consultation (eg, warm, empathic), and aims to reduce negative feelings such as anxiety and fear. FINDINGS: We identified 25 eligible randomised controlled trials. 19 examined the effects of influencing patients' expectations about treatment, half of which found significant effects. None of the studies examined the effects of emotional care alone, but four trials assessed a combination of both cognitive and emotional care. Three of these studies showed that enhancing patients' expectations through positive information about the treatment or the illness, while providing support or reassurance, significantly influenced health outcomes. INTERPRETATION: There is much inconsistency regarding emotional and cognitive care, although one relatively consistent finding is that physicians who adopt a warm, friendly, and reassuring manner are more effective than those who keep consultations formal and do not offer reassurance.

Cognition↗
PubMed2001

Prognostic significance of p53, bax and bcl-2 gene expression in patients with laryngeal carcinoma.

AIM: This study was designed to examine the prognostic significance of the coexpression of three genes (bax, bcl-2 and p53) which play a critical role in the apoptotic mechanisms in patients with squamous cell laryngeal carcinoma. MATERIALS AND METHODS: The immunohistochemical expression of bcl-2, bax and p53 genes was retrospectively examined in 38 patients with squamous cell laryngeal carcinoma and in five controls (necrotomic tissue). Tissue specimens were obtained both during the diagnostic biopsy and at the time of surgery. Clinicopathological and survival data were correlated with the staining results. RESULTS: Bcl-2 protein expression (P=0.0472), stage (P=0.0087) and lymph-node involvement (P=0.0488) were found to be independent prognostic factors. Increased bcl-2 protein expression correlated with a better 5-year survival (P=0.0472). Patients who were bcl-2(-)/p53(-) (n=25) or bax(+)/bcl-2(-) (n=13) had a significantly worse overall survival (P=0.0305 and P=0.0482, respectively). Similarly, patients who were bax(+)/bcl-2(-)/p53(-) (n=11) also had a worse 5-year survival compared with the rest of the group (P=0.0088). Changes that were noticed in bax and p53 protein expression from the time of biopsy until the time of surgery did not correlate with a significant increase in the overall survival. CONCLUSIONS: The expression of bcl-2 gene appears to be an independent prognostic factor for patients with laryngeal carcinoma. The coexpression of the genes studied can be used to determine aggressive clinical phenotypes.

Adult↗
PubMed2001

Measuring the quality of urinary continence care in long-term care facilities: an analysis of outcome indicators.

BACKGROUND: the National Centre for Health Outcomes Development has produced outcome indicators for the assessment of quality of care in the management of urinary incontinence. Three measures relate to the management of older people in long-term care: the prevalence of incontinence, the use of indwelling catheters and clinical assessment rates. OBJECTIVE: to evaluate the recommended outcome measures in clinical practice. METHOD: participating centres included residential homes, nursing homes and long-stay wards. We sent a structured questionnaire to each centre for qualitative assessment of the acceptability of the outcome indicators. We analysed data collected by nurses and other staff who used the urinary incontinence section of the Royal College of Physicians Continuous Assessment Review and Evaluation scheme audit tool for long-term care. RESULTS: there were 1125 residents in 17 residential homes, 14 nursing homes and five long-stay wards. The overall prevalence of urinary incontinence was 34% in residential homes (range 2-86%), 70% in nursing homes (38-100%) and 71% in long-stay wards (4-97%). Catheterization rates were 5% in residential homes (0-20%), 10% in nursing homes (0-44%) and 6% in long-stay wards (0-20%). Rates of full clinical assessment were 48, 24 and 36% respectively. CONCLUSION: there is great variability in these outcome measures within and between settings. Interpretation of outcome results requires more precise details on case-mix and the definition of outcome measures. Individual units found the audit tool helpful, but we advise caution with interpretation of outcomes between units.

Aged↗
PubMed2001

Memorization of young people under loud pink noise of short duration.

Exposure of students to loud pink noise of short duration in schools with high background noise showed that memorization of the students under loud pink noise is correlated with noise level. For levels up to 91.5 dB(A) the performance of 275 students improved, but for louder noise performance was reduced.

Adolescent↗
PubMed2000

Transcription factor dosage affects changes in higher order chromatin structure associated with activation of a heterochromatic gene.

The mechanisms of transcriptional activation in heterochromatin were investigated by using FISH to directly visualize changes in chromatin organization during activation of a heterochromatic lambda5 transgene. A DNase I hypersensitive site was shown to relocate the transgene to the outside of the pericentromeric heterochromatin complex in the absence of transcription. Activation of transcription, which is dependent on the transcription factor EBF, occurs in a stochastic manner that resembles telomeric silencing in yeast, with the transcribed gene remaining closely associated with the heterochromatin complex. Reducing the dosage of EBF results in a reduced frequency of localization of the transgene to the outside of the heterochromatin complex and lower levels of transcription. These data provide evidence that transcription factors can initiate changes in higher order chromatin structure during the earliest stages of gene activation.

Animals↗
PubMed2000

Assessing payback from NHS reactive research programmes.

Aims to assess retrospectively the payback from NHS reactive research programmes in the Northern and Yorkshire region. A questionnaire was sent to all recipients of regional reactive research programme funding (biomedical, health services research (HSR), and primary and community care programmes) between 1 April 1991 and 31 March 1996. The sample available for analysis involved 174 respondents covering 119 projects, with a total financial value of 2.2 million Pounds. The main outcome measures used were peer-reviewed publications, changes in individual practice, changes in NHS service delivery and organisation, and impact on the careers of researchers. Overall, 119 projects produced 230 peer-reviewed publications: this was achieved at an average cost of 10,673 Pounds, 6,386 Pounds and 22,310 Pounds per publication for the biomedical, HSR, and primary and community care programmes respectively. From the qualitative data analysis, important changes in individual practice and NHS service delivery were identified by respondents. The researchers in our sample appeared to have attracted over 6 million Pounds in R&D funding related to the initial regional grant. Although based on self-report, there is evidence to suggest that the return on investment from NHS R&D can be substantial, taking a broad view of benefits to the NHS and to researchers. The findings also confirm the need for more effective dissemination and implementation of research findings.

Efficiency, Organizational↗
PubMed2000

Leukocytoclastic vasculitis: is propranolol implicated?

Drugs frequently cause cutaneous adverse reactions. The suspected agent is sometimes difficult to identify, especially in patients receiving multidrug treatment and with underlying illnesses that may contribute to the clinical picture. In our patient, propranolol-induced leukocytoclastic vasculitis was diagnosed by exclusion.

Adrenergic beta-Antagonists↗
PubMed1999

Analysis of mice with single and multiple copies of transgenes reveals a novel arrangement for the lambda5-VpreB1 locus control region.

The murine lambda5-VpreB1 locus encodes two proteins that form part of the pre-B-cell receptor and play a key role in B-lymphocyte development. We have identified a locus control region (LCR) which is responsible for coordinate activation of both genes in pre-B cells. Analysis of mice with single and multiple copies of transgenes shows a clear difference in the expression behavior of the genes depending on the transgene copy number. While expression of both lambda5 and VpreB1 in single- and two-copy integrations requires the presence of a set of DNase I hypersensitive sites located 3' of the lambda5 gene, small fragments containing the genes have LCR activity when arranged in multiple-copy tandem arrays, indicating that additional components of the LCR are located within or close to the genes. The complete LCR is capable of driving efficient copy-dependent expression of a lambda5 gene in pre-B cells even when it is integrated into centomeric gamma-satellite DNA. The finding that activation of expression of the locus by positively acting factors is fully dominant over the silencing effect of heterochromatin has implications for models for chromatin-mediated gene silencing during B-cell development.

Animals↗
PubMed1999

"First aid for scalds" campaign: reaching Sydney's Chinese, Vietnamese, and Arabic speaking communities.

OBJECTIVES: As a serious yet preventable problem, scald injuries in children have been a priority for prevention in Australia and other developed countries. Not only can the occurrence of scalds be prevented, but immediate first aid treatment offers an effective method for secondary prevention, reducing the severity of scalds. Despite the success of scald prevention initiatives, local evidence suggested that first aid knowledge was lacking in some minority ethnic groups. To redress this gap, the "First Aid for Scalds" campaign for those from a non-English speaking background was specifically targeted to three ethnic groups (Vietnamese, Chinese, and Arabic), with the aim of increasing the proportions of parents and caregivers who had correct knowledge of first aid treatment for scalds. The primary strategy was a media campaign, including advertisements on ethnic radio and in ethnic newspapers. METHODS: The evaluation design included formative research and impact evaluation. The impact evaluation study involved random population based telephone surveys with each of the three language groups, before and after the campaign, to assess the reach and effectiveness of the campaign. RESULTS: After the campaign, there were significant increases in the proportion of people who knew the correct first aid treatment for scalds. There were substantial variations in campaign recall and knowledge between each of the three language groups. The largest improvement was found in the Vietnamese group. CONCLUSION: The association between campaign recall and increase in correct knowledge, and the absence of any similar interventions during the campaign period, give credence to the conclusion that the changes observed were a result of the campaign. The results demonstrate the value of community based injury prevention campaigns specifically targeting linguistically diverse communities.

Accident Prevention↗
PubMed1998

Host genetic determinants of vaccine-induced eosinophilia during respiratory syncytial virus infection.

In BALB/c mice, sensitization with the attachment protein (G) of respiratory syncytial virus (RSV) leads to CD4+ T cell-mediated lung eosinophilia during subsequent challenge with RSV. To determine the host genetic influences on this model of lung eosinophilia, we tested 15 different inbred mouse strains. Eosinophilia developed in all H-2d (BALB/c, DBA/2n, and B10.D2), but not in H-2k (CBA/Ca, CBA/J, C3H, BALB.K, or B10.BR) mouse strains. Among H-2b mice, 129 and BALB.B developed eosinophilia, whereas C57BL/6 and C57BL/10 did not. Testing first generation crosses between sensitive and resistant strains showed that eosinophilia developed in all H-2dxk (n = 5), irrespective of background genes, but not in H-2dxb (n = 2) mice. In vivo depletion of CD8+ T cells or IFN-gamma rendered C57BL/6, but not BALB.K mice, susceptible to eosinophilia. Analysis of B10 recombinant mice showed that the Dd allele (in B10.A(5R) mice) prevented CD8+ T cell accumulation in the lung, resulting in intense lung eosinophilia. However, the Db allele (in B10.A(2R) and B10.A(4R) mice) supported CD8+ T cell expansion and prevented eosinophilia. Intracellular cytokine staining showed that lung eosinophilia correlated with reduced IFN-gamma and increased IL-10 expression in lung T cells. These results are compatible with the unifying model that Th2 cells mediate the disease but can be inhibited by CD8+ T cells secreting IFN-gamma. Our findings have important implications for the development of protective, nonpathogenic vaccines for RSV disease.

Animals↗
PubMed1998

Rescue of dorsal root sensory neurons by nerve growth factor and neurotrophin-3, but not brain-derived neurotrophic factor or neurotrophin-4, is dependent on the level of the p75 neurotrophin receptor.

Sensory neurons isolated from dorsal root ganglia of postnatal mice were analysed for cell surface p75, using fluorescent antibody staining with flow cytometry. They were found to follow a single bell-shaped distribution of p75 level, with no discrete group of p75-negative neurons. Sensory neurons were then separated by fluorescence-activated cell sorting into high- and low-p75 populations, consisting of cells within the highest and lowest 15th percentiles, respectively, of p75 expression levels. The sorted neurons were tested for trkA staining. All high-p75 neurons were positive for trkA, while many low-p75 cells were negative for trkA. The sorted neurons were placed in culture, and their survival in the absence and presence of various neurotrophins was measured. Low-p75 cells were found to have enhanced survival in the absence of neurotrophins, while cells with high p75 levels had reduced survival, compared to the overall population. Almost all high-p75 neurons were rescued with nerve growth factor, whereas less than half of the low-p75 cells were rescued. The slope of the dose response to nerve growth factor did not differ markedly between high- and low-p75 cells. High-p75, but not low-p75, neurons were responsive to neurotrophin-3. There was only a small response to either brain-derived neurotrophic factor or neurotrophin-4 in both high- and low-p75 neurons. All low-p75 neurons, and 68% of high-p75 neurons, survived in the presence of ciliary neurotrophic factor. These results, while consistent with our hypothesis that p75 may act as a death factor in postnatal sensory neurons, also imply a role for p75 in the modulation of trk responsiveness to neurotrophins. They also indicate overlapping neurotrophin responses in sensory neurons, especially in those with high p75 levels. A large proportion of low-p75 cells were not responsive to any of the nerve growth factor-related neurotrophins, suggesting an important role for cytokines such as ciliary neurotrophic factor and leukaemia inhibitor factor in the survival of sensory neurons.

Animals↗
PubMed1998

Prospective randomized study of once-daily versus twice-daily amikacin regimens in patients with systemic infections.

The efficacy and safety of amikacin administered once-daily versus twice-daily was evaluated in adult patients with systemic infections. Patients over 23 years of age with suspected or documented systemic infections were randomly divided into two groups: one group received amikacin intravenously 15 mg/kg once-daily, and the other group received amikacin 15 mg/kg divided into 2 doses. The efficacy of both dosage regimens was very good with a satisfactory clinical response in 90.2% and 89%, respectively. The bacteriological cure rate was 82.2% and 76%, respectively. There were no significant differences between the 2 regimens as far as what efficacy and safety are concerned. Nephrotoxicity appeared in 2 patients of the first group and 3 patients of the second, but did not lead to discontinuation of amikacin. No significant differences between the regimens with regard to hearing loss or prodromal signs of ototoxicity. We concluded that amikacin administered once-daily appears to be as effective and safe as the twice-daily dosing. However, the once-daily administration is more convenient and less costly.

Adult↗
PubMed1997

Phenotypic and functional characterization of long-lived NK cell lines of different maturational status obtained from mouse fetal liver.

Culture of day 14 mouse fetal liver (FL) cells in high dose IL-2, together with appropriate combinations of IL-4 and PMA, resulted in the generation of cell lines, termed FL-A lines, that were phenotypically and functionally indistinguishable from cultured adult splenic NK cell populations with the single important exception that no Ly49-expressing cells were present. By contrast, when FL cells were cultured in low-dose IL-2 alone, a second population of slow-growing NK-like cells, termed FL-B cells, emerged. These cells expressed the NK markers asialoGM1, 10A7, 2B4, and Fc gammaRII/III but differed from FL-A and splenic NK cells in expressing IL-2R alpha and stem cell factor receptor (SCFR) but no B220. Most lines derived in this manner had minimal or no cytolytic activity and only very low levels of NK1.1. However, they could secrete substantial quantities of several lymphokines including IL-3, granulocyte-macrophage (GM)-CSF, TNF-alpha, and, most surprisingly, IL-2. A minority of FL-B lines, typified by line 903, displayed marked cytolytic activity, moderate levels of NK1.1, reduced production of IL-2, and the capacity for accelerated growth in high-dose IL-2. FL-B lines generally expressed mRNA for CD3gamma but not for other CD3 chains, whereas FL-A and fetal thymic (FT) NK lines often expressed mRNA for all four CD3 chains. Despite many similarities to pro-T cells, FL-B cells showed no capacity to differentiate into mature T cells. Taken together, our results suggest that NK lines of different maturity can be obtained from fetal liver, with FL-B lines being the most immature, FL-A lines the most mature, and lines such as FL-B 903 representing an intermediate state of differentiation.

Animals↗
PubMed1996

The low-affinity nerve growth factor receptor p75NGFR mediates death of PC12 cells after nerve growth factor withdrawal.

We have investigated the role of the low-affinity nerve growth factor (NGF) receptor p75NGFR in determining the death of neuronally differentiated PC12 cells after withdrawal of NGF. A range of high and low p75NGFR-expressing cells were obtained by a combination of fluorescence activated cell sorting (FACS) and stable transfection with a p75NGFR expression vector. Cells were readily differentiated to a neuronal phenotype irrespective of the level of p75NGFR expression. However, the rate and extent of neuronal death following NGF deprivation were extremely sensitive to the level of p75NGFR expression. The highest expressing cells died most rapidly. Cells selected for very low levels of p75NGFR expression exhibited resistance to NGF withdrawal, and remained as viable, differentiated neurons, with minimal cell death, for at least 5 days in the absence of NGF. Antisense oligonucleotides against p75NGFR were shown to down-regulate p75NGFR in PC12 cells and, further, to significantly enhance survival in the absence of NGF. These results consolidate and generalize our previous findings that p75NGFR induces cell death in postnatal sensory neurons in the absence of NGF. The ability to induce cell death in the absence of NGF appears to be a more general role of p75NGFR in differentiated neurons, and an important new paradigm for the mechanism of NGF-dependent survival.

Animals↗
PubMed1996

Description of a symptomless cystic fibrosis L346P/M348K compound heterozygous Cypriot individual.

During the past few years we have been testing the hypothesis that Cyprus may have been spared many severe cystic fibrosis (CF) cases but not cystic fibrosis transmembrane conductance regulator (CFTR) mutations. We have been analysing by molecular methods patients with atypical mild phenotypes where CF enters the differential diagnosis. With this approach we identified a mutation, L346P, which in association with the severe mutation delta F508 or 1677delTA, confers a mild and atypical presentation. Recently, we identified another entirely symptomless 48-year-old individual, with genotype L346P/M348K. The fact that M348K was initially identified in a severely affected Italian patient strengthens the hypothesis that L346P, a putative mild mutation, is dominant over severe ones. One other explanation is that M348K is not a causative defect but a rare polymorphism. These findings have important implications for genetic counselling, especially when the counselling is sought by concerned couples for prenatal diagnostic purposes.

Child, Preschool↗