PubMed Health⌕ Search

Biomedical subjects

M Elliott

Publications and source records attributed to M Elliott.

At least 37 records · Page 2Linked to original sources
PubMed1995

The cellular RING finger protein PML is not a functional counterpart of the herpes simplex virus type 1 RING finger protein Vmw110.

Herpes simplex virus type 1 (HSV-1) immediate early protein Vmw110 (also known as ICP0) is required for the fully efficient expression of viral genes during onset of lytic growth and for normal reactivation from latency. Both Vmw110 and the cellular protein PML are members of the RING finger family of zinc binding domain proteins, a family which includes an increasing number of examples from a wide evolutionary range. The function of the RING finger domain is unknown, and the question arises whether the RING finger (like several other examples of conserved domains) fulfils similar functions in these diverse proteins. Another link between Vmw110 and PML is that at early times of HSV-1 infection Vmw110 migrates to distinct nuclear structures which contain the PML protein. In order to test the possibility that PML and Vmw110, or their RING finger domains, fulfill similar functions, we have constructed recombinant viruses that express either intact PML, or a chimeric Vmw110 protein which contains the PML RING finger in place of its own. The results indicate that the PML and Vmw110 RING fingers are not functionally interchangeable, and that PML is not a cellular functional counterpart of Vmw110.

Animals↗
PubMed1995

The equine herpesvirus 1 gene 63 RING finger protein partially complements Vmw110, its herpes simplex virus type 1 counterpart.

All alpha herpesviruses of known DNA sequence have been found to encode a protein with similarities to immediate early protein Vmw110 (ICP0) of herpes simplex virus type 1 (HSV-1). The conserved portion of this family of proteins is a characteristic zinc binding module, known as a RING finger or C3HC4 domain. Examples of RING finger domains occur in many other proteins of diverse evolutionary origin and function. Recently, the solution structure of the equine herpesvirus 1 (EHV-1) RING finger protein, encoded by gene 63, has been solved. To investigate whether this structure could be considered to be a paradigm of herpesvirus RING domains, we have constructed a recombinant HSV-1 which expresses the EHV-1 gene 63 protein (EHVg63) in place of Vmw110. Comparison of the growth properties of the recombinant with those of wild-type and Vmw110-defective viruses indicates that EHVg63 is able to fulfil partially, but not completely, the roles of Vmw110 during virus growth in tissue culture.

Animals↗
PubMed1995

Coeur en santé St-Henri--a heart health promotion programme in a low income, low education neighbourhood in Montreal, Canada: theoretical model and early field experience.

STUDY OBJECTIVE: Coeur en santé St-Henri is a five year, community based, multifactorial, heart health promotion programme in a low income, low education neighbourhood in Montreal, Canada. The objectives of this programme are to improve heart-healthy behaviours among adults of St-Henri. This paper describes the theoretical model underlying programme development as well as our early field experience implementing interventions. DESIGN: The design of the intervention programme is based on a behaviour change model adapted from social learning theory, the reasoned action model, and the precede-proceed model. The Ottawa charter for health promotion provided the framework for the development of specific interventions. Each intervention is submitted to formative, implementation, and impact evaluations using simple and inexpensive methods. PARTICIPANTS: The target population consists of adults living in St-Henri, a neighbourhood of 23,360 residents. Because of costs constraints, the intervention strategy targets women more specifically. The community is one of the poorest in Canada with 46% of the population living below the poverty line and 20% being very poor. The age-sex adjusted ischaemic heart disease mortality in 1985-87 was 317 per 100,000 compared with 126 per 100,000 in an affluent adjacent neighbourhood. RESULTS: Thirty nine distinct interventions have been developed and tested in the community, eight related to tobacco, 10 to diet, seven to physical activity, and 14 which are multifactorial. The interventions include smoking cessation and healthy recipes contests, a menu labelling and healthy food discount programme in restaurants, a point of choice nutrition education campaign, healthy eating and smoking cessation workshops, a walking club, educational material, print and electronic media campaigns, heart health fairs, and community events. CONCLUSION: An integrated heart health promotion programme is feasible in low income urban neighbourhoods but not all interventions are successful. Such a programme requires substantial energy and resources as well as long term commitment from public health departments.

Cardiovascular Diseases↗
PubMed1995

Distribution of integrins alpha v beta 6 and alpha 9 beta 1 and their known ligands, fibronectin and tenascin, in human airways.

We have previously identified two integrins, alpha 9 beta 1 and alpha v beta 6, from guinea pig airway epithelium. The extracellular matrix protein tenascin is a ligand for both of these receptors, and fibronectin is also a ligand for alpha v beta 6. In the present study, we used immunohistochemistry to examine the expression and spatial distribution of the alpha 9 subunit, alpha v beta 6, tenascin, and fibronectin in the proximal airways of 10 normal nonsmoking subjects and eight patients undergoing lung resection for cancer. We also performed the same analyses on sections of peripheral lung obtained from an additional seven subjects undergoing lung resection. alpha 9 was highly expressed throughout the airway epithelium (but not on alveolar epithelium) irrespective of clinical status. In contrast, alpha v beta 6 was expressed on proximal airway epithelial cells in four of eight smokers undergoing lung resection, but in none of the normal subjects and none of the distal airways examined. On bronchial epithelial cells cultured from resected airways, alpha v beta 6 was highly expressed on cells grown from patients who did not appear to express the receptor in vivo, as well as from subjects who did, suggesting that some component of the in vitro environment can induce expression. Although both tenascin and fibronectin were present below the proximal airway epithelium of both normal nonsmoking subjects and smokers, the spatial patterns of integrin and ligand expression were not congruent, because the integrins were present diffusely on the cell surface and on some cells that were not in contact with the basement membrane, whereas the ligands were present principally in the subepithelial layer. These findings are compatible with the existence of as-yet unidentified ligands for each of these integrins--for example, ligands involved in homotypic cell-cell interactions within the epithelium.

Biopsy↗
PubMed1995

Pharmacokinetics of isepamicin.

Isepamicin is a new aminoglycoside that has activity against many bacteria resistant to other aminoglycosides. The pharmacokinetics of isepamicin have been characterized in neonatal, pediatric, adult, elderly and renally impaired human populations as well as in clinical trials using the techniques of population pharmacokinetics. The pharmacokinetics of isepamicin are uncomplicated and generally similar to those of other aminoglycosides, although there is some evidence that it may have less tissue accumulation. The drug is completely absorbed following intramuscular administration. The drug is not metabolized and unchanged isepamicin accounts for all of the drug substance in plasma and urine. It is completely eliminated via the renal route; consequently dosing in patients with renal insufficiency has to be adjusted according to the degree of renal impairment. The pharmacokinetics of isepamicin are generally linear. Thus peak plasma concentrations and area under the plasma concentration curve (AUC) values are proportional to the administered dose while clearance (1.1-1.3 mL/min/kg), volume of distribution at steady state (0.23-0.29 L/kg) and half-life (2-2.5 h) are independent of dose. There is no significant accumulation of drug in the plasma with once- or twice-daily dosing. The isepamicin plasma concentration curve following a 1 g intravenous dose to healthy volunteers can be best characterized by a tri-exponential curve corresponding to a t1/2 alpha of 0.17 h, a t1/2 beta of 2.1 h, and a gamma-phase of 34 h. The t1/2 beta represents the elimination phase and changes with age and renal functions, while the gamma-phase represents the return of drug to plasma from a deep compartment including binding in renal tissue. The gamma-phase represents less than 3% of the total AUC and does not change with age. Isepamicin readily distributes to extracellular fluid and pulmonary tissue. In conclusion, isepamicin demonstrates predictable linear kinetics and is similar pharmacokinetically to other aminoglycosides. Preliminary indications of decreased tissue accumulation implied from pharmacokinetic and pharmacodynamic characteristics of isepamicin favour once-daily dosing.

Adolescent↗
PubMed1995

Pharmacokinetics of isepamicin in paediatric patients.

The pharmacokinetics of isepamicin were evaluated in 50 paediatric patients ranging from newborn to 13 years old. Children with subdivided according to age: Group I (6-13 years); Group II (4 months to 6 years); Group III (16 days to 4 months); and Group IV (newborn to 16 days). All patients received isepamicin 7.5 mg/kg every 12 hours except those in Group IV who received 7.5 mg/kg once daily. Isepamicin was administered initially as an intravenous 30-minute infusion and then either intravenously or intramuscularly for between 4 and 12 days. Plasma samples were obtained after the first or second dose on day 1 at 0, 0.5, 1, 4, 6, 8 and 12 hours after the initiation of dosing and at 0.5 and 12 hours on other dosing days. Additional samples were collected in the Group IV patients at 18, 20 and 24 hours. Isepamicin showed a similar plasma concentration-time profile in Groups I, II and III (children from 16 days to 13 years), and in these groups the profile was generally similar to that observed in adults. Neonates up to the age of 16 days (Group IV) showed a distinctly different pharmacokinetic profile: a significantly larger AUC, longer half-life, lower Cmax and lower total body clearance. Isepamicin 7.5 mg/kg administered once daily to children less than 16 days old and twice daily to children aged 16 days to 13 years appears to be pharmacokinetically appropriate. The drug was very well tolerated by children of all age groups.

Adolescent↗
PubMed1994

Structure of the C3HC4 domain by 1H-nuclear magnetic resonance spectroscopy. A new structural class of zinc-finger.

A recently identified sequence motif, referred to as "C3HC4" (also "RING finger" and "A Box") for its distinctive pattern of putative metal-binding residues, has been found in a wide range of proteins. In a previous paper we described the expression and purification of fragments encompassing this motif from the Vmw110 (IPC0) protein family. We showed that the equine herpes virus protein binds zinc ions and adopts a beta beta alpha beta fold. We now report the tertiary structure of this domain in solution, as determined by two-dimensional 1H-NMR An amphipathic alpha-helix lies along one surface of a triple-stranded beta-sheet. Four pairs of metal-binding residues sequester two zincs at distinct tetrahedral sites. The first and third pairs bind one metal ion, while the second and fourth pairs bind the other, forming an interleaved whole. The first and the fourth pairs are contained within two prominent, well-defined loops related by an approximate dyad symmetry. Conserved residues within the helix, sheet and loops contribute to a compact hydrophobic core. The region comprising the first two beta-strands and the alpha-helix has remarkable structural similarity with a TFIIIA type of zinc finger, even though the C3HC4 domain appears not to bind specifically to DNA or RNA. Using site-directed mutagenesis we demonstrate that exposed polar side-chains of the C3HC4 alpha-helix are essential for trans-activation of gene expression by an intact herpes virus regulatory protein.

Amino Acid Sequence↗
PubMed1994

The Vancouver sedative recovery scale for children: validation and reliability of scoring based on videotaped instruction.

We originally developed and tested the Vancouver Sedative Recovery Scale (VSRS) to measure recovery from sedation following paediatric open heart surgery and reported excellent clinical inter-observer reliability. We now report a new study using videotape instruction of novice raters and videotaped case examples to determine whether the instruction produces adequate skill with the VSRS. Inter-rater reliability was assessed using videotapes of 16 children across a range of ages (six months to six years), and all levels of sedation (unresponsive to fully awake). Variably randomized subsets of six of the 16 test cases were randomly assigned to be rated by each of 16 video-instructed ICU staff volunteers, according to a balanced incomplete block design, such that every pair of raters assessed two children in common. The validity of the ratings from the video-instructed raters was assessed by comparison with "gold standard" scores from two experts who rated all 16 children clinically as the test cases were videotaped. The experts were in agreement themselves (intraclass correlation of 0.976). The correlation between the novice scores (average of six ratings per video) and the live clinical scores (average of two expert ratings) was 0.977 over the 16 test cases. On average, the mean expert rating was slightly higher, but the difference was negligible. (The differences between the mean ratings of the experts and novices for 13 of the 16 videos are very close to zero, while the other three differences, from technically less good videos, are two standard deviations away from zero). The VSRS, video instruction method and incomplete block design may be of use to other clinicians and investigators.

Anesthesia Recovery Period↗
PubMed1994

An inter-district audit of the school entry medical examination in Cheshire.

An inter-district audit was carried out on the benefit to children of universal school entry medical examination, the appropriate use of professional time and to establish a baseline against which to measure future changes in services to under-fives and schoolchildren. The school health records of 1127 Cheshire schoolchildren, a random 10% sample, were scrutinised. There were significant district variations. Overall, 45% of children had problems not previously noted: 21% were serious enough to be referred; 11% could have had their problems managed by a well-trained school nurse but 9.8% would have required a medical examination for detection and assessment. These included conditions such as undescended testes, heart murmurs, squints and hernias and 8% required immediate action. The selection criteria, based on the absence of a three-year health check and/or parental or nurse concern, would have failed to identify 217 of the 491 children with new problems, some of which were serious. Targeting only an area of high deprivation or poor health would equally miss significant conditions. The inter-district variation of the numbers and diagnoses of new problems detected at school entry, and the difficulty in predicting which children will have important conditions, provide a good case for the continuation of the school entry medical examination for all children.

Child↗
PubMed1994

Allelic methylation of H19 and IGF2 in the Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth syndrome with associated embryonal tumours. Most BWS cases are sporadic but familial cases occur in 15% of patients and in these there is linkage to chromosome 11p15. In addition, a small number of patients have cytogenetic abnormalities involving chromosome 11p15. Approximately 20% of sporadic BWS patients have uniparental paternal disomy (UPD) of chromosome 11p15. This finding together with the observation that penetrance in familial cases depends on parental transmission, suggests that the gene(s) for BWS are imprinted. The recent demonstration of biallelic expression of the otherwise maternally imprinted IGF2 gene in some BWS patients implicates excess IGF2 expression in the disease. Here we have analysed the allele-specific methylation patterns in the IGF2 gene and in the neighbouring and reciprocally imprinted H19 gene in a group of 42 BWS patients, 10 of which were mosaic UPD cases. We found that allelic methylation of both genes was normal in all non-UPD cases, with the paternal allele being methylated, and was increased in UPD cases in proportion with the disomic lineage. These findings suggest that sporadic BWS is not associated with a general alteration of methylation imprinting of the IGF2 and H19 genes. The methylation assay used in this study thus also offers a simple and reliable diagnostic test of UPD for 11p15.5. An unexpected finding was a distortion of the frequency of AvaII alleles at the IGF2 locus exclusively in UPD BWS cases (P < 0.001). This further implicates the IGF2 gene in aspects of the BWS phenotype.

Alleles↗
PubMed1994

Accuracy of Javal's rule in the determination of spectacle astigmatism.

Javal's rule and Grosvenor's simplification of it are commonly used formulas for predicting spectacle astigmatism from keratometric measurements. We assessed the accuracy of these two rules. Spectacle astigmatism was estimated using both rules from measurements of corneal astigmatism on 100 eyes of 100 subjects. These estimates were then compared to the subjectively determined spectacle astigmatism. Grosvenor's simplification of Javal's rule gave slightly more accurate assessments than the original rule. However, only 66% of results gave estimates within 0.50 D, and 7% differed by more than 1.00 D. This can be compared to previous reports on the accuracy of autorefractors, where approximately 95% of cylinder results were within 0.50 D of the spectacle astigmatism. These results indicate that using Javal's rule or Grosvenor's simplification of it to determine spectacle astigmatism from corneal cylinder readings is of limited clinical value.

Adult↗
PubMed1994

Clinical features and natural history of Beckwith-Wiedemann syndrome: presentation of 74 new cases.

Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth syndrome with variable expression. To define the range and frequency of complications in BWS, we have studied a cohort of 76 affected patients (two previously reported). The most frequent complications were macroglossia (97%), abdominal wall defect (80%) and birth weight or postnatal growth > 90th centile (88%). Other common features were ear creases/pits (76%), facial naevus flammeus (62%), nephromegaly (59%) and hypoglycaemia (63%). Rarer complications included hemihypertrophy (24%), moderate/severe developmental delay (4%), congenital heart defects (6.5%), polydactyly (4%), neoplasia (4%) and cleft palate (2.5%). Pre-term labour occurred in 53% and polyhydramnios in 33% of BWS pregnancies. The six deaths all occurred in babies born pre-term, three of whom had major congenital abnormalities. Five patients (6.5%) from four kindreds had an unequivocal family history of BWS, but 15 of 68 apparently sporadic cases had a relative with possible BWS (minor features only). Incomplete penetrance may lead to familial BWS being underdiagnosed.

Adolescent↗
PubMed1994

Mosaic uniparental disomy in Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth syndrome with variable expression. The major features are anterior abdominal wall defects, macroglossia, and gigantism and less commonly neonatal hypoglycaemia, organomegaly, congenital renal anomalies, hemihypertrophy and embryonal tumours occur. BWS is a genetically heterogeneous disorder; most cases are sporadic but approximately 15% are familial and a small number of BWS patients have cytogenetic abnormalities involving chromosome 11p15. Genomic imprinting effects have been implicated in familial and non-familial BWS, and uniparental disomy (UPD) for chromosome 11 has been reported in sporadic cases. We investigated the incidence, pathogenesis, and clinical associations of UPD in 49 patients with non-familial BWS and a normal karyotype. UPD for chromosome 11p15 was detected in nine of 32 (28%) informative patients. A further two patients appeared to be disomic at the WT1 locus in chromosome 11p13, but were uninformative at chromosome 11p15.5 loci tested. In all cases with UPD the affected person was mosaic for a paternal isodisomy and a normal cell line indicating that UPD had arisen as a postzygotic event. Compared to cases in which paternal isodisomy for chromosomes 11p15.5 had been excluded (n = 23), BWS patients with UPD was more likely to have hemihypertrophy (6/9 versus 1/23, p < 0.001) and less likely to have exomphalos (0/9 versus 13/23, p < 0.01), but there were no significant differences between disomic and non-disomic cases in the incidence of hypoglycaemia, nephromegaly, neoplasia, and developmental delay. The detection of UPD in BWS patients allows accurate genetic counselling to be provided and provides an insight into the molecular pathogenesis of BWS.

Adolescent↗
PubMed1994

TNF alpha as a therapeutic target in rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease with inflammatory manifestations in the peripheral synovial joints, which are infiltrated by activated T cells, macrophages, and plasma cells. We have investigated the role of cytokines in RA and have proposed that tumour necrosis factor has a pivotal role in the pathogenesis of this disease. This chapter describes those studies, which led to the first clinical trial in RA patients using a chimeric anti TNF alpha antibody. In addition to pro-inflammatory cytokine production, at sites of inflammation such as the RA synovial joint, there is also evidence for homeostatic immunoregulatory mechanisms which include the production of cytokine inhibitors, such as soluble TNF-R and the IL-1 receptor antagonist, and cytokines with immunoregulatory properties like IL-10. The evidence for these inhibitors in RA is presented, and the relevance of this homeostatic mechanism in relation to chronic inflammatory diseases is discussed.

Animals↗
PubMed1993

Phosducin-like protein: an ethanol-responsive potential modulator of guanine nucleotide-binding protein function.

Acute and chronic exposure to ethanol produces specific changes in several signal transduction cascades. Such alterations in signaling are thought to be a crucial aspect of the central nervous system's adaptive response, which occurs with chronic exposure to ethanol. We have recently identified and isolated several genes whose expression is specifically induced by ethanol in neural cell cultures. The product of one of these genes has extensive sequence homology to phosducin, a phosphoprotein expressed in retina and pineal gland that modulates trimeric guanine nucleotide-binding protein (G protein) function by binding to G-protein beta gamma subunits. We identified from a rat brain cDNA library an isolate encoding the phosducin-like protein (PhLP), which has 41% identity and 65% amino acid homology to phosducin. PhLP cDNA is expressed in all tissues screened by RNA blot-hybridization analysis and shows marked evolutionary conservation on Southern hybridization. We have identified four forms of PhLP cDNA varying only in their 5' ends, probably due to alternative splicing. This 5'-end variation generates two predicted forms of PhLP protein that differ by 79 aa at the NH2 terminus. Treatment of NG108-15 cells for 24 hr with concentrations of ethanol seen in actively drinking alcoholics (25-100 mM) causes up to a 3-fold increase in PhLP mRNA levels. Induction of PhLP by ethanol could account for at least some of the widespread alterations in signal transduction and G-protein function that are known to occur with chronic exposure to ethanol.

Amino Acid Sequence↗