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C Davies

Publications and source records attributed to C Davies.

At least 91 records · Page 5Linked to original sources
PubMed1998

Contig maps and genomic sequencing identify candidate genes in the usher 1C locus.

Usher syndrome 1C (USH1C) is a congenital condition manifesting profound hearing loss, the absence of vestibular function, and eventual retinal degeneration. The USH1C locus has been mapped genetically to a 2- to 3-cM interval in 11p14-15.1 between D11S899 and D11S861. In an effort to identify the USH1C disease gene we have isolated the region between these markers in yeast artificial chromosomes (YACs) using a combination of STS content mapping and Alu-PCR hybridization. The YAC contig is approximately 3.5 Mb and has located several other loci within this interval, resulting in the order CEN-LDHA-SAA1-TPH-D11S1310-(D11S1888/KCNC1 )-MYOD1-D11S902D11S921-D11S 1890-TEL. Subsequent haplotyping and homozygosity analysis refined the location of the disease gene to a 400-kb interval between D11S902 and D11S1890 with all affected individuals being homozygous for the internal marker D11S921. To facilitate gene identification, the critical region has been converted into P1 artificial chromosome (PAC) clones using sequence-tagged sites (STSs) mapped to the YAC contig, Alu-PCR products generated from the YACs, and PAC end probes. A contig of >50 PAC clones has been assembled between D11S1310 and D11S1890, confirming the order of markers used in haplotyping. Three PAC clones representing nearly two-thirds of the USH1C critical region have been sequenced. PowerBLAST analysis identified six clusters of expressed sequence tags (ESTs), two known genes (BIR, SUR1) mapped previously to this region, and a previously characterized but unmapped gene NEFA (DNA binding/EF hand/acidic amino-acid-rich). GRAIL analysis identified 11 CpG islands and 73 exons of excellent quality. These data allowed the construction of a transcription map for the USH1C critical region, consisting of three known genes and six or more novel transcripts. Based on their map location, these loci represent candidate disease loci for USH1C. The NEFA gene was assessed as the USH1C locus by the sequencing of an amplified NEFA cDNA from an USH1C patient; however, no mutations were detected.

Bacteriophage P1↗
PubMed1998

Measuring outcome in community-based rehabilitation services for people who have suffered traumatic brain injury: the Community Outcome Scale.

OBJECTIVE: To develop a way of measuring long-term outcomes after traumatic brain injury (TBI) that takes account of individual circumstances. DESIGN: Reports by head-injured people and their families about problems and coping strategies were elicited via semi-structured interviews. Specially designed computer software was used to record problems and strengths and to measure their impact for the individual on four handicap dimensions. SETTING: Interviews took place in the respondents' homes. SUBJECTS: Between 1992 and 1997 the services at 10 rehabilitation centres in England were evaluated. Subjects were men and women aged between 16 and 65 who had suffered TBI and who had been referred for treatment to one of the centres under study. INTERVENTIONS: Head-injured people and their families were interviewed three months, 18 months and in some cases 36 months after recruitment. MAIN OUTCOME MEASURES: The Hospital Anxiety and Depression Scale (HAD) and the Functional Independence/Assessment Measure (FIM/FAM) were used to validate relevant dimensions of the new scale. RESULTS: A measure of long-term outcome was developed and called the Community Outcome Scale. Relevant dimensions of the scale showed significant correlation with the HAD and with items of the FIM/FAM. CONCLUSION: The scale captures information which no other instrument does, and merits further validation.

Adolescent↗
PubMed1998

Joint estimation of Down syndrome risk and ascertainment rates: a meta-analysis of nine published data sets.

In this paper we present an analysis of nine data sets in which ascertainment and maternal age risk of Down syndrome are estimated jointly using maximum likelihood. We include data on 4825 Down syndrome cases from nine previously published data sets. These include data from studies carried out before the introduction of prenatal screening and from recent studies involving women who had not received prenatal testing. Our results show that, allowing for under-ascertainment, there is a good degree of consistency between the different data sets. We compare the three- and five-parameter constant plus exponential model with a three-parameter logistic model for maternal age-specific risk. We show that the three-parameter logistic model provides a good fit to the data and compare rates from this model with those derived from published studies of uncertain completeness (Cuckle et al., 1987) and those from data sets believed to be complete (Halliday et al., 1995; Hecht and Hook, 1994, 1996). In general, our results agree closely with those of the latter, but achieve greater precision because of the inclusion of additional data. Our derived rates are considerably higher than those of Cuckle et al. (1987), which are embedded in many computer systems for generating risks.

Down Syndrome↗
PubMed1998

[Duration of adjuvant treatment with tamoxifen in patients with resectable breast cancer].

Tamoxifen administered in patients after breast cancer surgery is one of the most effective adjuvant treatments in this pathology. A large number of randomized studies including thousands of patients allowed to quantify the treatment benefits in terms of recurrence, contralateral breast cancer and overall survival rates. The treatment is generally given for more than 2 years. However, the optimal treatment duration is unknown. Uncertainties appeared when adverse effects were described after some years of treatment (e.g. a higher incidence of endometrial adenocarcinoma). New ongoing multicentric trials will clearly define in the next years the optimal duration of this adjuvant treatment.

Antineoplastic Agents, Hormonal↗
PubMed1998

Effects of a prostaglandin E1 analogue, misoprostol, on renal function in dogs receiving nephrotoxic doses of gentamicin.

OBJECTIVE: To determine whether the prostaglandin E1 analogue, misoprostol, could preserve renal function in dogs receiving nephrotoxic doses of gentamicin. ANIMALS: 12 (6/group) healthy sexually intact male dogs. PROCEDURE: All dogs were given high doses of gentamicin (10 mg/kg of body weight, i.v., q 8 h, for 8 consecutive days). Six dogs (treatment group) received misoprostol (3 microgram/kg, p.o., q 8 h for the duration of the study) and 6 dogs (control group) received vehicle (1 capsule, p.o., q 8 h). Renal function was assessed before treatment (day 0) and on days 3, 6, 9, and 11 after initiation of treatment by measurement of serum biochemical variables, urine specific gravity, and exogenous creatinine clearance. Serum electrolyte and protein concentrations and presence of proteinuria, glycosuria, and cylindruria were also determined. At the end of the study, renal histopathologic changed were evaluated. RESULTS: Dogs receiving misoprostol had significant reduction in exogenous creatinine clearance with time, compared with dogs receiving vehicle (P = 0.0264). Dogs receiving misoprostol tended to develop more severe azotemia, hyperphosphatemia, and renal histopathologic changes; however, results were not significantly different between groups. CONCLUSION: Misoprostol (3 microgram/kg, p.o., q 8 h) did not preserve renal function and may have exacerbated gentamicin-induced nephrotoxicosis in this group of dogs. CLINICAL RELEVANCE: Supplementation of vasodilatory prostanoids may exacerbate renal dysfunction in dogs receiving high doses of gentamicin.

Animals↗
PubMed1997

Functional characterization of human nucleosome assembly protein-2 (NAP1L4) suggests a role as a histone chaperone.

Histones are thought to play a key role in regulating gene expression at the level of DNA packaging. Recent evidence suggests that transcriptional activation requires competition of transcription factors with histones for binding to regulatory regions and that there may be several mechanisms by which this is achieved. We have characterized a human nucleosome assembly protein, NAP-2, previously identified by positional cloning at 11p15.5, a region implicated in several disease processes including Wilms tumor (WT) etiology. The deduced amino acid sequence of NAP-2 indicates that it encodes a protein with a potential nuclear localization motif and two clusters of highly acidic residues. Functional analysis of recombinant NAP-2 protein purified from Escherichia coli demonstrates that this protein can interact with both core and linker histones. We demonstrate that recombinant NAP-2 can transfer histones onto naked DNA templates. Deletion mutagenesis of NAP-2 demonstrates that both NH3- and COOH-terminal domains are required for histone transfer activity. Subcellular localization studies of NAP-2 indicate that it can shuttle between the cytoplasm and the nucleus, suggesting a role as a histone chaperone. Given the potential role of the human NAP-2 gene (HGMW-approved symbol NAP1L4) in WT etiology, we have elucidated the exon/intron structure of this gene and have analyzed the mutational status of NAP-2 in sporadic WTs. Our results, coupled with tumor suppression assays in G401 WT cells, do not support a role for NAP-2 in the etiology of WT. A putative role for NAP-2 in regulating cellular differentiation is discussed.

Amino Acid Sequence↗
PubMed1997

A 1-Mb physical map and PAC contig of the imprinted domain in 11p15.5 that contains TAPA1 and the BWSCR1/WT2 region.

We have constructed a 1-Mb contig in human chromosomal band 11p15.5, a region implicated in the etiology of several embryonal tumors, including Wilms tumor, and in Beckwith-Wiedemann syndrome. Cosmid, P1, PAC, and BAC clones were characterized by NotI/SalI digestion and hybridized to a variety of probes to generate a detailed physical map that extends from D11S517 to L23MRP. Included in the map are the CARS, NAP2, p57/KIP2, KVLQT1, ASCL2, TH, INS, IGF2, H19, and L23MRP genes as well as end probes isolated from PACs. The TAPA1 gene, whose protein product can transmit an antiproliferative signal, was also localized in the contig. However, Northern blot analysis demonstrated that its expression did not correlate with tumorigenicity in G401 Wilms tumor hybrids, suggesting that TAPA1 is not responsible for the tumor suppression associated with 11p15.5. Genomic clones were used as probes in FISH analysis to map the breakpoints from three Beckwith-Wiedemann syndrome patients and a rhabdoid tumor. Interestingly, each of the breakpoints disrupts the KVLQT1 gene, which is spread over a 400-kb region of the contig. Since 11p15.5 contains several genes with imprinted expression and one or more tumor suppressor genes, our contig and map provide a framework for characterizing this intriguing genetic environment.

Antigens, CD↗
PubMed1997

The Q-Prep system: effects on the apparent expression of leucocyte cell surface antigens.

To facilitate the analysis of immunolabelled peripheral blood or bone marrow leucocytes by flow cytometry, a number of reagents are available commercially that lyse erythrocytes and fix leucocytes. This study has investigated the effect on antibody-labelled whole blood of the Q-Prep procedure, in which erythrocytes are lysed with formic acid, and leucocytes are fixed with formaldehyde. Whole blood samples were labelled with the nuclear dye LDS-751 and with antibodies to HLA-DR or belonging to CD2, CD3, CD4, CD7, CD8, CD10, CD13, CD14, CD19, CD20, CD29, CD33, CD45, CD45RA, CD56, and CD62L (TQ-1) that were directly conjugated to either phycoerythrin (PE) and/or fluorescein isothiocyanate (FITC). Leucocytes were analysed by flow cytometry either in unfixed, unlysed whole blood (15) or after preparation using the Q-Prep system. The binding of eight antibodies, CD19-FITC, CD2-PE, CD3-PE, CD4-PE, CD19-PE, CD29-PE, CD45RA-PE, and CD56-PE, to the surface of lymphocytes was reduced, resulting in significant changes (P < 0.05) in the percentages of cells that stained positively and/or their mean molecules of equivalent fluorochrome (MEF). Further analysis revealed that this was due to the formic acid used during the erythrocyte lysis stage.

Antibodies, Monoclonal↗
PubMed1997

The activation domain of the MotA transcription factor from bacteriophage T4.

Bacteriophage T4 encodes a transcription factor, MotA, that binds to the -30 region of middle-mode promoters and activates transcription by host RNA polymerase. We have solved the structure of the MotA activation domain to 2.2 A by X-ray crystallography, and have also determined its secondary structure by NMR. An area on the surface of the protein has a distinctive patch that is populated with acidic and hydrophobic residues. Mutations within this patch cause a defective T4 growth phenotype, arguing that the patch is important for MotA function. One of the mutant MotA activation domains was purified and analyzed by NMR, and the spectra clearly show that the domain is properly folded. The mutant full-length protein appears to bind DNA normally but is deficient in transcriptional activation. We conclude that the acidic/hydrophobic surface patch is specifically involved in transcriptional activation, which is reminiscent of eukaryotic acidic activation domains.

Amino Acid Sequence↗
PubMed1997

Structure of the Fab fragment from a neutralizing monoclonal antibody directed against an epitope of gp41 from HIV-1.

The structure of a Fab fragment of a monoclonal antibody (1583) that neutralizes a broad range of HIV-1 isolates has been solved by X-ray crystallography. This antibody is directed against a poliovirus/HIV-I chimaera which presents a conserved epitope of the envelope protein gp41. Crystals of 1583 were obtained in the space group P2(1)2(1)2(1) and the structure solved by molecular replacement. The model has been refined against all data in the range 10-2.9 A to a final crystallographic R factor of 0.198. The antigen-binding site features a well defined groove, typical of antibodies that bind to small antigens, created in part by a relatively short CDR H3. The variable regions of 1583 were sequenced and, given the hydrophilic nature of the epitope, revealed a surprising lack of charged residues in the CDR's. However, the antigen-binding cleft is indeed very polar, due in part to the presence of two charged residues that emanate from outside the recognized CDR's.

Journal Article↗
PubMed1997

Case-control study of GP attendance rates by suicide cases with or without a psychiatric history.

BACKGROUND: Targets for reduction in suicide deaths have been set against a background of an increasing number of people committing suicide. It is often assumed that a reduction can be effected by increasing the detection in primary care of patients at risk. This presupposes that there are indicators that enable suicide risk to be detected reliably. AIM: To compare the characteristics of those who commit suicide with an age- and sex-matched control group in terms of level of general practitioner attendance, diagnosis and pharmacological treatment of mental illness, and to compare those suicides with and without a psychiatric history in terms of general practitioner attendance and history of pharmacological treatment. METHOD: From a total of 48 deaths attributed to suicide and undetermined causes in the Forth Valley in 1993, general practice case notes were located for 41. Live controls were matched to index cases by age, sex and practice. Information on consultations, referrals to secondary care, medication and diagnoses in the previous 10 years was extracted from general practice and, for suicides, psychiatric case notes. RESULTS: Over the 10-year period, suicide patients attended their general practitioner at a higher level than control subjects. However, the number of suicide patients who attended their general practitioner in the month before their death did not differ in comparison with control subjects over a similar period. Suicide cases, in comparison with control subjects, were more likely to have received a psychiatric diagnosis from their general practitioner, been prescribed psychotropic medication and received referral to specialist mental health services. Those suicide patients with a psychiatric history had a significantly higher number of general practitioner consultations than those without a psychiatric history in four out of the five years preceding death. Those suicide patients without a psychiatric history did not differ significantly from control subjects on any of the variables assessed. CONCLUSION: For those people committing suicide who do not have a psychiatric history and whose consultation patterns do not differ from the norm, it is difficult to suggest how general practitioners might improve their detection of relevant suicidal risk factors. For those patients with a psychiatric history who commit suicide, until we have more detailed information regarding the specific content of general practitioner's consultations before death and how these differed from other consultations of the deceased, then it is premature to assume that general practitioners are failing to identify indicators of impending suicide.

Adult↗
PubMed1997

[Adjuvant tamoxifen duration: more large-scale randomized evidence is needed].

The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) overview of worldwide evidence has demonstrated that a few years of adjuvant tamoxifen produces a moderate but definite benefit in long-term survival. However, there is major uncertainty regarding the optimal duration of tamoxifen treatment and in particular, as to whether, after a few years on tamoxifen, most women should stop or should continue for several years longer. ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) is a large international randomized trial designed to assess reliably the balance of benefits and risks of prolonging tamoxifen duration by an additional five years in women who have already had some years of adjuvant tamoxifen and for whom there is uncertainty about whether to stop, or to continue for longer. It is important that most of the clinicians are aware of the uncertainties regarding the optimal duration of tamoxifen and should consider entering their patients into ATLAS, which has the potential to provide reliable evidence to answer this question that affects the management of many hundreds of thousands of women worldwide and thereby may contribute to the further downward trend in breast cancer mortality which is already being seen.

Antineoplastic Agents, Hormonal↗
PubMed1996

Ribosomal protein L9: a structure determination by the combined use of X-ray crystallography and NMR spectroscopy.

The structure of protein L9 from the Bacillus stearothernophilus ribosome has been determined at 2.5 A resolution by refinement against single crystal X-ray diffraction data with additional constraints provided by NMR data. This highly elongated protein consists of two domains separated by a nine-turn connecting helix. Conserved aromatic and positively charged amino acid residues on the surface of each domain are likely to be directly involved in binding 23 S ribosomal RNA. The shape of the protein, with its two widely spaced RNA-binding sites, suggests that it may serve as a "molecular strut", most likely playing a role in ribosome assembly and/or maintaining the catalytically active conformation of the ribosomal RNA. The combined use of X-ray and NMR data in the refinement procedure was essential in defining the N-terminal domain of the protein, which was relatively poorly determined by the X-ray data alone. In addition to resolving the ambiguities in defining the hydrophobic core and side-chain conformations with the N-terminal domain, this combined NMR-X-ray analysis provides the first detailed and accurate view of the N-terminal RNA-binding site. NMR data also showed that the N-terminal domain is stable in solution, indicated by amide protons that are protected from solvent exchange. The lack of definition of the N-terminal domain in the X-ray structure is therefore likely due to packing disorder within the crystal rather than structural instability. This combined NMR-X-ray analysis provides a useful model as to how X-ray and NMR data can be practically and logically combined in the determination of the structure of a single protein molecule.

Amino Acid Sequence↗