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Biomedical subjects

J Close

Publications and source records attributed to J Close.

At least 19 recordsLinked to original sources
PubMed2001

Targeted deletion of 5'HS1 and 5'HS4 of the beta-globin locus control region reveals additive activity of the DNaseI hypersensitive sites.

The mammalian beta-globin locus is a multigenic, developmentally regulated, tissue-specific locus from which gene expression is regulated by a distal regulatory region, the locus control region (LCR). The functional mechanism by which the beta-globin LCR stimulates transcription of the linked beta-like globin genes remains unknown. The LCR is composed of a series of 5 DNaseI hypersensitive sites (5'HSs) that form in the nucleus of erythroid precursors. These HSs are conserved among mammals, bind transcription factors that also bind to other parts of the locus, and compose the functional components of the LCR. To test the hypothesis that individual HSs have unique properties, homologous recombination was used to construct 5 lines of mice with individual deletions of each of the 5'HSs of the endogenous murine beta-globin LCR. Here it is reported that deletion of 5'HS1 reduces expression of the linked genes by up to 24%, while deletion of 5'HS4 leads to reductions of up to 27%. These deletions do not perturb the normal stage-specific expression of genes from this multigenic locus. In conjunction with previous studies of deletions of the other HSs and studies of deletion of the entire LCR, it is concluded that (1) none of the 5'HSs is essential for nearly normal expression; (2) none of the HSs is required for proper developmental expression; and (3) the HSs do not appear to synergize either structurally or functionally, but rather form independently and appear to contribute additively to the overall expression from the locus.

Age Factors↗
PubMed2001

Duplicate mitf genes in zebrafish: complementary expression and conservation of melanogenic potential.

Mutations in the zebrafish nacre/mitfa gene, expressed in all embryonic melanogenic cells, perturb only neural crest melanocytes, suggesting redundancy of mitfa with another gene in the zebrafish retinal pigment epithelium (RPE). Here, we describe a second zebrafish mitf gene, mitfb, which may fulfill this role. The proteins encoded by the two zebrafish mitf genes appear homologous to distinct isoforms generated by alternately spliced mRNAs of the single mammalian Mitf gene, suggesting specialization of the two zebrafish genes following a duplication event. Consistent with this hypothesis, expression of mitfa and mitfb is partially overlapping. mitfb is coexpressed with mitfa in the RPE at an appropriate time to compensate for loss of mitfa function in the nacre mutant but is not expressed in neural crest melanoblasts. Additionally, mitfb is expressed in the epiphysis and olfactory bulb where mitfa is not, and where Mitf expression has not previously been reported in other species. mitfb, but not a zebrafish ortholog of the closely related gene tfe3, can rescue neural crest melanophore development in nacre/mitfa mutant embryos when expressed via the mitfa promoter. These data suggest that mitfa and mitfb together may recapitulate the expression and functions of a single ancestral Mitf gene, and that mitfb may serve additional novel functions.

3T3 Cells↗
PubMed2000

p27(Kip1) regulates cell cycle withdrawal of late multipotent progenitor cells in the mammalian retina.

The cyclin-dependent kinase inhibitor protein, p27(Kip1), is necessary for the timing of cell cycle withdrawal that precedes terminal differentiation in oligodendrocytes of the optic nerve. Although p27(Kip1) is widely expressed in the developing central nervous system, it is not known whether this protein has a similar role in neuronal differentiation. To address this issue, we have examined the expression and function of p27(Kip1) in the developing retina, a well-characterized part of the central nervous system. p27(Kip1) is expressed in a pattern coincident with the onset of differentiation of most retinal cell types. In vitro analyses show that p27(Kip1) accumulation in retinal cells correlates with cell cycle withdrawal and differentiation, and when overexpressed, p27(Kip1) inhibits proliferation of the progenitor cells. Furthermore, the histogenesis of photoreceptors and Müller glia is extended in the retina of p27(Kip1)-deficient mice. Finally, we examined the adult retinal dysplasia in p27(Kip1)-deficient mice with cell-type-specific markers. Contrary to previous suggestions that the dysplasia is caused by excess production of photoreceptors, we suggest that the dysplasia is due to the displacement of reactive Müller glia into the layer of photoreceptor outer segments. These results demonstrate that p27(Kip1) is part of the molecular mechanism that controls the decision of multipotent central nervous system progenitors to withdraw from the cell cycle. Second, postmitotic Müller glia have a novel and intrinsic requirement for p27(Kip1) in maintaining their differentiated state.

Animals↗
PubMed2000

An integrated map of human 6q22.3-q24 including a 3-Mb high-resolution BAC/PAC contig encompassing a QTL for fetal hemoglobin.

Genetic studies have previously assigned a quantitative trait locus (QTL) for hemoglobin F and F cells to a region of approximately 4 Mb between the markers D6S408 and D6S292 on chromosome 6q23. An initial yeast artificial chromosome contig of 13 clones spanning this region was generated. Further linkage analysis of an extended kindred refined the candidate interval to 1-2 cM, and key recombination events now place the QTL within a region of <800 kb. We describe a high-resolution bacterial clone contig spanning 3 Mb covering this critical region. The map consists of 223 bacterial artificial chromosome (BAC) and 100 P1 artificial chromosome (PAC) clones ordered by sequence-tagged site (STS) content and restriction fragment fingerprinting with a minimum tiling path of 22 BACs and 1 PAC. A total of 194 STSs map to this interval of 3 Mb, giving an average marker resolution of approximately one per 15 kb. About half of the markers were novel and were isolated in the present study, including three CA repeats and 13 single nucleotide polymorphisms. Altogether 24 expressed sequence tags, 6 of which are unique genes, have been mapped to the contig.

Base Sequence↗
PubMed2000

Beta-globin gene switching and DNase I sensitivity of the endogenous beta-globin locus in mice do not require the locus control region.

We have generated mice with a targeted deletion of the beta-globin locus control region (LCR). Mice homozygous for the deletion die early in embryogenesis but can be rescued with a YAC containing the human beta-globin locus. After germline passage, deletion of the LCR leads to a severe reduction in expression of all mouse beta-like globin genes, but no alteration in the developmental specificity of expression. Furthermore, a DNase I-sensitive "open" chromatin conformation of the locus is established and maintained. Thus, the dominant role of the LCR in the native locus is to confer high-level transcription, and elements elsewhere in the locus are sufficient to establish and maintain an open conformation and to confer developmentally regulated globin gene expression.

Animals↗
PubMed1999

Prevention of falls in the elderly trial (PROFET): a randomised controlled trial.

BACKGROUND: Falls in elderly people are a common presenting complaint to accident and emergency departments. Current practice commonly focuses on the injury, with little systematic assessment of the underlying cause, functional consequences, and possibilities for future prevention. We undertook a randomised controlled study to assess the benefit of a structured inderdisciplinary assessment of people who have fallen in terms of further falls. METHODS: Eligible patients were aged 65 years and older, lived in the community, and presented to an accident and emergency department with a fall. Patients assigned to the intervention group (n=184) underwent a detailed medical and occupational-therapy assessment with referral to relevant services if indicated; those assigned to the control group (n=213) received usual care only. The analyses were by intention to treat. Follow-up data were collected every 4 months for 1 year. FINDINGS: At 12-month follow-up, 77% of both groups remained in the study. The total reported number of falls during this period was 183 in the intervention group compared with 510 in the control group (p=0.0002). The risk of falling was significantly reduced in the intervention group (odds ratio 0.39 [95% CI 0.23-0.66]) as was the risk of recurrent falls (0.33 [0.16-0.68]). In addition, the odds of admission to hospital were lower in the intervention group (0.61 [0.35-1.05]) whereas the decline in Barthel score with time was greater in the control group (p<0.00001). INTERPRETATION: The study shows that an interdisciplinary approach to this high-risk population can significantly decrease the risk of further falls and limit functional impairment.

Accidental Falls↗
PubMed1998

Description and targeted deletion of 5' hypersensitive site 5 and 6 of the mouse beta-globin locus control region.

The most upstream hypersensitive site (HS) of the beta-globin locus control region (LCR) in humans (5' HS 5) and chickens (5' HS 4) can act as an insulating element in some gain of function assays and may demarcate a beta-globin domain. We have mapped the most upstream HSs of the mouse beta-globin LCR and sequenced this region. We find that mice have a region homologous to human 5' HS 5 that is associated with a minor HS. In addition we map a unique HS upstream of 5' HS 5 and refer to this novel site as mouse 5' HS 6. We have also generated mice containing a targeted deletion of the region containing 5' HS 5 and 6. We find that after excision of the selectable marker in vivo, deletion of 5' HS 5 and 6 has a minimal effect on transcription and does not prevent formation of the remaining LCR HSs. Taken together these findings suggest that the most upstream HSs of the mouse beta-globin LCR are not necessary for maintaining the beta-globin locus in an active configuration or to protect it from a surrounding repressive chromatin environment.

Animals↗
PubMed1995

The reliability of upper airway landmark identification.

Research involving the upper airway has assessed linear measurements of certain structures on the assumption that the landmarks involved can be reliably identified. This study was conducted to determine the reliability of landmark identification for those structures most commonly reported in the obstructive sleep apnoea literature. Three judges were asked to identify specific landmarks on 20 randomly selected radiographs and 10 superior quality radiographs. This was repeated one week later. The results of the analysis of variance (ANOVA) indicated that the majority of the landmarks could be reliably identified, irrespective of the quality of the radiograph. However, the quality of the radiograph did affect identification of the horizontal position of the hyoid bone and the linear measure of posterior airway space although these were not clinically significant. The vertical position of the tip of the soft palate was highly unreliable, irrespective of the quality of the radiograph. This resulted in errors in the measurement of soft palate length. Future airway-related research should consider the potential inaccuracies when attempting to identify these dynamic three-dimensional structures on static two-dimensional images.

Analysis of Variance↗
PubMed1994

The effect of carbamide peroxide bleach on the tensile bond strength of ceramic brackets: an in vitro study.

Recent advances in cosmetic dentistry have led to the development of a variety of new products and techniques including vital bleaching and ceramic brackets. Therefore this study was conducted to see whether the use of an at-home carbamide peroxide bleaching agent before bonding affected the tensile bond strength of a precoated ceramic orthodontic bracket. Sixty extracted human premolar teeth were randomly separated into three groups of 20. Group 1 was a control group that was etched and bonded in the usual manner. Group 2 was immersed in a carbamide peroxide home bleaching agent for 72 hours before pumicing and bonding. Group 3 was also bleached for 72 hours but was immersed in distilled water for 1 week before bonding. The results indicated that recently bleached teeth have significantly reduced bond strength values when compared with both groups 1 and 3. We suggest that if a patient is using a tooth whitening product, that they discontinue its use at least 1 week before the bonding of orthodontic attachments.

Acid Etching, Dental↗
PubMed1994

The validity of the prediction of Soft Tissue profile changes after LeFort I osteotomy using the dentofacial planner (computer software).

The purpose of this study was to examine the validity of the prediction of soft tissue changes after LeFort I osteotomy with the DentoFacial Planner (DFP) (computer software). The preoperative and postoperative lateral cephalograms of 21 white adult orthodontic patients (10 males and 11 females) who underwent only LeFort I osteotomy as part of their overall treatment were digitized. A coordinate system of X and Y axes were used to assess the amount and direction of movement of the maxilla. The SN + 7 degrees was the X axis, and a perpendicular to this plane from nasion was the Y axis. The sample was divided into two groups depending on the amount of forward movement of the maxilla. More than 2 mm of anterior placement of the maxilla comprised the advancement group (13 patients) and less than 2 mm comprised the impaction group (8 patients). The selection criteria for the sample were (1) before and after cephalograms taken with lips in repose and in centric occlusion; (2) all preoperative records taken almost immediately before surgery; (3) postoperative records taken at least 6 months after surgery and checked by regional superimposition of the preoperative and postoperative lateral cephalograms onto the maxilla and the mandible. No tooth movement occurred between the time the records were taken. The following soft tissue landmarks were examined: pronasale, subnasale, stomion superior, middle upper lip, stomion inferior, middle lower lip, labrale inferior, labiomental fold, and pogonion. The results indicate that for some of these landmarks the amount and direction of soft tissue changes differed between the DFP prediction and the actual surgical changes by LeFort I osteotomy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMedDate not supplied

Antibiotics alter interactions of Staphylococcus aureus with collagenous substrata.

The effects of sub-minimum inhibitory concentrations (sub-MICs) of three antibiotics affecting the biosynthesis of peptidoglycan on the interactions of Staphylococcus aureus strains with collagenous substrata were evaluated. In a system measuring binding of 125I-labeled collagen, growth of bacteria in the presence of one-quarter MIC of cloxacillin and vancomycin reduced the number of collagen binding sites on the surface of bacteria. Growth in the presence of cefpodoxime reduced the number of collagen binding sites in one strain and increased it in another. Cefpodoxime also increased the dissociation constant of collagen binding to bacteria, 2- to 3-fold, while the other two antibiotics did not affect the affinity of the interaction. In a system measuring adhesion of 125I-labeled bacteria to collagen-coated surfaces or cartilage, bacteria grown in the presence of cloxacillin and vancomycin attached to varying degrees depending on the strain. In contrast, compared to untreated controls as well as to bacteria treated with the other two antibiotics, growth in the presence of cefpodoxime significantly reduced adhesion of the majority of strains tested. Sub-MICs of antibiotics appear to affect staphylococcal adhesion to collagenous substrata with cefpodoxime exhibiting the strongest effect. The critical factor in reducing bacterial adhesion seems not to be the number of bacterial binding sites for collagen, but the affinity of the interaction.

Ceftizoxime↗
PubMedDate not supplied

Dose-responsive characteristics of meperidine sedation in preschool children.

Using double-blind conditions, 60 uncooperative and fearful preschool children (24-66 months) received intramuscular injections of meperidine 0.25, 0.50, 1.00 mg/lb or placebo prior to restorative dental treatment. Behavior was assessed by the dentist and an independent observer during five specific treatment procedures. Behavioral ratings found meperidine to be an effective sedative, with 0.50 mg/lb and 1.00 mg/lb being significantly more effective than placebo (P less than 0.05, Kruskal-Wallis). Children receiving 1.0 mg/lb of meperidine had significantly more nausea and vomiting than patients receiving lower doses of the drug (P less than 0.05, Chisquare). Physiologic monitoring demonstrated that the highest dose of meperidine was associated with transient drops in arterial oxygen saturation. Meperidine sedation was found to be more effective for older children (37-66 months) and for children initially rated as being only moderately uncooperative and fearful.

Anxiety↗
PubMedDate not supplied

Efficacy of a prebrushing rinse for orthodontic patients.

The oral health benefits of a prebrushing rinse, when used in conjunction with an established twice-a-day brushing regimen, was investigated in a population of orthodontic patients. Twenty children (ages 11-18) who were undergoing orthodontic treatment that required brackets and labial wires were enrolled. This randomized, double-blind, cross-over clinical trial compared five weeks of twice-daily use of a commercial prebrushing rinse (Plax) to five weeks of a placebo rinse. Three investigators rated plaque accumulation (Simplified Oral Hygiene Index) and gingival health (modified O'Leary Index) prior to treatment and after each five week session. Because one child exited from the project and three children did not satisfactorily comply with the treatment protocol, sixteen children were used for the analysis. Although both treatment groups showed plaque and gingival improvement from pretreatment scores, no differences in plaque accumulation ratings and gingival health ratings were noted between the active and placebo rinse treatments.

Adolescent↗