Biomedical subjects

R L Dunn

Publications and source records attributed to R L Dunn.

At least 55 records · Page 3Linked to original sources

PubMed1996

Periodontal pocket treatment in beagle dogs using subgingival doxycycline from a biodegradable system. I. Initial clinical responses.

The present study evaluated the clinical response of periodontal pockets in beagle dogs after treatment with a biodegradable delivery system containing 10% doxycycline hyclate (ABDS-D). Eight adult, female beagle dogs had generalized, severe periodontitis with plaque and calculus-laden pockets. In each animal, 3 teeth with multiple pocket sites > or = 4 mm (mean depth = 6.0 mm) associated with attachment loss (mean = 5.4 mm) and which bled on probing (mean score = 2.5) were treated with a single application of either ABDS-D (experimental group) or the delivery system alone without the doxycycline (control group). Residual polymer was removed at day 7. Bioassay of doxycycline in gingival crevicular fluid associated with presence of ABDS-D gave mean levels of bioactivity of approximately 250 micrograms/ml. Levels of bioactive doxycycline were detected for approximately 7 days after ABDS-D removal. Periodontal maintenance consisted of thrice-weekly toothbrushing the treated sites. Clinical responses were evaluated at 2 weeks, and at bi-weekly intervals thereafter for 4 months. Analyses of the data from the control group showed that there was only slight clinical improvement. In contrast, in the experimental group, bleeding on probing and probing depths were significantly reduced from baseline at all post-treatment time points. At 1 month, mean probing depth reduction was 2.4 mm and this was maintained at 4 months (mean reduction = 2.5 mm). These probing depth reductions occurred primarily through gain of clinical attachment which was 2.0 mm at 4 months. Bleeding had been virtually eliminated (mean = 0.2). It was concluded that, for the beagle dogs with severely infected periodontal pockets in this study, treatment with subgingival doxycycline using the delivery system resulted in substantial improvement in periodontal health.

Administration, Topical↗

PubMed1995

Whole mouth microbiota effects following subgingival delivery of sanguinarium.

An increased incidence of antibiotic-resistant bacteria and yeast overgrowth has been reported following various periodontal treatments. The objective of this study was to detect possible overgrowth of opportunistic bacteria and fungi as well as changes in normal microbiota after application of a biodegradable delivery system containing 5% sanguinarium (ABDS-S) to one quadrant in a split-mouth study. An oral hygiene quadrant served as a control. The ABDS-S treated and control periodontal sites as well as the saliva of 17 subjects were sampled prior to treatment, immediately after ABDS-S removal at 7 days, and again at 30 and 60 days. At Day 7 sanguinarium-resistant bacteria increased in both control and ABDS-S periodontal sites as well as in the saliva. Enteric Gram-negative bacilli in both control and ABDS-S periodontal sites were 2.2 to 3.4 log colony forming units higher at Day 7 compared to baseline. This overgrowth was transient in that levels became undetectable at Days 30 and 60. No such overgrowth was observed for C. albicans or other fungi, or for S. aureus or other staphylococci in any periodontal sites. Levels of Actinomyces increased at Days 30 and 60 in both control and ABDS-S sites as well as saliva. These changes strongly suggest that a 7 day ABDS-S treatment in one quadrant of the mouth led to significant microbiota changes in the treated and control quadrants as well as in the saliva. Future microbial studies involving antimicrobials delivered by local delivery systems must consider the crossover effects of treatment inherent in the split-mouth design.

Adult↗

PubMed1995

Initial study of guided tissue regeneration in Class II furcation defects after use of a biodegradable barrier.

This study evaluated guided tissue regeneration in Class II furcation defects after use of a polylactic acid biodegradable barrier in nine patients with mandibular molar defects. Following an initial hygienic phase, surgical flaps were elevated, and the sites were scaled and root planed. Defect perimeter was measured, and a customized barrier (600 to 750 mm thick) that adhered directly to tooth and bone was applied. At baseline, sites were measured for probing depth (6.2 +/- 0.5 mm), gingival margin location (-0.6 +/- 0.6 mm), and attachment level both vertically (6.9 +/- 0.7 mm) and horizontally (5.3 +/- 0.5 mm). Clinically, barriers fragmented and became displaced in 3 to 6 weeks. Substantial granulation tissue was sometimes present between barrier and root surfaces. Six months postsurgery, gingival margin location was close to the presurgical level (-0.4 +/- 0.8 mm). There was clinically and statistically significant improvement in all other parameters: a mean reduction of 3.1 mm in probing depth, a gain of 3.3 mm in vertical attachment level, and a gain of 3.0 mm in horizontal attachment level. These results suggested favorable regenerative outcomes.

Adult↗

PubMed1995

Periodontal healing after guided tissue regeneration with Atrisorb barriers in beagle dogs.

Periodontal healing after use of Atrisorb barrier material (polylactic acid) for guided tissue regeneration was studied in the premolar and molar teeth of six beagle dogs. Defects studied were surgically induced or were caused by naturally occurring periodontitis. Barriers fragmented and became displaced in 2 to 5 weeks after application. Granulation tissue was sometimes present between the barrier and root surface at 10 days to 4 weeks. Several sites were surgically reentered at 4 months, and new bone covered 60% to 100% of the formerly exposed furcations and root surfaces. Sites obtained for histologic evaluation 9 to 12 months after the baseline surgery showed new connective tissue attachment, cementum, and alveolar bone. Histomorphometric analyses quantitated these tissue changes, and new connective tissue attachment covered 72% of surgically exposed root surfaces and 77% of periodontitis-exposed root surfaces. It was concluded that new periodontal supporting tissues became reconstituted on root and furcation surfaces after use of the Atrisorb barrier material for GTR.

Alveolar Bone Loss↗

PubMed1993

The role of psychologists in the treatment, management, and prevention of chronic mental illness.

In addition to suffering from the severe psychiatric symptoms of chronic mental illness (CMI), people with this type of disorder suffer from a variety of secondary disabilities and face societal obstacles that interfere with their ability to maximize their personal, social, and vocational potentials. Following the deinstitutionalization of long-term psychiatric patients in recent decades, many different understandings of the etiology, treatment, and management of CMI have evolved, including those derived from the biological, vulnerability, cognitive, case management, rehabilitation, and psychoeducational models. Because psychologists are trained in a wide range of psychological theories and a broad repertoire of applications, they have unique contributions to make within each model, particularly, as discussed here, to prevent, treat, and manage CMI through research, assessment, and intervention.

Chronic Disease↗

PubMed1993

Mutants of Escherichia coli with increased fidelity of DNA replication.

To improve our understanding of the role of DNA replication fidelity in mutagenesis, we undertook a search for Escherichia coli antimutator strains with increased fidelity of DNA replication. The region between 4 and 5 min of the E. coli chromosome was mutagenized using localized mutagenesis mediated by bacteriophage P1. This region contains the dnaE and dnaQ genes, which encode, respectively, the DNA polymerase (alpha subunit) and 3' exonucleolytic proofreading activity (epsilon subunit) of DNA polymerase III holoenzyme, the enzyme primarily responsible for replicating the bacterial chromosome. The mutated bacteria were screened for antimutator phenotype in a strain defective in DNA mismatch repair (mutL), using a papillation assay based on the reversion of the galK2 mutation. In a mutL strain, mutations result primarily from DNA replication errors. Among 10,000 colonies, seven mutants were obtained whose level of papillation was reduced 5-30-fold. These mutants also displayed decreased mutation frequencies for rifampicin or nalidixic acid resistance as well as for other markers. Mapping by P1 transduction and complementation showed each to reside in dnaE. These observations support the idea that the mutants represent antimutators which replicate their DNA with increased fidelity. Mutation rates were reduced in both mutL and mutT backgrounds, but mutagenesis by ultraviolet light was not significantly affected, suggesting that the antimutator effect may be largely restricted to normal DNA replication.

Bacterial Proteins↗

PubMed1993

Healing patterns associated with an Atrisorb barrier in guided tissue regeneration.

The current guided tissue regeneration clinical technique uses synthetic membranes at the time of the surgical procedure to separate the gingival and periodontal tissue components. These membranes are tied to the tooth surface and have to be ++removed during a second surgical procedure. The material Atrisorb is currently under development as a guided tissue regeneration barrier in Class II furcation defects. This material is applied directly over the furcation defect and is not tied to the tooth surface. Because of its biodegradability, Atrisorb does not have to be removed. A case study is presented.

Aged↗

PubMed1992

Transcription-repair coupling determines the strandedness of ultraviolet mutagenesis in Escherichia coli.

We have analyzed the spectra of UV-induced mutations in the lacI gene of a wild-type and an mfd strain of Escherichia coli. mfd strains have been recently proposed to be deficient in a factor coupling DNA repair and transcription. Analysis of UV-induced mutations occurring at adjacent pyrimidines showed that mutations in the wild-type strain arose largely from the nontranscribed strand but arose predominantly from the transcribed strand in the mfd strain. The overall strand switch was 14-fold. One mutation, G.C-->A.T in the lacI initiation codon, showed a > 300-fold shift. No effect was observed for mutations at non-pyrimidine-pyrimidine sequences. These results provide in vivo evidence for a key role of the mfd gene in controlling the strandedness of mutagenesis and support the proposed role of the mfd gene product in directing DNA excision repair to the transcribed strand of a damaged gene.

Base Composition↗

PubMed1991

Spontaneous mutation in the Escherichia coli lacI gene.

To gain more detailed insight into the nature and mechanisms of spontaneous mutations, we undertook a DNA sequence analysis of a large collection of spontaneous mutations in the N-terminal region of the Escherichia coli lacI gene. This region of circa 210 base pairs is the target for dominant lacI mutations (i-d) and is suitable for studies of mutational specificity since it contains a relatively high density of detectable mutable sites. Among 414 independent i-d mutants, 70.8% were base substitutions, 17.2% deletions, 7.7% additions and 4.3% single-base frameshifts. The base substitutions were both transitions (60%) and transversions (40%), the largest single group being G.C----A.T (47% of base substitutions). All four transversions were observed. Among the 71 deletions, a hotspot (37 mutants) was present: an 87-bp deletion presumably directed by an 8-bp repeated sequence at its endpoints. The remaining 34 deletions were distributed among 29 different mutations, either flanked (13/34) or not flanked (21/34) by repeated sequences. The 32 additions comprised 29 different events, with only two containing a direct repeat at the endpoints. The single-base frameshifts were the loss of a single base from either repeated (67%) or nonrepeated (33%) bases. A comparison with the spectrum obtained previously in strains defective in DNA mismatch correction (mutH, mutL, mutS strains) yielded information about the apparent efficiency of mismatch repair. The overall effect was 260-fold but varied substantially among different classes of mutations. An interesting asymmetry was uncovered for the two types of transitions, A.T----G.C and G.C----A.T being reduced by mismatch repair 1340- and 190-fold, respectively. Explanations for this asymmetry and its possible implications for the origins of spontaneous mutations are discussed.

Bacterial Proteins↗

PubMed1987

Escherichia coli mutT mutator effect during in vitro DNA synthesis. Enhanced A.G replicational errors.

The mechanism of the Escherichia coli mutT mutator effect was investigated using single-stranded phage as a mutational target. In vivo experiments showed that two M13mp2 lacZ alpha nonsense mutants reverted at a higher rate on a mutT1 host than on the wild-type host. The specificity of this mutator effect was identical to that observed for E. coli genes: A.T----C.G transversions. The mutT effect was subsequently demonstrated in vitro during DNA replication of M13mp2 DNA in cell-free extracts of E. coli. Replication (the single-stranded----replicative form conversion) in mutT1 extracts proceeded with a higher error rate than in wild-type extracts, and DNA sequence analysis of the in vitro revertants revealed the specific induction of A.T----C.G transversions. On the basis of the template specificity of the mutT effect in vitro, we conclude that the mutT effect involves the aberrant processing of A.G rather than T.C mispairs.

Bacterial Proteins↗

PubMed1987

Mechanisms of ultraviolet-induced mutation. Mutational spectra in the Escherichia coli lacI gene for a wild-type and an excision-repair-deficient strain.

We have analyzed the DNA sequence changes in a total of 409 ultraviolet light-induced mutations in the lacI gene of Escherichia coli: 227 in a Uvr+ and 182 in a UvrB- strain. Both differences and similarities were observed. In both strains the mutations were predominantly (60 to 75%) base substitutions, followed by smaller contributions of single-base frameshifts, deletions and frameshift hotspot mutations. The base substitutions proved largely similar in the two strains but differences were observed among the single-base frameshifts, the deletions and the hotspot mutations. Among the base substitutions, both transitions (72.5%) and transversions (27.5%) were observed. The largest single group was G.C----A.T (60% of all base substitutions). The sites where G.C----A.T changes occurred were strongly correlated (97.5%) with sequences of adjacent pyrimidines, indicating mutation targeted ultraviolet photoproducts. Comparable amounts of mutation occurred at cytosine/cytosine and (mixed) cytosine/thymine sites. From an analysis of the prevalence of mutation at either the 5' or 3' side of a dipyrimidine, we conclude that both cyclobutane dimers and (6-4) lesions may contribute to mutation. Despite the general similarity of the base-substitution spectra between the wild-type and excision-defective strains, a number of sites were uniquely mutable in the UvrB- strain. Analysis of their surrounding DNA sequences suggested that, in addition to damage directly at the site of mutation, the potential for nearby opposite-strand damage may be important in determining the mutability of a site. The ultraviolet light-induced frameshift mutations were largely single-base losses. Inspection of the DNA sequences at which the frameshifts occurred suggested that they resulted from targeted mutagenesis, probably at cyclobutane pyrimidine dimers. The prevalence of frameshift mutations at homodimers (TT or CC) suggests that their formation involves local misalignment (slippage) and that base-pairing properties are partially retained in cyclobutane dimers. While the frameshift mutations in the Uvr+ strain were distributed over many different sites, more than half in the UvrB- strain were concentrated at a single site. Ultraviolet light-induced deletions as well as frameshift hotspot mutations (+/- TGGC at positions 620 to 632) are considered to be examples of untargeted or semitargeted mutagenesis. Hotspot mutations in the Uvr+ strain showed an increased contribution by (-)TGGC relative to (+)TGGC, indicating that ultraviolet light may specifically promote the loss of the four bases.(ABSTRACT TRUNCATED AT 400 WORDS)

Base Sequence↗

PubMed1987

Spectra of spontaneous mutations in Escherichia coli strains defective in mismatch correction: the nature of in vivo DNA replication errors.

We have determined the DNA sequence changes in 487 spontaneous mutations in the N-terminal part of the lacI gene in mutH, mutL, and mutS strains of Escherichia coli. These strains display elevated spontaneous mutation rates because of a deficiency in the process of postreplicative mismatch correction. As a consequence the mutational spectra reveal the nature of spontaneous DNA replication errors. The spectra consist of base substitutions (75%) and single-base deletions (25%). Among the base substitutions, transitions (both A.T----G.C and G.C----A.T) are strongly favored over transversions (96% versus 4%). Large site-to-site differences are observed among identical base substitutions, presumably reflecting the modulating effects of neighboring bases. The single-base-deletion spectrum is dominated by a large hotspot at a run of adjacent identical base pairs, implying a Streisinger-slippage mechanism. The data, when compared to a previously determined wild-type spectrum, also provide information on the specificity of the mismatch repair system.

Base Sequence↗

PubMed1986

The C-C (6-4) UV photoproduct is mutagenic in Escherichia coli.

Mutation induced by ultraviolet light is predominantly targeted by UV photoproducts. Two primary candidates for the premutagenic lesion are the cyclobutane pyrimidine dimer and the less frequent (by a factor of 10) pyrimidine-pyrimidone (6-4) photoproduct. Methylation of the 3'-cytosine in the sequence 5' CCAGG 3' reduces the yield of (6-4) lesions, but not of cyclobutane dimers, at these sites. By taking advantage of mutants deficient in cytosine methylation, we show here that at the three sites in the lacI gene of Escherichia coli having this sequence, the specific increase in the formation of the (6-4) photoproducts is accompanied by a concomitant increase in mutation. At each site, a G X C to A X T transition results in an amber mutation. In the unmethylated state, these sites become among the most frequent nonsense mutations recovered. We conclude that the (6-4) photoproduct constitutes a major premutagenic lesion in E. coli.

Cytosine↗

PubMed1986

The use of prostacyclin analogue-containing suture for the prevention of postoperative venous thrombosis in the rat.

The ability of prostacyclin analogue incorporated into a controlled-release suture to prevent postoperative venous thrombosis was investigated. Thirteen rats underwent bilateral transection and anastomosis of the common femoral vein. In each animal, polycaprolactone suture containing 0.25 micrograms/cm of the prostacyclin analogue Iloprost (Schering Ag, Berlin, West Germany) was used to perform the anastomosis on one vessel. Similar suture without prostacyclin analogue was used on the contralateral vessel, which served as a control. Functional patency and luminal surface morphology were assessed 24 hours postoperatively. All anastomoses performed using suture containing prostacyclin analogue were patent. Among controls, five anastomoses were patent and eight were occluded. This difference was highly significant (p less than 0.005). All anastomoses performed with prostacyclin analogue-containing suture exhibited a uniform absence of thrombosis. In contrast, eight control veins exhibited a dense, well-organized fibrinous clot that filled the entire lumen, effectively sealing off the vessel. These results suggest that the prostacyclin analogue released from the suture was highly effective in inhibiting thrombus formation without adversely affecting the vessel's ability to achieve hemostasis.

Animals↗

PubMed1983

Poly(DL-lactide-co-glycolide)/norethisterone microcapsules: an injectable biodegradable contraceptive.

Microcapsules made from a biocompatible, biodegradable polymeric excipient, poly(DL-lactide-co-glycolide) (DL-PLGA) that contained 22 weight percent (wt %) norethisterone (NET), were prepared by a solvent-evaporation microencapsulation process. The effects of changing both the lactide-to-glycolide ratio of the DL-PLGA and the size of the microcapsules on the rate of NET release and the rate of excipient biodegradation were determined in vivo. NET release rates were determined in baboons after injecting the microcapsule formulations intramuscularly. Serum samples obtained at various times following treatment were analyzed for NET, progesterone, and estrogen by radioimmunoassay (RIA). Biodegradation kinetics were determined by injecting NET microcapsules made from radiolabeled DL-PLGA intramuscularly into the hind legs of rats. Residual radioactivity at the injection site was determined at various times after treatment by combustion analysis of the muscle tissue. Changing the ratio of the comonomers to include more glycolide (DL-lactide:glycolide-96:4, 92:8, 87:13, 74:26) increased the rate of NET release and accelerated the biodegradation of the copolymer excipient. Decreasing the size of the microcapsules increased the rate of NET release. On the basis of these studies a NET microcapsule formulation has been identified for clinical testing which releases NET for 3 months and biodegrades completely within 6 months.

Animals↗

PubMed1983

Monolithic tetracycline-containing fibers for controlled delivery to periodontal pockets.

For the purpose of developing controlled delivery devices for periodontal therapy which would release over several days, six fiber types made of tetracycline-loaded biocompatible polymers were manufactured and tested. Polyethylene, polypropylene, polycaprolactone, polyurethane and cellulose acetate propionate all released their drug load within 1 day. Ethylene vinyl acetate fibers, however, provided in vitro sustained release for periods up to 9 days. A bioassay was designed to measure levels of tetracycline achieved by local delivery which used growth inhibition of Bacillus cereus as a measure of the amount of tetracycline in measured volumes of gingival sulcus fluid on filter paper strips. By this assay, fibers made from 25% loaded ethylene vinyl acetate established initial concentrations of approximately 500 micrograms/ml. The measurement of tetracycline concentration resulting from the placement of these fibers into deep periodontal pockets as a packing material provided indication that concentrations of greater than 50 micrograms/ml could be maintained for months by weekly to monthly replacement. These studies indicate that monolithic fibers made of tetracycline-loaded ethylene vinyl acetate have characteristics which could prove useful as the basis of a tetracycline delivery system for the treatment of periodontal disease.

Delayed-Action Preparations↗

PubMed1981

Sister-chromatid exchange analyses in rodent maternal, embryonic and extra-embryonic tissues: transplacental and direct mutagen exposures.

Sister-chromatid exchange (SCE) analyses were conducted in maternal, embryonic and extraembryonic tissues of pregnant rats and mice. The various tissues were substituted in vivo with 5-bromodeoxyuridine (BrdU) by implantation of a BrdU tablet in pregnant animals at mid-gestation. Following maternal exposure to 5-20 mg/kg cyclophosphamide, embryonic liver cells demonstrated dose-dependent SCE increases up to 10-fold that of control. Rat embryos revealed little intralitter variability for this transplacental effect. Maternal marrow and yolk sac cells examined in the rat also underwent significant increases in SCE, although to different extents. While marrow SCE frequencies were similar to those of embryo liver, yolk sac SCE frequencies were generally much lower. SCE analyses were also conducted in rat yolk sac cells substituted in vivo with BrdU and subsequently explanted to whole-embryo culture. In vitro exposure to cyclophosphamide at concentrations up to 100 microgram/ml had no SCE-inducing effect. However, similar exposures to phosphoramide mustard, a presumed metabolite of cyclophosphamide, caused dose-dependent increases in SCE up to 8-fold higher than control at 2 microgram/ml. Thus, cyclophosphamide appears to require maternal metabolic activation in order to cause an increased SCE frequency in yolk sac cells. The system described permits versatile SCE analyses which can help to define relative maternal and embryo tissue-specific sensitivities to chemical-induced genetic damage.

Animals↗

PubMedDate not supplied

Controlling for systematic selection in retrospective analyses: an application to fluoxetine and sertraline prescribing in the United Kingdom.

BACKGROUND: Criticism has been made of observational studies in clinical practice because of their failure to control for unobserved factors that correlate with both initial treatment selection and observed outcomes. METHOD: A two-stage statistical model was applied to data obtained from a large general practitioner medical records database (DIN-LINK) to estimate the effect of initial antidepressant selection on the duration of antidepressant therapy and on the likelihood of being prescribed an average daily dose above the minimum recommended dose. The statistical model controlled for unobserved factors correlated with initial treatment selection and the observed outcomes as well as for observed confounders. RESULTS: Unobserved factors correlated with treatment selection were not a statistically significant determinant of the number of days of antidepressant therapy. However, unobserved factors correlated with treatment selection were a statistically significant determinant of the likelihood of receiving an average dose during therapy greater than the minimum recommended. After controlling for relevant confounders, those patients who began treatment with sertraline as opposed to fluoxetine had fewer days of antidepressant therapy and were more likely to receive average doses greater than the minimum recommended during therapy. CONCLUSION: Unobserved factors correlated with treatment selection can impact outcomes in observational studies and should be tested and controlled for whenever possible.

Journal Article↗