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PubMedDate not supplied

[Clinical predictors of the presence of perfusion defects in more than than one territory in myocardial scintigraphy with GATED-SPECT].

BACKGROUND AND OBJECTIVE: Extension of perfusion defects is associated with outcome in patients undergoing myocardial scintigraphy. The study aimed to identify the clinical characteristics that can predict the existence of perfusion defects in more than one territory in patients referred for myocardial scintigraphy with GATED-SPECT. PATIENTS AND METHODS: A total of 193 patients undergoing myocardial scintigraphy with GATED-SPECT (99mTc-tetrofosmine) were studied. Clinical variables and scintigraphy results were studied to determine what clinical variables are associated with perfusion defects in more than one territory. RESULTS: The number of territories with perfusion defects per patient was 1.1 0.8 and 29% had perfusion defects in > 1 territory. Patients with greater probability of having perfusion defects in > 1 territory were those with previous myocardial infarction (44% vs 21%, p = 0.030) and males (33% vs 10%, p = 0.006). In addition, patients with > 2 coronary risk factors had a statistical tendency to have defects in > 1 territory (47% vs 20%, p = 0.057). Only 15% of the patients with one of these three characteristics had perfusion defects in > 1 territory in comparison with 45% and 83% in those with 2 or 3 factors, respectively. CONCLUSION: Considering 3 simple clinical characteristics (male gender, previous infarction and existence of > 2 coronary risk factors), it is possible to predict which patients are more likely to show perfusion defects in > 1 territory during GATED-SPECT myocardial scintigraphy.

Coronary Disease↗
PubMed1996

The effect of L-dopa on the healing of a rat mandibular defect.

PURPOSE: This study was designed to evaluate the effect of L-dopa on healing of a surgically created bony defect in the adult male rat. MATERIALS AND METHODS: Thirty-six animals underwent surgery to create a 4-mm circular defect in the left mandibular angle. They were then randomly divided into two equal groups, one receiving 0.2 g/kg/day of L-dopa for 10 days by orogastric gavage, the other group acting as a control. Six experimental and six control animals were killed at 2 weeks, and five experimental and six control animals were killed at 4 and 6 weeks postoperation. Healing was classified as complete, partial, or incomplete based on gross and radiographic observations. RESULTS: Gross observation of the experimental mandibles showed five completely healed defects (31.25%), five partially healed defects (31.25%), and six defects with no healing (37.5%). Control mandibles showed three defects with partial healing (16.67%) and 15 with no healing (83.33%). Radiographs were taken of randomly chosen mandibles in each control and experimental group. Of the six experimental mandibles, one showed no healing, three showed partial healing, and two showed complete healing of the defect. The six control mandibles showed three defects with no bone formation and three with partial healing. CONCLUSIONS: The data from this study indicate that L-dopa had a promoting effect on the bony healing of defects in the rat mandible.

Administration, Oral↗
PubMed1981

Transplantation of free tibial periosteal graft on alveolar bone defect in adult rabbit.

The healing of bone defect in eight adult rabbits was studied. The age range of animals was 5-23 months. The bone defects were made symmetrically in the inferior surface of the mandibles. At the defect site the root surface of continuously erupting mandibular incisors was exposed. On the left side, the bone defect was covered with a local periosteal flap (control side) and on the right side the defect was covered with a free periosteal graft from the tibia (test side). The healing of bone defects and the amount of new bone were studied. The quality of the bone formed was investigated histologically. The findings of this investigation led to the following conclusions: (1) The bone defects healed on both sides. The amount of bone on the control side was identical to that in the anatomical region. On the test side the amount of bone formed was in seven cases two to threefold that formed on the control side. (2) The histological study proved that the bone formed was lamellar bone, being identical on both the control and the test side. (3) The ages of the animals or the length of follow-up time did not affect the amount of new bone, the healing of the defect or the quality of new bone. (4) The eruption of the incisors was symmetrical. In this study the free periosteal graft from the tibia led to better bone formation than the local periosteal flap in the induced bone defects of the tooth-bearing region in the mandible of the adult rabbit.

Age Factors↗
PubMed1998

Accuracy and feasibility of contrast echocardiography for detection of perfusion defects in routine practice: comparison with wall motion and technetium-99m sestamibi single-photon emission computed tomography. The Nycomed NC100100 Investigators.

OBJECTIVES: We sought to assess the feasibility and accuracy of myocardial contrast echocardiography (MCE) using standard imaging approaches for the detection of perfusion defects in patients who had a myocardial infarction (MI). BACKGROUND: Myocardial contrast echocardiography may be more versatile than perfusion scintigraphy for identifying the presence and extent of perfusion defects after MI. However, its reliability in routine practice is unclear. METHODS: Fundamental or harmonic MCE was performed with continuous or triggered imaging in 203 patients with a previous MI using bolus doses of a perfluorocarbon-filled contrast agent (NC100100). All patients underwent single-photon emission computed tomography (SPECT) after the injection of technetium-99m (Tc-99m) sestamibi at rest. Quantitative and semiquantitative SPECT, wall motion and digitized echocardiographic data were interpreted independently. The accuracy of MCE was assessed for detection of segments and patients with moderate and severe sestamibi-SPECT defects, as well as for detection of patients with extensive perfusion defects (>12% of left ventricle). RESULTS: In segments with diagnostic MCE, the segmental sensitivity ranged from 14% to 65%, and the specificity varied from 78% to 95%, depending on the dose of contrast agent. Using both segment- and patient-based analysis, the greatest accuracy and proportion of interpretable images were obtained using harmonic imaging in the triggered mode. For the detection of extensive defects, the sensitivity varied from 13% to 48%, with specificity from 63% to 100%. Harmonic imaging remained the most accurate approach. Time since MI and SPECT defect location and intensity were all determinants of the MCE response. The extent of defects on MCE was less than the extent of either abnormal wall motion or SPECT abnormalities. The combination of wall motion and MCE assessment gave the best balance of sensitivity (46% to 55%) and specificity (82% to 83%). CONCLUSIONS: Although MCE is specific, it has limited sensitivity for detection of moderate or severe perfusion defects, and it underestimates the extent of SPECT defects. The best results are obtained by integration with wall motion. More sophisticated methods of acquisition and interpretation are needed to enhance the feasibility of this technique in routine practice.

Contrast Media↗
PubMed2002

Subchondral defects in caprine femora augmented with in situ setting hydroxyapatite cement, polymethylmethacrylate, or autogenous bone graft: biomechanical and histomorphological analysis after two-years.

Juxta-articular defects pose significant challenges due to the high risk of fracture of the subchondral plate and articular cartilage. We evaluated the mechanical and histomorphological repair process of caprine subchondral femoral defects augmented with either a bioresorbable in situ setting hydroxyapatite cement (HAC), polymethylmethacrylate (PMMA), autogenous bone graft (AG), or left empty. Twelve-mm subchondral defects were made bilaterally in the medial femoral condyles of skeletally mature goats and augmented with a test material or left empty. Femurs were harvested at varying time periods out to 2 years and evaluated for subchondral stiffness and histomorphological indices. Several defects augmented using autograft or left empty sustained focal fracture of the subchondral plate. No HAC or PMMA augmented defects showed evidence of subchondral fracture. The HAC and PMMA augmented defects showed comparable stiffness at all time points. The mean volume fraction of HAC remaining within the defects progressively decreased from 96% at 24 h to 38% at 2 years. The new bone replacing the HAC appeared to have normal physiological architecture and orientation. In situ setting hydroxyapatite cement may be a viable alternative for the repair of subchondral defects with an important advantage that while undergoing gradual resorption and replacement with host bone, mechanical integrity of the skeletal defect is maintained.

Animals↗
PubMed1995

Chondrocyte-laden collagen scaffolds for resurfacing extensive articular cartilage defects.

Chondrocyte-collagen composites were evaluated for resurfacing of large articular defects. Isolated chondrocytes were cultured in expanded collagen scaffolds for 7-10 days to provide a composite containing 3.6 x 10(4) cells/mm3. The graft was transplanted into 15 mm full thickness articular defects in the femoropatellar joint of 12 horses using arthroscopic techniques. Ungrafted defects in the opposite femoropatellar joint served as controls. Synovial fluid, clinical progress and pain responses were evaluated in groups of 6 horses over 4-month and 8-month periods. Following termination, gross, histochemical and histologic evaluations of the repair tissues and synovial membrane were performed. Arthroscopic defect debridement and chondrocyte implantation resulted in minimal post-operative effusion or pain, and synovial fluid constituents were not significantly different in grafted and ungrafted joints. Gross differences in grafted defects were not apparent. Increased chondrocyte numbers and cartilage histochemical staining were evident in the deeper layers of grafted defects, whereas ungrafted defects were almost entirely fibrous tissue. The surface layers of grafted defects were fibrous tissue. There were no synovial fluid cellular responses, synovial membrane histiocytic reaction or subchondral bone infiltrates to suggest immune-related reaction to the allograft cells. Chondrocyte-collagen grafts were arthroscopically implanted and resulted in improved cartilage healing in extensive defects. However, the structural organization of the surface layers was inadequate and suggested poor long-term durability.

Animals↗
PubMed1995

Local and remote matrix responses to chondrocyte-laden collagen scaffold implantation in extensive articular cartilage defects.

Chondrocyte-laden collagen scaffolds were evaluated in extensive cartilage defects in an equine model. Arthroscopic techniques were used to implant a chondrocyte-collagen culture product in 15-mm defects in the lateral trochlear ridge of the femoropatellar joint of 12 horses. Ungrafted control defects were formed in the opposite joint. Groups of six horses were terminated at 4 and 8 months after implantation and the repair sites, adjacent cartilage, and remote cartilage within each femoropatellar joint examined biochemically. Eight months following surgery the relative proportions of type II collagen in grafted and ungrafted defects, determined using the ratio of cyanogen bromide cleavage products alpha 1(II)CB10/alpha 2(I)CB3,5, were not significantly different (31.57 +/- 2.76% and 26.88 +/- 2.76%, respectively). Aggrecan content was significantly improved in grafted defects (85.61 +/- 6.51 and 74.91 +/- 10.31 micrograms/mg dry weight). Cartilage surrounding grafted defects also showed improved maintenance of cartilage glycosaminoglycan content. Thus, chondrocyte grafting in collagen scaffold vehicles improved the aggrecan content in extensive cartilage defects and surrounding normal cartilage. However, given the continued disparity between repair tissue and normal cartilage aggrecan content, and the low proportion of type II collagen in grafted defects, the utility of collagen scaffolds for chondrocyte grafting of large cartilage defects seems limited.

Animals↗
PubMed1996

Effect of pulmonary volume loss on the size and appearance of experimentally produced scintigraphic perfusion defects.

RATIONALE AND OBJECTIVES: Atelectasis is a frequent concomitant of pulmonary embolism (PE) and other conditions that mimic PE. Accordingly, we developed an animal model to study the effect of regional loss of pulmonary volume on the size and configuration of experimentally induced perfusion defects that simulated PE. METHODS: After baseline anteroposterior and lateral chest radiographs were taken, 11 pulmonary vascular occlusions were created in 10 anesthetized, intubated mongrel dogs. Three were created by balloon occlusions of segmental pulmonary arteries, and eight were created by release of autologous PE. The size and shape of the affected lung zones were determined by perfusion scintigraphy (technetium-99m-macroaggregrated albumin [99mTc-MAA]) and the results recorded. A balloon-tip Fogarty catheter then was passed through the trachea and inflated at preselected endobronchial sites to produce bronchial occlusion and volume loss, which were documented radiographically. Because one animal had two such occlusions sequentially, a total of 12 volume reduction experiments were performed. After inducing volume loss, perfusion imaging was repeated without reinjection of 99mTc-MAA to allow any changes in the perfusion defects to be recorded, measured, and compared with the degree of volume loss visualized radiographically. RESULTS: Volume loss did not alter the shape of ipsilateral scintigraphic perfusion defects, but it did result in the expansion of eight of the 12 perfusion defects (range = 18-137% increase in area, Mdn = 33%) and a 28% decrease in the size of one defect located within a lobe that lost volume. Despite these quantitative changes, only three of the perfusion defects appeared substantially larger. When independently interpreted radiographs demonstrated large volume losses, quantitative changes in perfusion defects were no greater on average than when radiographic volume loss was modest. CONCLUSION: Loss of pulmonary volume is occasionally associated with considerable ipsilateral alterations in the size of scintigraphic perfusion defects. It is probably advisable to consider the effects of anatomic distortions such as volume loss when interpreting the significance of scintigraphic perfusion defects in patients suspected of having PE.

Animals↗
PubMed1999

Osteogenic effect of a gastric pentadecapeptide, BPC-157, on the healing of segmental bone defect in rabbits: a comparison with bone marrow and autologous cortical bone implantation.

Gastrectomy often results in increased likelihood of osteoporosis, metabolic aberration, and risk of fracture, and there is a need for a gastric peptide with osteogenic activity. A novel stomach pentadecapeptide, BPC-157, improves wound and fracture healing in rats in addition to having an angiogenic effect. Therefore, in the present study, using a segmental osteoperiosteal bone defect (0.8 cm, in the middle of the left radius) that remained incompletely healed in all control rabbits for 6 weeks (assessed in 2 week intervals), pentadecapeptide BPC-157 was further studied (either percutaneously given locally [10 microg/kg body weight] into the bone defect, or applied intramuscularly [intermittently, at postoperative days 7, 9, 14, and 16 at 10 microg/kg body weight] or continuously [once per day, postoperative days 7-21 at 10 microg or 10 ng/kg body weight]). For comparison, rabbits percutaneously received locally autologous bone marrow (2 mL, postoperative day 7). As standard treatment, immediately after its formation, the bone defect was filled with an autologous cortical graft. Saline-treated (2 mL intramuscularly [i.m.] and 2 mL locally into the bone defect), injured animals were used as controls. Pentadecapeptide BPC-157 significantly improved the healing of segmental bone defects. For instance, upon radiographic assessment, the callus surface, microphotodensitometry, quantitative histomorphometry (10 microg/kg body weight i.m. for 14 days), or quantitative histomorphometry (10 ng/kg body weight i.m. for 14 days) the effect of pentadecapeptide BPC-157 was shown to correspond to improvement after local application of bone marrow or autologous cortical graft. Moreover, a comparison of the number of animals with unhealed defects (all controls) or healed defects (complete bony continuity across the defect site) showed that besides pentadecapeptide intramuscular application for 14 days (i.e., local application of bone marrow or autologous cortical graft), also following other pentadecapeptide BPC-157 regimens (local application, or intermittent intramuscular administration), the number of animals with healed defect was increased. Hopefully, in the light of the suggested stomach significance for bone homeostasis, the possible relevance of this pentadecapeptide BPC-157 effect (local or intramuscular effectiveness, lack of unwanted effects) could be a basis for methods of choice in the future management of healing impairment in humans, and requires further investigation.

Animals↗
PubMed2007

Microscopic description of elementary growth processes and classification of structural defects in pentacene thin films.

Elementary growth processes such as kink initiation, adding a molecule to a kink, and adding a molecule between two neighboring kinks and between two grains are theoretically studied in pentacene films by adding one molecule at a time to a predefined aggregate. For each molecule, the potential energy surface is calculated using the MM3 molecular mechanics force field, which allowed one to identify useful parameters like the energy barrier for diffusion and the energy to create kinks, as well as defect configurations. Depending on the properties of the potential energy surface and the resulting growth-condition-dependent probabilities of initiating defect configurations in the film, three types of pentacene defects are identified: a thermally activated defect, an intrinsic defect, and a kinetic defect. Upon film growth, most defects relax into the ideal crystal configuration. Bulk defects that resist relaxation have densities lower than 10(16) defects/cm3 at typical growth conditions. Grain boundary defects, on the other hand, are very stable. Moreover, interstitial molecules at grain boundaries are identified as a source of compressive stress.

Journal Article↗
PubMedDate not supplied

Effect of membranes and porous hydroxyapatite on healing in bone defects around titanium dental implants. An experimental study in monkeys.

The purpose of the present study was to examine the effect of treating bony craters around titanium dental implant with polytetrafluoroethylene membranes (PTFE), with and without grafting of hydroxyapatite (HA), and with HA alone. 4 standardized bone defects were prepared in the alveolar ridge of edentulous areas in each of 7 monkeys. A titanium implant was then placed centrally in each defect, and in each monkey, the defects were treated with 1 of the following 4 treatment modalities: (1) coverage with PTFE membrane; (2) grafting of HA and covering with a PTFE membrane; (3) HA grafting; (4) no treatment. Following a healing period of 12 weeks, all animals were sacrificed and mesio-distal ground sections of the treated areas were prepared. The histological analysis showed that all bone defects around the implants treated with PTFE membranes and 5 of the defects treated with HA and PTFE membranes were completely filled with new bone. The defects treated with HA alone and thecontrol defects with no treatment only demonstrated new bone formation in the bottom of the defects. The results suggest that bone defects around titanium implants can be treated wuccessfully with PTFE membranes.

Alveolar Bone Loss↗
PubMed1994

Guided bone regeneration in mandibular defects in rats using a bioresorbable polymer.

The aim of this study was to explore the possibility of obtaining bone regeneration in jaw bone defects in rats after coverage of the defects with an occlusive bioresorbable membrane. The experiment was carried out in 31 rats. The mandibular ramus was exposed in both sides and a 2 x 3 mm defect was produced at its lower border. A gutta-percha point was placed to indicate the original level of the border. The defect on one side was covered with a polyhydroxybutyrate resorbable membrane, whereas the contralateral side received no membrane before closure of the wound. Macerated jaw specimens representing 3 and 6 months of healing demonstrated minimal bone fill in the control defects, whereas all test defects healed to or close to the gutta-percha point, indicating the original inferior border of the jaw. The histological analysis demonstrated increasing bone fill in the test specimens from 15-180 days, whereas only 35-40% of the defect area in the control sides was filled with bone after 3-6 months. Ingrowth of muscular, glandular and connective tissue was consistently occurring in the control defects during healing. It can be concluded that selective repopulation of bone defects with bone-forming cells can be ensured by excluding surrounding soft tissues from the wound area with an occlusive bioresorbable membrane.

Alveolar Bone Loss↗
PubMed1999

Reconstruction of anatomically complicated periodontal defects using a bioresorbable GTR barrier supported by bone mineral. A 6-month follow-up study of 6 cases.

6 anatomically complicated periodontal intrabony defects in 6 patients were surgically reconstructed using a bioresorbable GTR barrier supported by cancellous bovine bone mineral. Following cause-related periodontal treatment, open-flap surgery was performed to expose the defects. After debridement, the defects were filled with the bone mineral and covered with the barrier. All patients were advised to rinse 2 x daily with an 0.2% chlorhexidine digluconate solution and to avoid brushing in the operated area for 6 weeks. The treatment results were evaluated clinically and radiographically 6 months after surgery. All defects healed uneventfully and all patients maintained a high standard of plaque control throughout the study. Probing assessments during surgery showed a bone defect depth and width of on average 7.2 and 2.8 mm. The corresponding measures on presurgical intra-oral radiographs were 7.9 and 2.6 mm, respectively. Clinical attachment level (CAL) gain averaged 5.3 mm, corresponding to 73% of the original bone defect depth. Radiographically, the defect fill averaged 6.2 mm or 80% of the original radiographic bone defect. It was concluded that the placement of bovine bone mineral beneath bioresorbable GTR barriers facilitates the clinical handling of the barrier and enhances the space for potential periodontal reconstruction of anatomically complicated defects. It remains, however, to be ascertained to what degree the achieved clinical and radiographic results reflect a gain in new connective tissue attachment and alveolar bone.

Adult↗
PubMed1999

Clinical evaluation of Bio-Oss: a bovine-derived xenograft for the treatment of periodontal osseous defects in humans.

The purpose of this study was to compare the bovine derived xenograft (BDX) Bio-Oss to demineralized freeze dried bone allograft (DFDBA) in human intrabony defects. 17 healthy patients with no systemic disease with moderate-severe periodontitis (7 males, 10 females; aged 34-67), were treated. Surgically, defects were included only if the intraosseous defect depth was >3.0 mm. Final selection included 30 defects. The sites were randomly assigned treatment with DFDBA or BDX. Soft tissue and osseous defect measurements were taken the day of surgery and 6 months post-operatively at re-entry. Average baseline PD, CAL, and surgical defect depth for the DFDBA group were not statistically different from the BDX group. No adverse healing response occurred. The results showed a statistically significant improvement in PD and AL for both materials at 6 months in 26 defects (4 defects did not respond to therapy). Soft tissue measurements for the DFDBA group included PD reduction of 2.0+/-1.3 mm, and AL gain of 2.6+/-1.6 mm, while the BDX group showed a PD reduction of 3.0+/-1.7 mm, and AL gain of 3.6+/-1.8 mm. Osseous measurements showed bone fill of 2.4 mm (46.8%) for the DFDBA group and 3.0 mm (55.8%) for the BDX group. Defect resolution was 59.4% for the DFDBA group and 77.6% for the BDX group. Statistical analysis revealed there was no statistical difference between the 2 materials in all measurements.

Adult↗
PubMed1995

Diffuse and localised visual field defects to automated perimetry in primary open angle glaucoma.

The occurrence of generalised or diffuse visual field depression in primary open angle glaucoma (POAG), in contrast to the presence of characteristic localised defects, is controversial. The frequency of diffuse visual field loss to automated static perimetry in the early stages of POAG was determined and compared with the frequency of localised defects. Twenty-five eyes of 25 consecutive POAG patients who met the selection criteria were tested on the Humphrey Visual Field Analyser with the Central 30-2 Threshold Test. Patients' mean age was 68 years. All eyes had visual acuity better than 6/9 with correction, refractive error of less than +/- 7 dioptres, no media opacities and normal pupils (3-6 mm). For all eyes, the frequency of abnormality on the STATPAC Total Deviation (TD) and Pattern Deviation (PD) plots were determined for all individual test points. Mean values and standard deviations were compared. The TD plots represent a composite of both diffuse and localised visual field depression, while PD plots are intended to reflect localised field defects. The frequency of involvement of the test points on the TD plots was higher than on the PD plots (mean +/- SD: 41.5 +/- 11.2% vs 27.5 +/- 10.9%) for all presenting defects. When only deep defects (STATPAC p < 1% and p < 0.5%) were evaluated, TD involvement was still more frequent than the PD (20.1 +/- 9.4% vs 13.2 +/- 7.2%). The topographical pointwise incidence of pure generalised sensitivity loss in the visual field was less frequent when only deep defects were taken into consideration (6.9 +/- 5.7%), and the incidence increased progressively with the inclusion of intermediate and shallow field defects (9.6 +/- 6.8% and 14.0 +/- 8.4% respectively). A component of diffuse sensitivity depression is present at all significant levels of visual field loss in glaucoma. This component of generalised loss decreases as the depth of the field defects increases. This finding suggests that early diffuse field loss converts into well-defined pattern defects at later stages.

Adult↗
PubMed2006

DNA mismatch repair and TP53 defects are early events in uterine carcinosarcoma tumorigenesis.

Growing molecular evidence shows that uterine carcinosarcomas are clonal tumors. The carcinoma component has a dominant effect in the aggressive clinical behavior of these tumors. Defective DNA mismatch repair affects up to 30% of endometrial adenocarcinomas. The frequency and importance of defective DNA mismatch repair in the histiogenesis of uterine carcinosarcomas remains controversial. We studied the pattern and frequency of defective DNA mismatch repair and TP53 alterations in the epithelial and mesenchymal components of 28 uterine carcinosarcomas. We found evidence of defective DNA mismatch repair in six cases (21%) with a concordance rate of 83% for carcinoma-sarcoma pairs (kappa=0.887, P<0.001). Lack of immunostaining for the MLH1 protein was demonstrated in both components in two of these tumors. TP53 defects were evaluated by 17p deletion analysis and p53 immunostaining. Nineteen carcinoma (68%) and 18 sarcoma (64%) components had evidence of either TP53 allelic loss or p53 overexpression. These defects proved clonal in 76% of cases (kappa=0.602, P=0.003). Our results indicate that defective DNA mismatch repair and TP53 defects are common early events in carcinosarcoma tumorigenesis. The high rate of concordance for these molecular defects between the carcinoma and sarcoma components adds to existing molecular evidence that carcinosarcomas are clonal malignancies.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Bone regeneration in a rat cranial defect with delivery of PEI-condensed plasmid DNA encoding for bone morphogenetic protein-4 (BMP-4).

Gene therapy approaches to bone tissue engineering have been widely explored. While localized delivery of plasmid DNA encoding for osteogenic factors is attractive for promoting bone regeneration, the low transfection efficiency inherent with plasmid delivery may limit this approach. We hypothesized that this limitation could be overcome by condensing plasmid DNA with nonviral vectors such as poly(ethylenimine) (PEI), and delivering the plasmid DNA in a sustained and localized manner from poly(lactic-co-glycolic acid) (PLGA) scaffolds. To address this possibility, scaffolds delivering plasmid DNA encoding for bone morphogenetic protein-4 (BMP-4) were implanted into a cranial critical-sized defect for time periods up to 15 weeks. The control conditions included no scaffold (defect left empty), blank scaffolds (no delivered DNA), and scaffolds encapsulating plasmid DNA (non-condensed). Histological and microcomputed tomography analysis of the defect sites over time demonstrated that bone regeneration was significant at the defect edges and within the defect site when scaffolds encapsulating condensed DNA were placed in the defect. In contrast, bone formation was mainly confined to the defect edges within scaffolds encapsulating plasmid DNA, and when blank scaffolds were used to fill the defect. Histomorphometric analysis revealed a significant increase in total bone formation (at least 4.5-fold) within scaffolds incorporating condensed DNA, relative to blank scaffolds and scaffolds incorporating uncondensed DNA at each time point. In addition, there was a significant increase both in osteoid and mineralized tissue density within scaffolds incorporating condensed DNA, when compared with blank scaffolds and scaffolds incorporating uncondensed DNA, suggesting that delivery of condensed DNA led to more complete mineralized tissue regeneration within the defect area. This study demonstrated that the scaffold delivery system encapsulating PEI-condensed DNA encoding for BMP-4 was capable of enhancing bone formation and may find applications in other tissue types.

Animals↗
PubMed2000

Spontaneous development of drug resistance: mismatch repair and p53 defects in resistance to cisplatin in human tumor cells.

The contributions of defective mismatch repair and mutated p53 to cisplatin resistance of human tumor cells were analysed. Mismatch repair defects were not associated with a predictable degree of resistance among several tumor cell lines. Repair defective variants of the A2780 ovarian carcinoma cell line which were isolated by selection for a methylation tolerant phenotype and did not express the hMLH1 mismatch repair protein, were highly resistant to cisplatin. Their cisplatin resistance was not a simple consequence of the mismatch repair defect. They were members of a drug-naive subpopulation of A2780 in which a silent hMLH1 gene accompanies a mutated p53. Two complementary approaches indicated that each defect contributes to cisplatin resistance independently and to a different extent. Firstly, separate introduction of a p53 defect into A2780 cells significantly increased their cisplatin resistance; defective hMLH1 provided less extensive protection. Secondly, azadeoxycytidine reactivation of the silent hMLH1 gene or expression of a transfected hMLH1 cDNA sensitized the doubly hMLH1/p53 deficient cells only slightly to cisplatin. Both approaches indicate that defective p53 status is a major determinant of cisplatin resistance and defective mismatch repair is a minor, and independent, contributor. The data have implications for the development of intrinsic cisplatin resistance.

Adaptor Proteins, Signal Transducing↗