Abstract Partial-thickness burns incite a multitude of responses which eventually culminate in cutaneous wound repair. We hypothesized that these events would evoke extensive alterations in gene ...expression thereby orchestrating the complexity of spatial and temporal events that characterize “normal” human wound healing. In the present study, gene expression from partial-thickness areas at defined temporal periods (1–3 days, 4–6 days, and 7–18 days) after injury were compared to normal non-wounded skin. Gene alterations proved extensive (2286 genes). Statistically significant alterations were noted among increased and decreased genes expressed in the three different temporal groupings. Our foundational data (based on samples from 45 individuals) provide a comprehensive molecular gene expression portrait of the cutaneous reparative responses that are initiated during the first 17 days after injury. Our efforts also represent an initial endeavor to move beyond the historically defined “morphological phases” of wound repair toward reporting molecular clues that define the temporal sequence of healing in human subjects. Further analysis of genes that are either affected or remain not affected following injury to normal skin is expected to identify potential targets for therapeutic augmentation or silencing.
Delayed Wound Healing in CXCR2 Knockout Mice Devalaraja, Radhika M.; Nanney, Lillian B.; Qian, Qinghua ...
Journal of investigative dermatology,
08/2000, Letnik:
115, Številka:
2
Journal Article
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Previous studies demonstrated that the CXC chemokine, MGSA/GRO-α and its receptor, CXCR2, are expressed during wound healing by keratinocytes and endothelial cells at areas where epithelialization ...and neovascularization occur. The process of wound healing is dependent on leukocyte recruitment, keratinocyte proliferation and migration, and angiogenesis. These processes may be mediated in part by CXC chemokines, such as interleukin-8 and MGSA/GRO-α. To examine further the significance of CXC chemokines in wound healing, full excisional wounds were created on CXCR2 wild-type (+/+), heterozygous (+/–), or knockout (–/–) mice. Wounds were histologically analyzed for neutrophil and monocyte infiltration, neovascularization and epithelialization at days 3, 5, 7, and 10 postwounding. The CXCR2 –/– mice exhibited defective neutrophil recruitment, an altered temporal pattern of monocyte recruitment, and altered secretion of interleukin-1β. Significant delays in wound healing parameters, including epithelialization and decreased neovascularization, were also observed in CXCR2 –/– mice. In vitro wounding experiments with cultures of keratinocytes established from –/– and +/+ mice revealed a retardation in wound closure in CXCR2 –/– keratinocytes, suggesting a role for this receptor on keratinocytes in epithelial resurfacing that is independent of neutrophil recruitment. These in vitro and in vivo studies further establish a pathophysiologic role for CXCR2 during cutaneous wound repair.
BACKGROUND & AIMS: Mutations in the APC gene result in an increased propensity to develop intestinal neoplasia; however, a complete understanding of the mechanisms resulting in tumor formation has ...remained elusive. Min mice possess a mutation in the APC gene and display a neoplastic phenotype similar to that observed in familial adenomatous polyposis coli in humans. Cyclooxygenase (COX) inhibitors decrease tumor multiplicity in the Min mouse intestine. The present study was designed to determine if there was an increase in COX-2 in adenomas harvested from Min mouse intestine.
METHODS: COX-2 messenger RNA levels were determined by Northern blots and reverse-transcription polymerase chain reactions of B6Min x 129 mouse-derived tumors. Protein levels and localization were determined by Western blots and immunohistochemical staining.
RESULTS: The Northern blots revealed an approximately threefold increase in the level of COX-2 messenger RNA in Min mouse adenoma compared with normal mucosa. COX-2 protein levels in adenomatous tissues were also approximately threefold higher compared with normal mucosa from the same mouse. Immunohistochemical staining with a monospecific COX-2 antibody confirmed that increases in COX-2 immunoreactivity were restricted to dysplastic and neoplastic foci within intestinal mucosa.
CONCLUSIONS: These data show that COX-2 levels may be increased at an early stage in colorectal neoplasia during polyp formation and before invasion. (Gastroenterology 1996 Oct;111(4):1134-40)
Introduction:
Multi-modality imaging is a crucial component of cardiovascular (CV) fellowship training and requires knowledge of CV anatomy for interpretation. We hypothesized that hands-on anatomy ...education would improve the imaging interpretation skills of CV fellows.
Methods:
The first-year CV fellowship class completed a hands-on cadaveric anatomy session correlated with clinical imaging. Fellows’ ability to identify CV structures on cardiac imaging was assessed using a 30-question assessment tool administered at baseline and 1 week and 6 months post intervention. Advanced CV fellows (second or third year) who had not attended the session were also tested. Scores were expressed as median interquartile range.
Results:
Among 9 first-year fellows, the majority reported no formal anatomy training since medical school (N = 7) and rated their knowledge of CV anatomy as fair or poor (N = 7) prior to the intervention. The median assessment score was higher 1 week after intervention vs baseline (24 23-25 vs 19 17-21; P = .013) and remained higher than baseline at 6 months (26 26-28 vs 19 17-21; P = .009). The 6-month post-intervention score for first-year fellows was not significantly different than that of senior fellows (n = 10) not exposed to the intervention (26 26-28 vs 26 23-27; P = .434).
Conclusions:
Gross anatomy instruction improved first-year CV fellows’ interpretation of CV imaging. Anatomic instruction may be a useful adjunct to multi-modality imaging education.
Continuous expression of the MGSA/GROalpha, beta, or gamma chemokine bestows tumor-forming capacity to the immortalized murine melanocyte cell line, melan-a. The mechanism for this transformation is ...unclear, although both autocrine and paracrine processes are possible because melan-a cells as well as endothelial cells express a low level of the receptor for this ligand. To further define the role of MGSA/GRO proteins in melanocyte transformation, two types of experiments were designed to neutralize the biological effects of MGSA/GRO in the transfected melan-a clones: (1) the effect of neutralizing antiserum to MGSA/GRO proteins on melan-a tumor growth was assessed; (2) the tumor-forming capacity of melan-a clones expressing ELR motif-mutated forms of MGSA/GRO with compromised receptor affinity was compared to the tumor-forming capacity of clones expressing wild-type MGSA/GRO. These experiments revealed that SCID mice inoculated with MGSA/GROalpha- or gamma-expressing melan-a cells and subsequently treated with antiserum to the respective chemokine exhibited decreased tumor growth. This reduction in tumor growth was accompanied by declining angiogenic activity in MGSA/GROgamma-expressing tumors. Moreover, athymic nude mice injected with melan-a cells expressing ELR-mutant forms of MGSA/GROalpha exhibited markedly impaired tumor-forming capacity compared with those mice injected with melan-a clones expressing wild-type MGSA/GRO. These data suggest that continuous expression of MGSA/GRO proteins may facilitate tumor growth by stimulating the growth of microvessels into the tumor (paracrine) and by affecting melanocyte growth (autocrine).
Adhesion formation after abdominal operations causes significant morbidity.
Adhesion formation in pigs was compared after placement of prosthetic mesh during celiotomy (group 1), laparoscopy with ...large incision (group 2), and laparoscopy (group 3). After peritoneum was excised, polypropylene mesh was fixed to the abdominal wall, then to the opposite abdominal wall in the preperitoneal space followed by peritoneal closure. Adhesion area, grade, and vascularity were measured.
More adhesions (p < 0.02) covered intraperitoneal mesh (7.57 +/- 1.89 cm2) than covered reperitonealized mesh (2.16 +/- 1.13 cm2), and adhesion grade was significantly greater (p < 0.02). Adhesion areas were significantly greater in groups 1 and 2 than in group 3 (p = 0.001 and 0.03, respectively). Adhesion grade was significantly greater in groups 1 and 2 than in group 3 (p = 0.02 and p = 0.04, respectively). Groups 1 and 2 had more vascular adhesions than group 3 (p < 0.01 and p = 0.02, respectively)
A foreign body within the peritoneum stimulates more numerous and denser adhesions. Tissue trauma distant from the site of adhesions increases their formation. A major advantage of laparoscopic surgery is decreased adhesion formation.
Selection of the ideal antiseptic or antimicrobial treatment for contaminated wounds remains a controversial decision. Clinical decisions are often made on the basis of in vitro studies and personal ...preference. Although topical solutions are widely used, their comparative in vivo effects on wound healing are largely unreported.A porcine wound model was used to compare five commonly used topical agents-5% mafenide acetate (Sulfamylon solution), 10% povidone with 1% free iodine (Betadine), 0.25% sodium hypochlorite ("half-strength" Dakin), 3% hydrogen peroxide, and 0.25% acetic acid-with a control group. Reepithelialization, angiogenesis, neodermal regeneration, fibroblast proliferation, collagen production, and bacterial colony counts were analyzed at 4 and 7 days after wounding (n = 4). Reepithelialization was not significantly influenced among the various treatment modalities tested. Sulfamylon and Dakin solutions significantly increased neodermal thickness (p < 0.05), whereas hydrogen peroxide and acetic acid significantly inhibited neodermal formation (p < 0.001). All treatments except hydrogen peroxide significantly increased fibroblast proliferation. Sulfamylon and Betadine significantly enhanced angiogenesis (p < 0.05). Sulfamylon proved most effective in maintaining an aseptic environment while concomitantly increasing angiogenesis, fibroblast proliferation, and dermal thickness compared with control. These data show that selection of a particular topical treatment can affect various aspects of wound repair in an animal model. These results suggest that the selection of topical treatments in the clinical setting should be carefully tailored to match unique wound situations and therapeutic endpoints.
Cyclin D1 is a known oncogene and a key regulator of cell cycle progression. Amplification of the cyclin D1 gene and its overexpression have been associated with aggressive forms of human ...hepatocellular carcinoma (HCC). In this study, two independent lines of transgenic mice have been generated that express cyclin D1 under the control of the rat liver fatty acid binding protein promoter. This transgene specifically directs expression in the liver and the intestines. RNA and protein analysis demonstrated increased expression of the cyclin D1 gene product in the liver and bowel when compared with wild-type siblings. Both transgenic lines developed progressive liver disease. Examination of H&E stained sections of the liver and bowel revealed hyperplastic changes in the liver by 3 months of age. By 6 months of age, transgenic mice had obvious hepatomegaly and histological evidence of dysplasia in the liver. These early changes were significantly more dramatic in male animals when compared with female animals. By 9 months of age adenomas of the liver appeared, progressing to HCC over the ensuing 6-month period. By 15-17 months of age, 87% of male and 69% of female animals had either adenomatous nodules or HCCs. By 17 months of age, 31% of male and female animals had disease that had progressed to HCC. These animals represent a unique and significant new model for the study of human HCC. This study demonstrates that overexpression of cyclin D1 is sufficient to initiate hepatocellular carcinogenesis.
No Trivial Pursuit NANNEY, DAVID L
Bioscience,
08/2004, Letnik:
54, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Nanney contends that a major outcome of the recent studies in molecular phylogeny--from the spiders of Hawaii to the corals of the Caribbean--is that similarity of form is no guarantee of genetic and ...ecological equivalence. This lesson applies with particular force to morphological studies of microscopic organisms, especially since genetic and molecular studies of the few protists happily established in the laboratory demonstrate them to be composed of multiple genetically distinct species.
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