Lack of Syndecan-1 promotes the pathogenesis of experimental rheumatoid arthritis.

Syndecan-1 (Sdc-1), a transmembrane heparan sulfate protein, is implicated in several pathophysiological processes including rheumatoid arthritis (RA). The exact role of Syndican-1 in this autoimmune disease is still undetermined. This study explores the involvement level of Sdc-1 in the development of RA in a collagen II-induced arthritis mice model. RA was induced in two mice strains (wild-type BALB/c group and Sdc-1 knockout) by collagen II. Mice underwent regular clinical observations and scoring. After sacrifice, leg biopsies were taken from mice for histological examination, using a variety of stains. In addition, proteins were extracted, and molecular assessment of TNF-α was performed using the western blot technique. In the Sdc-1 knockout group, clinical scoring results showed a significantly more severe experimental RA; histology showed a significant increase in bone erosion, cartilage destruction, inflammation, and less granulated mast cells than the wild-type. In addition, molecular assessment of TNF-α showed more increase in expression in the Sdc-1 knockout models compared to the wild-type. Data suggest that lack of Sdc-1 enhances the inflammatory characteristics in RA. However, more molecular studies and investigations are needed to determine its exact role and possible mechanisms involved.

Faculty leadership development: A case study of a synergistic approach.

INTRODUCTION: Ongoing leadership development is essential for academic health center faculty members to respond to increasing environmental complexity. At the George Washington University School of Medicine and Health Sciences, an 8-month program, based on Conger's leadership development approach emphasizing conceptual understanding, skill building, feedback and personal growth was offered to mid-level faculty charged with developing educational programs, clinical services, and/or research initiatives. We studied how specific learning methods catering to different learning approaches contributed to improving leadership competencies. METHODS: Session and program evaluations, participant interviews, mentor surveys, and supervisor interviews were used for data collection. Themes were identified through open coding with use of constant comparative methods to help find patterns in the data. RESULTS: Readings and classroom modules provided a broadened, holistic understanding of leadership; role plays and action plans helped participants apply and practice leadership skills; self-assessments and feedback from peers and mentors provided specifics for focusing development efforts; and personal growth exercises provided opportunities to reflect and consider fresh perspectives. Anchoring learning methods around a real-time project led to improved leadership competencies and personal confidence as reported by participants, supervisors and mentors. CONCLUSION: A faculty leadership development program that integrates understanding, skill building, feedback and personal growth and connects multiple learning methods can provide the synergy to facilitate behavior change and organizational growth.

The process of curricular integration and its effects on anatomical knowledge retention.

INTRODUCTION: Integration has been recognized as an important aspect of medical education. After transitioning from a discipline-specific to a systems-based preclinical curriculum, we examined faculty perceptions of the integrated approach and also whether it would lead to better anatomy knowledge retention. METHODS: To understand faculty perspectives, we reviewed curricular materials, interviewed block directors, and observed educational sessions. We analyzed knowledge retention through a 27-question anatomy test, comparing scores from the last class of the discipline-based curriculum and the first two classes of the integrated curriculum. RESULTS: Planning integrated content involves purposeful ordering, is challenging for faculty, and requires additional resources. Evaluation of the integrated approach for anatomy content demonstrated a significant increase in knowledge retention (p = .012; 56.28% vs. 63.98% for old vs. new curriculum). CONCLUSIONS: This study helps the understanding of what is required for curricular integration. Our anatomy evaluation results corroborated the view that contextually embedded information is easier to learn and retain.

Using ultrasound to teach living anatomy to non-medical graduate students.

PURPOSE: Ultrasound technology is used to supplement gross anatomy instruction in many medical sciences programs. However, this technology is not common practice for anatomy instruction in nonmedical graduate-level courses. Ultrasound sessions provide a clear view of local anatomy and could help graduate students transfer anatomical content from a didactic context onto a living, moving body. This approach to instruction complements the rapidly evolving technological advances in science education and may assist with spatial understanding, knowledge retention, and student engagement. The main objective of this article was to describe the methods used to incorporate ultrasound sessions into a graduate level gross anatomy course. METHODS: The goal of the curricula was to use ultrasound technology to create a supplemental hands-on and engaging method of learning anatomy that would appeal to graduate students and possibly reinforce content. Graduate students participated in three interactive, 2-h-long ultrasound sessions that corresponded to their gross anatomy lecture material. RESULTS: Questionnaire results showed that students overwhelmingly believed that the ultrasound sessions were beneficial and that ultrasound technology should be used for anatomical instruction in graduate programs. While students found the sessions to be helpful, they sought more and longer sessions with smaller group sizes. CONCLUSION: Overall, this article describes the methods used to incorporate multimodal learning into a graduate level anatomy course and found that students supported the methods as a potentially effective and engaging way to supplement traditional gross anatomy lectures and practical laboratory sessions.

The Mechanism and Potential Therapeutic Effects of Cyclosporin, Cyclophilin, Probiotics and Syndecan-1 in an Animal Model of Inflammatory Bowel Disease.

Background: Inflammatory bowel diseases (IBDs) have several treatment modalities including immunoregulators, like cyclosporine A, an immunosuppressant that interacts with cytoplasmic cyclophilin A, and probiotics. Aims: This study explored and compared the possible role of syndecan-1 in the IBD pathogenic process as well as the effectiveness of cyclophilin A, cyclosporine A, and their combination in the management of IBDs in the presence of probiotics. Methodology: IBD was induced in a total of 112 mice equally divided between syndecan-1 knock-out (KO) and Balb/c wild-type mice, using 2% dextran sulfate sodium (DSS) followed by intraperitoneal treatment with cyclosporine A, cyclophilin A, or a combination of both. In addition, a daily dose of probiotics was given in their drinking water. The animals were monitored for clinical signs and symptoms and checked for gross pathologies in the abdomen after 3 weeks. Descending and sigmoid colon biopsies were collected and fixed for routine microscopy or frozen for protein extraction and molecular testing for IL-6, CD3, CD147, and beta 1 integrins as well as pAkt expression. Results: The data showed that the induction of IBD in the syndecan-1 KO mice was more severe at the clinical, histological, and molecular levels than in the wild type. The combined CypA-CyA treatment showed no added inhibitory effect compared to single-drug treatment in both strains. Probiotics added to the combination was more effective in the wild type and, when used alone, its inhibition of IL-6 was the highest. As for the CD147 marker, there were more suppressions across the various groups in the KO mice except for the probiotics-alone group. Concerning CD3, it was significantly increased by the CypA-CyA complex, which led to more inflammation in the KO mice. Probiotics had little effect with the combination. In relation to beta 1 integrins, the CypA-CyA combination made no significant difference from CyA alone, and adding probiotics to the combination resulted in higher beta 1 integrin expression in the KO mice. As for pAkt, it was very well expressed and upregulated in both strains treated with DSS, but the effect was much larger in the KO mice. In brief, the CypA-CyA complex showed a decrease in the expression of pAkt, but there was no added effect of both drugs. Probiotics along with the complex had a similar reduction effects in both strains, with a greater effect in the wild-type mice, while probiotics alone led to a similar reduction in pAkt expressions in both strains. Conclusions: The differential effects of CyA, CypA, probiotics, and their combinations on the various inflammatory markers, as well as the histological alterations and clinical signs and symptoms, speak in favor of a clear role of syndecan-1 in reducing inflammation. However, probiotics need to be considered after more explorations into the mechanisms involved in the presence of CypA and CyA especially since pAkt is less active in their presence.

Probiotics, gut microbiome, and cardiovascular diseases: An update.

Cardiovascular diseases (CVD) are one of the most challenging diseases and many factors have been demonstrated to affect their pathogenesis. One of the major factors that affect CVDs, especially atherosclerosis, is the gut microbiota (GM). Genetics play a key role in linking CVDs with GM, in addition to some environmental factors which can be either beneficial or harmful. The interplay between GM and CVDs is complex due to the numerous mechanisms through which microbial components and their metabolites can influence CVDs. Within this interplay, the immune system plays a major role, mainly based on the immunomodulatory effects of microbial dysbiosis and its resulting metabolites. The resulting modulation of chronic inflammatory processes was found to reduce the severity of CVDs and to maintain cardiovascular health. To better understand the specific roles of GM-related metabolites in this interplay, this review presents an updated perspective on gut metabolites related effects on the cardiovascular system, highlighting the possible benefits of probiotics in therapeutic strategies.

Mechanism of Action of Melatonin as a Potential Adjuvant Therapy in Inflammatory Bowel Disease and Colorectal Cancer.

Inflammatory bowel disease (IBD), a continuum of chronic inflammatory diseases, is tightly associated with immune system dysregulation and dysbiosis, leading to inflammation in the gastrointestinal tract (GIT) and multiple extraintestinal manifestations. The pathogenesis of IBD is not completely elucidated. However, it is associated with an increased risk of colorectal cancer (CRC), which is one of the most common gastrointestinal malignancies. In both IBD and CRC, a complex interplay occurs between the immune system and gut microbiota (GM), leading to the alteration in GM composition. Melatonin, a neuroendocrine hormone, was found to be involved with this interplay, especially since it is present in high amounts in the gut, leading to some protective effects. Actually, melatonin enhances the integrity of the intestinal mucosal barrier, regulates the immune response, alleviates inflammation, and attenuates oxidative stress. Thereby, the authors summarize the multifactorial interaction of melatonin with IBD and with CRC, focusing on new findings related to the mechanisms of action of this hormone, in addition to its documented positive outcomes on the treatment of these two pathologies and possible future perspectives to use melatonin as an adjuvant therapy.

Highlights on two decades with microbiota and inflammatory bowel disease from etiology to therapy.

Inflammatory Bowel diseases (IBDs) constitute a complex panel of disorders characterized with chronic inflammation affecting the alimentary canal along with extra intestinal manifestations. Its exact etiology is still unknown; however, it seems to be the result of uncharacterized environmental insults in the intestine and their immunological consequences along with dysbiosis, in genetically predisposed individuals. It was the main target of our team since 2002 to explore the etiology of IBD and the related role of bacteria. For almost two decades, our laboratory, among others, has been involved in the reciprocal interaction between the host gastrointestinal lining and the homing microbiota. In the first decade, the attention of scientists focused on the possible role of enteropathogenic E. coli and its relationship to the mechanistic pathways involved in IBD induced in both rats and mice by chemicals like Iodoacetamide, Dextran Sodium Sulfate, Trinitrobenzene, thus linking microbial alteration to IBD pathology. A thorough characterization of the various models was the focus of research in addition to exploring how to establish an active homeostatic composition of the commensal microbiota, including its wide diversity by restoration of gut microbiota by probiotics and moving from dysbiosis to eubiosis. In the last six years and in order to effectively translate such findings into clinical practice, it was critical to explore their relationship to colorectal cancer CRC both in solid tumors and chemically induced CRC. It was also critical to explore the degree of intestinal dysbiosis and linking to IBD, CRC and diabetes. Remarkably, the active mechanistic pathways were proposed as well as the role of microbiota or bacterial metabolites involved. This review covers two decades of investigations in our laboratory and sheds light on the different aspects of the relationship between microbiota and IBD with an emphasis on dysbiosis, probiotics and the multiple mechanistic pathways involved.

Exposure to particulate hexavalent chromium exacerbates allergic asthma pathology.

Airborne hexavalent chromate, Cr(VI), has been identified by the Environmental Protection Agency as a possible health threat in urban areas, due to the carcinogenic potential of some of its forms. Particulate chromates are produced in many different industrial settings, with high levels of aerosolized forms historically documented. Along with an increased risk of lung cancer, a high incidence of allergic asthma has been reported in workers exposed to certain inhaled particulate Cr(VI) compounds. However, a direct causal association between Cr(VI) and allergic asthma has not been established. We recently showed that inhaled particulate Cr(VI) induces an innate neutrophilic inflammatory response in BALB/c mice. In the current studies we investigated how the inflammation induced by inhaled particulate Cr(VI) might alter the pathology of an allergic asthmatic response. We used a well-established mouse model of allergic asthma. Groups of ovalbumin protein (OVA)-primed mice were challenged either with OVA alone, or with a combination of OVA and particulate zinc chromate, and various parameters associated with asthmatic responses were measured. Co-exposure to particulate Cr(VI) and OVA mediated a mixed form of asthma in which both eosinophils and neutrophils are present in airways, tissue pathology is markedly exacerbated, and airway hyperresponsiveness is significantly increased. Taken together these findings suggest that inhalation of particulate forms of Cr(VI) may augment the severity of ongoing allergic asthma, as well as alter its phenotype. Such findings may have implications for asthmatics in settings in which airborne particulate Cr(VI) compounds are present at high levels.

A cell-impermeable cyclosporine A derivative reduces pathology in a mouse model of allergic lung inflammation.

Although the main regulators of leukocyte trafficking are chemokines, another family of chemotactic agents is cyclophilins. Intracellular cyclophilins function as peptidyl-prolyl cis-trans isomerases and are targets of the immunosuppressive drug cyclosporine A (CsA). Cyclophilins can also be secreted in response to stress factors, with elevated levels of extracellular cyclophilins detected in several inflammatory diseases. Extracellular cyclophilins are known to have potent chemotactic properties, suggesting that they might contribute to inflammatory responses by recruiting leukocytes into tissues. The objective of the present study was to determine the impact of blocking cyclophilin activity using a cell-impermeable derivative of CsA to specifically target extracellular pools of cyclophilins. In this study, we show that treatment with this compound in a mouse model of allergic lung inflammation demonstrates up to 80% reduction in inflammation, directly inhibits the recruitment of Ag-specific CD4(+) T cells, and works equally well when delivered at 100-fold lower doses directly to the airways. Our findings suggest that cell-impermeable analogs of CsA can effectively reduce inflammatory responses by targeting leukocyte recruitment mediated by extracellular cyclophilins. Specifically blocking the extracellular functions of cyclophilins may provide an approach for inhibiting the recruitment of one of the principal immune regulators of allergic lung inflammation, Ag-specific CD4(+) T cells, into inflamed airways and lungs.

Blocking cyclophilins in the chronic phase of asthma reduces the persistence of leukocytes and disease reactivation.

Allergic asthma is characterized by acute influxes of proinflammatory leukocytes in response to allergen stimulation, followed by quiescent (chronic) periods between allergen challenges, during which sustained, low-level inflammation is evident. These chronic phases of disease are thought to be mediated by populations of leukocytes persisting within airways and tissues. The lack of any in situ proliferation by these cells, along with their limited lifespan, suggests that a continual recruitment of leukocytes from the circulation is needed to maintain disease chronicity. The mechanisms regulating this persistent recruitment of leukocytes are unknown. Although classic leukocyte-attracting chemokines are highly elevated after acute allergen challenge, they return to baseline levels within 24 hours, and remain close to undetectable during the chronic phase. In the present study, we investigated whether an alternative family of chemoattractants, namely, extracellular cyclophilins, might instead play a role in regulating the recruitment and persistence of leukocytes during chronic asthma, because their production is known to be more sustained during inflammatory responses. Using a new murine model of chronic allergic asthma, elevated concentrations of extracellular cyclophilin A, but not classic chemokines, were indeed detected during the chronic phase of asthma. Furthermore, blocking the activity of cyclophilins during this phase reduced the number of persisting leukocytes by up to 80%. This reduction was also associated with a significant inhibition of acute disease reactivation upon subsequent allergen challenge. These findings suggest that blocking the function of cyclophilins during the chronic phase of asthma may provide a novel therapeutic strategy for regulating disease chronicity and severity.

Syndecan-1 regulates cell migration and fibronectin fibril assembly.

Corneal scarring is a major cause of blindness worldwide and can result from the deposition of abnormal amounts of collagen fibers lacking the correct size and spacing required to produce a clear cornea. Collagen fiber formation requires a preformed fibronectin (FN) matrix. We demonstrate that the loss of syndecan1 (sdc1) in corneal stromal cells (CSC) impacts cell migration rates, the sizes and composition of focal and fibrillar adhesions, the activation of integrins, and the assembly of fibronectin into fibrils. Integrin and fibronectin expression are not altered on sdc1-null CSCs. Cell adhesion, spreading, and migration studies using low compared to high concentrations of FN and collagen I (CNI) or vitronectin (VN) with and without activation of integrins by manganese chloride show that the impact of sdc1 depletion on integrin activation varies depending on the integrin-mediated activity evaluated. Differences in FN fibrillogenesis and migration in sdc1-null CSCs are reversed by addition of manganese chloride but cell spreading differences remain. To determine if our findings on sdc1 were specific to the cornea, we compared the phenotypes of sdc1-null dermal fibroblasts with those of CSCs. We found that without sdc1, both cell types migrate faster; however, cell-type-specific differences in FN expression and its assembly into fibrils exist between these two cell types. Together, our data demonstrate that sdc1 functions to regulate integrin activity in multiple cell types. Loss of sdc1-mediated integrin function results in cell-type specific differences in matrix assembly. A better understanding of how different cell types regulate FN fibril formation via syndecans and integrins will lead to better treatments for scarring and fibrosis.

Loss of syndecan-1 is associated with malignant conversion in skin carcinogenesis.

Syndecan-1 (sdc-1) is a cell surface proteoglycan that mediates the interaction of cells with their matrix, influencing attachment, migration, and response to growth factors. In keratinocytes, loss of sdc-1 delays wound healing, reduces migration, and increases Transforming growth factor beta (TGFbeta) 1 expression. In this study we show that sdc-1 expression is significantly reduced in basal cell, squamous cell, and metastatic human skin cancers compared to normal human skin. In experimental mouse skin tumor induction, compared to wildtype (wt) BALB/c mice, papilloma formation in sdc-1 null mice was reduced by 50% and the percent of papillomas converting to squamous cell carcinoma (SCC) was enhanced. sdc-1 expression on wt mouse papillomas decreased as they converted to SCC. Furthermore, papillomas forming on sdc-1 null mice expressed suprabasal alpha3 and beta4 integrins; suprabasal beta4 integrin is a marker of a high risk for progression. While the proliferative response to phorbol-12-myristate-13-acetate (TPA) did not differ among the genotypes, sdc-1 null mice had an enhanced inflammatory response and retained higher levels of total TGFbeta1 within their skin after TPA treatment. sdc-1 null keratinocytes, transduced in vitro by oncogenic ras(Ha), expressed higher levels of beta4 integrin and had enhanced pSmad2 signaling and reduced senescence when compared to wt ras(Ha)-transduced keratinocytes. When ras(Ha)-transduced cells of both genotypes were grafted onto nude mice, null tumors converted to SCC with higher frequency confirming the skin painting experiments. These data indicate that sdc-1 is important both early in the development of skin tumors and in progression of skin cancers suggesting that reduced expression of sdc-1 could be a useful marker for progression in neoplastic skin lesions.

Metformin and Probiotics in the Crosstalk between Colitis-Associated Colorectal Cancer and Diabetes in Mice.

The co-occurrence of colorectal cancer (CRC) and diabetes mellitus along with inflammation and dismicrobism has been frequently reported. Several studies shed light on the antioncogenic potential of metformin on colorectal carcinogenesis. This study aimed to demonstrate that metformin in association with probiotics acts in a synergic effect in breaking the crosstalk, thus inhibiting CRC progression, improving diabetes, and reducing inflammation. Ninety-six male Balb/c mice, 6-8 weeks old, were divided into 16 control and experimental groups to assess the effect of the different treatments and combinations at the clinical, histological, and molecular levels. Metformin and probiotics showed beneficial outcomes on CRC and diabetes, alone and most importantly in combination. Their effects were exerted by inhibiting the inflammatory process whereby a downregulation of IL-6 and TNF-α as well as oxidative stress were depicted. The characterization of the effects of probiotics and metformin on CRC and diabetes sheds light on the role of inflammation and microbiota in this crosstalk. Deciphering the downstream signaling pathways elicited by these compounds will help in developing new effective targeted treatment modalities.

Hsp60 as a Novel Target in IBD Management: A Prospect.

Inflammatory bowel disease (IBD) encompasses various pathological conditions similar but distinct that share a multifactorial etiology, including involvement of the intestinal barrier function, the immune system, and intestinal microorganisms. Hsp60 is a chaperonin component of the chaperoning system, present in all cells and tissues, including the intestine. It plays important roles in cell physiology outside and inside mitochondria, its canonical place of residence. However, Hsp60 can also be pathogenic in many conditions, the Hsp60 chaperonopathies, possibly including IBD. The various clinico-pathological types of IBD have a complicated mix of causative factors, among which Hsp60 can be considered a putatively important driver of events and could play an etiopathogenic role. This possibility is discussed in this review. We also indicate that Hsp60 can be a biomarker useful in disease diagnosing and monitoring and, if found active in pathogenesis, should become a target for developing new therapies. The latter are particularly needed to alleviate patient suffering and to prevent complications, including colon cancer.

BALB/c and C57BL6 mouse strains vary in their ability to heal corneal epithelial debridement wounds.

Genetically engineered mice are usually produced on a mixed genetic background and can be derived from several mouse strains including 129SvJ, C57BL6, and BALB/c. To determine whether differences in recurrent corneal epithelial erosions (RCEEs), corneal epithelial stem cell deficiency (CESCD), and cell migration rate vary between two different mouse strains (BALB/c and C57BL6), 8-week mice were subjected to 1.5 (small) or 2.8mm (large) manual debridement wounds and allowed to heal for 4 weeks. Syndecan-1 (sdc-1) null mice backcrossed seven generations onto a BALB/c genetic background were also included in the RCEE and CESCD studies to permit comparisons between genotypes within a single strain. After sacrifice, corneas were assessed for the presence of recurrent erosions; no fewer than 15 corneas were used for each strain or genotype studied. Data show that the frequency of recurrent erosions after small wounds was 81+/-9% in the C57BL6 mice, 73+/-2% in the BALB/c mice, and 32+/-6% in sdc-1 null mice. Neither strain developed CESCD after small wounds. The frequency of erosions after large wounds was greater (88+/-8%) in the C57BL6 mice compared to BALB/c (60+/-2%), and sdc-1 null mice (32+/-5%). Four weeks after the large wounds, fixed, flat mounted corneas were assessed for evidence of CESCD with antibodies against the conjunctival keratin K8 and the goblet cell marker, the mucin Muc5AC. The frequency of CESCD 4 weeks after the large wounds was significantly greater in the C57BL6 mice than in the BALB/c or sdc-1 null mice. To assess cell migration rates, corneas were subjected to 1.5mm wounds and allowed to heal for 12, 15, 18, 21, and 24h. After sacrifice, corneas were stained with Richardson stain (BALB/c) or propidium iodide (C57BL6) to assess reepithelialization rates. While reepithelialization rates were similar for the early times after wounding, by 24h the C57BL6 corneas had healed faster: 16 of 30 corneas from the C57BL6 mice were closed compared to 9 of 30 of the BALB/c wounds. BALB/c corneas appeared larger overall compared to C57BL6 corneas; measurements of the overall mass of the enucleated eyes and diameters of the flat-mounted corneas confirmed that C57BL6 eyes and corneas were 6.8% and 4.4% smaller respectively than those of BALB/c mice even though the masses of the two mouse strains at 8 weeks of age were identical. Using BrdU to label dividing cells, we found that 18 h after wounding, C57BL6 and BALB/c corneal epithelia showed similar numbers of proliferating cells. To determine if the enhanced corneal epithelial cell migration rate seen in the C57BL6 mice was specific to the cornea, we conducted time-lapse studies to assess random cell migration rates in vitro using primary cultures of mouse epidermal keratinocytes. Consistent with the in vivo data, epidermal keratinocytes derived from BALB/c mice migrated 60% slower than C57BL6 cells. These data prove that strain-specific differences in cell migration rate in vivo are present in the cornea and are accompanied by differences in the frequencies of recurrent erosions and corneal epithelial stem cell deficiency.

Primary dermal fibroblasts derived from sdc-1 deficient mice migrate faster and have altered alphav integrin function.

ABSTRACT The goal of this study is to determine whether dermal fibroblasts lacking syndecan-1 (sdc1) show differences in integrin expression and function that could contribute to the delayed skin and corneal wound healing phenotypes seen in sdc-1 null mice. Using primary dermal fibroblasts, we show that after 3 days in culture no differences in alpha-smooth muscle actin were detected but sdc-1 null cells expressed significantly more alphav and beta1 integrin than wildtype (wt) cells. Transforming growth factor beta1 (TGFbeta1) treatment at day 3 increased alphav- and beta1-integrin expression in sdc-1 null cells at day 5 whereas wt cells showed increased expression only of alphav-integrin. Using time-lapse studies, we showed that the sdc-1 null fibroblasts migrate faster than wt fibroblasts, treatment with TGFbeta1 increased these migration differences, and treatment with a TGFbeta1 antagonist caused sdc-1 null fibroblasts to slow down and migrate at the same rate as untreated wt cells. Cell spreading studies on replated fibroblasts showed altered cell spreading and focal adhesion formation on vitronectin and fibronectin-coated surfaces. Additional time lapse studies with beta1- and alphav-integrin antibody antagonists, showed that wt fibroblasts expressing sdc-1 had activated integrins on their surface that impeded their migration whereas the null cells expressed alphav-containing integrins which were less adhesive and enhanced cell migration. Surface expression studies showed increased surface expression of alpha2beta1 and alpha3beta1 on the sdc-1 null fibroblasts compared with wt fibroblasts but no significant differences in surface expression of alpha5beta1, alphavbeta3, or alphavbeta5. Taken together, our data indicates that sdc-1 functions in the activation of alphav-containing integrins and support the hypothesis that impaired wound healing phenotypes seen in sdc-1 null mice could be due to integrin-mediated defects in fibroblast migration after injury.

Inflammatory bowel disease in rats: bacterial and chemical interaction.

AIM: To develop a novel model of colitis in rats, using a combination of iodoacetamide and enteropathogenic E. coli (EPEC), and to elucidate the pathophysiologic processes implicated in the development of ulcerative colitis (UC). METHODS: Male Sprague-Dawley rats (n = 158) were inoculated intrarectally on a weekly basis with 4 different combinations: (a) 1% methylcellulose (MC), (b) 100 microL of 6% iodoacetamide (IA) in 1% MC, (c) 200 microL containing 4 x 10(8) colony factor units (CFU) of EPEC, and (d) combined treatment of (IA) followed by bacteria (B) after 2 d. Thirty days post treatment, each of the four groups was divided into two subgroups; the inoculation was stopped for one subgroup and the other subgroup continued with biweekly inoculation until the end of the experiment. Colitis was evaluated by the clinical course of the disease, the macroscopic and microscopic alterations, activity of myeloperoxidase (MPO), and by TNF-alpha gene expression. RESULTS: Findings indicative of UC were seen in the combined treatment (IA + B) as well as the IA continued treatment groups: the animals showed slow rate of increase in body weight, diarrhea, bloody stools, high colonic ulcer score, as well as histological alterations characteristic of UC, with an extensive inflammatory reaction. During the course of the experiment, the MPO activity was consistently elevated and the TNF-alpha gene expression was upregulated compared to the control animals. CONCLUSION: The experimental ulcerative colitis model used in the present study resembles, to a great extent, the human disease. It is reproducible with characteristics indicative of chronicity.

Colorectal Carcinogenesis: Role of Oxidative Stress and Antioxidants.

One of the contributory causes of colon cancer is the negative effect of reactive oxygen species on DNA repair mechanisms. Currently, there is a growing support for the concept that oxidative stress may be an important etiological factor for carcinogenesis. The purpose of this review is to elucidate the role of oxidative stress in promoting colorectal carcinogenesis and to highlight the potential protective role of antioxidants. Several studies have documented the importance of antioxidants in countering oxidative stress and preventing colorectal carcinogenesis. However, there are conflicting data in the literature concerning its proper use in humans, since these studies did not yield definitive results and were performed mostly in vitro on cell populations, or in vivo in experimental animal models.

Curricular response to increase recall and transfer of anatomical knowledge into the obstetrics/gynecology clerkship.

Deficits in retention of anatomy knowledge from the preclinical years to clinical application on the wards have been well documented in the medical education literature. We developed and evaluated a web and laboratory-based curriculum to address deficits in anatomy knowledge retention and to increase anatomy knowledge recall through repetition and application of clinical concepts during the obstetrics and gynecology (Ob/Gyn) core clinical clerkship. Using principles of adult learning and instructional design, a curriculum was designed consisting of (1) interactive, case-based e-modules reviewing clinically relevant anatomical topics and (2) a hands-on laboratory session reinforcing the content of the e-modules, with the practice of clinical techniques using anatomical cadaveric dissections. The curriculum's effectiveness was evaluated by using multiple choice testing and comparing baseline and final test scores. For questions testing content directly covered in this curriculum, mean final scores increased by 14.3% (P < 0.001). In contrast, for questions not directly addressed in this curriculum, mean final scores did not increase significantly, only by 6.0% (P = 0.31). Questions related to the uterus showed the greatest gains in final scores (30.3% improvement, P = 0.002). A curriculum with web-based preparatory material and a hands-on gross anatomy laboratory session effectively addresses deficits in anatomy retention and improves anatomical knowledge recall for medical students on a clinical clerkship. In the future, the authors plan to conduct a multicenter study to further evaluate the ability of this curriculum to improve clinically relevant anatomical knowledge. Anat Sci Educ 9: 337-343. © 2015 American Association of Anatomists.