Subject(s)
Dentistry/standards , Education, Dental/standards , Schools, Dental/organization & administration , Dentistry/organization & administration , Education, Dental/organization & administration , Health Status Disparities , Humans , Professional Autonomy , Schools, Dental/economics , Social Change , Social Responsibility , United StatesSubject(s)
Dental Care for Children/organization & administration , Societies, Dental , Child , Dental Care for Children/economics , Dentistry , Health Services Accessibility , Health Services Needs and Demand , Healthcare Disparities , Humans , Leadership , Maryland , Medicaid , Minority Groups , United States , Vulnerable Populations , WorkforceABSTRACT
Islet transplantation is a viable long-term therapeutic alternative to daily insulin replacement for type I diabetes. The allogeneic nature of the transplants poses immunological challenges for routine clinical utility. Gene transfer of immunoregulatory molecules and those that improve insulin release kinetics provides rational approaches to facilitate allogeneic islet transplantation as a potential therapy. We have examined the efficacy of a soluble type 1 tumor necrosis factor receptor (TNFR) immunoglobulin-Fc fusion transgene (TNFR-Ig) to protect human islets from cytokine-induced apoptosis in culture, as well as in facilitating allogeneic islet transplants in diabetic mice. Cultured human islets were transduced with an adenoviral vector encoding human TNFR-Ig (Ad-TNFR-Ig). TNFR-Ig protein was secreted by cultured islets, as well as by transduced mouse islet transplants recovered from mouse recipients. Glucose-induced insulin release kinetics were comparable among untransduced, Ad-TNFR-Ig-infected human islets and vector-transduced islets exposed to cytokines. In parallel, Ad-TNFR-Ig-infected islets were protected from cytokine-induced apoptosis activation. Finally, diabetic mice transplanted with allogeneic islets expressing TNFR-Ig returned to and maintained normoglycemia significantly longer than untransduced islet recipients. These data support the potential utility of TNFR-Ig gene transfer to islets as a means of facilitating allogeneic islet transplantation.
Subject(s)
Diabetes Mellitus/therapy , Genetic Therapy/methods , Immunoglobulin Fc Fragments/genetics , Islets of Langerhans Transplantation , Receptors, Tumor Necrosis Factor/genetics , Transduction, Genetic/methods , Adenoviridae/genetics , Adenovirus E1 Proteins/genetics , Adenovirus E3 Proteins/genetics , Analysis of Variance , Apoptosis/drug effects , Cell Culture Techniques , Diabetes Mellitus/pathology , Diabetes Mellitus/surgery , Gene Deletion , Gene Expression , Genetic Vectors/administration & dosage , Genetic Vectors/genetics , Graft Survival , Humans , Interleukin-1/pharmacology , Islets of Langerhans/metabolism , Islets of Langerhans/pathology , Recombinant Fusion Proteins/genetics , Transplantation, Homologous , Tumor Necrosis Factor-alpha/pharmacologyABSTRACT
The efficacy of a novel, proprietary topical formulation of ibuprofen 5% gel (Ibugel) was evaluated in a placebo-controlled study in patients with soft tissue injuries. Patients received either active gel (n=40) or placebo gel (n=41) for a maximum of seven days. Pain and interference with physical activity were assessed daily using visual analogue scales. There was a significant difference (p<0.001) in favour of active treatment for the time to achieve clinically meaningful reduction in pain. By day 7, 75% of patients in the active gel group had a clinically meaningful reduction of pain compared with 39% of patients who received placebo. Despite differences between study centres, the data for interference with physical activity also showed an advantage for active treatment. By day 7, 79% of patients in the active gel group had a clinically meaningful reduction in interference with physical activity, compared with 44% of patients who received placebo.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Ibuprofen/administration & dosage , Pain/drug therapy , Soft Tissue Injuries/drug therapy , Administration, Topical , Adolescent , Adult , Aged , Aged, 80 and over , Double-Blind Method , Female , Gels , Humans , Male , Middle Aged , Treatment OutcomeABSTRACT
Hepatocyte growth factor is an important multifunctional growth factor whose gene expression is tightly regulated at the transcriptional level. Previous studies from our laboratory have shown that several cis-acting elements are present in the promoter and proximal promoter region of the HGF gene. In this study, we have uncovered that AP2 transcription factor specifically binds to a regulatory site located at -230 to -260 in the upstream region of the HGF gene promoter. Gelshift and supershift assays confirmed that AP2 has high binding affinity to this region. Functional studies which introduced a mutation in the AP2 core binding region as well as cotransfection experiments using an AP2 expression vector revealed that AP2 exerts a repressive role on the HGF gene promoter activity. The AP2 binding site overlaps with those of NF1 and USF/E-box binding sites which we have recently shown to constitute a composite multifunctional docking site for the members of the NF1 and USF transcription factor families. An inverse correlation was noted between AP2 binding activity to this composite site and HGF gene expression in different cell lines. Therefore, AP2-mediated repression of the HGF gene promoter may be part of the molecular mechanism responsible for regulating HGF expression.
Subject(s)
DNA-Binding Proteins/metabolism , Gene Expression Regulation/genetics , Hepatocyte Growth Factor/genetics , Promoter Regions, Genetic/genetics , Repressor Proteins/metabolism , Transcription Factors/metabolism , 3T3 Cells , Animals , Base Sequence , Binding Sites , Consensus Sequence/genetics , DNA/genetics , DNA/metabolism , DNA-Binding Proteins/genetics , Humans , Mice , Mutation/genetics , Protein Binding , RNA, Messenger/analysis , RNA, Messenger/genetics , Repressor Proteins/genetics , Response Elements/genetics , Reverse Transcriptase Polymerase Chain Reaction , Transcription Factor AP-2 , Transcription Factors/genetics , Transfection , Tumor Cells, CulturedSubject(s)
Education, Medical, Graduate/trends , Financing, Organized/trends , Training Support/trends , Education, Dental/economics , Education, Dental/trends , Education, Medical, Graduate/economics , Financing, Organized/economics , Training Support/economics , United States , Universities/economicsSubject(s)
Faculty, Dental , Schools, Dental/economics , Administrative Personnel , Humans , MichiganSubject(s)
Education, Dental, Graduate , National Academies of Science, Engineering, and Medicine, U.S., Health and Medicine Division , National Academy of Sciences, U.S. , Oral Health , Research Personnel/education , Education, Dental, Graduate/economics , Faculty, Dental , Humans , National Institutes of Health (U.S.) , Research Support as Topic , Training Support , United States , WorkforceSubject(s)
Education, Dental/standards , General Practice, Dental/education , Curriculum , Humans , United StatesSubject(s)
Forecasting , Schools, Dental , Dental Care , Education, Dental , Education, Dental, Continuing , Humans , Research , Teaching , United StatesSubject(s)
Dental Caries/therapy , Oral Health , Periodontal Diseases/therapy , Adolescent , Humans , Malocclusion/therapyABSTRACT
The findings presented here provide support for the validity of the Children's Oral Health Status Index. The COHSI is a good predictor of dentists' ranking of the oral health of pairs of children when there are at least ten points difference between the scores.
