RESUMEN
The 802-2 peptide, designed from the conserved D1-CC' loop region of human CD4, can disrupt CD4(+) T cell activation in both human and murine systems. Here, 802-2 was investigated for efficacy in acute murine experimental allergic encephalomyelitis (EAE) models, and was found to significantly reduce the severity of disease when administered either before or after the onset of symptoms. 802-2 treatment during PLP139-151 induction of EAE rendered the mice more resistant to subsequent rechallenge with antigen, and was also efficacious when initially administered during a secondary EAE response. T cells from 802-2-treated mice proliferated poorly to in vitro restimulation with PLP139-151 and exhibited decreased frequencies of IL-2, IL-4, and IFN-gamma producing cells, but were still able to respond to third-party antigens. These combined results suggest the potential therapeutic value of 802-2 for inhibition of CD4(+) T cell neuroimmunological responses.
Asunto(s)
Antígenos CD4/fisiología , Encefalomielitis Autoinmune Experimental/prevención & control , Fragmentos de Péptidos/farmacología , Péptidos Cíclicos/farmacología , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Citocinas/metabolismo , Encefalomielitis Autoinmune Experimental/patología , Femenino , Humanos , Activación de Linfocitos , Ratones , Fragmentos de Péptidos/uso terapéutico , Factores de TiempoRESUMEN
Bcl-2 is a potent suppressor of apoptosis, and its overexpression contributes to tumorigenesis in many types of human cancers. To test the possibility of modulating Bcl-2 function as an anticancer strategy, a cell permeable Bcl-2 binding peptide, cell permeable moiety (cpm)-1285, was designed by chemically attaching a fatty acid to a peptide derived from the proapoptotic protein Bad. cpm-1285 entered HL-60 tumor cells, bound Bcl-2 protein, and induced apoptosis in vitro. In contrast, cpm-1285 had little effect on normal human peripheral blood lymphocytes. Furthermore, cpm-1285 had in vivo activity in slowing human myeloid leukemia growth in severe combined immunodeficient mice. These results demonstrate a novel approach for therapeutic intervention of tumor growth in vivo with small molecule inhibitors of Bcl-2.
Asunto(s)
Oligopéptidos/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Secuencia de Aminoácidos , Animales , Apoptosis/efectos de los fármacos , Proteínas Portadoras/química , Proteínas Portadoras/metabolismo , Proteínas Portadoras/farmacología , Permeabilidad de la Membrana Celular , Supervivencia Celular/efectos de los fármacos , Fragmentación del ADN/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Células HL-60/citología , Células HL-60/efectos de los fármacos , Células HL-60/metabolismo , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones SCID , Datos de Secuencia Molecular , Neoplasias Experimentales/mortalidad , Neoplasias Experimentales/patología , Neoplasias Experimentales/prevención & control , Oligopéptidos/síntesis química , Oligopéptidos/farmacología , Unión Proteica , Análisis de Supervivencia , Tasa de Supervivencia , Proteína Letal Asociada a bclRESUMEN
The percentages of Louisiana female residents who did not receive any prenatal care before giving birth in 1985, 1990, 1992, and 1995 are derived from birth certificate data. The amount of change between the percentages of women giving birth without receiving prenatal care was compared over time at the state and regional level for various characteristics of the mothers and infants. These characteristics include the mother's age, race, marital status, and education, and the infant's birth weight. The results are interpreted along with the expectations that the percentages of women giving birth without prenatal care should be declining over time. Specific information can be identified about where, and for whom, these percentages are increasing.
Asunto(s)
Embarazo/estadística & datos numéricos , Atención Prenatal/estadística & datos numéricos , Adolescente , Adulto , Distribución por Edad , Peso al Nacer , Etnicidad/estadística & datos numéricos , Femenino , Humanos , Recién Nacido , Louisiana , Estado Civil , Persona de Mediana EdadRESUMEN
The efficacy of a synthetic peptide analogue (rD-mPGPtide), mimicking the CDR3 region in the first domain of the CD4 surface molecule, was investigated in a murine model for CD4+ T cell-mediated skin allograft rejection. A single injection of rD-mPGPtide shortly before transplantation exhibited significantly prolonged graft survival in the B6 anti-B6.C-H2bm12 MHC class II-disparate strain combination. Long-term graft survival (>100 days) was achieved when thymectomized adult recipient mice were transplanted along with rD-mPGPtide treatment. The peptide also affected secondary rechallenge responses with MHC class II allografts. In addition, the inhibitory effect of the rD-mPGPtide in this transplantation model was directed against CD4+ T cells and was exclusively specific toward donor alloantigen. In vitro analysis of CD4+ T cells isolated from the draining lymph nodes of rD-mPGPtide-treated recipients indicated a 450-fold decrease in precursor frequency in response to donor allostimulation compared with the untreated control group. There was also significant down-regulation of the frequency of IL-2-, IFN-gamma-, and IL-4-producing CD4+ T cells upon in vitro allogeneic restimulation of host cells 4 days posttransplantation. However, these same CD4+ T cells maintained the capacity to produce normal cytokine levels upon third-party allostimulation. Thus, these studies demonstrate that a CD4-CDR3 peptide analogue can specifically and effectively prolong skin graft survival across MHC class II barriers.
Asunto(s)
Antígenos CD4/inmunología , Supervivencia de Injerto/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Inmunosupresores/farmacología , Oligopéptidos/farmacología , Trasplante de Piel/inmunología , Animales , Anticuerpos Monoclonales/farmacología , Linfocitos T CD4-Positivos/metabolismo , Citocinas/biosíntesis , Femenino , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Supervivencia de Injerto/efectos de los fármacos , Antígenos de Histocompatibilidad Clase II/efectos de los fármacos , Inmunización Secundaria , Inmunosupresores/administración & dosificación , Isoantígenos/inmunología , Recuento de Linfocitos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos , Ratones Desnudos , Oligopéptidos/administración & dosificación , Oligopéptidos/síntesis química , Células Madre/citología , Timectomía , Trasplante HomólogoRESUMEN
We used an approach of protein surface epitope mapping by synthetic peptides to analyze the surface structure-function relationship of the CD8 protein. Small synthetic peptide mimics of the CD8 DE loop were shown to effectively block CD8 binding to major histocompatibility complex (MHC) class I molecules and possess significant inhibitory activity on in vitro CD8(+) T cell function. These results suggested that the DE loop region of the CD8 protein is an important functional epitope mediating CD8-MHC class I interaction and the activation of CD8(+) T cells, a finding that is consistent with the recently reported crystal structure of the CD8-MHC class I complex. The structural basis for the biological activity of the DE loop peptide was further analyzed in a series of analogs containing alanine substitutions. This study provides support for the concept of bioactive peptide design based on protein surface epitopes and suggests that such an approach may be applicable to other protein-protein complexes, particularly those of immunoglobulin superfamily molecules.
Asunto(s)
Antígenos CD8/química , Antígenos CD8/metabolismo , Epítopos/química , Epítopos/metabolismo , Antígenos de Histocompatibilidad Clase I/metabolismo , Secuencia de Aminoácidos , Cristalografía por Rayos X , Humanos , Técnicas In Vitro , Modelos Moleculares , Datos de Secuencia Molecular , Mapeo Peptídico , Conformación Proteica , Estructura Secundaria de Proteína , Propiedades de SuperficieRESUMEN
CD8 molecules function as co-receptors on cytotoxic T lymphocytes (CTLs), interacting with a nonpolymorphic region of the major histocompatibility complex (MHC) class I a3 domain on antigen-presenting cells. Analogues were designed from a structural model of the mouse CD8a molecule to identify surfaces involved in CD8 function. Peptides were screened for in vitro biological activity on alloreactive CTLs, and analogue SC4 (p54-59) was found to be inhibitory during both the generation and effector stages. SC4 was also able to significantly prolong skin allograft survival across a MHC class I barrier. Thus, such CD8 analogues may have therapeutic potential as immunoregulators of CTL immune responses.
Asunto(s)
Antígenos CD8/farmacología , Supervivencia de Injerto/efectos de los fármacos , Oligopéptidos/farmacología , Fragmentos de Péptidos/farmacología , Linfocitos T Citotóxicos/efectos de los fármacos , Animales , Citotoxicidad Inmunológica/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Rechazo de Injerto/inmunología , Antígenos H-2 , Ratones , Modelos Moleculares , Trasplante de Piel/inmunología , Trasplante HomólogoRESUMEN
Two cases of "scalded mouth syndrome" are presented and discussed. This condition is a rare side effect of angiotensin converting enzyme inhibitors. Angiotensin converting enzyme inhibitors are known to cause several other oral and extra-oral side effects. In scalded mouth syndrome, the patient's complaints concern a burning pain of the oral soft tissues. There are no clinical findings.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Antihipertensivos/efectos adversos , Síndrome de Boca Ardiente/inducido químicamente , Anciano , Captopril/efectos adversos , Enalapril/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The interaction between CD4 and major histocompatibility complex class II proteins provides a critical co-receptor function for the activation of CD4(+) T cells implicated in the pathogenesis of a number of autoimmune diseases and transplantation responses. A small synthetic cyclic heptapeptide was designed and shown by high resolution NMR spectroscopy to closely mimic the CD4 domain 1 CC' surface loop. This peptide effectively blocked stable CD4-major histocompatibility complex class II interaction, possessed significant immunosuppressive activity in vitro and in vivo, and strongly resisted proteolytic degradation. These results demonstrate the therapeutic potential of this peptide as a novel immunosuppressive agent and suggest a general strategy of drug design by using small conformationally constrained peptide mimics of protein surface epitopes to inhibit protein interactions and biological functions.
Asunto(s)
Antígenos CD4/química , Antígenos CD4/efectos de los fármacos , Epítopos/química , Linfocitos/inmunología , Oligopéptidos/química , Oligopéptidos/farmacología , Péptidos Cíclicos/química , Estructura Secundaria de Proteína , Secuencia de Aminoácidos , Animales , Sitios de Unión , Adhesión Celular/efectos de los fármacos , Gráficos por Computador , Diseño de Fármacos , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/fisiopatología , Femenino , Genes MHC Clase II , Rechazo de Injerto/inmunología , Supervivencia de Injerto/efectos de los fármacos , Enfermedad Injerto contra Huésped , Humanos , Prueba de Cultivo Mixto de Linfocitos , Linfocitos/efectos de la radiación , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos , Modelos Moleculares , Oligopéptidos/síntesis química , Péptidos Cíclicos/síntesis química , Trasplante de Piel/inmunologíaRESUMEN
The interaction between CD4 and major histocompatibility complex (MHC) class II proteins is critical for the activation of CD4+ T cells, which are involved in transplantation reactions and a number of autoimmune diseases. In this study we have identified a CD4 surface pocket as a functional epitope implicated in CD4-MHC class II interaction and T-cell activation. A computer-based strategy has been used to screen approximately 150,000 non-peptidic organic compounds in a molecular data base and to identify a group of compounds as ligands of the proposed CD4 surface pocket. These small organic compounds have been shown to specifically block stable CD4-MHC class II binding, and exhibit significant inhibition of immune responses in animal models of autoimmune disease and allograft transplant rejection, suggesting their potential as novel immunosuppressants. This structure-based computer screening approach may have general implications for studying many immunoglobulin-like structures and interactions that share similar structural features. Furthermore, the results from this study have demonstrated that the rational design of small non-peptidic inhibitors of large protein-protein interfaces may indeed be an achievable goal.
Asunto(s)
Antígenos CD4/efectos de los fármacos , Diseño de Fármacos , Evaluación Preclínica de Medicamentos/métodos , Antígenos de Histocompatibilidad Clase II/efectos de los fármacos , Inmunosupresores/farmacología , Animales , Antígenos CD4/química , Antígenos CD4/metabolismo , Simulación por Computador , Relación Dosis-Respuesta a Droga , Femenino , Rechazo de Injerto/inmunología , Antígenos de Histocompatibilidad Clase II/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Unión Proteica/efectos de los fármacos , Conformación Proteica , Trasplante de Piel/inmunologíaRESUMEN
A clinical study was done at Howard University, College of Dentistry, to compare the difference in the incidence of radiographic technique faults between two similar intraoral film-holding, beam-aligning, devices in a series of 1,248 radiographs. The primary difference between a conventional Extension Cone Paralleling (XCP-I) film holder and a modified, all-metal, Extension Cone Paralleling (XCP-II) film holder is the incorporation of a collimated rectangular x-ray-beam-restricting plate. This latter film holder possessed an indicator rod attached to the bite block and a metal shield to reduce primary and back-scattered radiation behind the film. In the oral diagnosis clinic, 78 dentulous patients were randomly selected and randomly divided into two groups of 39 patients. One of the two film holders was used separately for the two groups of patients, and a full mouth series of 16 periapical radiographs were made for each patient. The difference in the occurrence of total errors between the two instruments was not statistically significant. However, the conventional instrument was associated with significantly more errors in improper film positioning, while the modified device had significantly more errors in cone cutting (p < 0.01).
Asunto(s)
Tejido Periapical/diagnóstico por imagen , Radiografía Dental/instrumentación , Estudiantes de Odontología , Película para Rayos X , Adulto , Errores Diagnósticos , Diseño de Equipo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Radiografía Dental/estadística & datos numéricosRESUMEN
Independent examinations of 300 patients were conducted to evaluate fiber optic transillumination's performance in caries detection. FOTI was used as an adjunct to clinical and radiographic examinations for caries, restoration or secondary caries of approximal surfaces in maxillary anterior permanent teeth. Clinical and radiographic examinations were significantly more effective.
Asunto(s)
Caries Dental/diagnóstico , Transiluminación , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Radiografía DentalRESUMEN
Microglia are the only immunocompetent cells resident in the central nervous system which are capable of protecting the brain from infection and tumors. These resident macrophages possess a vast array of mechanisms for the destruction of bacteria and tumor cells. One of these mechanisms involves the generation of nitric oxide which can kill cells by inhibition of glycolysis, the TCA cycle and DNA synthesis. In this regard, we demonstrate, for the first time, that the inducible form of nitric oxide synthase (NOS) in microglia involves both cytosolic and membrane bound pools. Both pools of NOS were potently and stereo-specifically inhibited by NOS inhibitors. In addition, while these pools were unaffected by Ca2+, they were partially inhibited by calmodulin antagonists. These data would suggest that inducible NOS in lipopolysaccharide (LPS) treated microglia, constitutes two major compartments and may involve a novel isoform which is membrane associated. With regard to the possible physiological relevance for the membrane-bound NOS, we speculate that this presents an efficient means of supplying nitric oxide to the extracellular environment where it could gain rapid access to tumors and bacteria. This would result in inhibition of cellular function in these invading cells while limiting access of nitric oxide to the intracellular environment of microglia where NO could lead to depressed microglial function.
Asunto(s)
Aminoácido Oxidorreductasas/biosíntesis , Microglía/enzimología , Aminoácido Oxidorreductasas/antagonistas & inhibidores , Animales , Células Cultivadas , Inducción Enzimática/fisiología , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Membranas/enzimología , Ratones , Microglía/efectos de los fármacos , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Óxido Nítrico Sintasa , Fracciones Subcelulares/efectos de los fármacos , Fracciones Subcelulares/enzimologíaRESUMEN
The objectives of the present study were to examine the effects of dental restorations, crowns and fillings, and carious lesions on the periodontal tissues. One hundred and one clinic patients were selected on the basis of each having one or more teeth with either carious lesions or restorations, and having contralateral teeth without restorations or carious lesions. Debris, calculus, gingivitis, pocket depths, and bone loss were evaluated using objective criteria of assessment for each condition. The results showed significantly greater gingivitis, pocket depth, and bone loss around teeth with restorations and carious lesions than around their controls.
Asunto(s)
Coronas , Caries Dental/complicaciones , Restauración Dental Permanente , Enfermedades Periodontales/etiología , Adulto , Pérdida de Hueso Alveolar/etiología , Coronas/efectos adversos , Cálculos Dentales/etiología , Depósitos Dentarios/etiología , Restauración Dental Permanente/efectos adversos , Gingivitis/etiología , Humanos , Persona de Mediana Edad , Bolsa Periodontal/etiologíaRESUMEN
A modification of the Rinn Snap-A-Ray film-holding device which facilitates more accurate visual alignment of cone and film is described. A double-blind study was undertaken to evaluate the modified instrument as compared to the standard instrument. The results indicated a reduction in the number of errors of all types by the modified instrument. The greatest reduction was observed in cone-cutting errors.
Asunto(s)
Educación en Odontología , Radiografía Dental/instrumentación , Radiología/educación , Diseño de Equipo , Humanos , Boca/diagnóstico por imagenRESUMEN
Studies were carried out on serum lipid levels in 30 women in good health who were pregnant for the first time with a pregnancy of between 15 and 20 weeks duration, who had the pregnancies terminated by the use of a hypertonic saline solution. They showed a rise only in the cholesterol level (5.83 mmol/l +/- 0.17) in the phase of actively aborting (a period of maximum stress) as compared with a level of cholesterol in the pre-abortion phase (4.93 mmol/l +/- 0.17). Between 12 and 15 hours after the termination the cholesterol level dropped sharply as did the levels of phospho-lipids and triglycerides. The levels became of the order of 4.1 mmol/l +/- 0.25, 2.73 mmol/l +/- 0.097 and 1.03 mmol/l +/- 0.06 respectively according to the phase the termination was in. The levels of serum lipids after the termination were, surprisingly, almost the same as those in non-pregnant women. The poor rise in serum lipids during termination induced by hypertonic saline solution shows that probably labour was of low intensity.
Asunto(s)
Aborto Inducido , Lípidos/sangre , Abortivos , Femenino , Humanos , Embarazo , Solución Salina HipertónicaRESUMEN
The effect of menstrual stress on serum lipid levels has been investigated in 28 healthy unmarried student nurses aged between 19 and 25 years, with histories of regular 26-30 day menstrual cycles. There were definite and similar patterns of changes in serum cholesterol, phospholipids and triglycerides during different phases of the menstrual cycle.