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INTRODUCTION: There has been little research to explore how adults financially value private orthodontic treatment and whether they have preferences for different attributes of treatment. This study used a discrete choice experiment and aimed to determine whether the recognized skill level of the dental professional and the type of orthodontic appliance influence the values that the public places on private adult orthodontic treatment. METHODS: In total, 206 adult patients or the parents/guardians of children attending general dental practices in the northeast of England were recruited to complete a discrete choice experiment. Three attributes were included: the type of dental professional providing treatment, the type of orthodontic appliance, and cost. Also collected were demographic and orthodontic history characteristics. Results were analyzed with conditional logistic regression and elicited marginal willingness to pay (MWTP). RESULTS: Participants value the training and expertise of the dental professional providing private orthodontic treatment greater than the type of orthodontic appliance. MWTP for orthodontic treatment increased in conjunction with the recognized skill level of the dental professional. Participants were willing to pay more for aesthetic appliances over a fixed metal appliance. CONCLUSIONS: Participants value the training and expertise of the dental professional providing private adult orthodontic treatment greater than the type of orthodontic appliance. These preferences concur with other discrete choice experiments undertaken in medical specialties that included attributes focusing on the qualification, skill, or expertise of the health care professional. MWTP for orthodontic treatment increased in conjunction with the recognized skill level of the dental professional. Participants were willing to pay more for aesthetic appliances than metal fixed appliances. The cost of orthodontics is significant, and adults appreciate the importance of having options and making choices.Knowledge Transfer Statement: The results of this study suggest that patients are willing to pay more for orthodontic services provided by clinicians with higher levels of formal training. In a competitive market where the public appears to prefer the provider over treatment modality, there is an incentive for clinicians to optimize their knowledge and skills to deliver the high-quality orthodontic treatment that patients are demanding. Orthodontic clinicians should be mindful of the demand for the different adult orthodontic appliances and tailor their skill sets accordingly.
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Estética Dental , Ortodoncia , Adulto , Niño , Atención Odontológica , Personal de Salud , Humanos , Aparatos OrtodóncicosRESUMEN
Cardiopulmonary bypass procedures are one of the most common operations and blood oxygenators are the centre piece for the heart-lung machines. Blood oxygenators have been tested as entire devices but intricate details on the flow field inside the oxygenators remain unknown. In this study, a novel method is presented to analyse the flow field inside oxygenators based on micro Computed Tomography (µCT) scans. Two Hollow Fibre Membrane (HFM) oxygenator prototypes were scanned and three-dimensional full scale models that capture the device-specific fibre distributions are set up for computational fluid dynamics analysis. The blood flow through the oxygenator is modelled as a non-Newtonian fluid. The results were compared against the flow solution through an ideal fibre distribution and show the importance of a uniform distribution of fibres and that the oxygenators analysed are not susceptible to flow directionality as mass flow versus area remain the same. However the pressure drop across the oxygenator is dependent on flow rate and direction. By comparing residence time of blood against the time frame to fully saturate blood with oxygen we highlight the potential of this method as design optimisation tool. In conclusion, image-based reconstruction is found to be a feasible route to assess oxygenator performance through flow modelling. It offers the possibility to review a product as manufactured rather than as designed, which is a valuable insight as a precursor to the approval processes. Finally, the flow analysis presented may be extended, at computational cost, to include species transport in further studies.
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Sangre/diagnóstico por imagen , Sangre/metabolismo , Oxigenación por Membrana Extracorpórea/instrumentación , Oxigenación por Membrana Extracorpórea/métodos , Modelos Cardiovasculares , Oxígeno/sangre , Tomografía Computarizada por Rayos X/métodos , Fenómenos Fisiológicos Sanguíneos , Simulación por Computador , Diseño Asistido por Computadora , Diseño de Equipo , Análisis de Falla de Equipo , Humanos , Imagenología Tridimensional/métodosRESUMEN
In response to the Educational Standards of the UK's General Dental Council, Newcastle University, School of Dental Sciences introduced a patient feedback card to gather and incorporate patient feedback into their undergraduate assessment framework. The cards ask for patient response to two questions about their experience, and also ask patients to identify 'Just One Thing' (JOT) the student could do to improve this. JOT cards completed during a two week period were collected to evaluate and analyse the nature of patient responses within this model. Over 90% of JOT cards scored the students as 'Excellent' with the remainder scoring the student as 'Good' or giving no response. Many of the free text comments complimented the students and also provided focused suggestions for improvement. While the overwhelming positive responses may suggest that this model for collecting feedback may not be effective at discriminating between students with varying levels of interpersonal/communication skills, the free text comments were seen to be of value in building confidence or identifying areas for improvement.
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Retroalimentación Formativa , Satisfacción del Paciente , Atención Odontológica/normas , Humanos , Estudiantes de OdontologíaRESUMEN
Background The 2013 Children's Dental Health Survey is the fifth in a series of national surveys.Aims This paper reports the orthodontic condition of 12- and 15-year-olds and how they and their parents feel about the appearance of their teeth.Methodology A representative sample of children (5y, 8y, 12y, 15y) in England, Wales and Northern Ireland were invited to participate in dental examinations. A modified Index of Orthodontic Treatment Need (IOTN) was used as a measure of orthodontic treatment need for 12- and 15-year-olds. Children and parents were invited to complete a questionnaire about oral health behaviour and attitudes.Results Nine percent of 12-year-olds and 18% of 15-year-olds were undergoing orthodontic treatment at the time of the survey. Forty-four percent of 12-year-olds and 29% of 15-year-olds expressed a desire for straighter teeth, however over half of this group would not qualify for NHS treatment. Unmet treatment need was higher in children eligible for free school meals (P <0.05 at 15y).Conclusions Provision of and demand for orthodontic treatment is increasing, with a significant proportion of children who desire orthodontic care not eligible to receive it. Children from deprived backgrounds have greater unmet orthodontic treatment need.
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Maloclusión , Ortodoncia Correctiva , Adolescente , Niño , Preescolar , Inglaterra , Femenino , Necesidades y Demandas de Servicios de Salud , Humanos , Masculino , Irlanda del Norte , GalesRESUMEN
Background The 2013 Children's Dental Health Survey is the fifth in a series of national surveys.Aims To describe caries prevalence and severity and factors affecting these, in children in England, Wales and Northern Ireland in 2013.Methodology A representative sample of children (aged 5, 8, 12 and 15 years) in England, Wales and Northern Ireland were invited to participate in dental examinations. Caries was measured at both the dentine ('obvious caries') and dentine plus enamel ('clinical caries') levels and analysis included identifying those with indicators of significant burden of caries and identifying predictive factors.Results In 5-year-olds, 40% had obvious caries experience increasing to 56% when enamel lesions were included. In 15-year-olds, the respective figures were 46% and 63%. Fourteen percent of 5-year-olds and 15% of 15-year-olds had a least one indicator of significant levels of caries and those from deprived backgrounds were more likely to fall into this group.Conclusions Overall, the prevalence of caries in children is continuing to decrease, but the rate is slowing. The level of disease for those with disease is much higher than the average values might suggest and there remain a sizeable minority with a significant burden of caries, associated with deprivation. This complex picture poses significant clinical and public health challenges.
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Índice CPO , Caries Dental/epidemiología , Adolescente , Niño , Preescolar , Inglaterra/epidemiología , Femenino , Humanos , Masculino , Irlanda del Norte/epidemiología , Prevalencia , Gales/epidemiologíaRESUMEN
AIM: To measure the polymerization of light-cured (Variolink Veneer, VLV) and dual-cured (Variolink II, VLII) resin luting cements after light activation through different lengths of fibre post ex vivo. METHODOLOGY: Degree of conversion after prolonged direct light activation (PLA) [12 min after LED light activation for 3 min] was determined using ATR-FTIR. Models were then produced to allow samples of VLV and VLII (n = 5 each group) to be light-activated through 3, 6 and 9 mm lengths of fibre post (Fiber Lux). Degree of conversion was assessed by ATR-FTIR and expressed as a percentage of the degree of conversion achieved after PLA. Data were analysed using anova and Tukey's test (P < 0.05). RESULTS: Mean [SD] degree of conversion for VLV and VLII after PLA was 57.97% [1.51] and 54.71% [3.77], respectively. Light activation of VLV through a 3 mm post produced 81.62% of the PLA value, compared with 71.03% for the 6 mm and 46.04% for the 9 mm post. Conversion after activation through 9 mm posts was significantly less than through 3 mm and 6 mm posts (P < 0.05). For VLII, activation through a 3 mm post produced 66.51% of the PLA value, compared with 54.38% for the 6 mm and 41.56% for the 9 mm post. A significant decrease in degree of conversion was noted for VLII as post length increased (P < 0.05). CONCLUSIONS: The degree of conversion for VLV reduced after light activation through 9 mm posts when compared to 3 mm and 6 mm posts, whilst the degree of conversion for VLII decreased with every increase in post length.
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Curación por Luz de Adhesivos Dentales , Técnica de Perno Muñón/instrumentación , Cementos de Resina/química , Dureza , Ensayo de Materiales , PolimerizacionRESUMEN
BACKGROUND: Despite initial evidence in the literature, nonsteroidal anti-inflammatory drugs (NSAIDs) have not been widely used to prevent post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). AIM: To complete a meta-analysis of high-quality RCTs that included the latest available literature published after past meta-analytical efforts METHODS: A comprehensive electronic literature search was carried out for RCTs comparing peri-procedural rectal indomethacin and placebo in preventing PEP. Methodological quality was assessed by the Cochrane risk of bias tool. Fixed model Mantel-Haenszel meta-analysis, Q test and I(2) index were used. Several subgroup and sensitivity analyses were planned. RESULTS: A total of four of 61 retrieved trials between 2007 and 2012 (n = 1470) were included. No significant publication bias existed. All studies used similar criteria to detect pancreatitis. The pooled proportion estimate of the rate of pancreatitis was 5.1% with indomethacin and 10.3% with placebo. After excluding the high-risk patients, the rates were 3.9% and 7.9% respectively. Fixed model meta-analysis showed that the rate of pancreatitis was significantly lower using indomethacin as compared with placebo [OR = 0.49(0.34-0.71); P = 0.0002]. Number needed to treat was 20. There was no significant statistical or clinical heterogeneity. In subgroup analysis, the difference remained unchanged for average-risk population [OR = 0.49(0.28-0.85); P = 0.01] or in preventing severe PEP [OR = 0.41(0.21-0.78); P = 0.007]. The result of the main outcome remained robust in multiple sensitivity analyses. CONCLUSIONS: Rectal indomethacin used immediately before or after ERCP significantly reduces the risk of PEP to half in both low- and high-risk patients, and with both statistically and clinically significant conclusions. These results suggest that a possible change in routine practice for patients at both low and high risk of developing PEP should be advocated.
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Colangiopancreatografia Retrógrada Endoscópica/efectos adversos , Indometacina/uso terapéutico , Pancreatitis/prevención & control , Administración Rectal , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/uso terapéutico , Humanos , Indometacina/administración & dosificación , Pancreatitis/etiología , RiesgoRESUMEN
As people are living longer and retaining their teeth into old age, root caries is an increasingly significant problem. A minimally invasive treatment strategy, involving sealing the root caries lesion with an antibacterial resin sealant, could be highly beneficial. The aim of this study was to compare the antibacterial properties of the primers of two proprietary dentine bonding agents, Clearfil SE Bond (SE; Kuraray Medical, Japan) and Clearfil Protect Bond (PB; Kuraray Medical), which contains the antibacterial monomer methacryloyloxydodecylpyridinium bromide. Fifty-two root caries lesions were identified and randomly assigned to a primer. The lesion was cleaned, isolated, sampled with a sharp spoon excavator, a primer applied and a second sample taken. Samples were transported in fastidious anaerobe broth, vortex-dispersed and serial dilutions inoculated onto selective agars. Reduction in colony-forming units (CFU, %) after primer application was calculated for both primers for bacterial growth on each selective agar and compared to a hypothesised mean of 100% (one-sample t test, p < 0.05). No significant differences between primers were seen, indicating efficient bacterial elimination by both materials. Comparing percent reduction between SE and PB for each agar (Mann-Whitney test, p < 0.05), a significantly greater CFU reduction by PB was seen for streptococci but not other bacteria. More lesions exhibited bacterial growth and several lesions demonstrated marked bacterial growth after treatment with SE compared with PB. Therefore, PB appears to exhibit superior antimicrobial properties, particularly against streptococci. Both primers are highly antibacterial towards root caries bacteria and may therefore be suitable for minimally invasive treatment.
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Recubrimientos Dentinarios/uso terapéutico , Caries Radicular/tratamiento farmacológico , Caries Radicular/microbiología , Streptococcus/efectos de los fármacos , Agar , Recuento de Colonia Microbiana , Medios de Cultivo , Tratamiento Restaurativo Atraumático Dental/métodos , Recubrimientos Dentinarios/química , Recubrimientos Dentinarios/farmacología , Humanos , Compuestos de Piridinio/farmacología , Compuestos de Piridinio/uso terapéutico , Cementos de Resina/farmacología , Cementos de Resina/uso terapéutico , Estadísticas no Paramétricas , Streptococcus/crecimiento & desarrolloRESUMEN
Most dental materials are designed to have a relatively 'neutral' existence in the mouth. It is considered that if they are 'passive' and do not react with the oral environment they will be more stable and have a greater durability. At the same time, it is hoped that our materials will be well accepted and will cause neither harm nor injury. This is an entirely negative approach to material tolerance and biocompatibility and hides the possibility that some positive gains can be achieved by using materials which behave in a more dynamic fashion in the environment in which they are placed. An example of materials which have potential for 'dynamic' behaviour exists with structures which are partly water-based or have phases or zones with significant water content and for which the water within the material can react to changes in the ambient conditions. Such materials may even be said to have the potential for 'smart' behaviour, i.e. they can react to changes in the environment to bring about advantageous changes in properties, either within the material itself or in the material-tooth complex. The controlled movement of water or aqueous media through the material may cause changes in dimensions, may be the carrier for various dissolved species, and may influence the potential for the formation of biofilms at the surface. Some of these issues may be closely interrelated. Clearly, materials which do not have the capacity for water transport or storage do not have the potential for this sort of behaviour. Some materials which are normally resistant to the healthy oral environment can undergo controlled degradation at low pH in order to release ions which may prove beneficial or protective. It is doubtful whether such behaviour should be classified as 'smart' because the material cannot readily return to its original condition when the stimulus is removed. Other materials, such as certain alloys, having no means of transporting water through their structure, can display smart behaviour by undergoing predictable changes in structure in response to applied mechanical or thermal stimuli. It has been difficult to harness such behaviour to the benefit of patients but progress in this area is slowly being made.
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Materiales Dentales , Materiales Biocompatibles , Materiales Biomiméticos , Materiales Dentales/química , Odontología , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Membranas Artificiales , Transición de Fase , HumectabilidadRESUMEN
The aim of this report is to provide guidance to assist in the international convergence of quality assurance, benchmarking and assessment systems to improve dental education. Proposals are developed for mutual recognition of qualifications, to aid international movement and exchange of staff and students including and supporting developing countries. Quality assurance is the responsibility of all staff involved in dental education and involves three levels: internal, institutional and external. Benchmarking information provides a subject framework. Benchmarks are useful for a variety of purposes including design and validation of programmes, examination and review; they can also strengthen the accreditation process undertaken by professional and statutory bodies. Benchmark information can be used by institutions as part of their programme approval process, to set degree standards. The standards should be developed by the dental academic community through formal groups of experts. Assessment outcomes of student learning are a measure of the quality of the learning programme. The goal of an effective assessment strategy should be that it provides the starting point for students to adopt a positive approach to effective and competent practice, reflective and lifelong learning. All assessment methods should be evidence based or based upon research. Mutual recognition of professional qualifications means that qualifications gained in one country (the home country) are recognized in another country (the host country). It empowers movement of skilled workers, which can help resolve skills shortages within participating countries. These proposals are not intended to be either exhaustive or prescriptive; they are purely for guidance and derived from the identification of what is perceived to be 'best practice'.
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Benchmarking , Educación en Odontología/normas , Gestión de la Calidad Total , Competencia Clínica , Educación Continua en Odontología/normas , Evaluación Educacional/normas , Medicina Basada en la Evidencia , Docentes de Odontología , Personal Profesional Extranjero/normas , Humanos , Cooperación Internacional , Desarrollo de Programa , Evaluación de Programas y Proyectos de Salud , Control de Calidad , Estudiantes de Odontología , Gestión de la Calidad Total/organización & administraciónRESUMEN
Clinical competency assessments are an important part of dental curricula-to satisfy national requirements, maintain professionalism and ensure graduates are prepared for independent clinical practice. It has been observed within Newcastle Dental School (UK) that students tend to undertake the majority of their competency assessments at a very late stage. A questionnaire was designed to investigate student perceptions of two different competency assessment processes (formative structured clinical operative tests vs. summative grading), assess why they chose to undertake competency exercises at a particular time, investigate how well prepared they felt, and finally to evaluate potential barriers that students perceived within the competency process. Data regarding the timing of competency assessments and grades achieved were analysed. Fifty-nine per cent of students reported preferring the summative grading system. Most students felt that they undertook their competency assessments at about the right time (54%: conservation department, 66%: paediatric department) and the majority felt adequately prepared to undertake each exercise (68-98%). The greatest barrier stated to undertaking competency assessments was a lack of suitable patients both on which to practise and to undertake the exercise. No correlation was found between when students took summative assessments and the grades achieved. Therefore, we must encourage students to undertake their competency assessments once they have accrued sufficient clinical experience and reassure them that timing has little effect on the grade achieved. We should assist them to locate suitable patients wherever possible.
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Actitud , Competencia Clínica , Educación Basada en Competencias , Educación en Odontología , Evaluación Educacional/métodos , Estudiantes de Odontología/psicología , Comunicación , Coronas , Prótesis Dental , Restauración Dental Permanente , Operatoria Dental/educación , Humanos , Control de Infección Dental , Relaciones Interprofesionales , Odontología Pediátrica/educación , Tratamiento del Conducto Radicular , Factores de TiempoAsunto(s)
Apoptosis , Efecto Espectador , Caenorhabditis elegans/citología , Caenorhabditis elegans/metabolismo , Mitocondrias/metabolismo , Transducción de Señal , Animales , Membranas Intracelulares/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/clasificación , Proteínas Proto-Oncogénicas c-bcl-2/metabolismoRESUMEN
AIM: To review the authors' experience with eosinophilic esophagitis. METHODS: Between 1993 and 2001, the authors identified 12 patients with eosinophilic esophagitis defined on histologic criteria (> or = 20 eosinophils per high-power field in the distal esophageal epithelium). The authors reviewed medical records for details of clinical presentation; laboratory data; radiologic, endoscopic, and histologic findings; and the results of continuous esophageal pH probe monitoring. RESULTS: Seventy-five percent of the patients were male. The median age at presentation was 10.8 years (range, 1-17 years). Commonly reported symptoms were dysphagia with solid food (66%), epigastric pain (42%), food impaction (50%), and vomiting (8%). Food allergy was reported in 50% and asthma in 33%. Peripheral eosinophilia (> 700/mm3) was found in 42%. Upper gastrointestinal series performed in eight patients, showed esophageal luminal narrowing in three. Computed tomography, performed in two patients, revealed thickening of the esophageal wall. Esophageal pH probe monitoring, performed in nine patients, revealed no abnormal acid reflux. All of the monitored patients had episodic alkalinization of the esophagus. Upper endoscopic analysis revealed white specks on the esophageal mucosa in 42%, esophageal narrowing in 33%, esophageal rings in 25%, and esophageal furrowing in 8%. The mean eosinophils per high-power field was 65 (range, 20-200). Histologic characteristics included juxtaluminar (33%) and peripapillary clusters of eosinophils (33%), increased papillary height (50%), and basal cell hyperplasia (34%). CONCLUSION: Solid food dysphagia was the most common feature of eosinophilic esophagitis in our patients. Alkalinization of the esophagus was found in all nine pH probe recordings of eosinophilic esophagitis patients and may represent a previously unreported characteristic of the condition.
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Eosinofilia , Esofagitis/diagnóstico , Esofagitis/patología , Adolescente , Niño , Preescolar , Trastornos de Deglución , Endoscopía Gastrointestinal , Esófago/patología , Femenino , Tracto Gastrointestinal/patología , Humanos , Concentración de Iones de Hidrógeno , Lactante , Modelos Logísticos , Masculino , Dolor , Tomografía Computarizada por Rayos X , VómitosRESUMEN
BACKGROUND: Post-transplant lymphoproliferative disorder (PTLD) can occur in patients maintained on immunosuppressive therapy following transplantation. This paper describes two cases of PTLD occurring in gingival tissues, in patients receiving ciclosporin following cardiac transplantation. TREATMENT: The lesions were localised to gingival tissues, mimicking ciclosporin-induced gingival overgrowth. They were removed surgically and the ciclosporin dose reduced to help prevent recurrence. CONCLUSION: The importance of histopathological examination of all tissue removed during routine gingivectomy procedures for ciclosporin-induced gingival overgrowth is highlighted.
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Ciclosporina/efectos adversos , Neoplasias Gingivales/diagnóstico , Sobrecrecimiento Gingival/inducido químicamente , Trasplante de Corazón/efectos adversos , Inmunosupresores/efectos adversos , Linfoma/diagnóstico , Diagnóstico Diferencial , Sobrecrecimiento Gingival/diagnóstico , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The definitions in the Diagnostic and Statistical Manual-4th Ed.-TR [5] relating to posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) after mechanical accidents do not reflect the range of dysfunctions, the significance of patient differences, and fluctuating intensity, direction, and symptoms with increasing time since an injury. The considerable overlapping of symptoms is not considered at all, nor is concussion given a diagnosis. Some anatomical and physiological considerations for these frequently comorbid conditions are specified to increase diagnostic precision, or call attention to unavoidable ambiguities. The current definitions lead to diagnostic error since there are many that are based upon symptoms that are not trauma related although they resemble those of TBI. A Taxonomy of Neurobehavioral Disorders draws attention to a wide range of physiological and behavioral functions, with implications for more accurate recognition of symptoms, diagnosis, and treatment. Persistent posttraumatic disorders, more complex than PTSD, exist, due to the effects of unhealed tissues, impairment, and the social consequences of impairment and rejection. There are recommendations for the improvement of the definitions of PTSD and traumatic brain injury when both may be co-morbid after a mechanical injury.
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Lesiones Encefálicas/diagnóstico , Escalas de Valoración Psiquiátrica/normas , Trastornos por Estrés Postraumático/diagnóstico , Accidentes , Lesiones Encefálicas/epidemiología , Lesiones Encefálicas/psicología , Comorbilidad , Femenino , Humanos , Puntaje de Gravedad del Traumatismo , Masculino , Sensibilidad y Especificidad , Índice de Severidad de la Enfermedad , Trastornos por Estrés Postraumático/epidemiología , Trastornos por Estrés Postraumático/psicología , Terminología como AsuntoRESUMEN
A number of genetic alterations have been described in colorectal cancers. They include allelic losses on specific chromosomal arms, mutations of oncogenes, tumor suppressor genes and mismatch repair genes, microsatellite instability in coding repeat sequences of target genes and methylation defects in gene promoters. Since these alterations have been reported by different groups on different tumors and cell lines, the complete repertoire of genetic alterations for any given tumor sample remains unknown. In the present study, we analysed a series of 22 colorectal cancer cell lines for 31 different genetic alterations. We found significant correlations between mutational profiles in these colorectal cell lines associated with differences in mismatch repair status. This panel of colon cancer cell lines is representative of the genetic heterogeneity occurring in sporadic colorectal carcinoma. Our results may prove to be very useful for understanding the different biological pathways involved in the development of colon cancer, and for groups studying cellular biology and pharmacology on the same cell lines.
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Neoplasias Colorrectales/genética , Transactivadores , Disparidad de Par Base , Proteínas del Citoesqueleto/genética , Reparación del ADN , Genes APC , Genes Supresores de Tumor , Genes p16 , Genes p53 , Genes ras , Humanos , Pérdida de Heterocigocidad , Repeticiones de Microsatélite , Mutación , Células Tumorales Cultivadas , beta CateninaRESUMEN
A number of human genes containing coding mononucleotide repeat sequences are particularly prone to mutations in tumors with defects in mismatch repair (MMR) genes (MSI-H cancers). In a large series of MSI-H colorectal tumors, we looked for mutations in 25 coding repeats contained in eight genes already known to be mutated in these cancers or in 17 other genes with an expected role in carcinogenesis. Mutations were found in 19 of the 25 candidate genes. Using a maximum likelihood statistical method, they were separated into two different groups that differed significantly in their mutation frequencies, and were likely to represent mutations that do or do not provide selective pressures during MSI-H tumoral progression, respectively. Three new target genes were found (GRB-14, RHAMM, RAD50). Our results provide evidence that MSI-H tumoral progression involves the cumulative mutations of a large number of genes. For each MSI-H tumor we calculated indexes representing the number of mutations found in genes of these groups. We also evaluated a shortening index at both the Bat-25 and Bat-26 non-coding mononucleotide tracts that are known to be almost always unstable in MSI-H cancers. A significant correlation was observed between instability at both coding and non-coding repeats, suggesting that Bat-25 and Bat-26 could be used as simple phenotypical markers of the tumoral evolution. A preferential order of mutations was deduced. During this process, hMSH3 alterations, a target gene encoding for a MMR protein, was found to play an important role by increasing the instability phenomenon characterizing these cancers.
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Neoplasias Colorrectales/genética , Reparación del ADN , Evolución Molecular , Secuencias Repetitivas de Ácidos Nucleicos , Disparidad de Par Base , Biomarcadores de Tumor , Neoplasias Colorrectales/patología , Progresión de la Enfermedad , Humanos , Fenotipo , Reacción en Cadena de la Polimerasa , Células Tumorales CultivadasRESUMEN
The human T cell transcription factor-4 (hTCF-4) interacts functionally with beta-catenin in the Wnt signaling pathway, which regulates many developmental processes. Moreover, inappropriate reactivation of this pathway attributable to APC or beta-catenin mutations has been described in colorectal cancers. Because only the human TCF-4 cDNA sequence was known, we determined its genomic structure. A total of 17 exons, of which 5 were alternative, were identified. Moreover, four alternative splice sites were observed either experimentally or in silico by a BLAST approach in expressed sequence tag databases. The alternative use of three consecutive exons localized in the 3' part of the hTCF-4 gene changes the reading frames used in the last exon, leading to the synthesis of a number of hTCF-4 isoforms with short, medium, or long-size COOH-terminal ends. We next screened the entire hTCF-4 gene for mutations in a series of 24 colorectal cancer cell lines by denaturing gradient gel electrophoresis and/or direct sequencing. Besides an already described deletion of an A in an (A)9 coding repeat in four cases, we found DNA variants in eight cases for a total of 12 variants, of which 8 were coding. These include one frameshift mutation in the beta-catenin binding domain (exon 1), and one missense mutation in exon 4. In the remaining six cases, nonsense or frameshift mutations were localized in the 3' part of the gene. These latter alterations have as a common consequence to decrease the proportion of the long COOH-terminal hTCF-4 isoform, which contains two binding domains for c-terminal binding protein, a protein implicated in the repression of the TCF family transcriptional activity. Thus, loss of the TCF-4 capacity to interact with COOH-terminal binding protein could be an important event during colorectal carcinogenesis by modifying Wnt signaling.
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Empalme Alternativo , Neoplasias Colorrectales/genética , Factores de Transcripción/genética , Secuencia de Bases , Neoplasias Colorrectales/metabolismo , Análisis Mutacional de ADN , Exones , Humanos , Modelos Genéticos , Datos de Secuencia Molecular , Mutación , Sistemas de Lectura Abierta , Isoformas de Proteínas , Estructura Terciaria de Proteína , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Secuencia de ADN , Factores de Transcripción TCF , Proteína 2 Similar al Factor de Transcripción 7 , Factores de Transcripción/biosíntesis , Factores de Transcripción/química , Células Tumorales CultivadasRESUMEN
The cI repressor of bacteriophage lambda is better-fitted to the proximal interactions in which it naturally takes part than to the long-distance cooperative interactions on DNA for which it has become representative. The first observation in support of this statement is the ambiguity of an untypical DNAase I footprint which has become a diagnostic for DNA circularisation (and thus for the capacity of the protein to control expression at a distance). However, it was also observed without effective DNA looping when lac repressor binds to nearly contiguous sites. Additionally, the surface of interaction between the two dimers seems to be more important than the one commonly admitted (via some contacts between the flexible arms), the biological function of the repressor is lost when the sites are separated and loops have not been observed for large separation of the sites. In fact, naturally distant interactions can conform to shorter distances, as an intrinsic property of DNA looping. On the contrary, interactions which are naturally optimised for contiguity are generally constrained to proximity. Alternative protein-protein contacts are generally responsible for this situation (cf. CRP versus NRI in Escherichia coli).