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1.
Br J Surg ; 108(4): 441-447, 2021 04 30.
Artículo en Inglés | MEDLINE | ID: mdl-33615351

RESUMEN

BACKGROUND: Complicated intra-abdominal infections (cIAIs) are associated with significant morbidity and mortality. The aim of this study was to describe the clinical characteristics of patients with cIAI in a multicentre study and to develop clinical prediction models (CPMs) to help identify patients at risk of mortality or relapse. METHODS: A multicentre observational study was conducted from August 2016 to February 2017 in the UK. Adult patients diagnosed with cIAI were included. Multivariable logistic regression was performed to develop CPMs for mortality and cIAI relapse. The c-statistic was used to test model discrimination. Model calibration was tested using calibration slopes and calibration in the large (CITL). The CPMs were then presented as point scoring systems and validated further. RESULTS: Overall, 417 patients from 31 surgical centres were included in the analysis. At 90 days after diagnosis, 17.3 per cent had a cIAI relapse and the mortality rate was 11.3 per cent. Predictors in the mortality model were age, cIAI aetiology, presence of a perforated viscus and source control procedure. Predictors of cIAI relapse included the presence of collections, outcome of initial management, and duration of antibiotic treatment. The c-statistic adjusted for model optimism was 0.79 (95 per cent c.i. 0.75 to 0.87) and 0.74 (0.73 to 0.85) for mortality and cIAI relapse CPMs. Adjusted calibration slopes were 0.88 (95 per cent c.i. 0.76 to 0.90) for the mortality model and 0.91 (0.88 to 0.94) for the relapse model; CITL was -0.19 (95 per cent c.i. -0.39 to -0.12) and - 0.01 (- 0.17 to -0.03) respectively. CONCLUSION: Relapse of infection and death after complicated intra-abdominal infections are common. Clinical prediction models were developed to identify patients at increased risk of relapse or death after treatment, these now require external validation.


Asunto(s)
Reglas de Decisión Clínica , Infecciones Intraabdominales/etiología , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Antibacterianos/uso terapéutico , Femenino , Humanos , Infecciones Intraabdominales/diagnóstico , Infecciones Intraabdominales/tratamiento farmacológico , Infecciones Intraabdominales/mortalidad , Masculino , Persona de Mediana Edad , Modelos Estadísticos , Recurrencia , Factores de Riesgo
2.
Anaesthesia ; 75(3): 359-365, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32022912

RESUMEN

Anaesthesia and positive pressure ventilation cause ventral redistribution of regional ventilation, potentially caused by the tracheal tube. We used electrical impedance tomography to map regional ventilation during anaesthesia in 10 patients with and without a tracheal tube. We recorded impedance data in subjects who were awake, during bag-mask ventilation, with the tracheal tube positioned normally, rotated 90° to each side and advanced until in an endobronchial position. We recorded the following measurements: ventilation of the right lung (proportion, %); centre of ventilation (100% = entirely ventral); global inhomogeneity (0% = homogenous); and regional ventilation delay, an index of temporal heterogeneity. We compared the results using Student's t-tests. Relative to subjects who were awake, anaesthesia with bag-mask ventilation reduced right-sided ventilation by 5.6% (p = 0.002), reduced regional ventilation delay by 1.6% (p = 0.025), and moved the centre of ventilation ventrally from 51.4% to 58.2% (p = 0.0001). Tracheal tube ventilation caused a further centre of ventilation increase of 1.3% (p = 0.009). With the tube near the carina, right-sided ventilation increased by 3.2% (p = 0.031) and regional ventilation delay by 2.8% (p = 0.049). Tube rotation caused a 1.6% increase in right-sided ventilation compared with normal position (p = 0.043 left and p = 0.031 right). Global inhomogeneity remained mostly unchanged. Ventral ventilation with positive pressure ventilation occurred with bag-mask ventilation, but was exacerbated by a tracheal tube. Tube position influenced ventilation of the right and left lungs, while ventilation overall remained homogenous. Tube rotation in either direction resulted in ventilation patterns being closer to when awake than either bag-mask ventilation or a normally positioned tube. These results suggest that even ideal tube positioning cannot avoid the ventral shift in ventilation.


Asunto(s)
Intubación Intratraqueal/métodos , Ventilación Pulmonar , Adulto , Anciano , Anestesia/métodos , Impedancia Eléctrica , Femenino , Humanos , Intubación Intratraqueal/efectos adversos , Máscaras Laríngeas , Pulmón/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Respiración con Presión Positiva , Respiración Artificial , Tomografía , Adulto Joven
3.
Br J Cancer ; 111(8): 1581-9, 2014 Oct 14.
Artículo en Inglés | MEDLINE | ID: mdl-25225903

RESUMEN

BACKGROUND: Colorectal cancer (CRC) progression is associated with suppression of host cell-mediated immunity and local immune escape mechanisms. Our aim was to assess the immune function in terms of expression of TNF, IFNG and FOXP3 in CRC. METHODS: Sixty patients with CRC and 15 matched controls were recruited. TaqMan quantitative PCR and methylation-specific PCR was performed for expression and DNA methylation analysis of TNF, IFNG and FOXP3. Survival analysis was performed over a median follow-up of 48 months. RESULTS: TNF was suppressed in tumour and IFNG was suppressed in peripheral blood mononuclear cells (PBMCs) of patients with CRC. Tumours showed enhanced expression of FOXP3 and was significantly higher when tumour size was >38 mm (median tumour size; P=0.006, Mann-Whitney U-test). Peripheral blood mononuclear cell IFNG was suppressed in recurrent CRC (P=0.01). Methylated TNFpromoter (P=0.003) and TNFexon1 (P=0.001) were associated with significant suppression of TNF in tumours. Methylated FOXP3cpg was associated with significant suppression of FOXP3 in both PBMC (P=0.018) and tumours (P=0.010). Reduced PBMC FOXP3 expression was associated with significantly worse overall survival (HR=8.319, P=0.019). CONCLUSIONS: We have detected changes in the expression of immunomodulatory genes that could act as biomarkers for prognosis and future immunotherapeutic strategies.


Asunto(s)
Adenocarcinoma/genética , Neoplasias Colorrectales/genética , Metilación de ADN , Factores de Transcripción Forkhead/genética , Interferón gamma/genética , Factor de Necrosis Tumoral alfa/genética , Adenocarcinoma/patología , Secuencia de Bases , Neoplasias Colorrectales/patología , Cartilla de ADN , Femenino , Expresión Génica , Humanos , Masculino , Inestabilidad de Microsatélites , Pronóstico , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Supervivencia
4.
BJOG ; 120(1): 113-8, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23078362

RESUMEN

The fullPIERS (Pre-eclampsia Integrated Estimate of RiSk) model is a promising tool for the prediction of adverse outcomes in pre-eclampsia, developed using the worst values for predictor variables measured within 48 hours of admission. We reassessed the performance of fullPIERS using predictor variables obtained within 6 and 24 hours of admission, and found that the stratification capacity, calibration ability, and classification accuracy of the model remained high. The fullPIERS model is accurate as a rule-in test for adverse maternal outcome, with a likelihood ratio of 14.8 (95% CI 9.1-24.1) or 17.5 (95% CI 11.7-26.3) based on 6- and 24-hour data, respectively, for the women identified to be at highest risk (predicted probability ≥ 30%).


Asunto(s)
Síndrome HELLP , Preeclampsia , Resultado del Embarazo , Adulto , Femenino , Humanos , Mortalidad Materna , Modelos Biológicos , Admisión del Paciente , Embarazo , Medición de Riesgo/métodos , Factores de Riesgo
5.
Nat Genet ; 1(5): 328-32, 1992 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-1302030

RESUMEN

Aniridia is an inherited ocular disorder of variable expressivity characterized by iris hypoplasia. A candidate aniridia gene, AN, which is the human homologue of the mouse Pax-6 gene, has recently been isolated by positional cloning from the WAGR region of 11p13. Here we describe mutations in this gene in two cases of sporadic aniridia, one detected at the DNA level and one at the RNA level, both of which are predicted to affect protein function. Mutations in Pax-6 have been described previously in Small eye, the proposed mouse model for aniridia. We present new phenotypic evidence for the validity of this mouse model.


Asunto(s)
Aniridia/genética , Cromosomas Humanos Par 11 , Mutación , Animales , Secuencia de Bases , Línea Celular , Mapeo Cromosómico , ADN/genética , ADN/aislamiento & purificación , Exones , Humanos , Ratones , Datos de Secuencia Molecular , Oligodesoxirribonucleótidos , Fenotipo , Reacción en Cadena de la Polimerasa/métodos , Eliminación de Secuencia
6.
Gut ; 61(2): 248-54, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21708826

RESUMEN

BACKGROUND AND AIMS: Shorter telomeres have been associated with increased risk of malignancy, including colorectal cancer (CRC). Telomere length is heritable and may be an intermediate phenotype linked to genetic susceptibility to CRC. METHODS: In a large sample, the study investigated whether candidate single nucleotide polymorphisms (SNP) in 'telomere biology' genes were associated with telomere length in leucocytes. SNP associated with an increased risk of CRC were searched for separately. RESULTS: Carriers of the common allele at SNP rs10936599, near the telomerase RNA component (TERC) locus, had significantly longer telomeres. It was independently found that the same rs10936599 allele was associated with increased risk of both CRC and colorectal adenomas. Neither telomere length nor CRC risk was associated with variation near telomerase reverse transcriptase or other telomere biology genes. In silico analysis showed that SNP rs2293607 was strongly correlated with rs10936599, mapped within TERC transcripts, had a predicted effect on messenger RNA folding and lay at a reported transcription factor binding site. TERC mRNA were expressed, differing only at the alleles of rs2293607, in CRC cell line HCT116. The long-telomere/CRC-risk allele was associated with higher levels of TERC mRNA and the formation of longer telomeres. CONCLUSIONS: Common genetic variation at TERC is associated with both longer telomeres and an increased risk of CRC, a potential mechanism being reduced levels of cell senescence or death. This finding is somewhat paradoxical, given retrospective studies reporting that CRC cases have shorter telomeres than controls. One possibility is that that association actually results from poorer survival in patients with longer telomeres.


Asunto(s)
Neoplasias Colorrectales/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , ARN/genética , Telomerasa/genética , Telómero/química , Adenoma/genética , Anciano , Carcinoma/genética , Estudios de Casos y Controles , Femenino , Técnicas de Genotipaje , Células HCT116 , Humanos , Leucocitos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Estudios Retrospectivos , Telómero/genética
7.
Colorectal Dis ; 14(9): e562-6, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22672595

RESUMEN

AIM: Patients with germline phosphatase and tensin homologue (PTEN) mutations develop hamartomatous lesions in several organs and are at increased risk of various malignancies. We assessed the lifetime risk of benign and malignant gastrointestinal lesions in patients with a proven PTEN mutation. METHOD: Data on gender, mutation, dates of birth, last contact, and diagnosis, location and type of gastrointestinal lesions were collected from nine countries. The lifetime risk of gastrointestinal lesions was calculated by Kaplan-Meier methods. RESULTS: A total of 156 patients (67 men, 43%) from 101 families with a PTEN mutation were included. Patients were born between 1928 and 2008. Benign gastrointestinal polyps were reported in 49 (31%) patients at a mean age of 38 years (range 18-62 years) and were most often hamartomas. Twenty-two (44%) patients had upper as well as lower gastrointestinal lesions, 14 (29%) had only colonic lesions and 13 (27%) had gastrointestinal lesions at unknown sites. The cumulative risk of developing benign gastrointestinal polyps was 70% at age 60. Four patients (two men) developed colorectal carcinoma at 53, 57, 59 and 62 years, respectively. The cumulative risk of developing colorectal carcinoma was 18% at age 60. Except for one carcinoid in the small intestine, no upper gastrointestinal cancers were observed. CONCLUSION: Benign gastrointestinal lesions are common in PTEN mutation carriers, and a three- to four-fold increased lifetime risk of colorectal cancer compared with the general population may exist. Colorectal screening of patients with germline PTEN mutations is recommended, starting at age 40 years.


Asunto(s)
Pólipos del Colon/genética , Neoplasias Colorrectales/genética , Síndrome de Hamartoma Múltiple/genética , Fosfohidrolasa PTEN/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Estudios de Cohortes , Pólipos del Colon/etiología , Neoplasias Colorrectales/etiología , Femenino , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Síndrome de Hamartoma Múltiple/complicaciones , Humanos , Lactante , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad
8.
J Laryngol Otol ; 136(7): 604-610, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-35042578

RESUMEN

BACKGROUND: Necrotising otitis externa is a severe ear infection for which there are no established diagnostic or treatment guidelines. METHOD: This study described clinical characteristics, management and outcomes for patients managed as necrotising otitis externa cases at a UK tertiary referral centre. RESULTS: A total of 58 (63 per cent) patients were classified as definite necrotising otitis externa cases, 31 (34 per cent) as probable cases and 3 (3 per cent) as possible cases. Median duration of intravenous and oral antimicrobial therapy was 6.0 weeks (0.49-44.9 weeks). Six per cent of patients relapsed a median of 16.4 weeks (interquartile range, 23-121) after stopping antimicrobials. Twenty-eight per cent of cases had complex disease. These patients were older (p = 0.042), had a longer duration of symptoms prior to imaging (p < 0.0001) and higher C-reactive protein at diagnosis (p = 0.005). Despite longer courses of intravenous antimicrobials (23 vs 14 days; p = 0.032), complex cases were more likely to relapse (p = 0.016). CONCLUSION: A standardised case-definition of necrotising otitis externa is needed to optimise diagnosis, management and research.


Asunto(s)
Otitis Externa , Antibacterianos/uso terapéutico , Humanos , Otitis Externa/diagnóstico , Otitis Externa/tratamiento farmacológico , Estudios Retrospectivos
9.
BJU Int ; 107(1): 28-39, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-20840664

RESUMEN

OBJECTIVE: To evaluate the role of targeted prostate cancer screening in men with BRCA1 or BRCA2 mutations, an international study, IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls), was established. This is the first multicentre screening study targeted at men with a known genetic predisposition to prostate cancer. A preliminary analysis of the data is reported. PATIENTS AND METHODS: Men aged 40-69 years from families with BRCA1 or BRCA2 mutations were offered annual prostate specific antigen (PSA) testing, and those with PSA > 3 ng/mL, were offered a prostate biopsy. Controls were men age-matched (± 5 years) who were negative for the familial mutation. RESULTS: In total, 300 men were recruited (205 mutation carriers; 89 BRCA1, 116 BRCA2 and 95 controls) over 33 months. At the baseline screen (year 1), 7.0% (21/300) underwent a prostate biopsy. Prostate cancer was diagnosed in ten individuals, a prevalence of 3.3%. The positive predictive value of PSA screening in this cohort was 47·6% (10/21). One prostate cancer was diagnosed at year 2. Of the 11 prostate cancers diagnosed, nine were in mutation carriers, two in controls, and eight were clinically significant. CONCLUSIONS: The present study shows that the positive predictive value of PSA screening in BRCA mutation carriers is high and that screening detects clinically significant prostate cancer. These results support the rationale for continued screening in such men.


Asunto(s)
Detección Precoz del Cáncer/métodos , Genes BRCA1 , Genes BRCA2 , Predisposición Genética a la Enfermedad/genética , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/diagnóstico , Adulto , Anciano , Detección Precoz del Cáncer/normas , Métodos Epidemiológicos , Predisposición Genética a la Enfermedad/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Mutación , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/epidemiología , Neoplasias de la Próstata/genética
10.
Gut ; 59(7): 975-86, 2010 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-20581245

RESUMEN

Peutz-Jeghers syndrome (PJS, MIM175200) is an autosomal dominant condition defined by the development of characteristic polyps throughout the gastrointestinal tract and mucocutaneous pigmentation. The majority of patients that meet the clinical diagnostic criteria have a causative mutation in the STK11 gene, which is located at 19p13.3. The cancer risks in this condition are substantial, particularly for breast and gastrointestinal cancer, although ascertainment and publication bias may have led to overestimates in some publications. Current surveillance protocols are controversial and not evidence-based, due to the relative rarity of the condition. Initially, endoscopies are more likely to be done to detect polyps that may be a risk for future intussusception or obstruction rather than cancers, but surveillance for the various cancers for which these patients are susceptible is an important part of their later management. This review assesses the current literature on the clinical features and management of the condition, genotype-phenotype studies, and suggested guidelines for surveillance and management of individuals with PJS. The proposed guidelines contained in this article have been produced as a consensus statement on behalf of a group of European experts who met in Mallorca in 2007 and who have produced guidelines on the clinical management of Lynch syndrome and familial adenomatous polyposis.


Asunto(s)
Síndrome de Peutz-Jeghers/diagnóstico , Adulto , Anciano , Neoplasias de la Mama/diagnóstico , Niño , Preescolar , Endoscopía Gastrointestinal , Medicina Basada en la Evidencia/métodos , Femenino , Neoplasias Gastrointestinales/diagnóstico , Neoplasias de los Genitales Femeninos/diagnóstico , Genotipo , Humanos , Cuidados a Largo Plazo/métodos , Masculino , Tamizaje Masivo/métodos , Persona de Mediana Edad , Síndrome de Peutz-Jeghers/genética , Síndrome de Peutz-Jeghers/terapia , Fenotipo , Vigilancia de la Población/métodos , Adulto Joven
11.
J Plast Reconstr Aesthet Surg ; 74(2): 396-400, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33051175

RESUMEN

Clinical governance is the structured approach to maintaining and improving the quality of patient care and is a vital part of global surgery. BFIRST and BSSH closely collaborate with local doctors on a number of overseas projects, seeking to strengthen and develop local knowledge and skills, aiming for an independent local practice in reconstructive and upper limb surgery. Thoughts on essential requirements, improvements and pitfalls in the ethical approach to global collaboratives are presented.


Asunto(s)
Misiones Médicas/organización & administración , Procedimientos de Cirugía Plástica/normas , Garantía de la Calidad de Atención de Salud/organización & administración , Cuidados Posteriores , Creación de Capacidad/organización & administración , Salud Global , Humanos , Consentimiento Informado , Garantía de la Calidad de Atención de Salud/métodos
12.
Science ; 272(5265): 1187-90, 1996 May 24.
Artículo en Inglés | MEDLINE | ID: mdl-8638166

RESUMEN

It is widely accepted that tumors are monoclonal in origin, arising from a mutation or series of mutations in a single cell and its descendants. The clonal origin of colonic adenomas and uninvolved intestinal mucosa from an XO/XY mosaic individual with familial adenomatous polyposis (FAP) was examined directly by in situ hybridization with Y chromosome probes. In this patient, the crypts of the small and large intestine were clonal, but at least 76 percent of the microadenomas were polyclonal in origin.


Asunto(s)
Poliposis Adenomatosa del Colon/genética , Colon/patología , Mucosa Intestinal/patología , Mosaicismo , Poliposis Adenomatosa del Colon/patología , Adulto , Células Clonales , Sondas de ADN , Genotipo , Humanos , Íleon/patología , Hibridación in Situ , Hibridación Fluorescente in Situ , Cariotipificación , Masculino , Fenotipo , Cromosoma Y
13.
Gut ; 57(5): 704-13, 2008 May.
Artículo en Inglés | MEDLINE | ID: mdl-18194984

RESUMEN

BACKGROUND: Familial adenomatous polyposis (FAP) is a well-described inherited syndrome, which is responsible for <1% of all colorectal cancer (CRC) cases. The syndrome is characterised by the development of hundreds to thousands of adenomas in the colorectum. Almost all patients will develop CRC if they are not identified and treated at an early stage. The syndrome is inherited as an autosomal dominant trait and caused by mutations in the APC gene. Recently, a second gene has been identified that also gives rise to colonic adenomatous polyposis, although the phenotype is less severe than typical FAP. The gene is the MUTYH gene and the inheritance is autosomal recessive. In April 2006 and February 2007, a workshop was organised in Mallorca by European experts on hereditary gastrointestinal cancer aiming to establish guidelines for the clinical management of FAP and to initiate collaborative studies. Thirty-one experts from nine European countries participated in these workshops. Prior to the meeting, various participants examined the most important management issues according to the latest publications. A systematic literature search using Pubmed and reference lists of retrieved articles, and manual searches of relevant articles, was performed. During the workshop, all recommendations were discussed in detail. Because most of the studies that form the basis for the recommendations were descriptive and/or retrospective in nature, many of them were based on expert opinion. The guidelines described herein may be helpful in the appropriate management of FAP families. In order to improve the care of these families further, prospective controlled studies should be undertaken.


Asunto(s)
Poliposis Adenomatosa del Colon/terapia , Poliposis Adenomatosa del Colon/diagnóstico , Poliposis Adenomatosa del Colon/genética , Edad de Inicio , Antiinflamatorios no Esteroideos/uso terapéutico , Neoplasias Duodenales/diagnóstico , Neoplasias Duodenales/terapia , Femenino , Fibromatosis Agresiva/diagnóstico , Fibromatosis Agresiva/terapia , Genes APC , Predisposición Genética a la Enfermedad , Pruebas Genéticas/métodos , Humanos , Masculino , Factores de Riesgo
14.
Colorectal Dis ; 10(7): 673-6, 2008 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-18400042

RESUMEN

INTRODUCTION: Before publication of the British Society of Gastroenterology and Association of Coloproctology of Great Britain and Ireland guidelines in 2002, screening for people with a family history of colorectal cancer was sporadic and largely dependant on unvalidated local guidelines. Since 1990 we have been screening patients with both high and moderate risk family histories of colorectal cancer using local protocols which were more liberal than the new guidelines. In this study, we have analysed the pathology that would have been missed if we had been using the new guidelines in the period 1990-2002. METHOD: A total of 399 consecutive patients with a positive family history of colorectal malignancy underwent screening endoscopy according to local guidelines. Demographic, endoscopic and pathologic data were prospectively collected. Patients were retrospectively divided into those who would have been screened under the new guidelines (group 1) and those who would not (group 2). The recorded pathology was graded as significant or insignificant and the findings compared between the two groups. RESULTS: A total of 399 patients underwent 557 endoscopies of which 278 (50%) were indicated under the new guidelines (group 1) and 279 (50%) were not indicated (group 2). A significant pathology or carcinoma was found in 15.8% of group 1 endoscopies and 10.0% of group 2 endoscopies. This difference was significant. CONCLUSION: If we had been using the new guidelines in the period 1990-2002, we would not have performed 279 (50%) of the 557 procedures, but would not have discovered significant pathology in 10% of the moderate risk endoscopies representing 39% of the significant pathology, which was actually present in this population.


Asunto(s)
Pólipos del Colon/diagnóstico , Colonoscopía/estadística & datos numéricos , Neoplasias Colorrectales/diagnóstico , Tamizaje Masivo/normas , Guías de Práctica Clínica como Asunto/normas , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Pólipos del Colon/patología , Neoplasias Colorrectales/patología , Predisposición Genética a la Enfermedad , Humanos , Irlanda , Tamizaje Masivo/métodos , Tamizaje Masivo/estadística & datos numéricos , Persona de Mediana Edad , Riesgo , Reino Unido , Adulto Joven
15.
J Med Genet ; 44(8): 516-20, 2007 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-17483304

RESUMEN

BACKGROUND: Reports of differential mutagen sensitivity conferred by a defect in the mismatch repair (MMR) pathway are inconsistent in their conclusions. Previous studies have investigated cells established from immortalised human colorectal tumour lines or cells from animal models. METHODS: We examined primary human MSH2-deficient neonatal cells, bearing a biallelic truncating mutation in MSH2, for viability and chromosomal damage after exposure to DNA-damaging agents. RESULTS: MSH2-deficient cells exhibit no response to interstrand DNA cross-linking agents but do show reduced viability in response to irradiation. They also show increased chromosome damage and exhibit altered RAD51 foci kinetics after irradiation exposure, indicating defective homologous recombinational repair. DISCUSSION: The cellular features and sensitivity of MSH2-deficient primary human cells are broadly in agreement with observations of primary murine cells lacking the same gene. The data therefore support the view that the murine model recapitulates early features of MMR deficiency in humans, and implies that the variable data reported for MMR-deficient immortalised human cells may be due to further genetic or epigenetic lesions. We suggest caution in the use of radiotherapy for treatment of malignancies in individuals with functional loss of MSH2.


Asunto(s)
Proteína 2 Homóloga a MutS/genética , Mutación , Recombinasa Rad51/genética , Tolerancia a Radiación/genética , Preescolar , Reparación del ADN , Femenino , Tamización de Portadores Genéticos , Genotipo , Humanos , Linfoma no Hodgkin/genética , Masculino , Proteína 2 Homóloga a MutS/deficiencia , Neoplasias/genética , Núcleo Familiar , Linaje , Polimorfismo de Nucleótido Simple , Recombinación Genética
16.
J Med Genet ; 44(6): 353-62, 2007 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-17327285

RESUMEN

Lynch syndrome (hereditary non-polyposis colorectal cancer) is characterised by the development of colorectal cancer, endometrial cancer and various other cancers, and is caused by a mutation in one of the mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. The discovery of these genes, 15 years ago, has led to the identification of large numbers of affected families. In April 2006, a workshop was organised by a group of European experts in hereditary gastrointestinal cancer (the Mallorca-group), aiming to establish guidelines for the clinical management of Lynch syndrome. 21 experts from nine European countries participated in this workshop. Prior to the meeting, various participants prepared the key management issues of debate according to the latest publications. A systematic literature search using Pubmed and the Cochrane Database of Systematic Reviews reference lists of retrieved articles and manual searches of relevant articles was performed. During the workshop, all recommendations were discussed in detail. Because most of the studies that form the basis for the recommendations were descriptive and/or retrospective in nature, many of them were based on expert opinion. The guidelines described in this manuscript may be helpful for the appropriate management of families with Lynch syndrome. Prospective controlled studies should be undertaken to improve further the care of these families.


Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/terapia , Guías de Práctica Clínica como Asunto , Colon/patología , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/epidemiología , Neoplasias Endometriales/epidemiología , Europa (Continente)/epidemiología , Femenino , Pruebas Genéticas , Humanos
17.
J Med Genet ; 43(4): e15, 2006 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-16582077

RESUMEN

BACKGROUND: Peutz-Jeghers syndrome (PJS) is a rare, autosomal dominant cancer predisposition syndrome characterised by oro-facial pigmentation and hamartomatous polyposis of the gastrointestinal tract. A causal germline mutation in STK11 can be identified in 30% to 80% of PJS patients. METHODS: Here we report the comprehensive mutational analysis of STK11 in 38 PJS probands applying conventional PCR based mutation detection methods and the recently introduced MLPA (multiplex ligation dependent probe amplification) technique developed for the identification of exonic deletions/duplications. RESULTS: Nineteen of 38 probands (50%) had detectable point mutations or small scale deletions/insertions and six probands (16%) had genomic deletions encompassing one or more STK11 exons. CONCLUSIONS: These findings demonstrate that exonic STK11 deletions are a common cause of PJS and provide a strong rationale for conducting a primary screen for such mutations in patients.


Asunto(s)
Exones , Síndrome de Peutz-Jeghers/genética , Proteínas Serina-Treonina Quinasas/genética , Eliminación de Secuencia , Quinasas de la Proteína-Quinasa Activada por el AMP , Adolescente , Adulto , Niño , Preescolar , Análisis Mutacional de ADN , Femenino , Predisposición Genética a la Enfermedad , Humanos , Recién Nacido , Masculino , Mutación , Técnicas de Amplificación de Ácido Nucleico , Síndrome de Peutz-Jeghers/diagnóstico , Síndrome de Peutz-Jeghers/epidemiología , Mutación Puntual
18.
J Shoulder Elbow Surg ; 16(2): 143-5, 2007.
Artículo en Inglés | MEDLINE | ID: mdl-17399621

RESUMEN

The 2-year results of a randomized, prospective, controlled trial of minimally displaced proximal humeral fractures treated either by immediate physiotherapy (group A) or after 3 weeks of immobilization (group B) are reported. At 1 year shoulder disability, as measured with the Croft shoulder disability questionnaire, was found in 42.8% of patients in group A and 72.5% in group B (P < .01). By 2 years, shoulder disability in group A remained unchanged (43.2%) but had reduced in group B (59.5%). This difference was not statistically significant. Immediate physiotherapy after a minimally displaced proximal humeral fracture results in faster recovery, with maximal functional benefit being achieved at 1 year. Delayed rehabilitation by 3 weeks of shoulder immobilization produces a slower recovery, which continues for at least 2 years after the time of injury.


Asunto(s)
Terapia por Ejercicio , Inmovilización , Fracturas del Hombro/rehabilitación , Anciano , Femenino , Estudios de Seguimiento , Humanos , Masculino , Estudios Prospectivos , Recuperación de la Función , Factores de Tiempo
19.
Radiat Prot Dosimetry ; 127(1-4): 55-9, 2007.
Artículo en Inglés | MEDLINE | ID: mdl-18003715

RESUMEN

With the experimental evolution of fusion power the levels of tritium used will increase as will the potential for human exposure. Tritium-loaded carbon particles produced during the experimental operation of the Joint European Torus fusion tokamak have been characterised in terms of size, elemental composition and specific activity of tritium elsewhere. The aim of this study was to characterise the dissolution of tritium from these particles in order to derive dose coefficients for this material and provide guidance on monitoring procedures should it be inhaled accidentally. The dissolution of tritium was measured for 100 d in lung serum simulant from two batches of materials, SG1 and SG2, which were obtained from carbon tiles originating from different positions in the reactor. Retention over this period followed a three-component exponential. About 1-5% dissolved within a minute, and up to a further 20% dissolved over 100 d for the SG1 materials but <1% for the SG2 materials. Dissolution between the SG1 materials varied greatly, whereas the SG2 materials were similar. As a result of this variability, the assessed dose from urinary excretion could be in error by up to two orders of magnitude depending on the material inhaled. It is recommended that (i) the dissolution is measured for a wider range of materials, preferably dusts collected in working areas, and (ii) in vivo studies are performed to characterise fully the urine excretion of tritium from these materials. This information could be used to provide improved guidance on dose assessment after special or routine monitoring, taking account of the likely variation of particle size and biological retention half times.


Asunto(s)
Contaminantes Atmosféricos/análisis , Fusión Nuclear , Reactores Nucleares/instrumentación , Monitoreo de Radiación/métodos , Protección Radiológica/métodos , Tritio/análisis , Diseño de Equipo , Análisis de Falla de Equipo , Tamaño de la Partícula , Dosis de Radiación
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