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1.
Semin Diagn Pathol ; 2024 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-38336505

RESUMEN

The unenlightened clinician may submit a skin specimen to the lab and expect an "answer." The experienced clinician knows that in performing skin biopsies, it is critical to select the most appropriate: 1) anatomic location for the biopsy1,2; 2) type of biopsy1,2; 3) depth and breadth of the biopsy; and 4) medium for hematoxylin and eosin staining (formalin) or direct immunofluorescence (Michel's Transport Medium or normal saline).2 Demographic information, anatomic location, clinical context, and differential diagnosis are all critical components of a properly completed requisition form.3-5 Proper biopsy design and appropriate grossing of the tissue at the bedside should be added to this list. In this article, we review the basics of gross pathologic examination and then provide four examples to demonstrate that optimal clinical-pathologic correlation requires the clinician consider the needs of the pathologist when tissue is presented to the lab.

2.
Br J Surg ; 110(4): 471-480, 2023 03 30.
Artículo en Inglés | MEDLINE | ID: mdl-36785496

RESUMEN

BACKGROUND: Faecal immunochemical test (FIT)-directed pathways based on a single test have been implemented for symptomatic patients. However, with a single test, the sensitivity is 87 per cent at 10 µg haemoglobin (Hb) per g faeces. This aims of this study were to define the diagnostic performance of a single FIT, compared with double FIT in symptomatic populations. METHODS: Two sequential prospective patient cohorts referred with symptoms from primary care were studied. Patients in cohort 1 were sent a single FIT, and those in cohort 2 received two tests in succession before investigation. All patients were investigated, regardless of having a positive or negative test (threshold 10 µg Hb per g). RESULTS: In cohort 1, 2260 patients completed one FIT and investigation. The sensitivity of single FIT was 84.1 (95 per cent c.i. 73.3 to 91.8) per cent for colorectal cancer and 67.4 (61.0 to 73.4) per cent for significant bowel pathology. In cohort 2, 3426 patients completed at least one FIT, and 2637 completed both FITs and investigation. The sensitivity of double FIT was 96.6 (90.4 to 99.3) per cent for colorectal cancer and 83.0 (77.4 to 87.8) per cent for significant bowel pathology. The second FIT resulted in a 50.0 per cent reduction in cancers missed by the first FIT, and 30.0 per cent for significant bowel pathology. Correlation between faecal Hb level was only modest (rs = 0.58), and 16.8 per cent of double tests were discordant, 11.4 per cent in patients with colorectal cancer and 18.3 per cent in those with significant bowel pathology. CONCLUSION: FIT in patients with high-risk symptoms twice in succession reduces missed significant colorectal pathology and has an acceptable workload impact.


Asunto(s)
Neoplasias Colorrectales , Humanos , Sensibilidad y Especificidad , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/patología , Estudios Prospectivos , Hemoglobinas/análisis , Heces/química , Sangre Oculta , Detección Precoz del Cáncer/métodos , Colonoscopía
3.
Matern Child Health J ; 26(Suppl 1): 137-146, 2022 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-35286520

RESUMEN

PURPOSE: The HRSA-funded maternal and child health pipeline training programs (MCHPTPs) are a response to the critical need to diversify the MCH workforce, as a strategy to reduce health disparities in MCH populations. These MCHPTPs support students from undergraduate to graduate education and ultimately into the MCH workforce. DESCRIPTION: The models and components of training across the six MCHPTPs funded in 2016-2021 are summarized, to examine the design and delivery of undergraduate pipeline training and the insights gained across programs. ASSESSMENT: Strategies that emerged across training programs were organized into three themes: recruitment, support for student persistence (in education), and pipeline-to-workforce intentionality. Support for student persistence included financial support, mentoring, creating opportunity for students to develop a sense of belonging, and the use of research as a tool to promote learning and competitiveness for graduate education. Finally, the link to Maternal and Child Health Bureau (MCHB) long-term training and other MCHB opportunities for professional development contributed significant nuance to the pipeline-to-workforce objectives of these programs. CONCLUSIONS: The MCHPTPs not only increase the diversity of the MCH workforce, they also actively prepare the next generation of MCH leaders. The intentional connection of undergraduates to the infrastructure and continuum of MCH training, underscores the comprehensive impact of this funding.


Asunto(s)
Salud Infantil , Tutoría , Niño , Humanos , Centros de Salud Materno-Infantil , Desarrollo de Programa , Recursos Humanos
4.
J Dairy Sci ; 102(5): 4498-4505, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-30852016

RESUMEN

The objectives of this randomized clinical trial were to determine whether the utilization of a multispecies probiotic bolus (MSP) in dairy calves with diarrhea led to a rapid resolution of diarrhea and improved average daily gain (ADG). Calves, from a convenience sample of dairy farms with diarrhea challenges, having fecal scores of ≥2 were randomly assigned to receive MSP or a placebo (PLB). The MSP bolus contained Pediococcus acidilactici, Enterococcus faecium, Lactobacillus acidophilus, Lactobacillus casei, Bifidobacterium bifidum, peptide extract, an enzyme blend, killed yeast extract, dried whey, and natural flavors (Revive, Partnar Animal Health, Ilderton, ON, Canada). The enrolled calves were fecal scored daily for 7 consecutive days and resolution of diarrhea was defined as having 2 consecutive days with a fecal score ≤1. Calves were also weighed at enrollment, 7, and 14 d following enrollment and ADG was calculated. A Cox proportional hazards model was built to investigate time to resolution of an abnormal fecal score. Two mixed linear regression models were created to evaluate the effect of treatment group on ADG in the first and second weeks following enrollment. A total of 148 calves were enrolled in the experiment and no differences were observed between the groups with respect to the age or weight at enrollment. The mean time to resolution of abnormal fecal score was 5.1 and 5.9 d in the MSP and PLB groups, respectively. In the Cox proportional hazards model, the calves in the MSP group had faster resolution of diarrhea when compared with the PLB group; however, an interaction between time from enrollment of the first calf and treatment group was present. No differences were found between the 2 groups with respect to ADG. This study demonstrates a multispecies probiotic and yeast bolus administered to calves at the onset of diarrhea reduced the duration of diarrhea; however, the clinical and economic relevance of this reduction requires further exploration.


Asunto(s)
Enfermedades de los Bovinos/tratamiento farmacológico , Industria Lechera/métodos , Diarrea/veterinaria , Probióticos/farmacología , Alimentación Animal/análisis , Animales , Bacterias/metabolismo , Bovinos , Diarrea/tratamiento farmacológico , Dieta/veterinaria , Heces/microbiología , Femenino , Ontario , Distribución Aleatoria
5.
J Chem Theory Comput ; 20(1): 385-395, 2024 Jan 09.
Artículo en Inglés | MEDLINE | ID: mdl-38150288

RESUMEN

The tunable design of protein redox potentials promises to open a range of applications in biotechnology and catalysis. Here, we introduce a method to calculate redox potential changes by combining fluctuation relations with molecular dynamics simulations. It involves the simulation of reduced and oxidized states, followed by the instantaneous conversion between them. Energy differences introduced by the perturbations are obtained using the Kubo-Onsager approach. Using a detailed fluctuation relation coupled with Bayesian inference, these are postprocessed into estimates for the redox potentials in an efficient manner. This new method, denoted MD + CB, is tested on a de novo four-helix bundle heme protein (the m4D2 "maquette") and five designed mutants, including some mutants characterized experimentally in this work. The MD + CB approach is found to perform reliably, giving redox potential shifts with reasonably good correlation (0.85) to the experimental values for the mutants. The MD + CB approach also compares well with redox potential shift predictions using a continuum electrostatic method. The estimation method employed within the MD + CB approach is straightforwardly transferable to standard equilibrium MD simulations and holds promise for redox protein engineering and design applications.


Asunto(s)
Hemo , Simulación de Dinámica Molecular , Secuencia de Aminoácidos , Teorema de Bayes , Estructura Secundaria de Proteína , Hemo/química , Proteínas/química , Oxidación-Reducción
6.
Fish Physiol Biochem ; 38(1): 143-52, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21671025

RESUMEN

Increased aquaculture production has raised concerns about managing protocols to safeguard the welfare of farmed fish, as consumers demand responsible aquaculture practices to provide 'welfare friendly' products. Feeding is one of the largest production cost in a fish farm and can be one of the biggest stressors for fish. Under farming conditions, fish are challenged with artificial diets and feeding regimes, and inadequate feeding conditions cause stress, alteration of normal behavioural patterns, poor performance and eventually diseases and death, which are by no means acceptable neither economically nor ethically. This review aims to highlight the impact of feeding rhythms and feeding time upon physiological and behavioural welfare indicators, which show circadian rhythms as well. Therefore, all these variables should be considered when designing feeding strategies in farming conditions and assessing the welfare state of cultured fish.


Asunto(s)
Bienestar del Animal , Métodos de Alimentación/veterinaria , Explotaciones Pesqueras/normas , Peces/fisiología , Animales , Conducta Animal/fisiología , Ritmo Circadiano , Métodos de Alimentación/psicología , Peces/crecimiento & desarrollo , Estrés Fisiológico
7.
Am J Transplant ; 11(11): 2423-31, 2011 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-21714848

RESUMEN

Although end-stage renal disease related to AA amyloidosis nephropathy is well characterized, there are limited data concerning patient and graft outcome after renal transplantation. We performed a multicentric retrospective survey to assess the graft and patient survival in 59 renal recipients with AA amyloidosis. The recurrence rate of AA amyloidosis nephropathy was estimated at 14%. The overall, 5- and 10-year patient survival was significantly lower for the AA amyloidosis patients than for a control group of 177 renal transplant recipients (p = 0.0001, 0.028 and 0.013, respectively). In contrast, we did not observe any statistical differences in the 5- and 10- year graft survival censored for death between two groups. AA amyloidosis-transplanted patients exhibited a high proportion of infectious complications after transplantation (73.2%). Causes of death included both acute cardiovascular events and fatal septic complications. Multivariate analysis demonstrated that the recurrence of AA amyloidosis on the graft (adjusted OR = 14.4, p = 0.01) and older recipient age (adjusted OR for a 1-year increase = 1.06, p = 0.03) were significantly associated with risk of death. Finally, patients with AA amyloidosis nephropathy are eligible for renal transplantation but require careful management of both cardiovascular and infectious complications to reduce the high risk of mortality.


Asunto(s)
Amiloidosis/complicaciones , Amiloidosis/cirugía , Enfermedades Cardiovasculares/etiología , Supervivencia de Injerto , Fallo Renal Crónico/etiología , Trasplante de Riñón/mortalidad , Adulto , Femenino , Humanos , Infecciones/etiología , Infecciones/mortalidad , Estimación de Kaplan-Meier , Enfermedades Renales/mortalidad , Enfermedades Renales/cirugía , Fallo Renal Crónico/cirugía , Trasplante de Riñón/efectos adversos , Masculino , Persona de Mediana Edad , Recurrencia , Estudios Retrospectivos , Resultado del Tratamiento
8.
Pediatr Transplant ; 15(5): 451-4, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21615645

RESUMEN

UNLABELLED: Pediatric liver transplantation is a successful procedure with 10-yr survival rate of 70%; following transplantation, the emphasis on promoting good quality of life is important. The increasing prevalence of allergic disorders in the general population and an increase in food allergy following solid organ transplantation are described in patients, especially in children, but the contribution to morbidity post-OLT has not been addressed. OBJECTIVES: Identifying the incidence de novo allergies post-OLT performed by QLTS over 11 yr. METHODS: Comprehensive medical record review of OLT recipients during study period. RESULTS: From 1st July 1998 to 1st August 2009, 78 children received 85 cadaveric OLT; 60 children survived. Allergic disease was documented in 24/60 (40%) survivors. De novo food allergies were diagnosed in 12/60 (20%) (Table 2), 9/12 occurred in children who were infants at time of transplant. Ten of 12 had severe allergies, six anaphylactic; 6/60 (10%) carry an EpiPen. Only 31/60 (51%) diagnosed are followed in Queensland, suggesting severe allergic disease in our cohort is an underestimate. CONCLUSION: Serious allergic disease post-OLT is clinically important, especially in infants at time of transplant, and should be targeted for specialist allergist referral and risk management. [Table: see text].


Asunto(s)
Hipersensibilidad a los Alimentos/etiología , Hipersensibilidad/etiología , Trasplante de Hígado/efectos adversos , Adolescente , Anafilaxia/inmunología , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Inmunosupresores/uso terapéutico , Lactante , Recién Nacido , Masculino , Calidad de Vida , Queensland , Factores de Tiempo , Resultado del Tratamiento
9.
Rev Med Suisse ; 7(285): 528-32, 2011 Mar 09.
Artículo en Francés | MEDLINE | ID: mdl-21488391

RESUMEN

Transradial approach in interventional cardiology is performed heterogenously around the world. Nevertheless, this technique allows to decrease access site complications and major bleeding, and increases patient's comfort. All patient subgroups beneficiate from this approach, especially in the case of acute coronary syndromes in which the bleeding risk is the highest, in relation to aggressive anticoagulation and platelet antiaggregation treatment. Transradial approach requires a longer learning curve than transfemoral approach due to specific technical challenges that are often overcome with experience. Because of its clear benefits, transradial access should become the gold standard approach for coronary diagnostic and interventional procedures.


Asunto(s)
Angioplastia Coronaria con Balón/métodos , Angiografía Coronaria/métodos , Humanos
10.
Front Public Health ; 9: 751536, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34708019

RESUMEN

Alzheimer's Disease (AD) is a neurodegenerative irreversible brain disorder that gradually wipes out the memory, thinking skills and eventually the ability to carry out day-to-day tasks. The amount of AD patients is rapidly increasing due to several lifestyle changes that affect biological functions. Detection of AD at its early stages helps in the treatment of patients. In this paper, a predictive and preventive model that uses biomarkers such as the amyloid-beta protein is proposed to detect, predict, and prevent AD onset. A Convolution Neural Network (CNN) based model is developed to predict AD at its early stages. The results obtained proved that the proposed model outperforms the traditional Machine Learning (ML) algorithms such as Logistic Regression, Support Vector Machine, Decision Tree Classifier, and K Nearest Neighbor algorithms.


Asunto(s)
Enfermedad de Alzheimer , Algoritmos , Enfermedad de Alzheimer/diagnóstico , Humanos , Imagen por Resonancia Magnética , Redes Neurales de la Computación , Máquina de Vectores de Soporte
11.
Cardiovasc Eng Technol ; 11(3): 328-336, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32002814

RESUMEN

PURPOSE: Metabolic alterations underlie many pathophysiological conditions, and their understanding is critical for the development of novel therapies. Although the assessment of metabolic changes in vivo has been historically challenging, recent developments in molecular imaging have allowed us to study novel metabolic research concepts directly in the living subject, bringing us closer to patients. However, in many instances, there is need for sensors that are in close proximity to the organ under investigation, for example to study vascular metabolism. METHODS: In this study, we developed and validated a metabolic detection platform directly in the living subject under an inflammatory condition. The signal collected by a scintillating fiber is amplified using a photomultiplier tube and decodified by an in-house tunable analysis platform. For in vivo testing, we based our experiments on the metabolic characteristics of macrophages, cells closely linked to inflammation and avid for glucose and its analog 18F-fluorodeoxyglucose (18F-FDG). The sensor was validated in New Zealand rabbits, in which inflammation was induced by either a) high cholesterol (HC) diet for 16 weeks or b) vascular balloon endothelial denudation followed by HC diet. RESULTS: There was no difference in weight, hemodynamics, blood pressure, or heart rate between the groups. Vascular inflammation was detected by the metabolic sensor (Inflammation: 0.60 ± 0.03 AU vs. control: 0.48 ± 0.03 AU, p = 0.01), even though no significant inflammation/atherosclerosis was detected by intravascular ultrasound, underscoring the high sensitivity of the system. These findings were confirmed by the presence of macrophages on ex vivo aortic tissue staining. CONCLUSION: In this study, we validated a tunable very sensitive metabolic sensor platform that can be used for the detection of vascular metabolism, such as inflammation. This sensor can be used not only for the detection of macrophage activity but, with alternative probes, it could allow the detection of other pathophysiological processes.


Asunto(s)
Aorta/metabolismo , Aortitis/metabolismo , Aterosclerosis/metabolismo , Técnicas Biosensibles , Metabolismo Energético , Fluorodesoxiglucosa F18/metabolismo , Fibras Ópticas , Radiofármacos/metabolismo , Lesiones del Sistema Vascular/metabolismo , Animales , Aorta/lesiones , Aorta/patología , Aortitis/patología , Aterosclerosis/patología , Modelos Animales de Enfermedad , Macrófagos/metabolismo , Macrófagos/patología , Conejos , Reproducibilidad de los Resultados , Procesamiento de Señales Asistido por Computador , Lesiones del Sistema Vascular/patología
12.
Science ; 162(3850): 265-6, 1968 Oct 11.
Artículo en Inglés | MEDLINE | ID: mdl-17779379

RESUMEN

The radiogenic argon and helium contents of three basalts erupted into the deep ocean from an active volcano (Kilauea) have been measured. Ages calculated from these measurements increase with sample depth up to 22 million years for lavas deduced to be recent. Caution is urged in applying dates from deep-ocean basalts in studies on ocean-floor spreading.

13.
Pediatr Transplant ; 13(7): 827-30, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19067919

RESUMEN

Pediatric liver transplantation has proven so successful that 10-yr survival post-transplantation is in excess of 70% and following transplantation, emphasis of medical care switches from life saving to promotion of good quality of life. EE is an increasingly recognised phenomenon in the general population. Eosinophilic disorders of the GI tract are increasingly recognised in patient's post-solid organ transplantation but the contribution of EE to morbidity in this population has not been addressed to date. The objective of this study was to identify the incidence of EE in children receiving liver transplantation by the QLTS over the last 15.5 yr. Comprehensive review of medical records of all liver transplant recipients during study period via cross-checking procedural and electronic laboratory results was performed. All oesophageal biopsies reporting mucosal inflammation were reviewed. EE can be diagnosed when oesophageal biopsy reveals > or =5 eosinophils per HPF; however, we used a cut-off of 20 eosinophils per HPF, which is in accordance with current opinion. In the 159 children who received DD OLT, 130 survived and four have been diagnosed with EE (3%). Only 34 are currently followed in Queensland and all four patients diagnosed are in this cohort representing 12% of our follow-up clinic. Many patients are followed elsewhere so occurrence of EE in our total surviving population is an underestimate. EE is clinically important in the post-liver transplant community. Children post-OLT who have upper GI symptoms should be considered for endoscopic evaluation and biopsy to exclude EE.


Asunto(s)
Eosinofilia/diagnóstico , Eosinofilia/etiología , Esofagitis/diagnóstico , Esofagitis/etiología , Trasplante de Hígado/métodos , Adolescente , Biopsia , Niño , Preescolar , Estudios de Cohortes , Eosinofilia/complicaciones , Esofagitis/complicaciones , Femenino , Humanos , Lactante , Recién Nacido , Trasplante de Hígado/efectos adversos , Masculino , Complicaciones Posoperatorias , Resultado del Tratamiento
14.
Nephron Clin Pract ; 112(4): c268-75, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-19546587

RESUMEN

BACKGROUND/AIMS: In diabetics with end-stage renal disease (ESRD), risk of death has been reported to be non-constant after the first dialysis, and different outcomes have been observed between genders. We assessed the impact of type 2 diabetes (T2DM) on mortality in dialysis regarding its differential effect by gender using time-dependent analyses. METHODS: All T2DM and non-diabetic (no-DM) patients who started dialysis in two renal units in Lyon, France, between January 1, 1995, and December 31, 2007, were included. In multivariate analyses, the Cox model and Shoenfeld residual approach were used to assess the effect of T2DM on dialysis mortality by gender. RESULTS: We included 235 T2DM (males: 57.9%) and 480 no-DM (males: 65.6%) patients. In males, the adjusted hazard ratio (aHR) for death in T2DM versus no-DM was 0.83 (p = 0.20) and was constant over time after the first renal replacement therapy (RRT) (p = 0.88). In females, aHR for death in T2DM versus no-DM patients was not constant over time (p = 0.002). It was 0.64 (p = 0.13) within the first year after the first RRT and 2.10 (p = 0.002) after the first year. Evolutions with time of these aHR by gender were significantly different (p = 0.009). CONCLUSIONS: T2DM was associated with death only in females. This association was not constant over time after the first dialysis.


Asunto(s)
Diabetes Mellitus Tipo 2/mortalidad , Diabetes Mellitus Tipo 2/rehabilitación , Fallo Renal Crónico/mortalidad , Fallo Renal Crónico/rehabilitación , Modelos de Riesgos Proporcionales , Diálisis Renal/mortalidad , Anciano , Comorbilidad , Femenino , Francia/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Medición de Riesgo/métodos , Factores de Riesgo , Distribución por Sexo , Análisis de Supervivencia , Tasa de Supervivencia
15.
J Med Genet ; 45(1): 36-42, 2008 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-17693570

RESUMEN

BACKGROUND: DLG5 p.R30Q has been reported to be associated with Crohn disease (CD), but this association has not been replicated in most studies. A recent analysis of gender-stratified data from two case-control studies and two population cohorts found an association of DLG5 30Q with increased risk of CD in men but not in women and found differences between 30Q population frequencies for males and females. Male-female differences in population allele frequencies and male-specific risk could explain the difficulty in replicating the association with CD. METHODS: DLG5 R30Q genotype data were collected for patients with CD and controls from 11 studies that did not include gender-stratified allele counts in their published reports and tested for male-female frequency differences in controls and for case-control frequency differences in men and in women. RESULTS: The data showed no male-female allele frequency differences in controls. An exact conditional test gave marginal evidence that 30Q is associated with decreased risk of CD in women (p = 0.049, OR = 0.87, 95% CI 0.77 to 1.00). There was also a trend towards reduced 30Q frequencies in male patients with CD compared with male controls, but this was not significant at the 0.05 level (p = 0.058, OR = 0.87, 95% CI 0.74 to 1.01). When data from this study were combined with previously published, gender-stratified data, the 30Q allele was found to be associated with decreased risk of CD in women (p = 0.010, OR = 0.86, 95% CI 0.76 to 0.97), but not in men. CONCLUSION: DLG5 30Q is associated with a small reduction in risk of CD in women.


Asunto(s)
Alelos , Enfermedad de Crohn/genética , Frecuencia de los Genes , Población Blanca/genética , Estudios de Casos y Controles , Enfermedad de Crohn/etnología , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Proteínas de la Membrana/genética , Oportunidad Relativa , Factores Sexuales , Proteínas Supresoras de Tumor/genética
16.
Methods Inf Med ; 48(3): 299-305, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-19387511

RESUMEN

OBJECTIVE: To assess the time-dependent accuracy of a continuous longitudinal biomarker used as a test for early diagnosis or prognosis. METHODS: A method for accuracy assessment is proposed taking into account the marker measurement time and the delay between marker measurement and outcome. It dealt with markers having interval-censored measurements and a detection threshold. The threshold crossing times were assessed by a Bayesian method. A numerical study was conducted to test the procedures that were later applied to PCR measurements for prediction of cytomegalovirus disease after renal transplantation. RESULTS: The Bayesian method corrected the bias induced by interval-censored measurements on sensitivity estimates, with corrections from 0.07 to 0.3. In the application to cytomegalovirus disease, the Bayesian method estimated the area under the ROC curve to be over 75% during the first 20 days after graft and within five days between marker measurement and disease onset. However, the accuracy decreased quickly as that delay increased and late after graft. CONCLUSIONS: The proposed Bayesian method is easy to implement for assessing the time-dependent accuracy of a longitudinal biomarker and gives unbiased results under some conditions.


Asunto(s)
Biomarcadores , Sensibilidad y Especificidad , Teorema de Bayes , Infecciones por Citomegalovirus , Diagnóstico Precoz , Trasplante de Riñón , Estudios Longitudinales , Pronóstico
17.
Gut ; 57(10): 1398-405, 2008 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-18523026

RESUMEN

OBJECTIVE: To investigate differential intestinal gene expression in patients with ulcerative colitis and in controls. DESIGN: Genome-wide expression study (41,058 expression sequence tags, 215 biopsies). SETTING: Western General Hospital, Edinburgh, UK, and Genentech, San Francisco, USA. PATIENTS: 67 patients with ulcerative colitis and 31 control subjects (23 normal subjects and 8 patients with inflamed non-inflammatory bowel disease biopsies). INTERVENTIONS: Paired endoscopic biopsies were taken from 5 specific anatomical locations for RNA extraction and histology. The Agilent microarray platform was used and confirmation of results was undertaken by real time polymerase chain reaction and immunohistochemistry. RESULTS: In healthy control biopsies, cluster analysis showed differences in gene expression between the right and left colon. (chi(2) = 25.1, p<0.0001). Developmental genes, homeobox protein A13 (HOXA13), (p = 2.3x10(-16)), HOXB13 (p<1x10(-45)), glioma-associated oncogene 1 (GLI1) (p = 4.0x10(-24)), and GLI3 (p = 2.1x10(-28)) primarily drove this separation. When all ulcerative colitis biopsies and control biopsies were compared, 143 sequences had a fold change of >1.5 in the ulcerative colitis biopsies (0.01>p>10(-45)) and 54 sequences had a fold change of <-1.5 (0.01>p>10(-20)). Differentially upregulated genes in ulcerative colitis included serum amyloid A1 (SAA1) (p<10(-45)) the alpha defensins 5 and 6 (DEFA5 and 6) (p = 0.00003 and p = 6.95x10(-7), respectively), matrix metalloproteinase 3 (MMP3) (p = 5.6x10(-10)) and MMP7 (p = 2.3x10(-7)). Increased DEFA5 and 6 expression was further characterised to Paneth cell metaplasia by immunohistochemistry and in situ hybridisation. Sub-analysis of the inflammatory bowel disease 2 (IBD2) and IBD5 loci, and the ATP-binding cassette (ABC) transporter genes revealed a number of differentially regulated genes in the ulcerative colitis biopsies. CONCLUSIONS: Key findings are the expression gradient in the healthy adult colon and the involvement of novel gene families, as well as established candidate genes in the pathogenesis of ulcerative colitis.


Asunto(s)
Colitis Ulcerosa/genética , Colon/metabolismo , Adulto , Estudios de Casos y Controles , Susceptibilidad a Enfermedades/metabolismo , Femenino , Expresión Génica , Perfilación de la Expresión Génica , Genoma Humano/genética , Mutación de Línea Germinal/genética , Humanos , Íleon/metabolismo , Masculino , Reacción en Cadena de la Polimerasa , ARN/metabolismo , Regulación hacia Arriba
18.
Mucosal Immunol ; 11(1): 120-130, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-28401939

RESUMEN

The multidrug resistance-1 (MDR1) gene encodes an ATP-dependent efflux transporter that is highly expressed in the colon. In mice, loss of MDR1 function results in colitis with similarities to human inflammatory bowel diseases (IBD). Here, we show that MDR1 has an unexpected protective role for the mitochondria where MDR1 deficiency results in mitochondrial dysfunction with increased mitochondrial reactive oxygen species (mROS) driving the development of colitis. Exogenous induction of mROS accelerates, while inhibition attenuates colitis in vivo; these effects are amplified in MDR1 deficiency. In human IBD, MDR1 is negatively correlated to SOD2 gene expression required for mROS detoxification. To provide direct evidential support, we deleted intestinal SOD2 gene in mice and showed an increased susceptibility to colitis. We exploited the genome-wide association data sets and found many (∼5%) of IBD susceptibility genes with direct roles in regulating mitochondria homeostasis. As MDR1 primarily protects against xenotoxins via its efflux function, our findings implicate a distinct mitochondrial toxin+genetic susceptibility interaction leading to mitochondrial dysfunction, a novel pathogenic mechanism that could offer many new therapeutic opportunities for IBD.


Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Colitis/genética , Inflamación/genética , Enfermedades Inflamatorias del Intestino/genética , Intestinos/inmunología , Mitocondrias/fisiología , Superóxido Dismutasa/genética , Animales , Modelos Animales de Enfermedad , Predisposición Genética a la Enfermedad , Homeostasis , Humanos , Fase I de la Desintoxicación Metabólica/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Especies Reactivas de Oxígeno/metabolismo
19.
Aliment Pharmacol Ther ; 26(3): 411-9, 2007 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-17635376

RESUMEN

BACKGROUND: Forty per cent of patients with acute severe ulcerative colitis will not respond to intravenous corticosteroids and require second-line medical therapy or colectomy. A recent controlled trial has suggested that infliximab may be effective as rescue therapy. AIM: To assess the value of infliximab as rescue therapy for acute severe colitis in a retrospective cohort of ulcerative colitis patients in Scotland. METHODS: All patients satisfied Truelove and Witts criteria on admission, failed to respond to intravenous corticosteroids and received infliximab (5 mg/kg) as rescue therapy. Response was defined as need for colectomy at hospital discharge and by 90 days. RESULTS: A total of 39 patients (median age 31.7 years) were treated. 26/39 (66%) responded, avoiding colectomy during the acute admission, and were followed up for a median of 203 days (Interquartile range = 135.5-328.5). Hypoalbuminaemia was a consistent predictor of non-response on univariate and multivariate analysis. At day 3 of intravenous steroids, 9/18 (50.0%) with serum albumin <34 g/L had urgent colectomy vs. 1/13 (7.7%) >or=34 g/L (P = 0.02, OR = 12.0, C.I. 1.28-112.7). Two serious adverse events occurred - one death due to Pseudomonas pneumonia, and one post-operative fungal septicaemia. CONCLUSIONS: Infliximab represents a moderately effective rescue therapy for patients with acute severe ulcerative colitis. Serious adverse events, including death, do occur and should be discussed with patients prior to therapy.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Colitis Ulcerosa/tratamiento farmacológico , Fármacos Gastrointestinales/uso terapéutico , Enfermedad Aguda , Adulto , Anciano , Anticuerpos Monoclonales/efectos adversos , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Infliximab , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento
20.
Transplant Proc ; 39(8): 2574-5, 2007 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-17954178

RESUMEN

In a retrospective study, the impact of the level of pretransplantation soluble CD30 molecule (sCD30) was evaluated on 3 year transplant survival, as well as the number and grade of acute rejection episodes among kidney recipients engrafted between 2000 and 2002. One hundred and ninety sera of 190 patients sampled on the cross-match day were tested for sCD30 concentrations using an enzyme-linked immunosorbent assay (ELISA) kit (Biotest). For the analysis, a sCD30 cutoff level of 100 U/mL was chosen: 87 (46%) recipients had a level >100, and 103 (54%) <100. All cases (5) of immunological graft loss showed a high sCD30 level. The rate of biopsy-proven acute rejection was 26% in the sCD30 >100 group versus 22% in the sCD30 <100 groups. Among the first graft population (n = 157), the rate was 27% for sCD30 >100 versus 20% for the lower level. The difference was more important for grade II acute rejection (Banff criteria): 6/87 (7%) showed high sCD30 versus 2/103 (2%) with sCD30 <100. This analysis became significant for anti-HLA immunization: 11 (13%) recipients developed anti-HLA class II antibodies in the first group (sCD30 >100) versus 1 (1%) in the second group (sCD30 <100; P < .01). A high pretransplantation sCD30 was not a significant risk factor for an acute rejection episode, but it seemed to be more predictive for antibody-mediated acute rejection and immunological graft loss. However, many recipients showed an increased pretransplantation concentration without any rejection episode or graft loss. Consequently, sCD30 pregraft measurements cannot be used as a predictor for acute kidney rejection among our transplant center, nor as an aid to adapt the immunosuppressive regimen.


Asunto(s)
Rechazo de Injerto/inmunología , Antígeno Ki-1/sangre , Trasplante de Riñón/inmunología , Antígenos CD/sangre , Biomarcadores/sangre , Donantes de Sangre , Rechazo de Injerto/epidemiología , Antígenos HLA-D/inmunología , Humanos , Valores de Referencia
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