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1.
Osteoarthritis Cartilage ; 28(3): 316-323, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31877381

RESUMEN

OBJECTIVE: Bone marrow lesions (BMLs) on MRI are typically subchondral in location, however, a proportion occur at knee ligament attachments and also include a cyst-like component. Our aim was to determine whether the volume of BML subtypes and synovial tissue volume (STV) was associated with symptoms in symptomatic knee OA. METHOD: Images were acquired in a sub-sample who had taken part in a randomised trial of vitamin D therapy in knee OA (UK-VIDEO). Contrast-enhanced (CE) MRI was performed annually. In those who had ≥1 follow-up and a baseline scan (N = 50), STV and BML volume was assessed. BMLs were categorised by location and by the presence/absence of a cyst-like component. WOMAC was assessed annually. We used fixed-effects panel-regression modelling to examine the association between volume and symptoms. RESULTS: There was no association between knee pain and total subchondral BML volume (b = 0.3 WOMAC units, 95% CI -0.3 to 1.0) or total ligament-based BML volume (b = 1.9, 95% CI -1.6 to 5.3). The volume of subchondral BMLs with a cyst-like component was not associated with pain (b = 0.8, 95% CI -0.5 to 2.1) however, the volume of the cyst-like component itself was associated with pain (b = 51.8, 95% CI 14.2 to 89.3). STV was associated with pain (b = 2.2, 95% CI 0.6 to 3.7). CONCLUSION: The volume of the cyst-like component from subchondral BMLs with a cyst-like component was associated with knee pain. BML location, however, did not influence symptoms. STV was also associated with knee symptoms.


Asunto(s)
Enfermedades de la Médula Ósea/diagnóstico por imagen , Edema/diagnóstico por imagen , Fémur/diagnóstico por imagen , Osteoartritis de la Rodilla/diagnóstico por imagen , Rótula/diagnóstico por imagen , Sinovitis/diagnóstico por imagen , Tibia/diagnóstico por imagen , Anciano , Ligamento Cruzado Anterior , Enfermedades de la Médula Ósea/fisiopatología , Edema/fisiopatología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Tamaño de los Órganos , Osteoartritis de la Rodilla/fisiopatología , Ligamento Cruzado Posterior , Ensayos Clínicos Controlados Aleatorios como Asunto , Membrana Sinovial/patología , Sinovitis/fisiopatología
2.
BMC Vet Res ; 16(1): 180, 2020 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-32505206

RESUMEN

BACKGROUND: Additive manufacturing has allowed for the creation of a patient-specific custom solution that can resolve many of the limitations previously reported for canine cranioplasty. The purpose of this pilot study was to determine the schedule feasibility and workflow in manufacturing patient-specific titanium implants for canines undergoing cranioplasty immediately following craniectomy. RESULTS: Computed tomography scans from patients with tumors of the skull were considered and 3 cases were selected. Images were imported into a DICOM image processing software and tumor margins were determined based on agreement between a board-certified veterinary radiologist and veterinary surgical oncologist. Virtual surgical planning was performed and a bone safety margin was selected. A defect was created to simulate the planned intraoperative defect. Stereolithography format files of the skulls were then imported into a plate design software. In collaboration with a medical solution centre, a custom titanium plate was designed with the input of an applications engineer and veterinary surgery oncologist. Plates were printed in titanium and post-processed at the solution centre. Total planning time was approximately 2 h with a manufacturing time of 2 weeks. CONCLUSIONS: Based on the findings of this study, with access to an advanced 3D metal printing medical solution centre that can provide advanced software and printing, patient-specific additive manufactured titanium implants can be planned, created, processed, shipped and sterilized for patient use within a 3-week turnaround.


Asunto(s)
Enfermedades de los Perros/cirugía , Prótesis e Implantes/veterinaria , Neoplasias Craneales/veterinaria , Titanio , Animales , Craneotomía/veterinaria , Perros , Estudios de Factibilidad , Procesamiento de Imagen Asistido por Computador , Impresión Tridimensional , Cráneo , Neoplasias Craneales/cirugía , Tomografía Computarizada por Rayos X/veterinaria , Flujo de Trabajo
3.
Am J Transplant ; 18(1): 63-73, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-28654216

RESUMEN

Human organ allograft rejection depends on effector lymphocytes: NK cells in antibody-mediated rejection (ABMR) and effector T cells in T cell-mediated rejection (TCMR). We hypothesized that NK cell CD16a stimulation and CD8 T cell TCR/CD3 stimulation represent highly similar effector systems, and should lead to shared molecular changes between ABMR and TCMR. We studied similarity between soluble proteins and the transcripts induced in CD16a stimulated NK cells and TCR/CD3-stimulated T cells in vitro. Of 30 soluble mediators tested, CD16a-activated NK cells and CD3/TCR activated T cells produced the same limited set of five mediators-CCL3, CCL4, CSF2, IFNG, and TNF-and failed to produce 25 others. Many transcripts increased in stimulated NK cells were also increased in CD3-stimulated CD8 T cells (FDR < 0.05), including IFNG, CSF2, CCL3, CCL4, and XCL1. We hypothesized that shared transcripts not produced by other cell types should be expressed both in ABMR and TCMR kidney transplant biopsies. CD160, XCL1, TNFRSF9, and IFNG were selective for TCR/CD3-activated T cells and CD16a-NK cells and all were strongly increased in ABMR and TCMR. The molecules such as CD160 and XCL1 shared between NK cells in ABMR and effector T cells in TCMR may hold insights into important rejection mechanisms.


Asunto(s)
Anticuerpos/efectos adversos , Quimiocinas/metabolismo , Citocinas/metabolismo , Rechazo de Injerto/metabolismo , Trasplante de Riñón/efectos adversos , Células Asesinas Naturales/inmunología , Linfocitos T/inmunología , Rechazo de Injerto/etiología , Rechazo de Injerto/patología , Supervivencia de Injerto/inmunología , Humanos , Células Asesinas Naturales/metabolismo , Pronóstico , Linfocitos T/metabolismo
4.
Colorectal Dis ; 20(9): 797-803, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29569419

RESUMEN

AIM: Crohn's anal fistula should be managed by a multidisciplinary team. There is no clearly defined 'patient pathway' from presentation to treatment. The aim of this study was to describe the patient route from presentation with symptomatic Crohn's anal fistula to starting anti-tumour necrosis factor (anti-TNF) therapy. METHOD: Case note review was undertaken at three hospitals with established inflammatory bowel disease services. Patients with Crohn's anal fistula presenting between 2010 and 2015 were identified through clinical coding and local databases. Baseline demographics were captured. Patient records were interrogated to identify route of access, and clinical contacts during the patient pathway. RESULTS: Seventy-nine patients were included in the study, of whom 54 (68%) had an established diagnosis of Crohn's disease (CD). Median time from presentation to anti-TNF therapy was 204 days (174 vs 365 days for existing and new diagnosis of CD, respectively; P = 0.019). The mean number of surgical outpatient attendances, operations and MRI scans per patient was 1.03, 1.71 and 1.03, respectively. Patients attended a mean of 1.49 medical clinics. Seton insertion was the most common procedure, accounting for 48.6% of all operations. Where care episodes ('clinical events per 30 days') were infrequent this correlated with prolongation of the pathway (r = -0.87; P < 0.01). CONCLUSION: This study highlights two key challenges in the treatment pathway: (i) delays in diagnosis of underlying CD in patients with anal fistula and (ii) the pathway to anti-TNF therapy is long, suggesting issues with service design and delivery. These should be addressed to improve patient experience and outcome.


Asunto(s)
Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/tratamiento farmacológico , Fístula Rectal/diagnóstico , Fístula Rectal/tratamiento farmacológico , Tiempo de Tratamiento/estadística & datos numéricos , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adulto , Estudios de Cohortes , Comorbilidad , Vías Clínicas , Enfermedad de Crohn/epidemiología , Accesibilidad a los Servicios de Salud/estadística & datos numéricos , Hospitales de Enseñanza , Humanos , Incidencia , Persona de Mediana Edad , Evaluación de Necesidades , Pronóstico , Fístula Rectal/epidemiología , Estudios Retrospectivos , Medición de Riesgo , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/administración & dosificación , Adulto Joven
5.
Exp Physiol ; 102(12): 1567-1583, 2017 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-29052280

RESUMEN

NEW FINDINGS: What is the topic of this review? One of the major unanswered questions in physiology is that of how breathing matches metabolic rate. Venous chemoreceptors seem to have been dismissed since the 1960s. What advances does it highlight? New evidence shows that their apparent dismissal needs reappraisal. The paper on which this depends has more than one interpretation, and another paper obtained the opposite result. Previous search ignored all locations between skeletal muscle and the right heart. Oxygen sensors other than the arterial chemoreceptors do exist. Heymans and colleagues originally demonstrated some residual breathing response to hypoxia in sino-aortically denervated animals. Similar results occur in humans. One of the major unanswered questions in physiology is that of how breathing matches metabolic rate. The existence in humans of venous chemoreceptors that might control breathing seems to have been dismissed since the 1960s. New evidence has emerged showing that this apparent dismissal needs reappraisal. First, the paper in humans on which this depends has more than one interpretation. Moreover, a previous paper obtained the opposite result and is not cited. Secondly, previous search for venous chemoreceptors failed to examine all venous locations between skeletal muscle and the right heart and lungs. Thirdly, oxygen sensors other than the arterial chemoreceptors do exist. Heymans himself originally demonstrated some residual breathing response to hypoxia in sino-aortically denervated animals. Others confirm a residual breathing response to hypoxia in mammals, including humans. There is now considerable interest in the importance of afferent feedback in controlling the cardiovascular and respiratory systems. Moreover, it is now clear that arterial, aortic and central chemoreceptors have no role in explaining how breathing matches metabolic rate during exercise. These together provide a timely reminder that venous chemoreceptors remain ideal candidates still to be considered as metabolic rate sensors to explain matching in humans. Firstly, this is because venous PO2 and PCO2 values do change appropriately in proportion to metabolic rate, so a metabolic rate signal sufficient to drive breathing might already exist. Secondly, chemoreceptor-like anatomical structures are present in the systemic venous system but remain unexplored. Finally, no extant experimental evidence precludes their existence.


Asunto(s)
Células Quimiorreceptoras/fisiología , Metabolismo Energético , Ejercicio Físico , Pulmón/fisiología , Contracción Muscular , Músculo Esquelético/fisiología , Mecánica Respiratoria , Venas/inervación , Animales , Dióxido de Carbono/sangre , Células Quimiorreceptoras/metabolismo , Humanos , Hipoxia/sangre , Hipoxia/fisiopatología , Modelos Biológicos , Músculo Esquelético/metabolismo , Oxígeno/sangre
6.
Br J Sports Med ; 2017 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-28490457

RESUMEN

OBJECTIVES: To identify prognostic factors and models for spinal and lower extremity injuries in adult professional/elite football players from medical screening and training load monitoring processes. METHODS: The MEDLINE, AMED, EMBASE, CINAHL Plus, SPORTDiscus electronic bibliographic databases and the Cochrane Database of Systematic Reviews were searched from inception to July 2016. Searches were limited to original research, published in peer reviewed journals of any language. The Quality in Prognostic Studies (QUIPS) tool was used for appraisal and the modified GRADE approach was used for synthesis. Prospective and retrospective cohort study designs of spinal and lower extremity injury incidence were found from populations of adult professional/elite football players, between 16 and 40 years. Non-football or mixed sports were excluded. RESULTS: 858 manuscripts were identified. Removing duplications left 551 studies, which were screened for eligibility by title and abstract. Of these, 531 studies were not eligible and were excluded. The full text of the remaining 20 studies were obtained; a further 10 studies were excluded. 10 studies were included for appraisal and analysis, for 3344 participants. CONCLUSIONS: Due to the paucity and heterogeneity of the literature, and shortcomings in methodology and reporting, the evidence is of very low or low quality and therefore cannot be deemed robust enough to suggest conclusive prognostic factors for all lower limb musculoskeletal injury outcomes identified. No studies were identified that examined spinal injury outcomes or prognostic models.

7.
Osteoarthritis Cartilage ; 24(9): 1509-17, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27143362

RESUMEN

OBJECTIVE: International guidelines recommend intra-articular steroid injections (IASIs) in the management of hip osteoarthritis (OA), though these recommendations are extrapolated primarily from studies of knee OA. The aim of this systematic review was to assess the efficacy of IASI on pain in hip OA. METHODS: MEDLINE, EMBASE, AMED, CINAHL Plus, Web of Science and the Cochrane Central Register of Controlled Trials were searched to May 2015. Randomised controlled trials (RCTs) assessing the efficacy of hip IASI on pain were included. Pre-specified data was extracted using a standardised form. Quality was assessed using the Jadad score. RESULTS: Five trials met the inclusion criteria. All had a small number of participants (≤101). All studies reported some reduction in pain at 3-4 weeks post-injection compared to control. Based on data from individual trials the treatment effect size was large at 1 week post-injection but declined thereafter. A significant (moderate effect size) reduction in pain was reported in two trials up to 8 weeks following IASI. Pooled results of two trials (n = 90) showed an increased likelihood of meeting the Outcome measures in Rheumatology Clinical Trials (OMERACT)-Osteoarthritis Research Society International (OARSI) response criteria at 8 weeks post-IASI, odds ratio 7.8 (95% confidence interval (CI): 2.7-22.8). The number needed to treat to achieve one OMERACT-OARSI responder at 8 weeks post-injection was 2.4 (95% CI: 1.7-4.2). Hip IASI appear to be generally well tolerated. CONCLUSIONS: Hip IASI may be efficacious in short-term pain reduction in those with hip OA though the quality of the evidence was relatively poor. Further large, methodologically rigorous trials are required to verify whether intra-articular corticosteroids are beneficial and for how long.


Asunto(s)
Osteoartritis de la Cadera , Humanos , Inyecciones Intraarticulares , Osteoartritis de la Rodilla , Dolor
8.
Osteoarthritis Cartilage ; 24(8): 1392-8, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27038489

RESUMEN

OBJECTIVE: Synovium is increasingly a target of osteoarthritis (OA) treatment, yet its optimal measurement is unclear. Using dynamic contrast enhanced (DCE) MRI in knee OA patients before and after intraarticular steroid injection, we compared the responsiveness of static synovial volume measures to measures of dynamic changes in synovial enhancement, changes that are strongly related to synovial vascularity. METHODS: Ninety three patients underwent DCE-MRI before and 1-2 weeks after intra-articular injection of 80 mg methylprednisolone. Synovium was segmented and volume, relative enhancement rate (RER), maximum relative enhancement (REmax), late relative enhancement (RElate) and pharmacokinetic parameters (K(trans), ve) were calculated. KOOS (​knee injury and osteoarthritis outcome score) pain score was recorded before and after injection. Standardized change scores were calculated for each parameter. Linear regression and Pearson's correlations were used to investigate the relationship between change in MRI parameters and change in pain. RESULTS: The change in standardized score for the measures of synovial enhancement, RElate and REmax were -0.58 (95% CI -0.79 to -0.37) and -0.62 (95% CI -0.83 to -0.41) respectively, whereas the score for synovial volume was -0.30 (-0.52 to -0.09). Further, change in knee pain correlated more strongly with changes in enhancement (for both REmax and RElate, r = -0.27 (95% CI -0.45 to -0.07)) than with changes in synovial volume -0.15 (-0.35 to 0.05). CONCLUSION: This study suggests DCE-MRI derived measures of synovial enhancement may be more sensitive to the response to treatment and more strongly associated with changes in pain than synovial volume and may be better outcomes for assessment of structural effects of treatment in OA.


Asunto(s)
Osteoartritis de la Rodilla , Medios de Contraste , Humanos , Inyecciones Intraarticulares , Articulación de la Rodilla , Imagen por Resonancia Magnética , Membrana Sinovial , Sinovitis
9.
Osteoarthritis Cartilage ; 23(8): 1316-22, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25749010

RESUMEN

OBJECTIVE: Lateral wedge insoles are a potential simple treatment for medial knee osteoarthritis (OA) patients by reducing the external knee adduction moment (EKAM). However in some patients, an increase in their EKAM is seen. Understanding the role of the ankle joint complex in the response to lateral wedge insoles is critical in understanding and potentially identifying why some patients respond differently to lateral wedge insoles. METHOD: Participants with medial tibiofemoral OA underwent gait analysis whilst walking in a control shoe and a lateral wedge insole. We evaluated if dynamic ankle joint complex coronal plane biomechanical measures could explain and identify those participants that increased (biomechanical non-responder) or decreased (biomechanical responder) EKAM under lateral wedge conditions compared to the control shoe. RESULTS: Of the 70 participants studied (43 male), 33% increased their EKAM and 67% decreased their EKAM. Overall, lateral wedge insoles shifted the centre of foot pressure laterally, increased eversion of the ankle/subtalar joint complex (STJ) and the eversion moment compared to the control condition. Ankle angle at peak EKAM and peak eversion ankle/STJ complex angle in the control condition predicted if individuals were likely to decrease EKAM under lateral wedge conditions. CONCLUSIONS: Coronal plane ankle/STJ complex biomechanical measures play a key role in reducing EKAM when wearing lateral wedge insoles. These findings may assist in the identification of those individuals that could benefit more from wearing lateral wedge insoles.


Asunto(s)
Articulación del Tobillo/fisiología , Ortesis del Pié , Osteoartritis de la Rodilla/terapia , Zapatos , Caminata/fisiología , Fenómenos Biomecánicos/fisiología , Femenino , Marcha/fisiología , Humanos , Masculino , Persona de Mediana Edad , Osteoartritis de la Rodilla/fisiopatología
10.
Osteoarthritis Cartilage ; 22(6): 742-6, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24685526

RESUMEN

OBJECTIVES: Arthrogenous muscle inhibition (AMI) is thought to contribute to quadriceps weakness in knee osteoarthritis (OA), but its relationship with structural changes of bone marrow lesions (BMLs), capsular distension and pain is unclear. This study's objective was to investigate the factors associated with AMI in subjects with symptomatic patellofemoral joint OA (PFJOA). DESIGN: 126 Subjects with predominant PFJOA were assessed for pain by the visual analogue scale (VAS) for a nominated aggravating activity. Their more symptomatic knee underwent a magnetic resonance imaging (MRI) scan which was used to assess BMLs and synovitis which were scored using the Whole Organ MRI score (WORMS). Quadriceps AMI was measured by calculating the activation deficit and quadriceps strength assessed by isometric maximum voluntary contraction. Multiple linear regressions were used to assess factors associated with AMI. RESULTS: We studied 124 subjects [mean age 55.5 (SD 7.5); 57.14% female]. In regression analyses, higher levels of AMI were significantly associated with more severe knee pain and with lower BML score. CONCLUSION: Quadriceps AMI in knee OA is associated with severity of knee pain and surprisingly with lower BML scores.


Asunto(s)
Médula Ósea/patología , Imagen por Resonancia Magnética/métodos , Debilidad Muscular/patología , Dimensión del Dolor , Articulación Patelofemoral/patología , Músculo Cuádriceps/patología , Adulto , Anciano , Médula Ósea/fisiopatología , Estudios de Cohortes , Femenino , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Análisis Multivariante , Debilidad Muscular/fisiopatología , Osteoartritis de la Rodilla/diagnóstico , Articulación Patelofemoral/fisiopatología , Pronóstico , Músculo Cuádriceps/fisiopatología , Rango del Movimiento Articular/fisiología , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la Enfermedad
11.
J Physiol ; 596(7): 1307, 2018 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-29411885
12.
Nat Genet ; 14(2): 199-202, 1996 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-8841195

RESUMEN

Crohn's disease (CD) and ulcerative colitis (UC), the chronic inflammatory bowel diseases (CIBD), are common causes of gastro-intestinal disease in the Western world, with a combined prevalence of 100-200/100,000 (ref. 1). Epidemiological studies, particularly concordance rates in twin pairs and siblings, strongly implicate genetic susceptibility in the pathogenesis of CIBD. In fact, the relative contribution of genetic factors to the pathogenesis of CD may be greater than in schizophrenia, asthma or hypertension, and at least equivalent to that in insulin-dependent diabetes. Systematic screening of the entire human genome now provides a strategy for the identification of susceptibility genes in complex polygenic disorders. We undertook a two-stage genome search for susceptibility genes in inflammatory bowel disease involving 186 affected sibling pairs from 160 nuclear families. We provide strong evidence for the presence of susceptibility loci for both CD and UC on chromosome 3, 7 and 12. We obtained the highest lod score (5.47; P = 2.66 x 10(-7) with the marker D12S83 and lod scores of 3.08 and 2.69 for D7S669 and D3S1573, respectively. Our data suggest that CD and UC are closely related, but distinct, polygenic disorders that share some, but not all, susceptibility genes.


Asunto(s)
Mapeo Cromosómico , Cromosomas Humanos Par 12/genética , Cromosomas Humanos Par 3/genética , Cromosomas Humanos Par 7/genética , Colitis Ulcerosa/genética , Enfermedad de Crohn/genética , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Genoma Humano , Genotipo , Humanos , Escala de Lod , Repeticiones de Microsatélite , Núcleo Familiar
14.
Osteoarthritis Cartilage ; 20(12): 1514-8, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22944524

RESUMEN

OBJECTIVES: Knee osteoarthritis (OA) is thought to be a slowly evolving disease with glacial changes in cartilage morphology necessitating trials of potential treatments lasting 1-2 years with evidence that over 6 months change in cartilage is not detectable. In contrast to cartilage, bone has the capacity to adapt rapidly, such as after fracture. We tested whether bone marrow lesions (BMLs) change in volume in 6 and 12 weeks, suggesting they may provide evidence of short term fluctuations of joint damage. METHODS: In 62 patients with patellofemoral knee OA (mean age 55.7 years, 59.7% women, mean BMI 31.0), we obtained baseline, 6 and 12 week knee MRIs with contrast enhancement. Of those with BMLs at baseline, we assessed BML volume on the axial proton density fat saturated (FS) images and postcontrast sagittal T1 weighted FS images. We manually segmented BML volumes, testing repeatability of BML volumes in knees remeasured. Using the standard deviation of the difference between repeated measurements to calculate Bland-Altman Limits of Agreement, we determined how much BML volume change represented a change greater than due to chance. RESULTS: Fifty-two patients had BMLs at baseline. Test-retest reliability for BML volume was high (ICC 0.89, 95% CI 0.80-0.97). All knees showed at least some change in BML volume by 6 and 12 weeks. On the axial view at 6 weeks, 20/49 (40.8%) knees showed BML volume changes greater than the limits of agreement with similar results at 12 weeks. BML changes were evenly divided among knees with enlarging and shrinking BMLs. 63.3% of the knees had more than 50% change in BML volume at either 6 or 12 weeks on the axial view and 48.7% on the sagittal view. CONCLUSIONS: Knee BML volumes change in several weeks in many persons with knee OA. To the extent that they could be regarded as treatment targets, trials testing BML effects could avoid the usual prolonged structure modification trials.


Asunto(s)
Médula Ósea/patología , Cartílago/patología , Progresión de la Enfermedad , Articulación de la Rodilla/patología , Imagen por Resonancia Magnética/métodos , Osteoartritis de la Rodilla/patología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Factores de Tiempo
17.
Gut ; 60(12): 1739-53, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21300624

RESUMEN

Complex disease genetics has been revolutionised in recent years by the advent of genome-wide association (GWA) studies. The chronic inflammatory bowel diseases (IBDs), Crohn's disease and ulcerative colitis have seen notable successes culminating in the discovery of 99 published susceptibility loci/genes (71 Crohn's disease; 47 ulcerative colitis) to date. Approximately one-third of loci described confer susceptibility to both Crohn's disease and ulcerative colitis. Amongst these are multiple genes involved in IL23/Th17 signalling (IL23R, IL12B, JAK2, TYK2 and STAT3), IL10, IL1R2, REL, CARD9, NKX2.3, ICOSLG, PRDM1, SMAD3 and ORMDL3. The evolving genetic architecture of IBD has furthered our understanding of disease pathogenesis. For Crohn's disease, defective processing of intracellular bacteria has become a central theme, following gene discoveries in autophagy and innate immunity (associations with NOD2, IRGM, ATG16L1 are specific to Crohn's disease). Genetic evidence has also demonstrated the importance of barrier function to the development of ulcerative colitis (HNF4A, LAMB1, CDH1 and GNA12). However, when the data are analysed in more detail, deeper themes emerge including the shared susceptibility seen with other diseases. Many immune-mediated diseases overlap in this respect, paralleling the reported epidemiological evidence. However, in several cases the reported shared susceptibility appears at odds with the clinical picture. Examples include both type 1 and type 2 diabetes mellitus. In this review we will detail the presently available data on the genetic overlap between IBD and other diseases. The discussion will be informed by the epidemiological data in the published literature and the implications for pathogenesis and therapy will be outlined. This arena will move forwards very quickly in the next few years. Ultimately, we anticipate that these genetic insights will transform the landscape of common complex diseases such as IBD.


Asunto(s)
Enfermedades Inflamatorias del Intestino/genética , Artritis Reumatoide/genética , Asma/genética , Colitis Ulcerosa/genética , Enfermedad de Crohn/genética , Dermatitis Atópica/genética , Diabetes Mellitus Tipo 1/genética , Sitios Genéticos/genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Humanos , Lupus Eritematoso Sistémico/genética , Infecciones por Mycobacterium/genética , Psoriasis/genética , Espondilitis Anquilosante/genética
18.
J Hosp Infect ; 119: 49-53, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34562545

RESUMEN

This single-centre retrospective study reports the dynamics of the incidence of candida bloodstream infection (CBSI) in 145 patients receiving venovenous extracorporeal membrane oxygenation (ECMO) for respiratory support between January 2014 and December 2018. The incidence rate and odds ratio (OR) of CBSI were calculated, stratified by week of ECMO exposure. Weekly incidence increased throughout the ECMO run, with an increasing trend in OR (P=0.005), and a window of continued risk after decannulation was observed. Of the 13 patients who developed CBSI, five (38%) received empirical micafungin treatment before positive culture due to clinical suspicion. There is a need for prospective studies aiming to improve ECMO diagnostic stewardship practices and discourage unnecessary antifungal prophylaxis or empiric management.


Asunto(s)
Candidemia , Oxigenación por Membrana Extracorpórea , Candidemia/epidemiología , Oxigenación por Membrana Extracorpórea/efectos adversos , Humanos , Incidencia , Estudios Prospectivos , Estudios Retrospectivos
19.
Radiat Oncol ; 17(1): 99, 2022 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-35597956

RESUMEN

BACKGROUND: Due to respiratory motion, accurate radiotherapy delivery to thoracic and abdominal tumors is challenging. We aimed to quantify the ability of mechanical ventilation to reduce respiratory motion, by measuring diaphragm motion magnitudes in the same volunteers during free breathing (FB), mechanically regularized breathing (RB) at 22 breaths per minute (brpm), variation in mean diaphragm position across multiple deep inspiration breath-holds (DIBH) and diaphragm drift during single prolonged breath-holds (PBH) in two MRI sessions. METHODS: In two sessions, MRIs were acquired from fifteen healthy volunteers who were trained to be mechanically ventilated non-invasively We measured diaphragm motion amplitudes during FB and RB, the inter-quartile range (IQR) of the variation in average diaphragm position from one measurement over five consecutive DIBHs, and diaphragm cranial drift velocities during single PBHs from inhalation (PIBH) and exhalation (PEBH) breath-holds. RESULTS: RB significantly reduced the respiratory motion amplitude by 39%, from median (range) 20.9 (10.6-41.9) mm during FB to 12.8 (6.2-23.8) mm. The median IQR for variation in average diaphragm position over multiple DIBHs was 4.2 (1.0-23.6) mm. During single PIBHs with a median duration of 7.1 (2.0-11.1) minutes, the median diaphragm cranial drift velocity was 3.0 (0.4-6.5) mm/minute. For PEBH, the median duration was 5.8 (1.8-10.2) minutes with 4.4 (1.8-15.1) mm/minute diaphragm drift velocity. CONCLUSIONS: Regularized breathing at a frequency of 22 brpm resulted in significantly smaller diaphragm motion amplitudes compared to free breathing. This would enable smaller treatment volumes in radiotherapy. Furthermore, prolonged breath-holding from inhalation and exhalation with median durations of six to seven minutes are feasible. TRIAL REGISTRATION: Medical Ethics Committee protocol NL.64693.018.18.


Asunto(s)
Respiración Artificial , Respiración , Contencion de la Respiración , Humanos , Pulmón , Imagen por Resonancia Magnética/métodos , Planificación de la Radioterapia Asistida por Computador/métodos
20.
Toxicology ; 480: 153317, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-36096317

RESUMEN

At high exposure levels, organophosphorus insecticides (OPs) exert their toxicity in mammals through the inhibition of brain acetylcholinesterase (AChE) leading to the accumulation of acetylcholine in cholinergic synapses and hyperactivity of the nervous system. Currently, there is a concern that low-level exposure to OPs induces negative impacts in developing children and the chemical most linked to these issues is chlorpyrifos (CPF). Our laboratory has observed that a difference in the susceptibility to repeated exposure to CPF exists between juvenile mice and rats with respect to the inhibition of brain AChE. The basis for this difference is unknown but differences in the levels of the detoxification mechanisms could play a role. To investigate this, 10-day old rat and mice pups were exposed daily for 7 days to either corn oil or a range of dosages of CPF via oral gavage. Four hours following the last administration of CPF on day 16, brain, blood, and liver were collected. The inhibition of brain AChE activity was higher in juvenile rats as compared to juvenile mice. The levels of activity of the detoxification enzymes and the impact of CPF exposure on their activity were determined in the two species at this age. In blood and liver, the enzyme paraoxonase-1 (PON1) hydrolyzes the active metabolite of CPF (CPF-oxon), and the enzymes carboxylesterase (CES) and cholinesterase (ChE) act as alternative binding sites for CPF-oxon removing it from circulation and providing protection. Both species had similar levels of PON1 activity in the liver and serum. Mice had higher ChE activity in liver and serum than rats but, following CPF exposure, the percentage inhibition was similar between species at an equivalent dosage. Even though rats had slightly higher liver CES activity than mice, the level of inhibition following exposure was higher in rats. In serum, juvenile mice had an 8-fold higher CES activity than rats, and exposure to a CPF dosage that almost eliminated CES activity in rats only resulted in 22% inhibition in mice suggesting that the high serum CES activity in mice as compared to rats is a key component in this species difference. In addition, there was a species difference in the sensitivity of CES to inhibition by CPF-oxon with rats having a lower IC50 in both liver and serum as compared to mice. This greater enzyme sensitivity suggests that saturation of CES would occur more rapidly in juvenile rats than in mice, resulting in more CPF reaching the brain to inhibit AChE in rats.


Asunto(s)
Cloropirifos , Insecticidas , Acetilcolina , Acetilcolinesterasa/metabolismo , Animales , Arildialquilfosfatasa , Carboxilesterasa/metabolismo , Cloropirifos/análogos & derivados , Cloropirifos/toxicidad , Inhibidores de la Colinesterasa/toxicidad , Colinesterasas/metabolismo , Aceite de Maíz , Insecticidas/metabolismo , Insecticidas/toxicidad , Mamíferos/metabolismo , Ratones , Ratas , Ratas Sprague-Dawley
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