RESUMEN
Increasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health1. This is compounded by the limited efficacy of available treatments1 and high failure rates during drug development2, highlighting an urgent need to better understand disease mechanisms. Here we show how functional genomics could address this challenge. By investigating an intergenic haplotype on chr21q22-which has been independently linked to inflammatory bowel disease, ankylosing spondylitis, primary sclerosing cholangitis and Takayasu's arteritis3-6-we identify that the causal gene, ETS2, is a central regulator of human inflammatory macrophages and delineate the shared disease mechanism that amplifies ETS2 expression. Genes regulated by ETS2 were prominently expressed in diseased tissues and more enriched for inflammatory bowel disease GWAS hits than most previously described pathways. Overexpressing ETS2 in resting macrophages reproduced the inflammatory state observed in chr21q22-associated diseases, with upregulation of multiple drug targets, including TNF and IL-23. Using a database of cellular signatures7, we identified drugs that might modulate this pathway and validated the potent anti-inflammatory activity of one class of small molecules in vitro and ex vivo. Together, this illustrates the power of functional genomics, applied directly in primary human cells, to identify immune-mediated disease mechanisms and potential therapeutic opportunities.
Asunto(s)
Inflamación , Macrófagos , Proteína Proto-Oncogénica c-ets-2 , Femenino , Humanos , Masculino , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Células Cultivadas , Cromosomas Humanos Par 21/genética , Bases de Datos Factuales , Regulación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Genómica , Haplotipos/genética , Inflamación/genética , Enfermedades Inflamatorias del Intestino/genética , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/patología , Proteína Proto-Oncogénica c-ets-2/genética , Proteína Proto-Oncogénica c-ets-2/metabolismo , Reproducibilidad de los Resultados , Factores de Necrosis Tumoral/metabolismo , Interleucina-23/metabolismoRESUMEN
Rare variants are thought to contribute to the genetics of inflammatory bowel disease (IBD), which is more common amongst the Ashkenazi Jewish (AJ) population. A family-based approach using exome sequencing of AJ individuals with IBD was employed with a view to identify novel rare genetic variants for this disease. Exome sequencing was performed on 960 Jewish individuals including 513 from 199 multiplex families with up to eight cases. Rare, damaging variants in loci prioritized by linkage analysis and those shared by multiple affected individuals within the same family were identified. Independent evidence of association of each variant with disease was assessed. A number of candidate variants were identified, including in genes involved in the immune system. The ability to achieve statistical significance in independent case/control replication data was limited by power and was only achieved for variants in the well-established Crohn's disease gene, NOD2. This work demonstrates the challenges of identifying disease-associated rare damaging variants from exome data, even amongst a favorable cohort of familial cases from a genetic isolate. Further research of the prioritized rare candidate variants is required to confirm their association with the disease.
Asunto(s)
Predisposición Genética a la Enfermedad , Variación Genética , Enfermedades Inflamatorias del Intestino/genética , Judíos/genética , Proteína Adaptadora de Señalización NOD2/genética , Sistemas de Lectura Abierta , Estudios de Casos y Controles , Femenino , Ligamiento Genético , Humanos , Masculino , Linaje , Análisis de Secuencia de ADN/métodosRESUMEN
OBJECTIVES: Systemic sclerosis (SSc) is heterogenous. The objectives of this study were to evaluate the purpose, strengths and limitations of existing SSc subset criteria, and identify ideas among experts about subsets. METHODS: We conducted semi-structured interviews with randomly sampled international SSc experts. The interview transcripts underwent an iterative process with text deconstructed to single thought units until a saturated conceptual framework with coding was achieved and respondent occurrence tabulated. Serial cross-referential analyses of clusters were developed. RESULTS: Thirty experts from 13 countries were included; 67% were male, 63% were from Europe and 37% from North America; median experience of 22.5 years, with a median of 55 new SSc patients annually. Three thematic clusters regarding subsetting were identified: research and communication; management; and prognosis (prediction of internal organ involvement, survival). The strength of the limited/diffuse system was its ease of use, however 10% stated this system had marginal value. Shortcomings of the diffuse/limited classification were the risk of misclassification, predictions/generalizations did not always hold true, and that the elbow or knee threshold was arbitrary. Eighty-seven percent use more than 2 subsets including: SSc sine scleroderma, overlap conditions, antibody-determined subsets, speed of progression, and age of onset (juvenile, elderly). CONCLUSIONS: We have synthesized an international view of the construct of SSc subsets in the modern era. We found a number of factors underlying the construct of SSc subsets. Considerations for the next phase include rate of change and hierarchal clustering (e.g. limited/diffuse, then by antibodies).
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Medición de Riesgo/métodos , Esclerodermia Sistémica/diagnóstico , Adulto , Estudios Transversales , Progresión de la Enfermedad , Femenino , Humanos , Masculino , PronósticoRESUMEN
As scientific techniques for the detection of cytomegalovirus (CMV) improve, we are able to detect small amounts of CMV in the mucosal wall. As clinicians, we are unsure how to interpret the results of this novel test. There is controversy in the literature as to the significance of the detection of CMV in the gut. Whilst the importance of CMV and reactivation of the virus is clear in those patients such as allograft recipients with established immune compromise, the role is less clear in patients with less damaged immune systems. We explore whether the detection of CMV in such cases influences outcome and how it should be optimally managed. We discuss the optimal management of such cases, according to current guidelines, with a review of the literature.
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Colitis/diagnóstico , Colitis/virología , Infecciones por Citomegalovirus/diagnóstico , Citomegalovirus/aislamiento & purificación , Humanos , Mucosa Intestinal/virologíaRESUMEN
BACKGROUND: Constipation, diminished gut blood flow, ischaemic colitis and drug therapy may be associated. AIM: To study the effect of constipating medication on, and the regulation of, gut blood flow. METHODS: 24 healthy females (mean age 30) received, in a double-blind, three-way crossover study: (i) placebo, (ii) ipratropium 40 microg by inhalation (positive control known to reduce rectal mucosal blood flow) and (iii) oral loperamide 4 mg. Mucosal blood flow was measured at the splenic flexure and rectum using laser Doppler flowmetry. Blood flow in the superior and inferior mesenteric arteries was measured by trans-abdominal Doppler ultrasound. RESULTS: Ipratropium decreased rectal mucosal blood flow by 16% (P=0.009) and splenic flexure mucosal blood flow by 8% (P=0.075). Loperamide caused no change in rectal (P=0.40) or splenic flexure mucosal blood flow (P=0.73). Neither treatment changed superior or inferior mesenteric artery blood flow. Splenic flexure mucosal blood flow showed a positive correlation with rectal mucosal blood flow (r=0.69; P<0.0001). CONCLUSIONS: Vasoactive agents may reduce gut mucosal blood flow in the absence of reduced large vessel flow. Constipating drugs do not necessarily reduce gut blood flow. Rectal mucosal blood flow correlates with splenic flexure mucosal flow, and potentially may be used as a more convenient surrogate for studying splenic flexure blood flow.
Asunto(s)
Colon Transverso/irrigación sanguínea , Ipratropio/farmacología , Loperamida/farmacología , Recto/irrigación sanguínea , Circulación Esplácnica/efectos de los fármacos , Administración por Inhalación , Administración Oral , Adulto , Estreñimiento/tratamiento farmacológico , Estudios Cruzados , Método Doble Ciego , Femenino , Humanos , Mucosa Intestinal/irrigación sanguínea , Flujometría por Láser-Doppler , Arteria Mesentérica Inferior/efectos de los fármacos , Arteria Mesentérica Superior/efectos de los fármacos , Persona de Mediana Edad , Flujo Sanguíneo RegionalRESUMEN
Ghrelin has been shown to decrease firing of gastric vagal afferents at doses comparable with circulating levels in the fasted state. This raises the possibility that ghrelin may have a hormonal action on other vagal afferent populations. The aim of this study was to determine the effects of ghrelin on jejunal afferent activity; including responses to distension, 2-methyl-5-hydroxytryptamine (2-methyl-5-HT) and cholecystokinin (CCK) in both naïve and vagotomized rats. Ghrelin significantly augmented the afferent response to distension. No effect was observed on baseline afferent discharge, or the response to 2-methyl-5-HT and CCK. The effect of ghrelin was more pronounced at lower ramp distending pressures (0-30 mmHg). Similarly, ghrelin augmented the jejunal afferent responses to phasic distension at 10-30 mmHg, but had no effect at higher pressures. Chronic subdiaphragmatic vagotomy and administration of the growth hormone secretagogue receptor (GHS-R) antagonist [D-Lys3]-GHRP-6 prevented the augmentation of the afferent responses to distension indicating ghrelin is acting through the GHS-R on vagal afferent fibres. Ghrelin augments the mechanosensation of jejunal vagal afferents and hence may lead to increased perception of hunger contractions.
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Yeyuno/inervación , Yeyuno/fisiología , Hormonas Peptídicas/farmacología , Hormonas Peptídicas/fisiología , Aferentes Viscerales/efectos de los fármacos , Aferentes Viscerales/fisiología , Animales , Cateterismo , Colagogos y Coleréticos/farmacología , Colecistoquinina/farmacología , Adaptabilidad , Electrofisiología , Ghrelina , Hambre/fisiología , Técnicas In Vitro , Mecanorreceptores/efectos de los fármacos , Mecanorreceptores/fisiología , Oligopéptidos/farmacología , Ratas , Ratas Sprague-Dawley , Serotonina/análogos & derivados , Serotonina/farmacología , Cloruro de Sodio/farmacología , VagotomíaRESUMEN
BACKGROUND: Infliximab and adalimumab have established roles in inflammatory bowel disease (IBD) therapy. UK regulators mandate reassessment after 12 months' anti-TNF therapy for IBD, with consideration of treatment withdrawal. There is a need for more data to establish the relapse rates following treatment cessation. AIM: To establish outcomes following anti-TNF withdrawal for sustained remission using new data from a large UK cohort, and assimilation of all available literature for systematic review and meta-analysis. METHODS: A retrospective observational study was performed on 166 patients with IBD (146 with Crohn's disease (CD) and 20 with ulcerative colitis [UC) and IBD unclassified (IBDU)] withdrawn from anti-TNF for sustained remission. Meta-analysis was undertaken of all published studies incorporating 11 further cohorts totalling 746 patients (624 CD, 122 UC). RESULTS: Relapse rates in the UK cohort were 36% by 1 year and 56% by 2 years for CD, and 42% by 1 year and 47% by 2 years for UC/IBDU. Increased relapse risk in CD was associated with age at diagnosis [hazard ratio (HR) 2.78 for age <22 years], white cell count (HR 3.22 for >5.25 × 109 /L) and faecal calprotectin (HR 2.95 for >50 µg/g) at drug withdrawal. Neither continued immunomodulators nor endoscopic remission were predictors. In the meta-analysis, estimated 1-year relapse rates were 39% and 35% for CD and UC/IBDU respectively. Retreatment with anti-TNF was successful in 88% for CD and 76% UC/IBDU. CONCLUSIONS: Assimilation of all available data reveals remarkable homogeneity. Approximately one-third of patients with IBD flare within 12 months of withdrawal of anti-TNF therapy for sustained remission.
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Colitis Ulcerosa/tratamiento farmacológico , Enfermedad de Crohn/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adalimumab/administración & dosificación , Adulto , Heces/química , Femenino , Humanos , Factores Inmunológicos/uso terapéutico , Infliximab/administración & dosificación , Masculino , Modelos de Riesgos Proporcionales , Recurrencia , Estudios Retrospectivos , Factores de TiempoRESUMEN
PURPOSE: To gain an understanding of the embodied perceptual experience of successful prosthesis. METHOD: The data for this study were transcripts derived from in-depth semi-structured e-mail (n=21) and face-to-face (n=14) interviews, and the documentary analysis of an e-mail discussion group for prosthesis users. This qualitative data was subject to an Interpretative Phenomenological Analysis. RESULTS: Analysis of the research data identified six themes in the perceptually embodied experiences of prosthesis users: Adjusting to a prosthetic; The Balance of the Body; Awareness of the Prosthesis; The Knowing Body; The Phantom Becomes the Prosthesis: Extending the Body; and The Prosthesis as Tool or Corporeal Structure. CONCLUSION: The often-cited reasons for the rejection of prostheses are frequently part of the initial experiences of 'successful' prosthesis users also. This suggests the need to sufficiently motivate potential prosthesis users in the period between an experience of prosthesis use as unnatural and wieldy to one of pre-reflective, natural use. In addition, two broad forms of prosthesis experience were identified: one in which the prosthesis was experienced as a corporeal structure; and one in which it was viewed as a tool. While future work may be able to explore the psychosocial correlates of these experiences, it is nonetheless the case that persons with these differing experiences were able to enjoy the benefits imbued by prosthesis use.
Asunto(s)
Adaptación Psicológica , Miembros Artificiales/psicología , Imagen Corporal , Adolescente , Adulto , Anciano , Concienciación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Miembro Fantasma/psicología , Equilibrio Postural , Reino UnidoRESUMEN
PURPOSE: To investigate the meaning and experience of being a stroke survivor. METHOD: Qualitative in-depth semi-structured interviews were conducted with 10 stroke survivors (five face-to-face and five e-mail interviews). The interview data were transcribed verbatim (these were pre-transcribed in e-mail exchange) and analysed using Interpretative Phenomenological Analysis. RESULTS: Four themes emerged from the analysis: Disrupted embodiment and the loss of self; Invisibility of emotional difficulties; Gender, romance and sexuality; and Social interaction. These themes, respectively, revealed that participants often had difficulties with psychological adaptation to the physically disabling aspects of their stroke; they experienced enduring and disabling emotional difficulties; they had a particular concern for the viability and maintenance of romantic and sexual relationships; and they often became socially withdrawn, resulting in an increased pressure on familial caregivers. CONCLUSION: The findings of the present work suggest the need for post-stroke counselling regarding romantic and sexual relationships, as well as promoting acceptance of some of the physical disabilities that come with having a stroke and encouraging positive self-regard. There would also appear to be a need to address the issue of social withdrawal and familial relationships, perhaps when health professionals convey information regarding the person's stroke, and in counselling targeted specifically at family caregivers.
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Accidente Cerebrovascular/psicología , Sobrevivientes/psicología , Adaptación Psicológica , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Relaciones Interpersonales , Entrevistas como Asunto , Masculino , Hombres/psicología , Persona de Mediana Edad , Sexualidad/psicología , Aislamiento Social , Mujeres/psicologíaRESUMEN
PURPOSE: This study examines the relationship between prosthesis satisfaction and body image in lower limb prosthesis users, and the gendered variations within these relationships. METHOD: A total of 44 valid responses were obtained to an internet survey regarding prosthesis satisfaction, body image and phantom pain. Spearman Rho correlations were calculated for these three domains. RESULTS: Moderate to high negative correlations were observed between body image disturbance and prosthesis satisfaction. These were consistent across genders. Other relationships were also revealed, including positive correlations between prosthesis satisfaction with hours of use and negative correlations between prosthesis satisfaction and pain experience, although strong differences between genders were observed for these. The length of time for which respondents had had their prosthesis bore little relation to other variables. CONCLUSION: The present research is instructive of the close relationship between body image and prosthesis satisfaction, as well as gender variations in these relationships, in lower-limb prosthesis users. These findings have implications for targeted service provision in prosthetic rehabilitation.
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Amputados/psicología , Miembros Artificiales/psicología , Imagen Corporal , Satisfacción Personal , Adolescente , Adulto , Anciano , Amputados/rehabilitación , Femenino , Humanos , Pierna , Masculino , Persona de Mediana EdadRESUMEN
The documentary analysis of e-mail posts and archives for qualitative research has been outlined elsewhere. Although there is an increase in the number of studies being conducted on listserv and newsgroup material in health research, this has not always been accompanied by a careful, in-depth consideration of the concomitant ethical issues. Therefore, this article outlines the ethical considerations surrounding this form of research, including issues of accessing voices, consent, privacy, anonymity, interpretation, and ownership and authorship of research material.
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Redes de Comunicación de Computadores , Ética , Investigación sobre Servicios de Salud/normas , Internet , Comunicación , Confidencialidad , Propiedad , Estados UnidosRESUMEN
The recent proliferation of virtual reality technology has attracted the interest of social scientists who study human behavior and perceptual experience. Such computer simulations are able to present technologically rendered environments, where the properties of the physical world are approximated or manipulated to varying degrees. The present study sought to investigate the influence of an immersive virtual experience on the perceptual awareness of the body. A body awareness questionnaire was administered to users of a desktop and an immersive implementation of a virtual environment (the Cityscape). The results indicated a significant main effect for the mode of presentation (i.e., desktop or immersive), no gender effects, and no interaction effect between gender and the mode of presentation. Test of between-subjects effects for the mode of presentation found significant differences on a number of body awareness dimensions. The desktop group were found to experience higher levels of skin, muscular, and cardiovascular awareness, while the immersive group experienced higher levels of body boundary ambiguity and aural awareness.
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Imagen Corporal , Autoimagen , Interfaz Usuario-Computador , Adulto , Femenino , Humanos , Masculino , Encuestas y CuestionariosRESUMEN
PURPOSE: To determine the effect of oral acetazolamide on lowering the peak and duration of intraocular pressure (IOP) rise in glaucoma and glaucoma suspect patients, following intravitreal injection of ranibizumab for neovascular age-related macular degeneration. METHODS: The study was an open-label, parallel, randomised, controlled trial (EudraCT Number: 2010-023037-35). Twenty-four glaucoma or glaucoma suspect patients received either 500 mg acetazolamide or no treatment 60-90 min before 0.5 mg ranibizumab. The primary outcome measure was the difference in IOP immediately after injection (T0) and 5, 10, and 30 min following injection. ANCOVA was used to compare groups, adjusting for baseline IOP. The study was powered to detect a 9-mm Hg difference at T0. RESULTS: The IOP at T0 was 2.3 mm Hg higher in the non-treated group (mean 44.5 mm Hg, range (19-86 mm Hg)) compared with the treated group (mean 42.2 mm Hg, range (25-58 mm Hg)), but was not statistically significant after adjusting for baseline IOP (P=0.440). At 30 min, IOP was 4.9 mm Hg higher in the non-treated group (mean 20.6 mm Hg, range (11-46 mm Hg)) compared with the treated group (mean 15.7 mm Hg, range (8-21 mm Hg)). This was statistically significant after adjusting for baseline IOP (P=0.013). CONCLUSIONS: Although the primary end points were not reached, 500 mg oral acetazolamide, 60-90 min before intravitreal injection, results in a statistically significant reduction in IOP at 3O min post injection. Prophylactic treatment may be considered as an option to minimise neuro-retinal rim damage in high-risk glaucoma patients who are most vulnerable to IOP spikes and undergoing repeated intravitreal injections of ranibizumab.
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Acetazolamida/administración & dosificación , Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Inhibidores de Anhidrasa Carbónica/administración & dosificación , Glaucoma/prevención & control , Presión Intraocular/efectos de los fármacos , Degeneración Macular Húmeda/tratamiento farmacológico , Administración Oral , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Inyecciones Intravítreas , Masculino , Hipertensión Ocular/prevención & control , Soluciones Oftálmicas , Ranibizumab , Tonometría Ocular , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
PURPOSE: To describe the incidence and features of intraoperative retinal breaks caused by induction of posterior hyaloid face (PHF) separation during 23-gauge pars plana vitrectomy (PPV). METHODS: A prospective, consecutive, single surgeon, observational study of patients undergoing 23-gauge transconjunctival sutureless vitrectomy for macular pathology or floaters, was carried out between 2009 and 2011 at Calderdale Royal Hospital, UK. PHF separations were categorised as either suction induced or requiring membrane blue (DORC Limited) with suction (adherent). The outcome measure was dichotomised into retinal break or tear and no retinal break or tear. Forced entry and parsimonious multiple logistic regression analyses were conducted, using statistical software, to test for significance of association of the set of recorded factors and covariates with the dichotomised outcome measure. RESULTS: Data were collected and analysed from 137 patients. The incidence of iatrogenic retinal breaks associated with PHF separation during 23-gauge PPV was 18.2%. Under both forced entry and parsimonious multiple logistic regression models, the odds of a retinal break or tear reduce by about 3-4% for each increasing year of age. Findings also showed some substantive association in the forced entry model, with the odds of a retinal break or tear for adherent cases being around 3.8 times those for suction-only cases. CONCLUSIONS: Mechanical detachment of the PHF represents an important risk factor in the formation of retinal breaks. Particular care should be taken to examine intraoperatively for iatrogenic breaks in order to prevent missed breaks and subsequent rhegmatogenous retinal detachments.
Asunto(s)
Membrana Epirretinal/cirugía , Enfermedad Iatrogénica , Complicaciones Intraoperatorias , Perforaciones de la Retina/etiología , Vitrectomía/efectos adversos , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Enfermedad Iatrogénica/epidemiología , Incidencia , Modelos Logísticos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Perforaciones de la Retina/epidemiología , Factores de Riesgo , Reino Unido/epidemiología , Vitrectomía/métodosRESUMEN
We review our understanding of Saturn's rings after nearly 6 years of observations by the Cassini spacecraft. Saturn's rings are composed mostly of water ice but also contain an undetermined reddish contaminant. The rings exhibit a range of structure across many spatial scales; some of this involves the interplay of the fluid nature and the self-gravity of innumerable orbiting centimeter- to meter-sized particles, and the effects of several peripheral and embedded moonlets, but much remains unexplained. A few aspects of ring structure change on time scales as short as days. It remains unclear whether the vigorous evolutionary processes to which the rings are subject imply a much younger age than that of the solar system. Processes on view at Saturn have parallels in circumstellar disks.
Asunto(s)
Hielo , Saturno , Evolución Planetaria , Nave Espacial , AguaRESUMEN
BACKGROUND: Acute physical stress causes alteration in gut autonomic function and visceral hypersensitivity in patients with irritable bowel syndrome (IBS). We have developed a model to measure this stress response. AIM: To assess whether treatment with a drug effective in treating IBS (amitriptyline) alters the response to acute stress in IBS patients. METHODS: Nineteen patients with IBS were given amitriptyline 25-50 mg. Patients underwent physical stress (cold pressor) test at baseline and after 3 months of treatment. Physiological parameters measured were: stress perception; systemic autonomic tone [heart rate (HR) and blood pressure (BP)]; gut specific autonomic innervation [rectal mucosal blood flow (RMBF)] and visceral sensitivity (rectal electrosensitivity). RESULTS: Fourteen of 19 (74%) patients improved symptomatically after 3 months of amitriptyline. Acute stress induced increased perception of stress and systemic autonomic tone and reduced RMBF in symptomatic responders and nonresponders (P > 0.05 for all). All nonresponders but only 3 of 14 responders continued to exhibit stress-induced reduced pain threshold at 3 months (change from baseline -31% vs. +2%, P < 0.03 respectively). CONCLUSION: In this open study, amitriptyline appears to decrease stress-induced electrical hypersensitivity; this effect is independent of autonomic tone. The gut response to acute stress deserves further study as a model to study drug efficacy in IBS.
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Amitriptilina/uso terapéutico , Analgésicos no Narcóticos/uso terapéutico , Hipersensibilidad/tratamiento farmacológico , Síndrome del Colon Irritable/tratamiento farmacológico , Recto/efectos de los fármacos , Vísceras/efectos de los fármacos , Adulto , Femenino , Humanos , Hipersensibilidad/fisiopatología , Síndrome del Colon Irritable/fisiopatología , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Umbral del Dolor/efectos de los fármacos , Umbral del Dolor/fisiología , Recto/fisiopatología , Estadística como Asunto , Vísceras/fisiopatología , Adulto JovenRESUMEN
Cassini has identified a geologically active province at the south pole of Saturn's moon Enceladus. In images acquired by the Imaging Science Subsystem (ISS), this region is circumscribed by a chain of folded ridges and troughs at approximately 55 degrees S latitude. The terrain southward of this boundary is distinguished by its albedo and color contrasts, elevated temperatures, extreme geologic youth, and narrow tectonic rifts that exhibit coarse-grained ice and coincide with the hottest temperatures measured in the region. Jets of fine icy particles that supply Saturn's E ring emanate from this province, carried aloft by water vapor probably venting from subsurface reservoirs of liquid water. The shape of Enceladus suggests a possible intense heating epoch in the past by capture into a 1:4 secondary spin/orbit resonance.
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Saturno , Medio Ambiente Extraterrestre/química , Nave Espacial , Análisis EspectralRESUMEN
BACKGROUND: Diabetic gastroparesis is a disabling condition with no consistently effective treatment. In animals, ghrelin increases gastric emptying and reverses postoperative ileus. We present the results of a double blind, placebo controlled, crossover study of ghrelin in gastric emptying in patients with diabetic gastroparesis. METHODS: Ten insulin requiring diabetic patients (five men, six type I) referred with symptoms indicative of gastroparesis received a two hour infusion of either ghrelin (5 pmol/kg/min) or saline on two occasions. Blood glucose was controlled by euglycaemic clamp. Gastric emptying rate (GER) was calculated by real time ultrasound following a test meal. Blood was sampled for ghrelin, growth hormone (GH), and pancreatic polypeptide (PP) levels. Cardiovagal neuropathy was assessed using the Mayo Clinic composite autonomic severity score (range 0 (normal)-3). RESULTS: Baseline ghrelin levels were mean 445 (SEM 36) pmol/l. Ghrelin infusion achieved a peak plasma level of 2786 (188) pmol/l at 90 minutes, corresponding to a peak GH of 70.9 (19.8) pmol/l. Ghrelin increased gastric emptying in seven of 10 patients (30 (6)% to 43 (5)%; p = 0.04). Impaired cardiovagal tone correlated inversely with peak postprandial PP values (p < 0.05) but did not correlate with GER. CONCLUSIONS: Ghrelin increases gastric emptying in patients with diabetic gastroparesis. This is independent of vagal tone. We propose that analogues of ghrelin may represent a new class of prokinetic agents.