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OBJECTIVES: Achalasia is a chronic, progressive, and incurable esophageal motility disease. There is clinical uncertainty about which treatment should be recommended as first-line therapy. Our objective was to evaluate the effectiveness of pneumatic dilation compared with laparoscopic Heller myotomy with partial fundoplication in improving achalasia-specific quality of life. METHODS: This was a prospective, multicenter, randomized trial at five academic hospitals in Canada. Fifty previously untreated adults with a clinical diagnosis of primary achalasia, confirmed by manometric testing, were enrolled between November 2005 and March 2010, and followed for 5 years after treatment. Randomization was stratified by site, in random blocks of size four and with balanced allocation. Patients were treated with pneumatic dilation or laparoscopic Heller myotomy with partial fundoplication. The primary outcome was the difference between the treatments in the mean improvement of the achalasia severity questionnaire (ASQ) score at 1 year from baseline. Prespecified secondary outcomes included general and gastrointestinal quality of life, symptoms, esophageal physiology measures (lower esophageal sphincter relaxation and pressure, esophageal emptying, abnormal esophageal acid exposure), complications, and incidence of retreatment. Functional and imaging studies were performed blinded and all outcome assessors were blinded. RESULTS: There were no significant differences between treatments in the improvement of ASQ score at 1 year from baseline (27.5 points in the Heller myotomy arm vs. 20.2 points in the pneumatic dilation arm; difference 7.3 points, 95% confidence interval -4.7 to 19.3; P=0.23). There were no differences between treatments in improvement of symptoms, general and gastrointestinal quality of life, or measures of esophageal physiology. Improvements in ASQ score diminished over time for both interventions. At 5 years, there were no differences between treatments in improvement of ASQ score, symptoms, and general or gastrointestinal quality of life. There were no serious adverse events. No patient who received Heller myotomy required retreatment, whereas five patients treated initially with pneumatic dilation required retreatment. CONCLUSIONS: Treatment with pneumatic dilation or laparoscopic Heller myotomy similarly improves achalasia-specific disease severity at 1 year. Either of the therapeutic approaches can be used as first-line therapy for previously untreated adults with achalasia.
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Dilatación/métodos , Acalasia del Esófago/cirugía , Esfínter Esofágico Inferior/cirugía , Fundoplicación/métodos , Calidad de Vida , Adulto , Anciano , Canadá , Procedimientos Quirúrgicos del Sistema Digestivo , Acalasia del Esófago/diagnóstico , Femenino , Humanos , Laparoscopía , Masculino , Manometría , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
BACKGROUND & AIMS: Brain imaging studies have identified abnormal rectal-evoked responses and cortical thinning in patients with irritable bowel syndrome (IBS). However, it is not known whether these abnormalities are pre-existing or develop as result of long-term IBS. Therefore, we tested whether abnormal structural gray matter integrity in IBS correlates with individual disease symptoms, duration of the IBS, or the personality characteristic of pain catastrophizing. METHODS: Eleven IBS patients and 16 age-matched healthy subjects underwent structural magnetic resonance imaging. Voxel-based morphometry and cortical thickness analysis were used to identify abnormalities in subcortical and cortical regions, respectively, and their correlation to individual characteristics. RESULTS: The IBS group showed increased hypothalamic gray matter and cortical thinning in the anterior midcingulate cortex compared with controls, a strong negative correlation between dorsolateral prefrontal cortex thickness and pain catastrophizing, and a positive correlation between anterior insula thickness and pain duration. In the insula, there was cortical thinning in patients with short-term IBS, but long-term IBS pain was associated with a more normal insula thickness. CONCLUSIONS: Our findings provide new insight into IBS and chronic pain through evidence for structural changes that could fit with functional abnormalities. We report that patients with IBS have increased hypothalamic gray matter, which may be related to the association among IBS, stress, and the hypothalamic-pituitary-adrenal axis. Furthermore, we have identified some supraspinal abnormalities that may be pre-existing and contribute to vulnerability, and others that may develop over time, possibly because of chronic abnormal inputs.
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Encéfalo/patología , Síndrome del Colon Irritable/patología , Imagen por Resonancia Magnética , Dolor/etiología , Adulto , Estudios de Casos y Controles , Corteza Cerebral/patología , Enfermedad Crónica , Estreñimiento/etiología , Estreñimiento/patología , Diarrea/etiología , Diarrea/patología , Femenino , Humanos , Hipotálamo/patología , Síndrome del Colon Irritable/complicaciones , Síndrome del Colon Irritable/psicología , Dolor/patología , Dolor/psicología , Dimensión del Dolor , Corteza Prefrontal/patología , Índice de Severidad de la Enfermedad , Encuestas y Cuestionarios , Adulto JovenRESUMEN
OBJECTIVES: For clinical trials in functional bowel disorders (FBD), the definition of a responder, one who meets the predefined criteria for a clinical response, is needed. Factors that determine clinical response aside from treatment itself are unknown. The aim of this study was to determine what baseline and post-treatment factors affect treatment response. METHODS: Females (n=397) with FBD entering a 12-week, four-arm, randomized NIH treatment trial (desipramine (DES), CBT, pill placebo, and education) were studied at baseline and after treatment. Demographic, clinical, psychosocial, and physiological variables were considered in the analysis. A responder was defined as a patient obtaining a score>3.5 on an averaged eight-item, five-point satisfaction-with-treatment questionnaire. Baseline and post-treatment logistic regressions were performed for each treatment condition to predict the responder outcome variable. RESULTS: Similar cognitive features predisposed participants to treatment response across the treatment conditions: sense of control over the condition, positive relationship with therapist or study coordinator, confidence in treatment, improvement in maladaptive cognitions, and quality of life during treatment. Demographic and clinical variables studied were not predictive. Some treatment-specific effects predicting responder status were noted, including a reduction in stool frequency with DES treatment and lack of abuse history in the placebo group. CONCLUSIONS: For medication, psychological, and placebo treatment in FBD, satisfaction with treatment depends on cognitive factors of confidence in treatments, perceived control over illness and symptoms, and reduction in negative cognitions related to symptom experience. Addressing these issues among patients with FBD may enhance treatment response to a variety of treatments.
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Enfermedades Funcionales del Colon/psicología , Enfermedades Funcionales del Colon/terapia , Dolor Abdominal , Adolescente , Adulto , Anciano , Antidepresivos Tricíclicos/uso terapéutico , Cognición , Terapia Cognitivo-Conductual , Desipramina/uso terapéutico , Femenino , Humanos , Modelos Logísticos , Persona de Mediana Edad , Encuestas y Cuestionarios , Resultado del Tratamiento , Adulto JovenRESUMEN
The objectives of this study were (1) to compare and contrast the psychological issues perceived by patients with oropharyngeal dysphagia and explore if the differences relate to recovery trajectory, and (2) to determine whether patients, caregivers, and clinicians had different perceptions of how psychological issues interacted with the lung and nutrition issues as consequences of dysphagia. Two focus groups (one each of acute and chronic patients) were conducted with a total of 8 participants. Four focus groups (3 with clinicians and 1 with caregivers) were also conducted. Through the constant comparison method of grounded theory, the differences in perceptions between acute and chronic patients with dysphagia as well as clinicians and caregivers were explored using theoretical sampling. Two themes evolved: (1) acute and chronic patients differed on how they perceived and prioritized major psychological dimensions; (2) acute patients, chronic patients, caregivers, and clinicians varied in their perceptions of how psychological issues interacted with lung and nutrition issues. The qualitative methodology was successful in identifying contrasting opinions on psychological issues of dysphagia between acute and chronic patients, which differ from the perspectives of clinicians and caregivers. It is important for treating clinicians to be aware of psychological issues, to address them according to the patients' clinical recovery, and to consider the interplay between psychological and biomedical consequences.
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Trastornos de Ansiedad/epidemiología , Trastornos de Ansiedad/psicología , Trastornos de Deglución/epidemiología , Trastornos de Deglución/fisiopatología , Enfermedad Aguda , Trastornos de Ansiedad/diagnóstico , Enfermedad Crónica , Miedo , HumanosRESUMEN
BACKGROUND AND PURPOSE: Dysphagia occurs in 55% of all acute stroke patients. Early identification of dysphagia from screening can lead to earlier treatments and thereby reduce complications. We designed and validated a new bedside dysphagia screening tool-the Toronto Bedside Swallowing Screening Test (TOR-BSST) for stroke survivors in acute and rehabilitative settings. METHODS: The TOR-BSST initially contained 5 items with proven high predictive ability for dysphagia. Trained screeners administer and score the TOR-BSST in less than 10 minutes. Trained nurses from 2 acute and 2 rehabilitation facilities administered the TOR-BSST to consecutively admitted stroke inpatients. A positive screen identified patients at risk for dysphagia. Blinded repeat screenings were conducted within 24 hours. Test-retest reliability was established with the first 50 administrations at an ICC=0.92 (CI, 0.85 to 0.96). Items were eliminated if they contributed
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Trastornos de Deglución/diagnóstico , Deglución/fisiología , Sistemas de Atención de Punto , Accidente Cerebrovascular/diagnóstico , Anciano , Algoritmos , Interpretación Estadística de Datos , Trastornos de Deglución/etiología , Trastornos de Deglución/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Accidente Cerebrovascular/fisiopatología , Resultado del TratamientoRESUMEN
BACKGROUND & AIMS: Patients with functional gastrointestinal disorders treated with tricyclic antidepressants sometimes report nongastrointestinal symptoms; it is unclear whether these are drug side effects or reflect a behavioral tendency to report symptoms. We evaluated whether symptoms reported before treatment with a tricyclic antidepressant (desipramine) increased in number or worsened in severity after 2 weeks of treatment and assessed the baseline factors that predispose patients to report symptoms. METHODS: Female patients in a multicenter National Institutes of Health trial for functional bowel disorders completed a 15-item symptom questionnaire at baseline (before randomization), 2 weeks after they were given desipramine (n = 81) or placebo (n = 40), and at study completion (12 weeks). Patients were asked about the severity and frequency of 15 symptoms. Results were analyzed from 57 patients given desipramine who completed the questionnaires. RESULTS: Symptoms reported as side effects to have occurred more frequently and also worsened at week 2 in the group given desipramine included dizziness, dry mouth/thirstiness, lightheadedness, jittery feelings/tremors, and flushing. Symptoms that did not change in severity or showed improvement at week 2 in the group given desipramine included morning tiredness, nausea, blurred vision, headaches, appetite reduction, and trouble sleeping. Psychologic distress but not desipramine blood level correlated with symptom reporting. CONCLUSIONS: Most symptoms often attributed to side effects of desipramine were present before treatment; only a few, related to anticholinergic effects, worsened 2 weeks after treatment, suggesting that most so-called side effects were not associated specifically with desipramine use. Such symptoms might instead be associated with psychologic distress.
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Antidepresivos Tricíclicos/efectos adversos , Antidepresivos Tricíclicos/uso terapéutico , Enfermedades Gastrointestinales/tratamiento farmacológico , Adulto , Humanos , Persona de Mediana Edad , Placebos/administración & dosificación , Encuestas y CuestionariosRESUMEN
BACKGROUND: The implications of the Rome III recommendations to change the irritable bowel syndrome (IBS) subtype criteria for stool pattern are unknown. AIM: (1) Determine the level of agreement between Rome II and Rome III subtypes and (2) compare the behaviors of Rome II and Rome III subtypes over time. METHODS: Female patients (n=148) with Rome II defined IBS were prospectively tracked over 5 consecutive 3-month periods. At baseline, bowel habit reports on questionnaires were used to subclassify patients into Rome II and Rome III subtypes. Over the subsequent 15 months, bowel habit reports on diary cards were used to subclassify patients based on previously derived surrogate criteria into Rome II and Rome III IBS subtypes. RESULTS: The level of agreement between Rome II and Rome III subtype assignments was quite high (86.5%; kappa 0.79). The behavior of Rome II and Rome III subtypes over time was also similar in terms of subtype prevalence, subtype stability, and the proportion of subjects who met criteria for alternating irritable bowel syndrome. CONCLUSIONS: Rome II and Rome III IBS subtypes are in high agreement and behave similarly over time. Therefore, studies that used Rome II subtype criteria and studies that will use Rome III criteria will define comparable populations.
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Estreñimiento/epidemiología , Diarrea/epidemiología , Síndrome del Colon Irritable/clasificación , Estudios de Cohortes , Estreñimiento/etiología , Diarrea/etiología , Femenino , Humanos , Síndrome del Colon Irritable/patología , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Encuestas y CuestionariosRESUMEN
BACKGROUND: Various instruments may be used to measure health-related quality of life in patients with achalasia. METHODS: We administered four patient-centered measures used for evaluation of achalasia severity [an achalasia severity questionnaire we developed previously, an achalasia symptom checklist, the Gastrointestinal Quality-of-Life Index (GIQLI), and the Medical Outcomes Study 36-item Short-Form survey (SF-36)] to 25 subjects enrolled in a randomized controlled trial comparing pneumatic dilatation and laparoscopic Heller myotomy. We estimated correlations between the different measures. RESULTS: Twenty-five patients (13 male, 12 female) were studied; 12 were treated by pneumatic dilatation and 13 by laparoscopic myotomy. The average age of patients was 48.5 [range 25-69, standard deviation (SD) 13.7] years. Baseline scores demonstrated a substantial burden of impairment. The mean (SD) score on the achalasia severity measure [ranges from 0 (best) to 100 (worst)] was 62.3 (13.4). The mean (SD) symptom checklist score [ranges from 0 (best) to 36 (worst)] was 23.2 (6.6). The mean (SD) GIQLI [ranges from 0 (worst) to 144 (best)] was 77.04 (19.4). The SF-36 mean (SD) for the physical component score (PCS) was 45.29 (9.21) and the mean for the mental component score (MCS) was 37.61 (14.97). The achalasia severity measure correlated highly with the GIQLI (r = -0.57, p = 0.01), and the symptom checklist (r = 0.65, p = 0.004). The achalasia severity measure correlated well with the SF-36 PCS (r = -0.42, p = 0.039), but not with the MCS (r = -0.14, p = 0.501). CONCLUSION: Subjects recruited to a randomized controlled trial of achalasia treatment demonstrated impairment in both generic quality-of-life and disease-specific measures. Scores on achalasia-specific measures correlated well with each other, but less well with measures of generic quality-of-life and mental health scales. Because of the multidimensional nature of achalasia, disease-specific measures should be combined with generic health measures for the best assessment of patient outcome.
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Acalasia del Esófago/diagnóstico , Atención Dirigida al Paciente/métodos , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Índice de Severidad de la Enfermedad , Encuestas y CuestionariosRESUMEN
BACKGROUND AND AIMS: Our aim is to review the literature and provide guidelines for the assessment of uninvestigated dysphagia. METHODS: A systematic literature search identified studies on dysphagia. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) approach. Statements were discussed and revised via small group meetings, teleconferences, and a web-based platform until consensus was reached by the full group. RESULTS: The consensus includes 13 statements focused on the role of strategies for the assessment of esophageal dysphagia. In patients presenting with dysphagia, oropharyngeal dysphagia should be identified promptly because of the risk of aspiration. For patients with esophageal dysphagia, history can be used to help differentiate structural from motility disorders and to elicit alarm features. An empiric trial of proton pump inhibitor therapy should be limited to four weeks in patients with esophageal dysphagia who have reflux symptoms and no additional alarm features. For patients with persistent dysphagia, endoscopy, including esophageal biopsy, was recommended over barium esophagram for the assessment of structural and mucosal esophageal disease. Barium esophagram may be useful when the availability of endoscopy is limited. Esophageal manometry was recommended for diagnosis of esophageal motility disorders, and high-resolution was recommended over conventional manometry. CONCLUSIONS: Once oropharyngeal dysphagia is ruled out, patients with symptoms of esophageal dysphagia should be assessed by history and physical examination, followed by endoscopy to identify structural and inflammatory lesions. If these are ruled out, then manometry is recommended for the diagnosis of esophageal dysmotility.
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Glucose regulates pancreatic islet alpha-cell glucagon secretion directly by its metabolism to generate ATP in alpha-cells, and indirectly via stimulation of paracrine release of beta-cell secretory products, particularly insulin. How the cellular substrates of these pathways converge in the alpha-cell is not well known. We recently reported the use of the MIP-GFP (mouse insulin promoter-green fluorescent protein) mouse to reliably identify islet alpha- (non-green cells) and beta-cells (green cells), and characterized their ATP-sensitive K(+) (K(ATP)) channel properties, showing that alpha-cell K(ATP) channels exhibited a 5-fold higher sensitivity to ATP inhibition than beta-cell K(ATP) channels. Here, we show that insulin exerted paracrine regulation of alpha-cells by markedly reducing the sensitivity of alpha-cell K(ATP) channels to ATP (IC(50) = 0.18 and 0.50 mM in absence and presence of insulin, respectively). Insulin also desensitized beta-cell K(ATP) channels to ATP inhibition (IC(50) = 0.84 and 1.23 mM in absence and presence of insulin, respectively). Insulin effects on both islet cell K(ATP) channels were blocked by wortmannin, indicating that insulin acted on the insulin receptor-phosphatidylinositol 3-kinase signaling pathway. Insulin did not affect alpha-cell A-type K(+) currents. Glutamate, known to also inhibit alpha-cell glucagon secretion, did not activate alpha-cell K(ATP) channel opening. We conclude that a major mechanism by which insulin exerts paracrine control on alpha-cells is by modulating its K(ATP) channel sensitivity to ATP block. This may be an underlying basis for the proposed sequential glucose-insulin regulation of alpha-cell glucagon secretion, which becomes distorted in diabetes, leading to dysregulated glucagon secretion.
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Adenosina Trifosfato/química , Adenosina Trifosfato/metabolismo , Insulina/metabolismo , Potasio/química , Androstadienos/farmacología , Animales , Peso Corporal , Línea Celular , Diabetes Mellitus/metabolismo , Relación Dosis-Respuesta a Droga , Glucagón/metabolismo , Células Secretoras de Glucagón/citología , Glucosa/metabolismo , Ácido Glutámico/química , Ácido Glutámico/metabolismo , Proteínas Fluorescentes Verdes/metabolismo , Cobayas , Humanos , Concentración 50 Inhibidora , Islotes Pancreáticos/metabolismo , Ratones , Microscopía Confocal , Microscopía Fluorescente , Fosfatidilinositol 3-Quinasas/metabolismo , Potasio/metabolismo , Conejos , Transducción de Señal , WortmaninaRESUMEN
We recently reported a transgenic [mouse insulin promoter (MIP)-green fluorescent protein (GFP)] mouse in which GFP expression is targeted to the pancreatic islet beta-cells to enable convenient identification of beta-cells as green cells. The GFP-expressing beta-cells of the MIP-GFP mouse were functionally indistinguishable from beta-cells of normal mice. Here we characterized the ionic channel properties and exocytosis of MIP-GFP mouse islet beta- and alpha-cells. Beta-cells displayed delayed rectifying K+ and high-voltage-activated Ca2+ channels and exhibited Na+ currents only at hyperpolarized holding potential. Alpha-cells were nongreen and had both A-type and delayed rectifier K+ channels, both low-voltage-activated and high-voltage-activated Ca2+ channels, and displayed Na+ currents readily at -70 mV holding potential. Alpha-cells had ATP-sensitive K+ channel (KATP) channel density as high as that in beta-cells, and, surprisingly, alpha-cell KATP channels were more sensitive to ATP inhibition (IC50=0.16+/-0.03 mM) than beta-cell KATP channels (IC50=0.86+/-0.10 mM). Whereas alpha-cells were rather uniform in size [2-4.5 picofarad (pF)], beta-cells varied vastly in size (2-12 pF). Of note, small beta-cells (<4.5 pF) showed little exocytosis, whereas medium beta-cells (5-8 pF) exhibited vigorous exocytosis, but large beta-cells (>8 pF) had weaker exocytosis. We found no correlation between beta-cell size and their Ca2+ channel density, suggesting that Ca2+ influx may not be the cause of the heterogeneity in exocytotic responses. The MIP-GFP mouse therefore offers potential to further explore the functional heterogeneity in beta-cells of different sizes. The MIP-GFP mouse islet is therefore a reliable model to efficiently examine alpha-cell and beta-cell physiology and should greatly facilitate examination of their pathophysiology when the MIP-GFP mice are crossed with diabetic models.
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Proteínas Fluorescentes Verdes/genética , Insulina/genética , Islotes Pancreáticos/fisiología , Ratones Transgénicos/fisiología , Regiones Promotoras Genéticas , Adenosina Trifosfato/metabolismo , Adenosina Trifosfato/farmacología , Animales , Canales de Calcio/fisiología , Electrofisiología , Exocitosis , Técnicas In Vitro , Islotes Pancreáticos/citología , Islotes Pancreáticos/metabolismo , Ratones , Microscopía Confocal , Microscopía Fluorescente , Canales de Potasio/efectos de los fármacos , Canales de Potasio/fisiología , Canales de Potasio con Entrada de Voltaje/fisiología , Canales de Sodio/fisiologíaRESUMEN
OBJECTIVE: To determine the incidence of dysphagia and associated pulmonary compromise in stroke patients through a systematic review of the published literature. METHODS: Databases were searched (1966 through May 2005) using terms "cerebrovascular disorders," "deglutition disorders," and limited to "humans" for original articles addressing the frequency of dysphagia or pneumonia. Data sources included Medline, Embase, Pascal, relevant Internet addresses, and extensive hand searching of bibliographies of identified articles. Selected articles were reviewed for quality, diagnostic methods, and patient characteristics. Comparisons were made of reported dysphagia and pneumonia frequencies. The relative risks (RRs) of developing pneumonia were calculated in patients with dysphagia and confirmed aspiration. RESULTS: Of the 277 sources identified, 104 were original, peer-reviewed articles that focused on adult stroke patients with dysphagia. Of these, 24 articles met inclusion criteria and were evaluated. The reported incidence of dysphagia was lowest using cursory screening techniques (37% to 45%), higher using clinical testing (51% to 55%), and highest using instrumental testing (64% to 78%). Dysphagia tends to be lower after hemispheric stroke and remains prominent in the rehabilitation brain stem stroke. There is increased risk for pneumonia in patients with dysphagia (RR, 3.17; 95% CI, 2.07, 4.87) and an even greater risk in patients with aspiration (RR, 11.56; 95% CI, 3.36, 39.77). CONCLUSIONS: The high incidence for dysphagia and pneumonia is a consistent finding with stroke patients. The pneumonia risk is greatest in stroke patients with aspiration. These findings will be valuable in the design of future dysphagia research.
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Trastornos de Deglución/diagnóstico , Trastornos de Deglución/epidemiología , Neumonía/epidemiología , Accidente Cerebrovascular/epidemiología , Adulto , Comorbilidad , Humanos , IncidenciaRESUMEN
Cognate soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins are now known to associate the secretory vesicle with both the target plasma membrane and Ca(2+) channels in order to mediate the sequence of events leading to exocytosis in neurons and neuroendocrine cells. Neuroendocrine cells, particularly insulin-secreting islet beta-cells, t-SNARE proteins, 25-kDa synaptosomal-associated protein (SNAP-25), and syntaxin 1A, independently inhibit the L-type Ca(2+) channel (L(Ca)). However, when both are present, they actually exhibit stimulatory actions on the L(Ca). This suggests that the positive regulation of the L(Ca) is conferred by a multi-SNARE protein complex. We hypothesized an alternate explanation, which is that each of these SNARE proteins possess distinct inhibitory and stimulatory domains that act on the L(Ca). These SNARE proteins were recently shown to bind the Lc(753-893) domain corresponding to the II and III intracellular loop of the alpha1C subunit of the L(Ca). In this study, using patch-clamp methods on primary pancreatic beta-cells and insulinoma HIT-T15 cells, we examined the functional interactions of the botulinum neurotoxin A (BoNT/A) cleavage products of SNAP-25, including NH(2)-terminal (1-197 amino acids) and COOH-terminal (amino acid 198-206) domains, on the L(Ca), particularly at the Lc(753-893) domain. Intracellular application of SNAP-25(1-206) in primary beta-cells decreased L(Ca) currents by approximately 15%. The reduction in L(Ca) currents was counteracted by coapplication of Lc(753-893). Overexpression or injection of wild-type SNAP-25 in HIT cells reduced L(Ca) currents by approximately 30%, and this inhibition was also blocked by the recombinant Lc(753-893) peptide. Expression of BoNT/A surprisingly caused an even greater reduction of L(Ca) currents (by 41%), suggesting that the BoNT/A cleavage products of SNAP-25 might possess distinct inhibitory and positive regulatory domains. Indeed, expression of SNAP-25(1-197) increased L(Ca) currents (by 19% at 10 mV), and these effects were blocked by the Lc(753-893) peptide. In contrast, injection of SNAP-25(198-206) peptide into untransfected cells inhibited L(Ca) currents (by 47%), and more remarkably, these inhibitory effects dominated over the stimulatory effects of SNAP-25(1-197) overexpression (by 34%). Therefore, the SNARE protein SNAP-25 possesses distinct inhibitory and stimulatory domains that act on the L(Ca). The COOH-terminal 197-206 domain of SNAP-25, whose inhibitory actions dominate over the opposing stimulatory NH(2)-terminal domain, likely confers the inhibitory actions of SNAP-25 on the L(Ca). We postulate that the eventual accelerated proteolysis of SNAP-25 brought about by BoNT/A cleavage allows the relatively intact NH(2)-terminal SNAP-25 domain to assert its stimulatory action on the L(Ca) to increase Ca(2+) influx, and this could in part explain the observed weak or inconsistent inhibitory effects of BoNT/A on insulin secretion. The present study suggests that distinct domains within SNAP-25 modulate L(C) subtype Ca(2+) channel activity in both primary beta-cells and insulinoma HIT-T15 cells.
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Canales de Calcio Tipo L/metabolismo , Islotes Pancreáticos/metabolismo , Proteínas de la Membrana/química , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/genética , Animales , Toxinas Botulínicas Tipo A , Calcio/metabolismo , Línea Celular , Proteínas Fluorescentes Verdes , Indicadores y Reactivos/metabolismo , Activación del Canal Iónico/efectos de los fármacos , Activación del Canal Iónico/fisiología , Islotes Pancreáticos/citología , Proteínas Luminiscentes/genética , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Proteínas de la Membrana/farmacología , Proteínas del Tejido Nervioso/farmacología , Fármacos Neuromusculares , Técnicas de Placa-Clamp , Fragmentos de Péptidos/metabolismo , Fragmentos de Péptidos/farmacología , Estructura Terciaria de Proteína , Proteína 25 Asociada a Sinaptosomas , TransfecciónRESUMEN
A hallmark symptom of irritable bowel syndrome (IBS) is a lower pain threshold during rectal distension, but the mechanism underlying this disorder remains unclear. Examining the relationship between physiological and perceptual responses to rectal distension can provide insight into the underlying peripheral or central dysfunction in IBS. Therefore, we carried out a study of the rectal sensations of urge to defecate, pain and unpleasantness in relation to the varying states of the rectum. Ten IBS patients and 13 healthy controls underwent six sets of isobaric rectal distensions. The first set was ascending stepwise distensions terminating upon report of moderate pain where verbal ratings of urge, pain, and unpleasantness were acquired. The remaining sets were phasic or tonic distensions at a single pressure eliciting either moderate urge or moderate pain intensity where subjects gave continuous ratings of urge or pain percepts. The McGill Pain Questionnaire (MPQ) was used to assess different qualities of the pain experience during single pressure distensions. Abnormalities in IBS patients included: (1) higher incidence of distensions where unpleasantness is greater than pain intensity, (2) significantly longer persistence of ratings after stimulus termination during phasic distensions eliciting either moderate urge or moderate pain, (3) significantly smaller ratings fluctuations during tonic distensions, and (4) significantly higher MPQ scores for painful tonic distensions. Our study demonstrates that IBS patients have abnormal temporal and intensity properties of rectal sensation. These can be accounted for by either altered peripheral neuromuscular processing and/or processing of ascending rectal input in the central nervous system.
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Síndrome del Colon Irritable/fisiopatología , Umbral del Dolor/fisiología , Dolor/fisiopatología , Percepción/fisiología , Recto/fisiopatología , Humanos , Dolor/psicología , Dimensión del Dolor/métodos , Estimulación Física/métodos , Psicofísica , Tiempo de Reacción , Recto/inervación , Encuestas y Cuestionarios , Factores de TiempoRESUMEN
Rectal stimulation under normal or pathological conditions evokes numerous sensations. Previous studies have examined rectal stimulation-evoked pain and urge to defecate, but discrepancies in the findings remain because of the different methodologies used in each study and the reporting of sensations only at the end of or after the applied stimuli. Therefore, we conducted a psychophysical study of various aspects of rectal sensation in normal subjects using a variety of distension stimuli and continuous on-line rating of sensation. Ten normal healthy subjects (eight female and two male) were given rectal distension stimuli delivered by a computer-driven barostat. For some experiments, sensation was continuously monitored and rated on a visual analog scale. Subjects first underwent an ascending series of phasic (30 s) distensions to determine how urge, unpleasantness, and pain intensity varied and interrelated as rectal volume and pressure changed. A second series of distensions examined rectal physiology and perception during short phasic (30 s) or long (300 s) distensions at pressures that elicit either moderate urge or moderate pain and while continuously rating these sensations. The McGill Pain Questionnaire was used to assess the multidimensional aspects of rectal pain with each type of distension. The results of the ascending series revealed significant relationships between sensations as pressure and volume increased. The ratings of urge were double that of pain and unpleasantness, whereas unpleasantness and pain ratings were comparable. Isobaric phasic and tonic distensions were associated with an increase in volume (i.e. accommodation) with time. The magnitude of urge with repetitive short isobaric (30 s) distensions was overall not related to the slight increase in rectal volume, while phasic distensions at moderate pain intensity revealed a significant overall relationship between rectal volume and both unpleasantness and pain intensity. Long isobaric distensions evoked sensations that varied over time despite progressive increases in volume, but less variation in sensation was observed during short phasic distensions which also demonstrated a similar increase in rectal volume. Differences in temporal characteristics of sensations evoked by low-pressure distensions eliciting moderate urge versus high-pressure distensions eliciting moderate pain were illustrated by a significantly longer delay to the diminution of non-painful urge versus pain. Therefore, we conclude (1) Differences in the discrimination and the temporal characteristics of urge at subpainful rectal pressures and of pain at noxious pressures suggest that noxious and non-noxious stimuli are processed differently. (2) The overall unpleasantness and pain correlate with rectal volume during accommodation. However, instantaneous evoked sensations can vary independent of volume changes during constant pressure distension. (3) The reported sensation-related responses to tension and stretch will likely be different depending on the degree of accommodation that is occurring. Moreover, the peripheral receptor mechanisms which contribute to controlling this accommodation will also affect the perception of rectal stimuli. (4) Continuous ratings of rectal sensations are valuable in investigating rectal physiology and the multidimensional nature of rectal symptoms.
Asunto(s)
Defecación/fisiología , Dolor/fisiopatología , Dolor/psicología , Recto/fisiología , Adulto , Cateterismo , Adaptabilidad , Femenino , Humanos , Masculino , Dimensión del Dolor , Percepción , Psicofísica , Recto/inervación , Umbral SensorialRESUMEN
Dysphagia screening often includes administration of water. This study assessed the accuracy in identifying dysphagia with each additional teaspoon of water. The original research of the TOR-BSST(©) permitted this assessment. Trained nurses from acute and rehabilitation facilities prospectively administered the TOR-BSST(©) to 311 eligible stroke inpatients. A sensitivity analysis was conducted for the water item using 10 teaspoons plus a sip as the standard. The proportion of positive screenings was 59.2% in acute and 38.5% in rehabilitation. Of all four items that form the TOR-BSST(©), the water swallow item contributed to the identification of dysphagia in 42.7% in acute and 29.0% in rehabilitation patients. Across all patients, dysphagia accuracy was that five teaspoons resulted in a sensitivity of 79% (95% confidence interval [CI] = 70-86), eight a sensitivity of 92% (95% CI = 85-96) and 10 a sensitivity of 96% (95% CI = 90-99). Although a primary contributor, the water swallow item alone does not identify all patients with dysphagia. For a water swallow to accurately identify dysphagia, it is critical to administer 10 teaspoons. The TOR-BSST(©) water swallow item contributes largely to the total TOR-BSST(©)'s screening score and in making the test highly accurate and reliable.
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Trastornos de Deglución/diagnóstico , Deglución , Sistemas de Atención de Punto , Accidente Cerebrovascular/complicaciones , Agua , Anciano , Trastornos de Deglución/etiología , Trastornos de Deglución/fisiopatología , Trastornos de Deglución/rehabilitación , Femenino , Humanos , Masculino , Valor Predictivo de las Pruebas , Estudios Prospectivos , Reproducibilidad de los Resultados , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/fisiopatología , Rehabilitación de Accidente CerebrovascularRESUMEN
OBJECTIVES: Ramon y Cajal discovered interstitial cells in the pancreas associated with intrinsic nerves. It was our aim to provide evidence for or against the hypothesis that the pancreatic duct harbors interstitial cells of Cajal (ICCs) that may function as pacemakers for duct motility. METHODS: We used immunohistochemistry using c-Kit as the ICC marker and protein gene product 9.5 for nerves. Electron microscopy further characterized the cells and their interrelationships. RESULTS: c-Kit-positive cells were associated with smooth muscle cells and nerve fibers of the duct wall and were rich in mitochondria, rough endoplasmic reticulum, and intermediate filaments; they possessed occasional caveolae and had a discontinuous basal lamina. They were connected by small gap junctions to each other and to smooth muscle cells. c-Kit-positive cells around large blood vessels were similar. c-Kit-positive cells within acini were similar in structure but were not associated with smooth muscle cells. CONCLUSIONS: The c-Kit-positive cells around the main duct were identified as ICCs and have the morphological criteria to likely function as pacemaker cells for the previously observed spontaneous rhythmic pancreatic duct contractions. Interstitial cells of Cajal around the large blood vessels likely affect vessel wall rhythmicity.
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Células Intersticiales de Cajal/fisiología , Conductos Pancreáticos/citología , Animales , Gatos , Femenino , Inmunohistoquímica , Células Intersticiales de Cajal/ultraestructura , Masculino , Microscopía Electrónica , Conductos Pancreáticos/irrigación sanguínea , Conductos Pancreáticos/química , Proteínas Proto-Oncogénicas c-kit/análisisRESUMEN
Patients with irritable bowel syndrome (IBS) have abnormal cortical responses to rectal distension and grey matter thinning in brain areas associated with nociception. These abnormalities may be driven by white matter changes and individual factors. Therefore, we tested the hypothesis that WM subserving the pain system is compromised in IBS, and that disease characteristics and personality contribute to these abnormalities. MRI diffusion tensor imaging (DTI) images were obtained from 10 female IBS patients (20-54 years old, mean±SD 32.8±10.4), and 16 female healthy controls (20-44 years old, mean±SD 29.1±7.9). Mean fractional anisotropy (FA) was extracted from WM regions associated with nociception. The IBS group had higher FA in the fornix and external capsule adjacent to the right posterior insula. IBS chronic pain severity correlated with FA of the bilateral anterior insula and lateral thalamus and left anterior insula FA correlated with pain unpleasantness. IBS duration correlated with FA in the external capsule adjacent to the left posterior insula. Neuroticism correlated with FA in the left medial thalamus in IBS patients only. Pain catastrophizing correlated negatively to cingulum FA in IBS, whereas controls showed correlation between pain catastrophizing and FA of the external capsule adjacent to the left anterior and posterior insula. Thus, fornix and insular white matter is related to IBS symptoms. These data suggest that dysregulation of brain-gut communication via the neuroendocrine pathway or via abnormal visceral sensory and homeostatic input has a role in the pathology of IBS chronic pain.
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Encéfalo/patología , Síndrome del Colon Irritable/patología , Fibras Nerviosas Mielínicas/patología , Adulto , Anisotropía , Mapeo Encefálico , Imagen de Difusión por Resonancia Magnética/métodos , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Estadística como Asunto , Adulto JovenRESUMEN
AIM: To assess the effect of nitric oxide (NO) on the large conductance potassium channel (BK(Ca)) in isolated circular (CM) and sling (SM) muscle cells and muscle strips from the cat lower esophageal sphincter (LES) to determine its regulation of resting tone and relaxation. METHODS: Freshly enzymatically-digested and isolated circular smooth muscle cells were prepared from each LES region. To study outward K+ currents, the perforated patch clamp technique was employed. To assess LES resting tone and relaxation, muscle strips were mounted in perfused organ baths. RESULTS: (1) Electrophysiological recordings from isolated cells: (a) CM was more depolarized than SM (-39.7 ± 0.8 mV vs -48.1 ± 1.6 mV, P < 0.001), and maximal outward current was similar (27.1 ± 1.5 pA/pF vs 25.7 ± 2.0 pA/pF, P > 0.05); (b) The NO donor sodium nitroprusside (SNP) increased outward currents only in CM (25.9 ± 1.9 to 46.7 ± 4.2 pA/pF, P < 0.001) but not SM (23.2 ± 3.1 to 27.0 ± 3.4 pA/pF, P > 0.05); (c) SNP added in the presence of the BK(Ca) antagonist iberiotoxin (IbTX) produced no increase in the outward current in CM (17.0 ± 2.8 vs 13.7 ± 2.2, P > 0.05); and (d) L-NNA caused a small insignificant inhibition of outward K+ currents in both muscles; and (2) Muscle strip studies: (a) Blockade of the nerves with tetrodotoxin (TTX), or BK(Ca) with IbTX had no significant effect on resting tone of either muscle; and (b) SNP reduced tone in both muscles, and was unaffected by the presence of TTX or IbTX. CONCLUSION: Exogenous NO activates BK(Ca) only in CM of the cat. However, as opposed to other species, exogenous NO-induced relaxation is predominantly by a non-BK(Ca) mechanism, and endogenous NO has minimal effect on resting tone.
Asunto(s)
Esfínter Esofágico Inferior/fisiología , Canales de Potasio de Gran Conductancia Activados por el Calcio/metabolismo , Óxido Nítrico/metabolismo , Animales , Gatos , Esfínter Esofágico Inferior/efectos de los fármacos , Potenciales de la Membrana/fisiología , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Donantes de Óxido Nítrico/farmacología , Nitroprusiato/farmacología , Técnicas de Placa-Clamp , Péptidos/farmacología , Bloqueadores de los Canales de Sodio/farmacología , Tetrodotoxina/farmacologíaRESUMEN
OBJECTIVE: To compare and contrast clinician, patient, and caregiver perspectives to generate all important and salient items for a new scale to measure medical consequences relevant to adult patients with dysphagia. STUDY DESIGN AND SETTING: Six focus groups (three with clinicians, two with patients, and one with caregivers) were conducted with a total of 33 participants. Through the constant comparison method of Grounded Theory, analysis began with open coding and progressed with higher-order categorization to derive perceptions from differing vantage points. RESULTS: Three themes evolved: (1) clinicians, caregivers, and patients each limited the medical consequences of dysphagia to the same impairment domains: pulmonary, nutritional, and psychological; (2) these consequences were given the same priority by clinicians and caregivers, but patients ranked them differently; (3) within each impairment domain, few dimensions were derived by clinicians and many by patients. Patients were more elaborate in their descriptions of psychological consequences. CONCLUSIONS: The use of qualitative methodology to generate different perspectives derived different content. Clinicians, caregivers, and patients all agreed on the importance of three domains but differed in their prioritization and specific issues. These findings provide the necessary foundation for development of a comprehensive tool to measure medical consequences among patients with dysphagia.