RESUMEN
Background: Anal cancer is potentially preventable through screening. For screening to be implemented, the screening procedures must be acceptable to the affected population. The objective of the present study was to measure the acceptability of currently available anal cancer screening tests in a population of women living with hiv who had experienced the tests. Methods: The evva study ("Evaluation of Human Immunodeficiency Virus, Human Papillomavirus, and Anal Intraepithelial Neoplasia in Women") is a prospective cohort study of adult women living with hiv in Montreal, Quebec. Participants were screened with cervical or anal hpv testing and cervical or anal cytology every 6 months for 2 years. High-resolution anoscopy (hra) and digital anal rectal examination (dare) were also performed systematically, with biopsies, at baseline and at 2 years. An acceptability questionnaire was administered at the final visit or at study withdrawal. Results: Of 124 women who completed the acceptability questionnaire, most considered screening "an absolute necessity" in routine care for all women living with hiv [77%; 95% confidence interval (ci): 69% to 84%]. Yearly anal cytology or anal hpv testing was considered very acceptable by 81% (95% ci: 73% to 88%); hra every 2 years was considered very acceptable by 84% (95% ci: 77% to 90%); and yearly dare was considered very acceptable by 87% (95% ci: 79% to 92%). Acceptability increased to more than 95% with a longer proposed time interval. Pain was the main reason for lower acceptability. Conclusions: Most participating women considered anal cancer screening necessary and very acceptable. Longer screening intervals and adequate pain management could further increase the acceptability of repeated screening.
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Canal Anal/diagnóstico por imagen , Infecciones por VIH/diagnóstico , Adolescente , Adulto , Anciano , Detección Precoz del Cáncer , Femenino , Humanos , Tamizaje Masivo , Persona de Mediana Edad , Adulto JovenRESUMEN
The objective of this study was to determine the associations of rumination time (RT) and health status with milk yield and milk composition. This study used 339 dairy cows from 4 commercial dairy farms in Ontario, Canada (first lactation, n = 107; second lactation, n = 112; ≥third lactation, n = 120). Rumination time was monitored (24 h/d) using an automated system from 1 to 28 d in milk (DIM). Cows were milked 3×/d on each farm, and 2 farms recorded milk weights at each milking to determine daily milk yield (n = 170). Cows were also monitored for milk composition (fat and protein content) 1×/wk. Last, subclinical ketosis (SCK) was diagnosed 1×/wk; cows with at least one blood sample with ß-hydroxybutyrate ≥1.2 mmol/L postcalving were diagnosed with SCK. Cases of retained placenta, metritis, milk fever, or mastitis during the study period were also recorded. Cows were categorized into 1 of 4 groups: healthy cows that had no SCK or any other health issue (HLT; n = 139); cows that were treated for at least one health issue other than SCK (HLT+; n = 50); SCK cows with no other health problems during transition (HYK; n = 97); or cows that had SCK and one or more other health problems (HYK+; n = 53). All data were summarized by week across cows, and the associations between rumination time and milk yield (n = 170) and milk composition (n = 339) were modeled. Across all lactations, and including all health categories, milk yield increased by week, whereas fat and protein content both decreased by week. A positive association was found between summarized RT and milk yield in first-lactation (+0.006 ± 0.003 kg/min of RT) and second-lactation (+0.015 ± 0.004 kg/min of RT) cows from 4 to 28 DIM, as well as in ≥third-lactation cows; however, the relationship between RT and milk yield differed across weeks in those cows. A negative association between RT and milk fat content was found in ≥third-lactation cows (-0.002 ± 0.00059 percentage points/min of RT). From 4 to 28 DIM, ≥third-lactation HYK and HYK+ cows produced less protein (0.11 ± 0.051 and 0.13 ± 0.056 percentage points, respectively) than HLT cows. Over the 4-wk observation period, first-lactation HYK+ cows tended to deposit 0.11 ± 0.056 percentage points less protein in their milk compared with HLT cows. Second-lactation HYK+ cows produced less milk than HLT cows each week during early lactation. In summary, RT was positively associated with milk yield in early-lactation dairy cows, across all lactations, and negatively associated with milk fat content in ≥third-lactation cows. Further, the results showed that early-lactation cows that experience SCK, particularly with one or more other health problems, might have decreased milk yield and milk protein content.
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Ácido 3-Hidroxibutírico/sangre , Enfermedades de los Bovinos/sangre , Bovinos/fisiología , Estado de Salud , Cetosis/veterinaria , Leche/metabolismo , Animales , Enfermedades de los Bovinos/metabolismo , Femenino , Cetosis/sangre , Cetosis/diagnóstico , Leche/química , Proteínas de la Leche/análisis , Ontario , Embarazo , Factores de TiempoRESUMEN
The objective of this study was to characterize the association of lying behavior and subclinical ketosis (SCK) in transition dairy cows. A total of 339 dairy cows (107 primiparous and 232 multiparous) on 4 commercial dairy farms were monitored for lying behavior and SCK from 14d before calving until 28 d after calving. Lying time, frequency of lying bouts, and average lying bout length were measured using automated data loggers 24h/d. Cows were tested for SCK 1×/wk by taking a blood sample and analyzing for ß-hydroxybutyrate; cows with ß-hydroxybutyrate ≥1.2mmol/L postpartum were considered to have SCK. Cases of retained placenta, metritis, milk fever, or mastitis during the study period were recorded and cows were categorized into 1 of 4 groups: healthy (HLT) cows had no SCK or any other health problem (n=139); cows treated for at least 1 health issue other than SCK (n=50); SCK (HYK) cows with no other health problems during transition (n=97); or subclinically ketotic plus (HYK+) cows that had SCK and 1 or more other health problems (n=53). Daily lying time was summarized by week and comparisons were made between HLT, HYK, and HYK+, respectively. We found no difference among health categories in lying time, bout frequency, or bout length fromwk -2 towk +4 relative to calving for first-lactation cows. Differences in lying time for multiparous cows were seen inwk +1, when HYK+ cows spent 92±24.0 min/d more time lying down than HLT cows, and duringwk +3 and +4 when HYK cows spent 44±16.7 and 41±18.9 min/d, respectively, more time lying down than HLT cows. Increased odds of HYK+ were found to be associated with higher parity, longer dry period, and greater stall stocking density inwk -1 and longer lying time duringwk +1. When comparing HYK to HLT cows, the same variables were associated with odds of SCK; however, lying time was not retained in the final model. These results suggest that monitoring lying time may contribute to identifying multiparous cows experiencing SCK with another health problem after calving, but may not be useful in the early detection of SCK.
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Enfermedades de los Bovinos/sangre , Cetosis/veterinaria , Ácido 3-Hidroxibutírico/sangre , Animales , Bovinos , Femenino , Lactancia , Periodo PospartoRESUMEN
The objective of this study was to characterize the relationship between rumination and subclinical ketosis (SCK) in transition dairy cows. A study was conducted on 4 commercial dairy farms in eastern Ontario, Canada. A total of 339 Holstein dairy cows (107 primiparous and 232 multiparous) were monitored for rumination activity and SCK from 14 d before calving until 28 d after calving. Rumination was recorded daily using an automated monitoring system. A blood sample was taken from the coccygeal vein of each cow for measurement of ß-hydroxybutyrate (BHB) once weekly throughout the 6-wk observation period. Cows with BHB ≥1.2mmol/L in any of the 4 postpartum samples were considered to have SCK. Cases of retained placenta, metritis, milk fever, or mastitis during the study period were also recorded. Cows were categorized into 1 of 4 groups: healthy cows (HLT) that had no SCK or any other recorded health problem (n=139); cows treated for at least one health issue other than SCK (HLT+; n=50); cows with SCK (hyperketonemia; HYK) with no other health problems during transition (n=97); or cows (HYK+) that had SCK and one or more other health problems (n=53). Daily rumination time was summarized by week and comparisons were made between HLT and HYK and HYK+. From 2 wk before calving (wk -2) to 4 wk after calving (wk +4), there was no difference in rumination time (409±9.8min/d) among HLT, HYK, and HYK+ cows in their first lactation. Multiparous cows in HLT spent an average of 459±11.3min/d ruminating from wk -2 to wk +4. Multiparous HYK cows ruminated 25±12.8min/d less than HLT cows, whereas HYK+ cows ruminated 44±15.6min/d less than HLT cows. The largest differences in rumination time between HLT and HYK+ cows were seen during wk -1, +1, and +2, when HYK+ cows ruminated 48±17.2, 73±16.0, and 65±19.4min/d less than HLT cows, respectively. In multiparous cows, increased odds of HYK were associated with greater milk yield in the previous lactation, greater loss of body condition over the transition period, greater stall stocking density in wk -1, and reduced rumination time in wk -1. Increased odds of HYK+ were associated with higher parity, longer dry period, greater stall stocking density in wk -1, and reduced rumination time in wk +1. These results suggest that rumination monitoring across the transition period might contribute to identification of SCK and other health problems in multiparous cows.
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Enfermedades de los Bovinos/sangre , Cetosis/veterinaria , Ácido 3-Hidroxibutírico/sangre , Animales , Bovinos , Femenino , Lactancia , Periodo PospartoRESUMEN
Using integrative genomics and functional screening, we identified coiled-coil domain containing 68 (CCDC68) as a novel putative tumor suppressor gene (TSG) in pancreatic ductal adenocarcinoma (PDAC). CCDC68 allelic losses were documented in 48% of primary PDAC patient tumors, 50% of PDAC cell lines and 30% of primary patient derived xenografts. We also discovered a single nucleotide polymorphism (SNP) variant (SNP rs1344011) that leads to exon skipping and generation of an unstable protein isoform CCDC68Δ(69-114) in 31% of PDAC patients. Overexpression of full length CCDC68 (CCDC68(wt)) in PANC-1 and Hs.766T PDAC cell lines lacking CDCC68 expression decreased proliferation and tumorigenicity in scid mice. In contrast, the downregulation of endogenous CCDC68 in MIAPaca-2 cells increased tumor growth rate. These effects were not observed with the deletion-containing isoform, CCDC68Δ(69-114).
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Carcinoma Ductal Pancreático/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Pancreáticas/genética , Proteínas Supresoras de Tumor/genética , Animales , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Proliferación Celular/genética , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Ratones SCID , Mutación , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Polimorfismo de Nucleótido Simple , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Trasplante Heterólogo , Carga Tumoral/genética , Proteínas Supresoras de Tumor/metabolismo , Neoplasias PancreáticasRESUMEN
High-resolution esophageal manometry (HRM) is a recent development used in the evaluation of esophageal function. Our aim was to assess the inter-observer agreement for diagnosis of esophageal motility disorders using this technology. Practitioners registered on the HRM Working Group website were invited to review and classify (i) 147 individual water swallows and (ii) 40 diagnostic studies comprising 10 swallows using a drop-down menu that followed the Chicago Classification system. Data were presented using a standardized format with pressure contours without a summary of HRM metrics. The sequence of swallows was fixed for each user but randomized between users to avoid sequence bias. Participants were blinded to other entries. (i) Individual swallows were assessed by 18 practitioners (13 institutions). Consensus agreement (≤ 2/18 dissenters) was present for most cases of normal peristalsis and achalasia but not for cases of peristaltic dysmotility. (ii) Diagnostic studies were assessed by 36 practitioners (28 institutions). Overall inter-observer agreement was 'moderate' (kappa 0.51) being 'substantial' (kappa > 0.7) for achalasia type I/II and no lower than 'fair-moderate' (kappa >0.34) for any diagnosis. Overall agreement was somewhat higher among those that had performed >400 studies (n = 9; kappa 0.55) and 'substantial' among experts involved in development of the Chicago Classification system (n = 4; kappa 0.66). This prospective, randomized, and blinded study reports an acceptable level of inter-observer agreement for HRM diagnoses across the full spectrum of esophageal motility disorders for a large group of clinicians working in a range of medical institutions. Suboptimal agreement for diagnosis of peristaltic motility disorders highlights contribution of objective HRM metrics.
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Trastornos de la Motilidad Esofágica/diagnóstico , Interpretación de Imagen Asistida por Computador/normas , Manometría/normas , Adulto , Consenso , Deglución/fisiología , Acalasia del Esófago/clasificación , Acalasia del Esófago/diagnóstico , Trastornos de la Motilidad Esofágica/clasificación , Esófago/fisiopatología , Humanos , Interpretación de Imagen Asistida por Computador/métodos , Manometría/métodos , Variaciones Dependientes del Observador , Peristaltismo/fisiología , Estudios Prospectivos , Método Simple CiegoRESUMEN
BACKGROUND: The mechanism of reflux protection may involve a 'flap valve' at the oesophago-gastric junction (OGJ). AIM: To assess the effects of baclofen, a gamma-aminobutyric acid receptor type-B (GABA-B) agonist known to suppress reflux events, on the 'functional anatomy' of the OGJ and proximal stomach after a large test meal. METHODS: Twelve healthy volunteers (HVs) and 12 patients with gastro-oesophageal reflux disease (GERD); with erosive oesophagitis or pathological oesophageal acid exposure completed a randomised, double-blind, cross-over study. On 2 test days participants received 40-mg baclofen or placebo before ingestion of a large test meal. OGJ structure and function were assessed by high-resolution manometry (HRM) and magnetic resonance imaging (MRI) using validated methods. Measurements of the oesophago-gastric angle were derived from three-dimensional models reconstructed from anatomic MRI images. Cine-MRI and HRM identified postprandial reflux events. Mixed model analysis and Wilcoxon rank signed tests assessed differences between participant groups and treatment conditions. RESULTS: In both HVs and GERD patients, baclofen reduced the frequency of postprandial reflux events. The oesophago-gastric insertion angle in GERD patients was reduced (-4.1 ± 1.8, P = 0.025), but was unchanged in healthy controls. In both study groups, baclofen augmented lower oesophageal sphincter (LES) pressure (HVs: +7.3 ± 1.8 mmHg, P < 0.0001, GERD: +4.50 ± 1.49 mmHg, P < 0.003) and increased LES length (HVs: +0.48 ± 0.11 cm, P < 0.0003, GERD: +0.35 ± 0.06 cm, P < 0.0001). CONCLUSIONS: Baclofen inhibits transient LES relaxations and augments LES pressure and length. Additionally, baclofen has effects on the 'functional anatomy' of the OGJ and proximal stomach in GERD patients, which may suppress reflux by means of a 'flap valve' mechanism.
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Baclofeno/uso terapéutico , Esfínter Esofágico Inferior/efectos de los fármacos , Agonistas de Receptores GABA-B/uso terapéutico , Reflujo Gastroesofágico/tratamiento farmacológico , Estómago/efectos de los fármacos , Adulto , Estudios Cruzados , Método Doble Ciego , Esfínter Esofágico Inferior/fisiología , Femenino , Reflujo Gastroesofágico/fisiopatología , Voluntarios Sanos , Humanos , Imagen por Resonancia Magnética , Masculino , Manometría , Persona de Mediana Edad , Periodo Posprandial/efectos de los fármacos , Presión , Estómago/fisiología , Adulto JovenRESUMEN
BACKGROUND: Alginates form a raft above the gastric contents, which may suppress gastro-oesophageal reflux; however, inconsistent effects have been reported in mechanistic and clinical studies. AIMS: To visualise reflux suppression by an alginate-antacid [Gaviscon Advance (GA), Reckitt Benckiser, UK] compared with a nonraft-forming antacid using magnetic resonance imaging (MRI), and to determine the feasibility of pH-impedance monitoring for assessment of reflux suppression by alginates. METHODS: Two studies were performed: (i) GA and antacid (Alucol, Wander Ltd, Switzerland) were visualised in the stomach after ingestion in 12 healthy volunteers over 30 min after a meal by MRI, with reflux events documented by manometry. (ii) A randomised controlled, double-blind cross-over trial of post-prandial reflux suppression documented by pH-impedance in 20 patients randomised to GA or antacid (Milk of Magnesia; Boots, UK) after two meals taken 24 h apart. RESULTS: MRI visualized a "mass" of GA form at the oesophago-gastric junction (OGJ); simple antacid sank to the distal stomach. The number of post-prandial common cavity reflux events was less with GA than antacid [median 2 (0-5) vs. 5 (1-11); P < 0.035]. Distal reflux events and acid exposure measured by pH-impedance were similar after GA and antacid. There was a trend to reduced proximal reflux events with GA compared with antacid [10.5 (8.9) vs. 13.9 (8.3); P = 0.070]. CONCLUSIONS: Gaviscon Advance forms a 'mass' close to the OGJ and significantly suppresses reflux compared with a nonraft-forming antacid. Standard pH-impedance monitoring is suitable for clinical studies of GA in gastro-oesophageal reflux disease patients where proximal reflux is the primary outcome.
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Alginatos/uso terapéutico , Hidróxido de Aluminio/uso terapéutico , Antiácidos/uso terapéutico , Reflujo Gastroesofágico/tratamiento farmacológico , Óxido de Magnesio/uso terapéutico , Periodo Posprandial , Ácido Silícico/uso terapéutico , Bicarbonato de Sodio/uso terapéutico , Adulto , Anciano , Estudios Cruzados , Método Doble Ciego , Combinación de Medicamentos , Impedancia Eléctrica , Monitorización del pH Esofágico , Femenino , Reflujo Gastroesofágico/diagnóstico , Humanos , Concentración de Iones de Hidrógeno , Imagen por Resonancia Magnética , Masculino , Manometría , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
In this issue of British Journal of Pharmacology, Biffen and colleagues present a novel Toll-like receptor 7 (TLR7) antedrug to treat allergic disease that is rapidly metabolized in the lung to limit side effects due to systemic exposure. Asthma is characterized as an allergic disease of the lung, and TLR7 agonists are proposed to ameliorate allergic inflammation in the lung, a characteristic of prophylactic medications. We have previously shown that TLR7 agonists of multiple structural classes are acute bronchodilators, characteristic of rescue medication for asthma attacks. It will be interesting to determine whether the bronchodilating effect extends to the novel class of TLR7 agonists described here for a prophylactic and rescue therapy in one drug. Combined with the antedrug approach, this would further limit side effects improving on current combination therapies. LINKED ARTICLE This article is a commentary on Biffen et al., pp. 573-586 of this issue. To view this paper visit http://dx.doi.org/10.1111/j.1476-5381.2011.01790.x.
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Antiinflamatorios/uso terapéutico , Broncodilatadores/uso terapéutico , Hipersensibilidad Respiratoria/tratamiento farmacológico , Receptor Toll-Like 7/agonistas , Animales , Humanos , Neumonía/tratamiento farmacológicoRESUMEN
BACKGROUND: Magnetic resonance (MR) imaging provides direct, non-invasive measurements of gastric function and emptying. The inter-observer variability (IOV) of MR volume measurements and the most appropriate analysis of MR data have not been established. To assess IOV of total gastric volume (TGV) and gastric content volume (GCV) measurements from MR images and the ability of standard power exponential (PowExp), and a novel linear exponential (LinExp) model to describe MR data. METHODS: Ten healthy volunteers received three different volumes of a liquid nutrient test meal (200-800 mL) on 3 days in a randomized order. Magnetic resonance scans were acquired using a 1.5T system every 1-5 min for 60 min. Total gastric volume and GCV were measured independently by three observers. Volume data were fitted by PowExp and LinExp models to assess postprandial volume change and gastric emptying half time (T(50) ). KEY RESULTS: An initial rise in GCV and TGV was often observed after meal ingestion, thereafter GCV and TGV decreased in an approximately linear fashion. Inter-observer variability decreased with greater volumes from 12% at 200 mL to 6% at 600 and 800 mL. Inter-observer variability for T(50) was <5%. PowExp and LinExp models provided comparable estimates of T(50) ; however, only LinExp described dynamic volume change in the early postprandial period. CONCLUSIONS & INFERENCES: Gastric MR provides quantitative measurements of postprandial volume change with low IOV, unless the stomach is nearly empty. The novel LinExp model describes the dynamic volume changes in the early postprandial period more accurately than the PowExp model used in existing gastric emptying studies.
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Vaciamiento Gástrico/fisiología , Imagen por Resonancia Magnética/normas , Periodo Posprandial/fisiología , Estómago/anatomía & histología , Estómago/fisiología , Adulto , Ingestión de Alimentos , Ingestión de Energía , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Estudios Prospectivos , Distribución Aleatoria , Reproducibilidad de los Resultados , Método Simple Ciego , Adulto JovenRESUMEN
BACKGROUND: High-resolution manometry (HRM) with spatiotemporal representation of pressure data is a recent advance in esophageal measurement. At present, normal values are available for 5mL water swallows in the supine position. This study provides reference values for liquid and solid bolus swallows in the upright seated and supine positions. METHODS: A total of 23 asymptomatic volunteers (11M:12F, age 20-56) underwent HRM (Manoscan 360; Sierra Scientific Instruments) with 5mL water and 1cm3 bread swallows in the upright and supine positions. Normal values for primary parameters associated with effective bolus transport [proximal transition zone length (PTZ, assesses peristaltic coordination], contraction front velocity (CFV), distal contractile index (DCI) and integrated relaxation pressure (IRP)] are presented. For each parameter, median values along with the 5-95th percentile range are reported. Inter-observer agreement between independent observers is reported using the intra-class correlation coefficient. KEY RESULTS: A higher proportion of swallows were peristaltic for liquids than solids in both the upright and supine positions (both P<0.05). As workload increases with solid bolus and on moving from the upright to the supine position the esophageal contractile response resulted in a shorter PTZ, a slower CFV, and a more vigorous DCI. Also IRP increased during solid bolus transit (all P<0.01). There was significant agreement between independent observers for HRM parameters. CONCLUSIONS & INFERENCES: Normative values for esophageal function for solids as well as liquids and in the 'physiologic', upright position will optimize the utility of HRM studies. The high level of inter-observer agreement indicates that these can be applied as reference values in clinical practice.
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Deglución/fisiología , Esófago/fisiología , Manometría/métodos , Manometría/normas , Postura , Adulto , Esófago/anatomía & histología , Femenino , Humanos , Masculino , Manometría/instrumentación , Persona de Mediana Edad , Contracción Muscular/fisiología , Variaciones Dependientes del Observador , Peristaltismo/fisiología , Valores de Referencia , Adulto JovenRESUMEN
BACKGROUND: Non-specific esophageal dysmotility with impaired clearance is often present in patients with gastro-esophageal reflux disease (GERD), especially those with erosive disease; however the physio-mechanic basis of esophageal dysfunction is not well defined. METHODS: Retrospective assessment of patients with erosive reflux disease (ERD; n=20) and endoscopy negative reflux disease (ENRD; n=20) with pathologic acid exposure on pH studies (>4.2% time/24 h) and also healthy controls (n=20) studied by high resolution manometry. Esophageal motility in response to liquid and solid bolus swallows and multiple water swallows (MWS) was analyzed. Peristaltic dysfunction was defined as failed peristalsis, spasm, weak or poorly coordinated esophageal contraction (>3cm break in 30 mmHg isocontour). KEY RESULTS: Peristaltic dysfunction was present in 33% of water swallows in controls, 56% ENRD and 76% ERD respectively (P<0.023 vs controls, P=0.185 vs ENRD). The proportion of effective peristaltic contractions improved with solid compared to liquid bolus in controls (18%vs 33%, P=0.082) and ENRD (22%vs 54%, P=0.046) but not ERD (62%vs 76%, P=0.438). Similarly, MWS was followed by effective peristalsis in 83% of controls and 70% ENRD but only 30% ERD patients (P<0.017 vs controls and P<0.031 vs ENRD). The association between acid exposure and dysmotility was closer for solid than liquid swallows (r=0.52 vs 0.27). CONCLUSIONS & INFERENCES: Peristaltic dysfunction is common in GERD. ERD patients are characterized by a failure to respond to the physiologic challenge of solid bolus and MWS that is likely also to impair clearance following reflux events and increase exposure to gastric refluxate.
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Trastornos de la Motilidad Esofágica/fisiopatología , Esófago/fisiología , Esófago/fisiopatología , Reflujo Gastroesofágico/patología , Reflujo Gastroesofágico/fisiopatología , Peristaltismo/fisiología , Adulto , Deglución/fisiología , Esófago/patología , Femenino , Humanos , Masculino , Manometría/métodos , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: The frequency of MS increases with age and augments the cardiovascular risk. The criteria for distinguishing MS constantly evolve. The aim of the study was to estimate the reciprocal links between low-grade inflammation, selected serum androgens and prevalence of MS, according to NCEP and IDF criteria, in Polish men over the age of 40. MATERIALS AND METHODS: A sample of 160 men was randomly selected from men at the age of 40, 50, 60 and 70, residing in the rural south-western region of Poland. IL-18 and CRP, transferrin, α (1)-antichymotrypsin, dehydroepiandrosterone and its sulfate as well as free-testosterone levels were evaluated. RESULTS: The prevalence of MS was 37.5% using NCEP criteria and 46.25% employing IDF indices. Patients with MS diagnosed according to criteria proposed by NCEP and IDF exhibit a similar hormonal and immunological profile. Age was positively correlated with CRP (r=0.231; p<0.0005), and α (1)-ACT (r=0.191 p<0.05) and negatively with transferrin (r=-0.27; p<0.001), but not with IL-18 plasma levels. Both adrenal androgens were negatively correlated with age: DHEA r=-0.489; p<0.001 and DHEAS: r=-0.553; p<0.001 respectively, in contrast to free-testosterone. People suffering from MS have shown a significantly higher level of IL-18 and CRP. The number of MS components identified (according to NCEP) is positively correlated only with IL-18 serum levels (r=0.226; p=0.043). CONCLUSIONS: Inflammatory parameters were better than a deficit of androgens in identifying men suffering from MS. However, the best correlation with the number of MS components was revealed by IL-18 plasma levels.
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Deshidroepiandrosterona/sangre , Mediadores de Inflamación/sangre , Interleucina-18/sangre , Síndrome Metabólico/sangre , Testosterona/sangre , Adulto , Factores de Edad , Anciano , Humanos , Masculino , Persona de Mediana Edad , Polonia , PrevalenciaRESUMEN
Gastric emptying (GE) may be driven by tonic contraction of the stomach ('pressure pump') or antral contraction waves (ACW) ('peristaltic pump'). The mechanism underlying GE was studied by contrasting the effects of clonidine (alpha(2)-adrenergic agonist) and sumatriptan (5-HT(1) agonist) on gastric function. Magnetic resonance imaging provided non-invasive assessment of gastric volume responses, ACW and GE in nine healthy volunteers. Investigations were performed in the right decubitus position after ingestion of 500 mL of 10% glucose (200 kcal) under placebo [0.9% NaCl intravenous (IV) and subcutaneous (SC)], clonidine [0.01 mg min(-1) IV, max 0.1 mg (placebo SC)] or sumatriptan [6 mg SC (placebo IV)]. Total gastric volume (TGV) and gastric content volume (GCV) were assessed every 5 min for 90 min, interspersed with dynamic scan sequences to measure ACW activity. During gastric filling, TGV increased with GCV indicating that meal volume dictates initial relaxation. Gastric contents volume continued to increase over the early postprandial period due to gastric secretion surpassing initial gastric emptying. Clonidine diminished this early increase in GCV, reduced gastric relaxation, decreased ACW frequency compared with placebo. Gastric emptying (GE) rate increased. Sumatriptan had no effect on initial GCV, but prolonged gastric relaxation and disrupted ACW activity. Gastric emptying was delayed. There was a negative correlation between gastric relaxation and GE rate (r(2 )=49%, P < 0.001), whereas the association between ACW frequency and GE rate was inconsistent and weak (r2=15%, P = 0.05). These findings support the hypothesis that nutrient liquid emptying is primarily driven by the 'pressure pump' mechanism.
Asunto(s)
Clonidina/farmacología , Vaciamiento Gástrico/efectos de los fármacos , Motilidad Gastrointestinal/efectos de los fármacos , Periodo Posprandial/fisiología , Estómago/anatomía & histología , Sumatriptán/farmacología , Agonistas alfa-Adrenérgicos/farmacología , Adulto , Presión Sanguínea/fisiología , Vaciamiento Gástrico/fisiología , Motilidad Gastrointestinal/fisiología , Frecuencia Cardíaca/fisiología , Humanos , Imagen por Resonancia Magnética , Manometría , Tamaño de los Órganos/efectos de los fármacos , Peristaltismo/efectos de los fármacos , Peristaltismo/fisiología , Antro Pilórico/anatomía & histología , Antro Pilórico/fisiología , Agonistas de Receptores de Serotonina/farmacología , Estómago/fisiologíaRESUMEN
This study characterized the pharmacology of the peripherally restricted opioid receptor antagonists, alvimopan, its metabolite, ADL 08-0011, and methylnaltrexone. The activities of the compounds were investigated with respect to human or guinea pig opioid receptor binding and function in recombinant cell lines and mechanical responsiveness of the guinea pig ileum. Alvimopan and ADL 08-0011 had higher binding affinity than methylnaltrexone at human mu opioid receptors (pK (i) values of 9.6, 9.6, and 8.0, respectively). The compounds had different selectivities for the mu receptor over human delta and guinea pig kappa opioid receptors. ADL 08-0011 had the highest mu receptor selectivity. With respect to their mu opioid receptor functional activity ([(35)S]GTPgammaS incorporation), methylnaltrexone had a positive intrinsic activity, consistent with partial agonism, unlike alvimopan and ADL 08-0011, which had negative intrinsic activities. Alvimopan, ADL 08-0011, and methylnaltrexone antagonized inhibitory responses mediated by the mu opioid agonist, endomorphin-1 (pA (2) values of 9.6, 9.4, and 7.6, respectively) and by U69593, a kappa opioid agonist (pA (2) values of 8.4, 7.2, and 6.7, respectively). In morphine-naive guinea pig ileum, methylnaltrexone reduced, while alvimopan and ADL 08-0011 increased, the amplitude of electrically evoked contractions and spontaneous mechanical activity. In tissue from morphine-dependent animals, alvimopan and ADL 08-0011 increased spontaneous activity to a greater degree than methylnaltrexone. The data suggested that alvimopan-induced contractions resulted predominantly from an interaction with kappa opioid receptors. It is concluded that alvimopan, ADL 08-0011, and methylnaltrexone differ in their in vitro pharmacological properties, particularly with respect to opioid receptor subtype selectivity and intrinsic activity. The clinical significance of the data from this study remains to be determined.
Asunto(s)
Naltrexona/análogos & derivados , Antagonistas de Narcóticos , Piperidinas/farmacología , Analgésicos Opioides/metabolismo , Analgésicos Opioides/farmacología , Animales , Bencenoacetamidas/farmacología , Células CHO , Cricetinae , Cricetulus , Relación Dosis-Respuesta a Droga , Encefalina Ala(2)-MeFe(4)-Gli(5)/metabolismo , Encefalina Ala(2)-MeFe(4)-Gli(5)/farmacología , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Cobayas , Humanos , Íleon/efectos de los fármacos , Íleon/metabolismo , Íleon/fisiología , Técnicas In Vitro , Masculino , Morfina/farmacología , Contracción Muscular/efectos de los fármacos , Naltrexona/metabolismo , Naltrexona/farmacología , Antagonistas de Narcóticos/metabolismo , Antagonistas de Narcóticos/farmacología , Oligopéptidos/metabolismo , Oligopéptidos/farmacología , Piperidinas/metabolismo , Pirrolidinas/farmacología , Compuestos de Amonio Cuaternario/metabolismo , Compuestos de Amonio Cuaternario/farmacología , Receptores Opioides/agonistas , Receptores Opioides/genética , Receptores Opioides delta/agonistas , Receptores Opioides delta/antagonistas & inhibidores , Receptores Opioides delta/genética , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/antagonistas & inhibidores , Receptores Opioides kappa/genética , Receptores Opioides mu/agonistas , Receptores Opioides mu/antagonistas & inhibidores , Receptores Opioides mu/genética , Proteínas Recombinantes , TransfecciónRESUMEN
BACKGROUND AND PURPOSE: 5-HT(4) receptor agonists are used therapeutically to treat disorders of reduced gastrointestinal motility. Since such compounds are evaluated in guinea-pigs, we cloned, expressed and pharmacologically characterized the guinea-pig 5-HT(4) and human 5-HT(4(b)) splice variant, which share 95% homology. The functional properties of guinea-pig 5-HT(4(b)) receptors were compared with native receptors in guinea-pig colon. EXPERIMENTAL APPROACH: Membrane radioligand binding and whole cell cAMP accumulation assays were used to determine the affinities, potencies and intrinsic activities (IA). Contraction of the guinea-pig distal colon longitudinal muscle myenteric plexus preparation (LMMP) was monitored to evaluate functional activity. KEY RESULTS: pK(i) values for guinea-pig and human recombinant receptors, and guinea-pig striatum 5-HT(4) receptors, were in agreement, as were the potency and IA values for guinea-pig and human 5-HT(4) receptors expressed at a similar density ( approximately 0.2 pmol mg(-1) protein). Tegaserod was a potent (pEC(50)=8.4 and 8.7, respectively), full agonist at both guinea-pig and human 5-HT(4) receptors. In contrast, in the LMMP preparation, tegaserod was a potent, partial agonist (pEC(50)=8.2; IA=66%). CONCLUSIONS AND IMPLICATIONS: Close agreement between the pharmacological properties of guinea-pig and human 5-HT(4) receptors support the use of guinea-pig model systems for the identification of 5-HT(4) receptor therapeutics. However, the mechanisms underlying the different agonist properties of tegaserod in recombinant and isolated tissue preparations, and the extent to which these impact the clinical efficacy of tegaserod as a prokinetic agent, remain to be determined.
Asunto(s)
Receptores de Serotonina 5-HT4/genética , Receptores de Serotonina 5-HT4/metabolismo , Empalme Alternativo , Animales , Secuencia de Bases , Colon/efectos de los fármacos , Colon/metabolismo , Cartilla de ADN/genética , Sistema Digestivo/efectos de los fármacos , Sistema Digestivo/metabolismo , Fármacos Gastrointestinales/farmacología , Cobayas , Humanos , Técnicas In Vitro , Indoles/farmacología , Masculino , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas Recombinantes/agonistas , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Agonistas del Receptor de Serotonina 5-HT4 , Agonistas de Receptores de Serotonina/farmacologíaRESUMEN
The objectives of this study were to investigate the tolerability of a novel high-dose chemotherapy (HDC) regimen with peripheral blood progenitor cell (PBPC) support in patients with pretreated advanced ovarian cancer and to determine the maximum-tolerated dose (MTD) of topotecan in this setting. Advanced ovarian cancer patients previously treated with platinum-based first-line therapy were enrolled. After PBPC mobilization and harvesting, patients received three consecutive cycles of HDC with PBPC support. Cycle 1 was carboplatin area under the concentration curve 20 and paclitaxel 250 mg/m(2). Cycle 2 was topotecan starting at 5 mg/m(2), dose escalated in 2 mg/m(2) increments, and etoposide 600 mg/m(2). Cycle 3 was thiotepa 500 mg/m(2). After each cycle, PBPCs were infused. Granulocyte colony stimulating factor (5 microg/kg/day) was administered until neutrophil recovery occurred. Seventeen patients were enrolled; all were safety evaluable. The most common nonhematologic toxicity was grade 3 mucositis (44%). Engraftment of PBPCs was successful in all patients after each cycle, and no treatment-related deaths occurred. Of 14 patients with measurable disease, 5 (36%) had complete responses, 2 (14%) had partial responses, and 4 (29%) had stable disease. The median progression-free and overall survivals were 7 and 18 months, respectively. The MTD of topotecan was not reached. The tolerability and activity of this regimen in patients with advanced ovarian cancer warrant further investigation.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Invasividad Neoplásica/patología , Neoplasias Ováricas/terapia , Terapia Recuperativa , Adulto , Carcinoma/mortalidad , Carcinoma/patología , Terapia Combinada , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Dosis Máxima Tolerada , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Paclitaxel/administración & dosificación , Pronóstico , Análisis de Supervivencia , Tiotepa/administración & dosificación , Topotecan/administración & dosificación , Trasplante Autólogo , Resultado del TratamientoRESUMEN
The interaction of symmetrical lidocaine dimers with voltage-gated Na+ channels (VGSCs) was examined using a FLIPR membrane potential assay and voltage-clamp. The dimers, in which the tertiary amines of the lidocaine moieties are linked by an alkylene chain (two to six methylene units), inhibited VGSC activator-evoked depolarization of cells heterologously-expressing rat (r) Na(v)1.2a, human (h) Na(v)1.5, and rNa(v)1.8, with potencies 10- to 100-fold higher than lidocaine (compound 1). The rank order of potency (C4 (compound 4) > C3 (compound 3) > or = C2 (compound 2) = C5 (compound 5) = C6 (compound 6) >> compound 1) was similar at each VGSC. Compound 4 exhibited strong use-dependent inhibition of hNa(v)1.5 with pIC50 values < 4.5 and 6.0 for tonic and phasic block, respectively. Coincubation with local anesthetics but not tetrodotoxin attenuated compound 4-mediated inhibition of hNa(v)1.5. These data suggest that the compound 4 binding site(s) is identical, or allosterically coupled, to the local anesthetic receptor. The dissociation rate of the dimers from hNa(v)1.5 was dependent upon the linker length, with a rank order of compound 1 > compound 5 = compound 6 > compound 2 >> compound 3. The observation that both the potency and dissociation rate of the dimers was dependent upon linker length is consistent with a multivalent interaction at VGSCs. hNa(v)1.5 VGSCs did not recover from inhibition by compound 4. However, "chase" with free local anesthetic site inhibitors increased the rate of dissociation of compound 4. Together, these data support the hypothesis that compound 4 simultaneously occupies two binding sites on VGSCs, both of which can be bound by known local anesthetic site inhibitors.
Asunto(s)
Anestésicos Locales/farmacología , Membrana Celular/efectos de los fármacos , Lidocaína/farmacología , Bloqueadores de los Canales de Sodio/farmacología , Canales de Sodio/efectos de los fármacos , Anestésicos Locales/química , Animales , Bioensayo , Células Cultivadas , Dimerización , Ganglios Espinales/efectos de los fármacos , Humanos , Lidocaína/química , Potenciales de la Membrana , Ratas , Bloqueadores de los Canales de Sodio/química , Tetrodotoxina/farmacologíaRESUMEN
A novel, membrane potential sensitive dye and a fluorescence imaging plate reader (FLIPR) have been used to characterize the pharmacological properties of rat Na(v)1.8 voltage-gated sodium channels (VGSC) in parallel with rat Na(v)1.2a and human Na(v)1.5 VGSC subtypes, respectively. The sensitivity of recombinant Na(v)1.2a-CHO, Na(v)1.5-293-EBNA, and Na(v)1.8-F-11 cells to VGSC activators was subtype dependent. Veratridine evoked depolarization of Na(v)1.2a-CHO and Na(v)1.5-293-EBNA cells with pEC(50) values of 4.78 +/- 0.13 and 4.84 +/- 0.12, respectively (n = 3), but had negligible effect on Na(v)1.8-F-11 cells (pEC(50) < 4.5). Type I pyrethroids were without significant effect at all subtypes. In contrast, the type II pyrethroids deltamethrin and fenvalerate evoked direct depolarization of Na(v)1.8-F-11 and Na(v)1.5-293-EBNA cells. Deltamethrin potentiated the veratridine-evoked response in Na(v)1.8-F-11 cells by > or =20-fold, in contrast to a Asunto(s)
Proteínas Musculares/metabolismo
, Proteínas del Tejido Nervioso/metabolismo
, Canales de Sodio/metabolismo
, Sodio/metabolismo
, Animales
, Colorantes Fluorescentes
, Humanos
, Canal de Sodio Activado por Voltaje NAV1.5
, Canal de Sodio Activado por Voltaje NAV1.8
, Técnicas de Placa-Clamp
, Ratas
, Factores de Tiempo