RESUMEN
Small molecules that bind to allosteric sites on target proteins to alter protein function are highly sought in drug discovery. High-throughput screening (HTS) assays are needed to facilitate the direct discovery of allosterically active compounds. We have developed technology for high-throughput time-resolved fluorescence lifetime detection of fluorescence resonance energy transfer (FRET), which enables the detection of allosteric modulators by monitoring changes in protein structure. We tested this approach at the industrial scale by adapting an allosteric FRET sensor of cardiac myosin to high-throughput screening (HTS), based on technology provided by Photonic Pharma and the University of Minnesota, and then used the sensor to screen 1.6 million compounds in the HTS facility at Bristol Myers Squibb. The results identified allosteric activators and inhibitors of cardiac myosin that do not compete with ATP binding, demonstrating high potential for FLT-based drug discovery.
Asunto(s)
Transferencia Resonante de Energía de Fluorescencia , Ensayos Analíticos de Alto Rendimiento , Ensayos Analíticos de Alto Rendimiento/métodos , Transferencia Resonante de Energía de Fluorescencia/métodos , Miosinas Cardíacas , Descubrimiento de Drogas/métodosRESUMEN
Daily water use and wastage patterns of pigs have major effects on the efficacy of in-water antimicrobial dosing events when conducted for metaphylaxis or to treat clinical disease. However, daily water use and wastage patterns of pigs are not routinely quantified on farms and are not well understood. We conducted a prospective, observational 27-day study of the daily water use and wastage patterns of a pen group of 15 finisher pigs reared in a farm building. We found that the group of pigs wasted a median of 36.5% of the water used per day. We developed models of the patterns of water used and wasted by pigs over each 24-h period using a Bayesian statistical method with the brm() function in the brms package. Both patterns were uni-modal, peaking at 1400-1700, and closely aligned. Wastage was slightly greater during hours of higher water use. We have shown that it is feasible to quantify the water use and wastage patterns of pigs in farm buildings using a system that records and aggregates data, and analyses them using hierarchical generalised additive models. This system could support more efficacious in-water antimicrobial dosing on farms, and better antimicrobial stewardship, by helping to reduce the quantities of antimicrobials used and disseminated into the environment.
Asunto(s)
Antiinfecciosos , Enfermedades de los Porcinos , Animales , Antibacterianos , Antiinfecciosos/uso terapéutico , Teorema de Bayes , Ingestión de Líquidos , Estudios Prospectivos , Porcinos , Enfermedades de los Porcinos/tratamiento farmacológico , Enfermedades de los Porcinos/prevención & control , AguaRESUMEN
INTRODUCTION: Dyspnoea is common in patients with giant paraoesophageal hernia (PEH). Pulmonary aspiration has not previously been recognised as a significant contributory factor. Aspiration pneumonia in association with both gastro-oesophageal reflux disease (GORD) and PEH has a high mortality rate. There is debate about routine anti-reflux measures with surgical repair. Reflux aspiration has been examined in a consecutive cohort using scintigraphic scanning and symptoms. METHODS: Reflux aspiration scintigraphy (RASP) results and symptoms were evaluated in consecutive patients with PEH managed in our service between January 2012 and March 2017. RESULTS: PEH was diagnosed in 96 patients. Preoperative reflux pulmonary scanning was performed in 70 patients: 54 were female (77.1%) and the mean age was 68 years (range 49-85). Dyspnoea was the most common symptom (77.1%), and a symptomatic history of aspiration was seen in 18 patients (25.7%). Clinical aspiration was confirmed by RASP in 13 of these cases. Silent RASP aspiration occurred in a further 27 patients without clinical symptoms. RASP was negative in five patients with clinical symptoms of aspiration. No aspiration by either criterion was present in 27 patients. Dysphagia was negatively related to aspiration on RASP (p<0.01), whereas dyspnoea was not (p=0.857). CONCLUSION: GORD, dyspnoea and silent pulmonary aspiration are frequent occurrences in the presence of giant PEH. Subjective aspiration was the most specific and positive predictor of pulmonary aspiration. Dyspnoea in PEH patients may be caused by pulmonary aspiration, cardiac compression and gas trapping. The high rate of pulmonary aspiration in PEH patients may support anti-reflux repair.
Asunto(s)
Trastornos de Deglución , Reflujo Gastroesofágico , Hernia Hiatal , Anciano , Anciano de 80 o más Años , Trastornos de Deglución/complicaciones , Trastornos de Deglución/etiología , Femenino , Reflujo Gastroesofágico/complicaciones , Reflujo Gastroesofágico/epidemiología , Hernia Hiatal/complicaciones , Hernia Hiatal/diagnóstico , Hernia Hiatal/cirugía , Humanos , Incidencia , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: To examine the association between county-level caesarean delivery (CD) rates among women at low risk and morbidity among term newborns. DESIGN: Cross-sectional study. SETTING: Population-based study of US county-level birth data from 2015 to 2017. POPULATION: Nulliparous women with term, singleton, vertex-presenting infants (NTSV) at low risk for morbidity. METHODS: The primary exposure was county-level CD rates. MAIN OUTCOME MEASURES: The outcome was morbidity among the low-risk NTSV cohort, categorised as severe (5-minute Apgar score of ≤3, assisted ventilation for ≥6 hours, severe neurologic injury or seizure, transfer or death) or moderate (5-minute Apgar score of <7 but >3, administration of antibiotics or assisted ventilation at delivery). We used linear regression models to determine the association between county NTSV CD and neonatal morbidity rates with cluster robust standard errors. RESULTS: The analysis included data from 2 753 522 births in 952 counties from all 48 states. The mean NTSV CD rate was 23.6% (standard deviation 4.8%). The median severe and moderate neonatal morbidity rates were 15.2 (interquartile range, IQR 9.4-23.6) and 52.5 (IQR 33.4-75.7) per 1000 births, respectively. In the unadjusted analysis using the risk-adjusted exposure and outcome, every percentage point increase in the CD rate of a county was associated with 0.6 (95% CI -0.9, -0.3) and 2.3 fewer (95% CI -3.4, -1.1) cases of severe and moderate neonatal morbidity per 1000 live births. After adjustment for other county factors, the relationships remained significant. These findings were tested in multiple sensitivity analyses. CONCLUSIONS: Lower county-level NTSV CD rates were associated with a small increase in morbidity among term newborns in the USA. TWEETABLE ABSTRACT: Lower county-level caesarean delivery rates were associated with an increase in morbidity among term newborns in the USA.
Asunto(s)
Cesárea/estadística & datos numéricos , Resultado del Embarazo/epidemiología , Adulto , Cesárea/efectos adversos , Estudios Transversales , Femenino , Humanos , Lactante , Recién Nacido , Morbilidad , Embarazo , Nacimiento a Término , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND AND PURPOSE: Although many pediatric neuroradiology practices empirically use noncontrast brain and pituitary MR imaging for evaluation of growth hormone deficiency, central precocious puberty, and short stature, there are currently insufficient published data to support this practice in an evidence-based fashion. Therefore, the use of contrast-enhanced MR imaging for all pediatric pituitary endocrinopathies remains widespread. We evaluated whether noncontrast MR imaging has adequate diagnostic yield for the evaluation of pediatric growth hormone deficiency, central precocious puberty, and short stature. MATERIALS AND METHODS: Pituitary MR imaging studies obtained for growth hormone deficiency, central precocious puberty, or short stature in patients 0-18 years of age from 2010 to 2019 were analyzed. Separate blinded review of noncontrast images in cases with abnormalities on the original radiology report was performed by 2 subspecialty-trained pediatric neuroradiologists, with discrepancies resolved by consensus. RESULTS: Of the 134/442 MR imaging studies obtained for growth hormone deficiency, central precocious puberty, or short stature with hypothalamic-pituitary region abnormalities, there was 70% concordance with the original reports on blinded review of noncontrast images. Twenty-two of 40 discrepancies were deemed unrelated to the indication, and 9 cases originally interpreted as possible microadenoma were read as having normal findings on blinded review. Only 9 of 40 discrepancies required contrast for further characterization. CONCLUSIONS: In our study, most relevant radiologic findings in patients with growth hormone deficiency, central precocious puberty, and short stature were detectable without contrast, providing evidence that contrast can be avoided in routine MR imaging evaluation of these indications. We propose a "rapid noncontrast pituitary" MR imaging protocol for pediatric patients presenting with growth hormone deficiency, central precocious puberty, or short stature, which may increase efficiency and decrease contrast and anesthesia exposure.
Asunto(s)
Anestesia , Pubertad Precoz , Niño , Gadolinio , Humanos , Imagen por Resonancia Magnética , Hipófisis/diagnóstico por imagen , Pubertad Precoz/diagnóstico por imagenRESUMEN
Chronic granulomatous disease (CGD) is a primary immunodeficiency syndrome that results in increased risk for bacterial and fungal infections, as well as inflammatory/autoimmune complications. While CGD historically has been associated with early death in childhood, the life expectancy and morbidity of patients with CGD have greatly improved. Many patients with CGD now survive well into adulthood, and data on adult cohorts of patients with CGD have been published. However, reports of pregnancy management, complications, and outcomes for patients with CGD are sparse. In addition, management of invasive fungal infections, including use of newer triazole antifungals, during pregnancy has not been well described. We report a case of fungal lung infection in a pregnant woman with CGD, diagnosed during her second trimester, which was treated with multiple antifungal agents, including more than 12 weeks of isavuconazole therapy, resulting in resolution of infection and delivery of a healthy newborn at term.
RESUMEN
BACKGROUND AND PURPOSE: Contingent negative variation (CNV) is a negative cortical wave that precedes a pre-cued imperative stimulus requiring a quick motor response. It has been related to motor preparation and anticipatory attention. The aim was to ascertain whether the clinical improvement of functional movement disorders after physiotherapy would be associated with faster reaction times and modulation of CNV. METHODS: Motor performance and CNV were analysed during a pre-cued choice reaction time task with varying cue validity. Twenty-one patients with functional movement disorders and 13 healthy controls at baseline were compared. Patients then underwent physiotherapy. At follow-up after physiotherapy, patients were categorized as clinically improved (responders) or not improved (non-responders) and retested. RESULTS: At baseline, patients did not generate CNV, contrary to controls [mean amplitude (µV) at the end of preparation to move: patients -0.47 (95% CI -1.94, 1.00) versus controls -2.59 (95% CI -4.46, -0.72)]. Responders performed faster after physiotherapy [mean natural logarithm (ln) reaction time (RT) (ms): follow-up 6.112 (95% CI 5.923, 6.301) versus baseline 6.206 (95% CI 6.019, 6.394), P = 0.010], contrary to non-responders. Simultaneously, responders showed a recovery of CNV after physiotherapy [follow-up -1.95 (95% CI -3.49, -0.41) versus baseline -0.19 (95% CI -1.73, 1.35), P < 0.001], contrary to non-responders [follow-up -0.32 (95% CI -1.79, 1.14) versus baseline -0.72 (95% CI -2.19, 0.75), P = 0.381]. CONCLUSIONS: Clinical improvement of functional movement disorders after physiotherapy was associated with faster reaction times and normalization of CNV, which was absent at baseline. These findings suggest that CNV may constitute a useful neurophysiological biomarker related to abnormal attention in functional movement disorders.
Asunto(s)
Variación Contingente Negativa , Trastornos del Movimiento , Adulto , Atención , Biomarcadores , Electroencefalografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Movimiento , Trastornos del Movimiento/diagnóstico , Trastornos del Movimiento/terapia , Tiempo de ReacciónRESUMEN
On many Australian commercial pig farms, groups of growing pigs are mass-medicated through their drinking water with selected antimicrobials for short periods to manage herd health. However, delivery of medication in drinking water cannot be assumed to deliver an equal dose to all animals in a group. There is substantial between-animal variability in systemic exposure to an antimicrobial (i.e. the antimicrobial concentration in plasma), resulting in under-dosing or over-dosing of many pigs. Three sources of this between-animal variability during a water medication dosing event are differences in: (1) concentration of the active constituent of the antimicrobial product in water available to pigs at drinking appliances in each pen over time, (2) medicated water consumption patterns of pigs in each pen over time, and (3) pharmacokinetics (i.e. oral bioavailability, volume of distribution and clearance between pigs and within pigs over time). It is essential that factors operating on each farm that influence the range of systemic exposures of pigs to an antimicrobial are factored into antimicrobial administration regimens to reduce under-dosing and over-dosing.
Asunto(s)
Antibacterianos/administración & dosificación , Agua Potable , Enfermedades de los Porcinos/prevención & control , Animales , PorcinosRESUMEN
We report a case of delayed presentation of a gastro-oesophageal fistula following a Heller myotomy and anterior fundoplication for achalasia in a 28-year-old man. After a period of symptom resolution following initial operation, dysphagia and severe heartburn commenced temporarily, related to non-steroidal anti-inflammatory drug (NSAID) use. Endoscopy demonstrated a secondary opening in the lower oesophagus and a barium swallow showed an oesophageal fistula to the stomach. Currently, reasonable symptom control has been obtained on double dose pantoprazole. Barium study best demonstrated the abnormality. NSAIDs should possibly be avoided in cases of severe dysmotility of the oesophagus.
Asunto(s)
Acalasia del Esófago/cirugía , Fístula Esofágica/diagnóstico , Fundoplicación , Fístula Gástrica/diagnóstico , Pirosis/etiología , Miotomía , Complicaciones Posoperatorias/diagnóstico , Adulto , Fístula Esofágica/etiología , Fístula Gástrica/etiología , Humanos , MasculinoRESUMEN
Periodontitis is characterized by the progressive destruction of tooth-supporting alveolar bone, which is mainly caused by chronic inflammation in response to persistent bacterial insult. It has recently become clear that the pathogenesis of periodontitis is associated with a high ratio of proinflammatory M1 (classically activated) macrophages to anti-inflammatory M2 (alternatively activated). To decrease the inflammatory activity, we locally delivered the C-C motif chemokine ligand 2 (CCL2) using controlled-release microparticles (MPs). CCL2 is known to promote chemotaxis of M0 or M2 phenotype macrophages to the inflamed site and induce M2 phenotype polarization locally. Our in vitro data showed that CCL2 increased the number of M2 phenotype macrophages, decreased TNF-α secretion, and enhanced chemotaxis of RAW264.7 cells toward CCL2 MPs. Moreover, we induced periodontal disease in 2 animal models through inoculation of Porphyromonas gingivalis and ligature around the murine molar. Micro-computed tomography analysis showed significant reduction of alveolar bone loss in the CCL2 MP treatment group when compared with a blank MP group and a no-treatment periodontitis group in both models. Immunohistologic analysis showed a significant increase in the M2 phenotype subset and a decrease in the M1 phenotype subset in the CCL2 MP group of the P. gingivalis-induced model. Also, in both models, tartrate-resistant acidic phosphatase staining showed significantly fewer numbers of osteoclasts in the CCL2 MP group in alveolar bone area. Moreover, quantitative polymerase chain reaction results showed a significant increase in IL-1RA (interleukin 1 receptor antagonist) mRNA expression and a decrease in RANKL (receptor activator of nuclear factor kappa-Β ligand) mRNA expression in the CCL2 MP group in the ligature model. In summary, manipulation of endogenous M2 phenotype macrophages with CCL2 MPs decreased the M1 phenotype:M2 phenotype ratio and prevented alveolar bone loss in mouse periodontitis models. The delivery of CCL2 MPs provides a novel approach to treat periodontal disease.
Asunto(s)
Pérdida de Hueso Alveolar/prevención & control , Macrófagos/fisiología , Periodontitis/fisiopatología , Animales , Modelos Animales de Enfermedad , Femenino , Ratones , Porphyromonas gingivalis , Microtomografía por Rayos XRESUMEN
OBJECTIVE: For emergency medicine personnel (EMP), there is little evidence concerning the adequate timing for refresher courses to maintain routine in the application of extraglottic airways. The aim of this study was to evaluate the efficacy and long-term results of a simulator-based education concept teaching the basic airway management skills with extraglottic airways for EMP and also to draw conclusions concerning the adequate time interval for refresher courses. METHODS: By use of an explorative, prospective simulator-study with nonphysician EMP, airway management skills using the Larynxmaske Supreme® (LMAS) after an introduction lecture were examined. The application of an endotracheal tube (ETT) served as control. Time for preparation of the airway devices, insertion success, and resulting apnea time were assessed immediately after the first introduction lecture (t1) and unannounced 9-12 months thereafter (t2). RESULTS: Comparison of the times for preparation of the LMAS at t1 and t2 demonstrated similar results. After the introduction lecture, all paramedics were able to insert the LMAS successfully after maximal 2 attempts; 9-12 months later success rates with the LMAS were unchanged. Apnea time during airway management was shorter with the LMAS compared to the ETT (pâ¯< 0.01). Times needed for preparation of the airway devices were similar. CONCLUSION: The results of this simulator study indicate that a standardized introduction lecture is appropriate to ensure long-lasting procedural skills up to 12 months, so that subsequent refresher courses in basic airway management with the LMAS once a year may be adequate. A simulator-based education in basic airway management skills with extraglottic airways is recommended for facilitation of further clinical education according to the current guidelines.
Asunto(s)
Simulación por Computador , Educación Médica Continua , Intubación Intratraqueal/métodos , Máscaras Laríngeas , Manejo de la Vía Aérea/métodos , Urgencias Médicas , Estudios de Seguimiento , Humanos , Estudios Prospectivos , EnseñanzaRESUMEN
OBJECTIVES: Nasal disease imposes a significant disease burden upon the individual in the general population, but is relatively under studied in athletes. This study sought to define the frequency of nasal symptoms in the active population, and to quantify the impact of these symptoms on quality of life and on the frequency of upper respiratory tract infections. RESULTS: A total of 296 participants completed the study (246 athletes and 50 sedentary controls). Nasal symptoms were significantly more frequent in the active group than in the sedentary controls (70 per cent vs 52 per cent). Upper respiratory tract infections were significantly more common in athletes with regular nasal symptoms than in athletes without nasal symptoms. Quality-of-life scores, as measured by the 22-item Sino-Nasal Outcome Test, were significantly worse in athletes with regular nasal symptoms. CONCLUSION: This study suggests that regular exercise is associated with a significant increase in the prevalence of troubling nasal symptoms, and nasal symptoms in athletes are associated with increased susceptibility to upper respiratory tract infections. Quality of life was negatively affected, confirming the importance of nasal health to athlete welfare.
Asunto(s)
Atletas/psicología , Enfermedades Nasales/complicaciones , Enfermedades Nasales/psicología , Infecciones del Sistema Respiratorio/epidemiología , Adolescente , Adulto , Anciano , Ejercicio Físico/fisiología , Femenino , Humanos , Hipersensibilidad/complicaciones , Hipersensibilidad/epidemiología , Masculino , Persona de Mediana Edad , Enfermedades Nasales/epidemiología , Enfermedades Nasales/patología , Prevalencia , Estudios Prospectivos , Calidad de Vida , Infecciones del Sistema Respiratorio/etiología , Rinitis/complicaciones , Rinitis/epidemiología , Encuestas y Cuestionarios , Adulto JovenRESUMEN
INTRODUCTION: Differentiating between functional jerks (FJ) and organic myoclonus can be challenging. At present, the only advanced diagnostic biomarker to support FJ is the Bereitschaftspotential (BP). However, its sensitivity is limited and its evaluation subjective. Recently, event related desynchronisation in the broad beta range (13-45â¯Hz) prior to functional generalised axial (propriospinal) myoclonus was reported as a possible complementary diagnostic marker for FJ. Here we study the value of ERD together with a quantified BP in clinical practice. METHODS: Twenty-nine patients with FJ and 16 patients with cortical myoclonus (CM) were included. Jerk-locked back-averaging for determination of the 'classical' and quantified BP, and time-frequency decomposition for the event related desynchronisation (ERD) were performed. Diagnostic gain, sensitivity and specificity were obtained for individual and combined techniques. RESULTS: We detected a classical BP in 14/29, a quantitative BP in 15/29 and an ERD in 18/29 patients. At group level we demonstrate that ERD in the broad beta band preceding a jerk has significantly higher amplitude in FJ compared to CM (respectively -0.14 ± 0.13 and +0.04 ± 0.09 (pâ¯<â¯0.001)). Adding ERD to the classical BP achieved an additional diagnostic gain of 53%. Furthermore, when combining ERD with quantified and classical BP, an additional diagnostic gain of 71% was achieved without loss of specificity. CONCLUSION: Based on the current findings we propose to the use of combined beta ERD assessment and quantitative BP analyses in patients with a clinical suspicion for all types of FJ with a negative classical BP.
Asunto(s)
Ritmo beta/fisiología , Variación Contingente Negativa/fisiología , Sincronización de Fase en Electroencefalografía/fisiología , Electroencefalografía/normas , Mioclonía/diagnóstico , Mioclonía/fisiopatología , Adolescente , Adulto , Anciano , Biomarcadores , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: Oral immunotherapy (OIT) successfully desensitizes patients with food allergies, but the immune mechanisms mediating its efficacy remain obscure. OBJECTIVES: We tested the hypothesis that allergen-specific regulatory T (Treg) cell function is impaired in food allergy and is restored by anti-IgE antibody (omalizumab)-supplemented OIT. METHODS: Peanut-specific T effector (Teff) and Treg cell proliferative responses, activation markers and cytokine expression were analysed by flow cytometry in 13 peanut-allergic subjects before the start of omalizumab-supplemented OIT and periodically in some subjects thereafter for up to 2 years. Peripheral blood regulatory T cells (Treg cells) were analysed for their peanut-specific suppressor function before and at 1 year following OIT. This study was registered on ClinicalTrials.gov (NCT01290913). RESULTS: Proliferation of allergen-specific Teff and Treg cells precipitously declined following the initiation of omalizumab therapy prior to OIT, followed by partial recovery after the initiation of OIT. At baseline, peanut-specific Treg cells exhibited a Th2 cell-like phenotype, characterized by increased IL-4 expression, which progressively reversed upon OIT. Peanut-specific Treg cell suppressor activity was absent at the start of omalizumab/OIT therapy but became robust following OIT. Absent peanut-specific Treg cell function could also be recovered by the acute blockade of IL-4/IL-4R receptor signalling in Treg cells, which inhibited their IL-4 production. CONCLUSIONS AND CLINICAL RELEVANCE: OIT supplemented by omalizumab promotes allergen desensitization through an initial omalizumab-dependent step that acutely depletes allergen-reactive T cells, followed by an increase in allergen-specific Treg cell activity due to the reversal of their Th2 cell-like programme. Improved Treg cell function may be a key mechanism by which OIT ameliorates food allergy.
Asunto(s)
Antialérgicos/administración & dosificación , Omalizumab/administración & dosificación , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Células Th2/efectos de los fármacos , Células Th2/inmunología , Administración Oral , Alérgenos/inmunología , Biomarcadores , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Islas de CpG , Citocinas/metabolismo , Metilación de ADN , Desensibilización Inmunológica , Epigénesis Genética , Humanos , Inmunización , Memoria Inmunológica , Inmunofenotipificación , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Fenotipo , Transducción de Señal , Linfocitos T Reguladores/metabolismo , Células Th2/metabolismoRESUMEN
The chronic inflammatory immune response triggered by the infection of the tooth root canal system results in the local upregulation of RANKL, resulting in periapical bone loss. While RANKL has a well-characterized role in the control of bone homeostasis/pathology, it can play important roles in the regulation of the immune system, although its possible immunoregulatory role in infectious inflammatory osteolytic conditions remains largely unknown. Here, we used a mouse model of infectious inflammatory periapical lesions subjected to continuous or transitory anti-RANKL inhibition, followed by the analysis of lesion outcome and multiple host response parameters. Anti-RANKL administration resulted in arrest of bone loss but interfered in the natural immunoregulation of the lesions observed in the untreated group. RANKL inhibition resulted in an unremitting proinflammatory response, persistent high proinflammatory and effector CD4 response, decreased regulatory T-cell (Treg) migration, and lower levels of Treg-related cytokines IL-10 and TGFb. Anti-RANKL blockade impaired the immunoregulatory process only in early disease stages, while the late administration of anti-RANKL did not interfere with the stablished immunoregulation. The impaired immunoregulation due to RANKL inhibition is characterized by increased delayed-type hypersensitivity in vivo and T-cell proliferation in vitro to the infecting bacteria, which mimic the effects of Treg inhibition, reinforcing a possible influence of RANKL on Treg-mediated suppressive response. The adoptive transfer of CD4+FOXp3+ Tregs to mice receiving anti-RANKL therapy restored the immunoregulatory capacity, attenuating the inflammatory response in the lesions, reestablishing normal T-cell response in vivo and in vitro, and preventing lesion relapse upon anti-RANKL therapy cessation. Therefore, while RANKL inhibition efficiently limited the periapical bone loss, it promoted an unremitting host inflammatory response by interfering with Treg activity, suggesting that this classic osteoclastogenic mediator plays a role in immunoregulation.
Asunto(s)
Osteólisis/inmunología , Enfermedades Periapicales/inmunología , Ligando RANK/inmunología , Linfocitos T Reguladores/inmunología , Traslado Adoptivo , Pérdida de Hueso Alveolar/inmunología , Pérdida de Hueso Alveolar/microbiología , Animales , Anticuerpos Monoclonales/farmacología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Expresión Génica , Inmunidad Mucosa , Inflamación/inmunología , Inflamación/microbiología , Infliximab/farmacología , Interleucina-10/inmunología , Activación de Linfocitos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Osteólisis/microbiología , Enfermedades Periapicales/microbiología , Ligando RANK/antagonistas & inhibidores , Reacción en Cadena en Tiempo Real de la Polimerasa , Factor de Crecimiento Transformador beta/inmunologíaRESUMEN
OBJECTIVES: The aim of this study was to evaluate the perceptions and opinions of Canadian pet owners about anaesthesia, pain and surgery in dogs and cats. METHODS: Six Canadian veterinary hospitals participated. Each practice received 200 copies of a questionnaire that were distributed to pet owners. Questions regarding the use of analgesics, anaesthesia, surgery and onychectomy (cats) were included. Responses were transformed into ordinal scores and analysed with a Cochran-Mantel-Haenszel test. RESULTS: A total of 849 out of 1200 questionnaires were returned. Owners believed more frequently that analgesics are needed for surgical procedures than for the medical conditions. Owners rated as very important/important: "knowing what to expect during illness/injury/surgery" (99·3%), "being assured that all necessary analgesic drugs/techniques will be used" (98·6%), "being informed about procedures/risk" (98·5%), and having a board-certified anaesthesiologist (90·5%). Most owners agreed/partly agreed that pain impacts quality of life (94·2%), and affects their pet's behaviour (89·5%). Most respondents (69%) were women; they were significantly more concerned than men about anaesthesia, pain, cost and client-communication. Cat owners believed that analgesics were necessary for some procedures/conditions significantly more often than canine-only owners. Pet owners with previous surgery disagreed more frequently that "pain after surgery can be helpful" and that "pain in animals is easy to recognize" than those without previous surgery. Most owners think onychectomy should be banned in cats (56·4%). CLINICAL SIGNIFICANCE: This study identified important areas of client communication regarding pain and its control in pets.
Asunto(s)
Anestesia/veterinaria , Bienestar del Animal , Propiedad , Dolor Postoperatorio/veterinaria , Animales , Canadá , Gatos/psicología , Perros/psicología , Femenino , Humanos , Masculino , Dolor Postoperatorio/epidemiología , Dolor Postoperatorio/prevención & control , Calidad de Vida , Cirugía Veterinaria , Encuestas y Cuestionarios , Resultado del TratamientoRESUMEN
OBJECTIVE: This study seeks to determine if the increasing rate of postpartum readmissions is related to the increasing rate of cesarean delivery. STUDY DESIGN: Readmitted patients were identified in the State Inpatient Databases of California, Florida and New York from 2004 to 2011. Relevant maternal comorbidities, pregnancy complications and intrapartum events were collected using ICD-9 diagnosis and procedure codes. The effects of cesarean delivery were first examined via univariate logistic regression to calculate the odds of readmission by year for patients who had delivered via cesarean section. Then, we used multivariate logistic regression models to isolate the effect of mode of delivery on the odds of readmission by adjusting for the effects of patient demographics, hospital characteristics and maternal comorbidities. RESULTS: Nearly one million deliveries were identified each year, and ~600 000 deliveries per year met inclusion criteria. During this time, the readmission rate increased from 1.72 to 2.16%, and the cesarean delivery rate increased from 30.4 to 33.9%. The odds of readmission for patients delivered via cesarean section decreased yearly, from 1.343 (95% CI: 1.295 to 1.392) in 2004 to 1.046 (95% CI: 1.012 to 1.108) in 2011. In a multivariate model, the odds based on year were 1.032 (95% CI: 1.030 to 1.035), demonstrating an increased odds of readmission over time. When cesarean delivery was added to the model, this odds estimate did not change (OR: 1.031, 95% CI: 1.028 to 1.035), suggesting it did not account for the increased odds of readmission over time, even though cesarean delivery rates increased. However, when maternal comorbidities were added to the model, the odds ratio for year became insignificant (OR: 1.001, 95% CI: 0.998 to 1.005), suggesting that they accounted for the increasing rate of readmissions. CONCLUSIONS: The increasing cesarean delivery rate does not explain the increasing rate of postpartum readmissions. Rather, the increasing postpartum readmission rate appears to be related to maternal comorbidities.
Asunto(s)
Cesárea/estadística & datos numéricos , Cesárea/tendencias , Readmisión del Paciente/estadística & datos numéricos , Readmisión del Paciente/tendencias , Adulto , Comorbilidad , Femenino , Humanos , Clasificación Internacional de Enfermedades , Modelos Logísticos , Análisis Multivariante , Oportunidad Relativa , Periodo Posparto , Embarazo , Factores Socioeconómicos , Estados Unidos/epidemiología , Adulto JovenRESUMEN
Rhinitis has been demonstrated to impose a significant disease burden upon the general population. We sought to determine the prevalence of rhinitis in athletes; to investigate its relationship with co-existing allergic symptoms; and to quantify the impact of rhinitis on quality of life in the athlete.3 subgroups were studied: elite field hockey players (FHP); non-elite FHP; and a sedentary control group.Participants were asked to complete a rhinitis self-report questionnaire; the "Allergic Questionnaire for Athletes" (AQUA), and quality of life Sinonasal Outcome Test - 22 (SNOT-22).142 participants completed the study (52 elite FHP; 40 non-elite FHP; 50 controls). There was a significantly higher prevalence of rhinitis in the elite and non-elite FHP groups than the sedentary control group (52% and 43% vs. 22%, p<0.05). Mean AQUA score was significantly higher in athletes with rhinitis. Quality of life scores were significantly worse in athletes with rhinitis than those without rhinitis (p<0.05).This study suggests regular exercise is associated with a significant increase in the prevalence of rhinitis. Elite FHP were most likely to report rhinitis, but the least likely to be using regular treatment. Quality of life was negatively affected, confirming the importance of nasal health to athlete welfare.
Asunto(s)
Atletas , Hockey , Calidad de Vida , Rinitis/epidemiología , Adulto , Estudios de Casos y Controles , Estudios Transversales , Femenino , Humanos , Masculino , Prevalencia , Encuestas y Cuestionarios , Reino Unido , Adulto JovenAsunto(s)
Endoscopía , Obstrucción Nasal/diagnóstico por imagen , Obstrucción Nasal/cirugía , Teléfono Inteligente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tabique Nasal/diagnóstico por imagen , Tabique Nasal/cirugía , Evaluación de Resultado en la Atención de Salud , Adulto JovenRESUMEN
OBJECTIVE: Recent diagnostic criteria for functional movement disorders have proposed a "laboratory supported" level of diagnostic certainty where the clinical diagnosis is supported by a positive test. For functional myoclonus the Bereitschaftspotential (BP) is generally accepted as a positive laboratory test. We hypothesised that a different EEG measure, event-related desynchronisation (ERD), might be more effective. METHODS: We analysed 20 patients with functional propriospinal myoclonus (fPSM) and 9 controls with organic myoclonus and performed back-averaging for BPs plus time-frequency decomposition to assess ERD and calculated sensitivity and specificity for both techniques. RESULTS: The BP was present in only 25% of patients with fPSM while the majority showed a significant ERD (mean 38 Hz; sensitivity 65%). ERD was significant at the group level (p < 0.001), but not the BP (p > 0.05). Both BP and ERD were absent in our control group. CONCLUSION: ERD in high-beta may be a useful new test for positive diagnosis of functional myoclonus.