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1.
Infect Immun ; : e0022224, 2024 Aug 16.
Artículo en Inglés | MEDLINE | ID: mdl-39150267

RESUMEN

Pneumocystis species are respiratory fungal pathogens that cause life-threatening opportunistic infections in immunocompromised hosts. Pneumocystis typically evade pulmonary innate immunity but are efficiently eradicated by a functional adaptive immune response. FVB/NJ mice are unique in that they display protective alveolar macrophage-dependent innate immunity against Pneumocystis, and remain resistant to infection even in the absence of CD4+ T lymphocyte function. FVB/NJ alveolar macrophages (AMs) were found to display an M2-biased phenotype at baseline, which was potentiated after stimulation with Pneumocystis, suggesting that macrophage polarization may dictate the outcome of the Pneumocystis-macrophage interaction. To determine whether Stat6, a key global regulator of M2 polarization, was required for FVB/NJ innate immunity, FVB Stat6-/- mice were generated. FVB Stat6-deficient AMs were markedly impaired in their ability to polarize to an M2 phenotype when stimulated with Th2 cytokines. However, FVB Stat6-/- mice remained highly resistant to infection, indicating that Stat6 signaling is dispensable for innate FVB/NJ resistance. Despite the loss of Stat6 signaling, primary AMs from FVB Stat6-/- mice maintained baseline expression of M2 markers, and also strongly upregulated M2-associated genes following direct stimulation with Pneumocystis. Additional FVB/NJ knockout strains were generated, but only FVB MerTK-/- mice showed a marginally increased susceptibility to Pneumocystis infection. Together, these findings demonstrate that effective FVB/NJ innate immunity against Pneumocystis does not require Stat6 signaling and suggest that alternative pathways regulate M2 bias and macrophage-mediated innate resistance in FVB/NJ mice.

2.
Phys Rev Lett ; 130(20): 202501, 2023 May 19.
Artículo en Inglés | MEDLINE | ID: mdl-37267578

RESUMEN

We demonstrate a new technique for obtaining fission data for nuclei away from ß stability. These types of data are pertinent to the astrophysical r process, crucial to a complete understanding of the origin of the heavy elements, and for developing a predictive model of fission. These data are also important considerations for terrestrial applications related to power generation and safeguarding. Experimentally, such data are scarce due to the difficulties in producing the actinide targets of interest. The solenoidal-spectrometer technique, commonly used to study nucleon-transfer reactions in inverse kinematics, has been applied to the case of transfer-induced fission as a means to deduce the fission-barrier height, among other variables. The fission-barrier height of ^{239}U has been determined via the ^{238}U(d,pf) reaction in inverse kinematics, the results of which are consistent with existing neutron-induced fission data indicating the validity of the technique.

3.
J Dairy Sci ; 106(5): 3477-3492, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-36935242

RESUMEN

In the context of understanding lameness and injury from slipping, our objective was to characterize hoof impact and slide of 5 cows walking on 6 flooring surfaces commonly used in Ontario dairy farms: diamond-grooved concrete (DC), sanded epoxy-covered concrete (EC), grooved rubber mat (GR), high-profile rubber mat (HR), low-profile rubber mat (LR), and turf grass (TG; Kentucky bluegrass/fescue mix). Surface hardness was measured on each surface using a Clegg Impact Soil Tester. Five trained lactating Holstein cows were each walked over all 6 surfaces sequentially in a randomized order. Walking speeds were determined from 60-fps videos. A 3-axis accelerometer attached to the lateral claw of each hindfoot captured continuous horizontal (aH), vertical (aV), lateral (aTLat), and medial (aTMed) accelerations at 2,500 Hz during each trial, from which peak values were identified. Data from 45°-rosette strain gauges glued to the dorsal surface of both medial and lateral hooves allowed for the calculation of principal strains (ε1 and ε2). From continuous data, several data points were extracted from 3 to 6 stances/trial: peak values of aH, aV, and aT for the impact phase of the stance; midstance values of ε1 and ε2 as proxies for force on the foot; magnitudes of normal (i.e., consistent and repeatable) sliding on the surface during the support phase; and 3 timing events to capture the cadence of the motion. All aH and aV signals were inspected onscreen to identify irregularities between the end of impact and beginning of breakover that indicated hoof slipping, which was observed on all surfaces. The effects on all measured variables of surface, cow, speed, and hoof (and all significant higher-order factors) were assessed by ANOVA in SAS 9.4 (SAS Institute Inc.), after verifying data normality. Values of aHmax, indicating grip on the surface from highest to lowest, ranked the surfaces in this order: LR, DC, HR, GR, EC, and TG. Ranking on aVmax, indicating most to least cushioning of the hoof on impact, ranked the surfaces in this order: DC, HR, GR, EC, LR, and TG. Differences in ranking among these and other significant impact variables indicate that future studies of lameness on different surfaces need to include all significant variables identified here. We detected no surface and strain interactions in either the ε1 or ε2 strain, indicating that the surfaces do not affect the overall loads on the foot at midstance. Additionally, lateral and medial hooves may have different roles in a stance. The results highlight the capacity to evaluate flooring types with this technology, and the study provides a tool for future work to examine the role of flooring types in the causation of lameness.


Asunto(s)
Enfermedades de los Bovinos , Pezuñas y Garras , Femenino , Bovinos , Animales , Granjas , Lactancia , Goma , Cojera Animal , Ontario , Vivienda para Animales
4.
Phys Rev Lett ; 129(20): 203603, 2022 Nov 11.
Artículo en Inglés | MEDLINE | ID: mdl-36462023

RESUMEN

Quantum frequency conversion of single photons between wavelength bands is a key enabler to realizing widespread quantum networks. We demonstrate the quantum frequency conversion of a heralded 1551 nm photon to any wavelength within an ultrabroad (1226-1408 nm) range in a group-velocity-symmetric photonic crystal fiber, covering over 150 independent frequency bins. The target wavelength is controlled by tuning only a single pump laser wavelength. We find internal, and total, conversion efficiencies of 12(1)% and 1.4(2)%, respectively. For the case of converting 1551 to 1300 nm we measure a heralded g^{(2)}(0)=0.25(6) for converted light from an input with g^{(2)}(0)=0.034(8). We expect that this photonic crystal fiber can be used for myriad quantum networking tasks.

5.
Child Psychiatry Hum Dev ; 52(5): 978-993, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-33067711

RESUMEN

Youth with a family history of substance use disorder (FH+) are more prone to have externalizing and internalizing problems compared to youth without a family history of substance use disorder (FH-), increasing the likelihood of later maladjustment. However, mechanisms for this association remain understudied. In this longitudinal study, we examined if FH+ youth are more likely to experience early-life stressors (ELS), which in turn would increase impulsivity and the expression of externalizing and internalizing behaviors. Data were collected from youth and a parent (n = 386) during a baseline assessment (age 10-12 years) and every six months when the youth was 13-16 years old. In support of the primary hypothesis, FH+ youth reported higher levels of externalizing and internalizing behaviors through ELS to impulsivity providing a developmental pathway through which FH+ youth are more prone to externalizing and internalizing problems.


Asunto(s)
Experiencias Adversas de la Infancia , Trastornos Relacionados con Sustancias , Adolescente , Niño , Humanos , Conducta Impulsiva , Estudios Longitudinales , Padres
6.
Opt Lett ; 45(16): 4587-4590, 2020 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-32797016

RESUMEN

We report a resource-efficient scheme in which a single pump laser was used to achieve frequency conversion by Bragg-scattering four-wave mixing in a photonic crystal fiber. We demonstrate bidirectional conversion of coherent light between Sr+2P1/2→2D3/2 emission wavelength at 1092 nm and the telecommunication C band with conversion efficiencies of 4.2% and 37% for up- and down-conversion, respectively. We discuss how the scheme may be viably scaled to meet the temporal, spectral, and polarization stability requirements of a hybrid light-matter quantum network.

7.
Osteoarthritis Cartilage ; 27(10): 1526-1536, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31265883

RESUMEN

OBJECTIVE: Mechanical loading and joint health have a unique relationship in osteoarthritis (OA) onset and progression. Although high load levels adversely affect cartilage health, exercise that involves low to moderate load levels can alleviate OA symptoms. We sought to isolate the beneficial effects of mechanical loading using controlled in vivo cyclic tibial compression. We hypothesized that low-level cyclic compression would attenuate post-traumatic OA symptoms induced by destabilization of the medial meniscus (DMM). METHODS: 10-week-old C57Bl/6J male mice underwent DMM surgery (n = 51). After a 5-day post-operative recovery period, we applied daily cyclic tibial compression to the operated limbs at low (1.0N or 2.0N) or moderate (4.5N) magnitudes for 2 or 6 weeks. At the completion of loading, we compared cartilage and peri-articular bone features of mice that underwent DMM and loading to mice that only underwent DMM. RESULTS: Compared to DMM alone, low-level cyclic compression for 6 weeks attenuated DMM-induced cartilage degradation (OARSI score, P = 0.008, 95% confidence interval (CI): 0.093 to 0.949). Low-level loading attenuated DMM-induced osteophyte formation after 2 weeks (osteophyte size, P = 0.033, 95% CI: 3.27-114.45 µm), and moderate loading attenuated subchondral bone sclerosis after 6 weeks (tissue mineral density (TMD), P = 0.011, 95% CI: 6.32-70.60 mg HA/ccm) compared to limbs that only underwent DMM. Finally, loading had subtle beneficial effects on cartilage cellularity and aggrecanase activity after DMM. CONCLUSION: Low-level cyclic compression is beneficial to joint health after an injury. Therefore, the progression of early OA may be attenuated by applying well controlled, low-level loading shortly following joint trauma.


Asunto(s)
Osteoartritis/prevención & control , Soporte de Peso , Animales , Progresión de la Enfermedad , Articulaciones/lesiones , Masculino , Meniscos Tibiales/cirugía , Ratones , Ratones Endogámicos C57BL , Osteoartritis/etiología , Tibia/fisiología , Factores de Tiempo
8.
Pediatr Surg Int ; 35(5): 569-574, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-30806765

RESUMEN

BACKGROUND AND AIM: Currently, there is a paucity of the literature describing the natural history of cholelithiasis (CL) and choledocholithiasis (CDL) in adolescent children. This study aims to analyse the changing demographics of paediatric and adolescent gallstones. METHODOLOGY: Retrospective review of all children (Age 0-18 years) presenting with symptomatic gallstones over the last 15 years (2002-2017) at a single tertiary institution. Demographics, diagnostic and therapeutic information were collected, with a 5-year median follow-up. Statistics were accomplished by Chi-squared analysis of trend and Student t test. RESULTS AND DISCUSSIONS: 188 children were seen with symptomatic CL. In the 0-11-year-old group, there were 13 females and 16 males (0.8: female to male ratio). There were 130 females and 29 males in the 12-18-year-old group (4.5:1 female to male ratio). The mean weight at presentation was 81.78 kg and the median age was 16 years. Idiopathic gallstones were found in 131 patients (82%). 137 required cholecystectomy (86%) and ERCP was required in 32 patients (20%). 48 adolescents (30.2%) with gallstones had an associated CDL, compared to six children (20%). All of the adolescent patients with CDL had idiopathic gallstones. Gallstone pancreatitis was noted in eighteen adolescents (11%) and one child (3%). We analysed the ideal time to operate on adolescent patients with symptomatic gallstones using the relationship between the length of delay from initial diagnosis to definitive management of CDL and incidence of complications. The analysis demonstrated that for every 10 days treatment was delayed, the risk of subsequent presentations with a symptomatic episode was increased by 5% (p = 0.0004). CONCLUSION: The current trend of gallstones in adolescent children seems to be a disease primarily of adolescent girls. Symptomatic idiopathic gallstones in adolescents are associated with high rates of common bile duct obstruction and pancreatitis and consequently warrant an early cholecystectomy for all adolescents. LEVEL OF EVIDENCE: Level IV Treatment Study.


Asunto(s)
Cálculos Biliares/diagnóstico por imagen , Adolescente , Sistema Biliar/diagnóstico por imagen , Niño , Preescolar , Colangiopancreatografia Retrógrada Endoscópica , Pancreatocolangiografía por Resonancia Magnética , Colecistectomía , Coledocolitiasis/complicaciones , Diagnóstico Precoz , Femenino , Estudios de Seguimiento , Cálculos Biliares/complicaciones , Cálculos Biliares/cirugía , Humanos , Lactante , Recién Nacido , Masculino , Pancreatitis/complicaciones , Estudios Retrospectivos , Ultrasonografía
9.
Clin Exp Allergy ; 48(6): 641-649, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29383778

RESUMEN

BACKGROUND: Adipose tissue-derived inflammation is linked to obesity-related comorbidities. This study aimed to quantify and immuno-phenotype adipose tissue macrophages (ATMs) from obese asthmatics and obese non-asthmatics and to examine associations between adipose tissue, systemic and airway inflammation. METHODS: Visceral (VAT) adipose tissue and subcutaneous (SAT) adipose tissue were collected from obese adults undergoing bariatric surgery and processed to obtain the stromovascular fraction. Pro-inflammatory (M1) and anti-inflammatory (M2) macrophages were quantified by flow cytometry. Cytospins of induced sputum were stained for differential cell counts. Plasma C-reactive protein (CRP) and CD163 were measured by ELISA. RESULTS: VAT contained a higher number of ATMs compared to SAT. A higher percentage of M1 ATMs was observed in VAT of obese asthmatics compared to obese non-asthmatics. The M1:M2 ratio in VAT was negatively associated with FEV1 %. Sputum macrophage count was correlated positively with M1 ATMs and negatively with M2 ATMs in VAT. In obese asthmatics, CRP was positively associated with M1:M2 ratio in VAT. There were no associations with CD163. An elevated ratio of M1:M2 ATMs was observed in VAT of obese asthmatics with increased disease severity. CONCLUSIONS AND CLINICAL RELEVANCE: Visceral inflammation with increased pro-inflammatory macrophages (M1) occurs in obese asthma and may be a determinant of systemic inflammation and asthma severity.


Asunto(s)
Tejido Adiposo/inmunología , Asma/diagnóstico , Asma/etiología , Activación de Macrófagos/inmunología , Macrófagos/inmunología , Obesidad/complicaciones , Tejido Adiposo/patología , Adulto , Biomarcadores , Composición Corporal , Estudios Transversales , Femenino , Citometría de Flujo , Perfilación de la Expresión Génica , Humanos , Inflamación/metabolismo , Inflamación/patología , Macrófagos/metabolismo , Masculino , Persona de Mediana Edad , Fenotipo , Pruebas de Función Respiratoria
10.
J Dairy Sci ; 101(5): 4343-4356, 2018 May.
Artículo en Inglés | MEDLINE | ID: mdl-29454684

RESUMEN

Associations of electronically recorded data were examined before diagnosis of health disorders in early-lactation cows in herds with automated milking systems (AMS). Rumination time, activity, and milk yield data were collected for 8 mo for 605 early-lactation cows in 9 commercial AMS herds. Using multivariable generalized linear regression models controlling for parity and days in milk, data were examined relative to the day of diagnosis for health disorders occurring in absence of, or at least 14 d before, another disorder: mastitis (n = 13), new cases of lameness (n = 45), subclinical ketosis (SCK; n = 113), and purulent vaginal discharge (n = 49). All cases of displaced abomasum (DA; n = 8) occurred in conjunction with other disorders. Deviations from baseline among affected cows were examined, as well as differences compared with a group of healthy cows and an average group of all cows, who were given mock diagnosis days using the mean days in milk at diagnosis for each disorder. On 6 to 14 d of the 2 wk before diagnosis, cows with DA or mastitis had lower milk yield, rumination time, milking frequency, activity, and milk temperature compared with healthy cows as well as deviations from their own baseline rumination time and milk data starting 4 to 12 d before diagnosis. Cows with DA had lower AMS supplement intake than healthy cows and deviations from their baseline activity and milk temperature starting 6 and 4 d before diagnosis, respectively. Cows with mastitis had greater milk conductivity than healthy cows and deviated from their baseline milking frequency and conductivity 8 and 12 d before diagnosis, respectively. Compared with healthy cows, those with SCK or new cases of lameness generally had lower milk yield, rumination time, milk temperature, supplement intake, and milking and refusal frequencies. Only the milk temperature of lame cows deviated from baseline. Thus, acute health disorders (i.e., DA and mastitis) were associated with deviations from those cows' baseline AMS data, whereas more chronic disorders (i.e., SCK and lameness) were associated with significant but subtle longer term changes in milk production and behavior. Because cows with health disorders deviated from a group of healthy cows before they deviated from their own baseline and from the average of all other cows, including a healthy reference group in health alerts could refine the ability of detection models to identify subtle deviations in early lactation.


Asunto(s)
Enfermedades de los Bovinos/diagnóstico , Bovinos/fisiología , Industria Lechera/instrumentación , Leche/metabolismo , Animales , Automatización , Conducta Animal , Enfermedades de los Bovinos/fisiopatología , Industria Lechera/métodos , Femenino , Lactancia , Modelos Lineales , Paridad , Embarazo
11.
Clin Otolaryngol ; 43(5): 1226-1234, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-29733111

RESUMEN

BACKGROUND: The number of potential options for rehabilitation of patients with conductive or mixed hearing loss is continually expanding. To be able to inform patients and other stakeholders, there is a need to identify and develop patient-centred outcomes for treatment of hearing loss. OBJECTIVE OF REVIEW: To identify outcome measures in the physical core area used when reporting the outcome after treatment of conductive and mixed hearing loss in adult patients. TYPE OF REVIEW: Systematic review. SEARCH STRATEGY: Systematic review of the literature related to reported physical outcome measures after treatment of mixed or conductive hearing loss without restrictions regarding type of intervention, treatment or device. EVALUATION METHOD: Any measure reporting the physical outcome after treatment or intervention of mixed or conductive hearing loss was sought and categorised. The physical outcome measures that had been extracted were then grouped into domains. RESULTS: The literature search resulted in the identification of 1434 studies, of which 153 were selected for inclusion in the review. The majority (57%) of papers reported results from middle ear surgery, with the remainder reporting results from either bone conduction hearing devices or middle ear implants. Outcomes related to complications were categorised into 17 domains, whereas outcomes related to treatment success was categorised into 22 domains. CONCLUSIONS: The importance of these domains to patients and other stakeholders needs to be further explored in order to establish which of these domains are most relevant to interventions for conductive or mixed hearing loss. This will allow us to then assess which outcome measures are most suitable for inclusion in the core set.


Asunto(s)
Pérdida Auditiva Conductiva/terapia , Perdida Auditiva Conductiva-Sensorineural Mixta/terapia , Humanos , Evaluación de Resultado en la Atención de Salud
12.
Osteoarthritis Cartilage ; 25(12): 2108-2118, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-28919430

RESUMEN

OBJECTIVE: Animal models recapitulating post-traumatic osteoarthritis (OA) suggest that subchondral bone (SCB) properties and remodeling may play major roles in disease initiation and progression. Thus, we investigated the role of SCB properties and its effects on load-induced OA progression by applying a tibial loading model on two distinct mouse strains treated with alendronate (ALN). DESIGN: Cyclic compression was applied to the left tibia of 26-week-old male C57Bl/6 (B6, low bone mass) and FVB (high bone mass) mice. Mice were treated with ALN (26 µg/kg/day) or vehicle (VEH) for loading durations of 1, 2, or 6 weeks. Changes in articular cartilage and subchondral and epiphyseal cancellous bone were analyzed using histology and microcomputed tomography. RESULTS: FVB mice exhibited thicker cartilage, a thicker SCB plate, and higher epiphyseal cancellous bone mass and tissue mineral density than B6 mice. Loading induced cartilage pathology, osteophyte formation, and SCB changes; however, lower initial SCB mass and stiffness in B6 mice did not attenuate load-induced OA severity compared to FVB mice. By contrast, FVB mice exhibited less cartilage damage, and slower-growing and less mature osteophytes. In B6 mice, inhibiting bone remodeling via ALN treatment exacerbated cartilage pathology after 6 weeks of loading, while in FVB mice, inhibiting bone remodeling protected limbs from load-induced cartilage loss. CONCLUSIONS: Intrinsically lower SCB properties were not associated with attenuated load-induced cartilage loss. However, inhibiting bone remodeling produced differential patterns of OA pathology in animals with low compared to high SCB properties, indicating that these factors do influence load-induced OA progression.


Asunto(s)
Hueso Esponjoso/diagnóstico por imagen , Cartílago Articular/diagnóstico por imagen , Osteoartritis de la Rodilla/diagnóstico por imagen , Tibia/diagnóstico por imagen , Soporte de Peso , Alendronato/farmacología , Animales , Densidad Ósea , Conservadores de la Densidad Ósea/farmacología , Remodelación Ósea/efectos de los fármacos , Hueso Esponjoso/efectos de los fármacos , Hueso Esponjoso/patología , Cartílago Articular/patología , Modelos Animales de Enfermedad , Epífisis/diagnóstico por imagen , Epífisis/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Osteoartritis de la Rodilla/patología , Osteofito , Tibia/efectos de los fármacos , Tibia/patología , Microtomografía por Rayos X
13.
J Dairy Sci ; 100(8): 6139-6150, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28601462

RESUMEN

The objective of this study was to determine if the addition of glycerol to the diet of dairy cows would stimulate milk protein yield in the same manner as the addition of corn grain. Twelve multiparous lactating dairy cows at 81 ± 5 d in milk were subjected to 3 dietary treatments in a replicated 3 × 3 Latin square design for 28-d periods. The diets were a 70% forage diet considered the basal diet, the basal diet with 19% ground and high-moisture corn replacing forages, and the basal diet with 15% refined glycerol and 4% added protein supplements to be isocaloric and isonitrogenous with the corn diet. Cows were milked twice a day and samples were collected on the last 7 d of each period for compositional analysis. Within each period, blood samples were collected on d 26 and 27, and mammary tissue was collected by biopsy on d 28 for Western blot analysis. Dry matter intake increased from 23.7 kg/d on the basal diet to 25.8 kg/d on the corn diet and 27.2 kg/d on the glycerol diet. Dry matter intake tended to be higher with glycerol than corn. Milk production increased from 39.2 kg/d on the basal diet to 43.8 kg/d on the corn diet and 44.2 kg/d on the glycerol diet. However, milk yield did not differ between corn and glycerol diets. Milk lactose yields were higher on the corn and glycerol diets than the basal diet. Milk fat yield significantly decreased on the glycerol diet compared with the basal diet and tended to decrease in comparison with the corn diet. Mean milk fat globule size was reduced by glycerol feeding. Milk protein yield increased 197 g/d with addition of corn to the basal diet and 263 g/d with addition of glycerol, and the glycerol effect was larger than the corn effect. The dietary treatments had no effects on plasma glucose concentration, but plasma acetate levels decreased 27% on the glycerol diet. Amino acid concentrations were not affected by dietary treatments, except for branched-chain amino acids, which decreased 22% on the glycerol diet compared with the corn diet. The decreases in plasma acetate and branched-chain amino acid concentrations with glycerol and the larger effects of glycerol than corn on milk protein and fat yields suggest that glycerol is more glucogenic for cows than corn grain.


Asunto(s)
Alimentación Animal , Bovinos/metabolismo , Glicerol/administración & dosificación , Proteínas de la Leche/biosíntesis , Animales , Dieta/veterinaria , Femenino , Lactancia/metabolismo , Leche/química , Rumen , Zea mays
14.
Opt Express ; 24(16): 18209-16, 2016 Aug 08.
Artículo en Inglés | MEDLINE | ID: mdl-27505785

RESUMEN

We report the reflectance, ~1° from normal incidence, of six different mirrors as a function of photon energy, using monochromatic vacuum ultraviolet (VUV) and extreme ultraviolet (XUV) radiation with energies between 7.5 eV and 24.5 eV. The mirrors examined included both single and multilayer optical coatings, as well as an uncoated substrate. We discuss the performance of each mirror, paying particular attention to the potential application of suppression and selection of high-order harmonics of a Ti:sapphire laser.

15.
Clin Exp Immunol ; 182(2): 139-48, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26178412

RESUMEN

During clinical trials of a tumour necrosis factor (TNF)-R1 domain antibody (dAb™) antagonist (GSK1995057), infusion reactions consistent with cytokine release were observed in healthy subjects with high levels of a novel, pre-existing human anti-VH (HAVH) autoantibody. In the presence of HAVH autoantibodies, GSK1995057 induced cytokine release in vitro due to binding of HAVH autoantibodies to a framework region of the dAb. The epitope on GSK1995057 was characterized and dAbs with reduced binding to HAVH autoantibodies were generated; pharmacological comparability was determined in human in-vitro systems and in-vivo animal experiments. A Phase I clinical trial was conducted to investigate the safety and tolerability of the modified dAb (GSK2862277). A significant reduction in HAVH binding was achieved by adding a single alanine residue at the C-terminus to create GSK2862277. Screening a pool of healthy donors demonstrated a reduced frequency of pre-existing autoantibodies from 51% to 7%; in all other respects, GSK2862277 and the parent dAb were comparable. In the Phase I trial, GSK2862277 was well tolerated by both the inhaled and intravenous routes. One subject experienced a mild infusion reaction with cytokine release following intravenous dosing. Subsequently, this subject was found to have high levels of a novel pre-existing antibody specific to the extended C-terminus of GSK2862277. Despite the reduced binding of GSK2862277 to pre-existing HAVH autoantibodies, adverse effects associated with the presence of a novel pre-existing antibody response specific to the modified dAb framework were identified and highlight the challenge of developing biological antagonists to this class of receptor.


Asunto(s)
Anticuerpos Monoclonales/farmacocinética , Autoanticuerpos/inmunología , Cadenas Pesadas de Inmunoglobulina/inmunología , Región Variable de Inmunoglobulina/inmunología , Receptores Tipo I de Factores de Necrosis Tumoral/inmunología , Administración por Inhalación , Administración Intravenosa , Adulto , Anciano , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/sangre , Especificidad de Anticuerpos/inmunología , Autoanticuerpos/sangre , Línea Celular , Línea Celular Tumoral , Epítopos/inmunología , Femenino , Humanos , Interleucina-8/inmunología , Interleucina-8/metabolismo , Macaca fascicularis , Masculino , Persona de Mediana Edad , Unión Proteica/inmunología , Receptores Tipo I de Factores de Necrosis Tumoral/antagonistas & inhibidores , Factores de Tiempo , Adulto Joven
16.
Clin Exp Allergy ; 45(5): 859-871, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25443673

RESUMEN

Peanut and tree nut allergies are the commonest cause of life-threatening food-allergic reactions and significantly affect quality of life in children and their families. Dietary nut avoidance and provision of emergency medication is currently the mainstay of treatment. Nut avoidance has consequences on both quality of life and nutrition. We review the terminology that may cause confusion and lead to unnecessary dietary restrictions. In peanut or tree nut-allergic children, introduction of specific nuts to which the child is not allergic may improve quality of life and should be considered in patients with multiple foods allergies, vegan or ethnic-specific diets, in whom nuts are an important source of protein. Nut-allergic consumers do not just need to avoid foods containing nuts as an ingredient, but also contend with pre-packed foods which frequently have precautionary allergen labelling (PAL) referring to possible nut contamination. Although the published rate of peanut contamination in 'snack' foods with PAL (see Box ) ranges from 0.9-32.4%, peanut contamination in non-snack items with PAL is far less common. We propose that in some peanut-allergic patients (depending on history of reactivity to trace levels of peanut, reaction severity, other medical conditions, willingness to always carry adrenaline, etc.), consideration may be given to allow the consumption of non-snack foods containing PAL following discussion with the patient's (and their family's) specialist. More work is needed to provide consumers with clearer information on the risk of potential nut contamination in pre-packed food. We also draw attention to the change in legislation in December 2014 that require mandatory disclosure of allergens in non-pre-packed foods.


Asunto(s)
Arachis/efectos adversos , Dieta , Hipersensibilidad a la Nuez/prevención & control , Nueces/efectos adversos , Hipersensibilidad al Cacahuete/prevención & control , Alérgenos/inmunología , Manejo de la Enfermedad , Hipersensibilidad a los Alimentos/inmunología , Hipersensibilidad a los Alimentos/prevención & control , Humanos , Hipersensibilidad a la Nuez/inmunología , Hipersensibilidad al Cacahuete/inmunología , Factores de Riesgo
17.
J Evol Biol ; 28(10): 1782-92, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26189657

RESUMEN

Learning has been traditionally thought to accelerate the evolutionary change of behavioural traits. We evaluated the evolutionary rate of learned vocalizations and the interplay of morphology and ecology in the evolution of these signals. We examined contact calls of 51 species of Neotropical parrots from the tribe Arini. Parrots are ideal subjects due to their wide range of body sizes and habitats, and their open-ended vocal learning that allows them to modify their calls throughout life. We estimated the evolutionary rate of acoustic parameters of parrot contact calls and compared them to those of morphological traits and habitat. We also evaluated the effect of body mass, bill length, vegetation density and species interactions on acoustic parameters of contact calls while controlling for phylogeny. Evolutionary rates of acoustic parameters did not differ from those of our predictor variables except for spectral entropy, which had a significantly slower rate of evolution. We found support for correlated evolution of call duration, and fundamental and peak frequencies with body mass, and of fundamental frequency with bill length. The degree of sympatry between species did not have a significant effect on acoustic parameters. Our results suggest that parrot contact calls, which are learned acoustic signals, show evolutionary rates similar to those of morphological traits. This is the first study to our knowledge to provide evidence that change through cultural evolution does not necessarily accelerate the evolutionary rate of traits acquired through life-long vocal learning.


Asunto(s)
Acústica , Comunicación Animal , Aprendizaje , Loros/fisiología , Animales , Loros/clasificación , Filogenia
18.
J Dairy Sci ; 98(1): 349-56, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25468697

RESUMEN

The objective of this study was to determine the effect of enhanced whole-milk (WM) feeding systems in calves from birth to 8wk of age on subsequent first-lactation performance. The experiment was conducted as a completely randomized design consisting of 2 treatment groups. At birth, 152 Holstein heifer calves were randomly assigned to 1 of 2 treatments: (i) 4L of WM/d or (ii) 8L of WM/d. The calves were bucket fed 2 or 4L of WM twice daily at 0700 and 1600h. Each calf was housed individually in temperature-controlled nurseries and had ad libitum access to water and textured calf starter daily. Calves consumed greater volumes of textured calf starter when fed 4 versus 8L of WM/d. Water intakes mirrored starter intakes, leading to greater water consumption at weaning. Calves reared on 8L of WM/d were heavier at d 56 than calves reared on 4L of WM/d. The average daily gain of the calves offered 8L of WM/d from d 0 to 56 was greater than that of calves offered 4L of WM/d. Structural measurements were significantly greater for calves that consumed 8L of WM/d. The differences observed in withers height and live BW due to WM feeding level were not apparent by 3 and 12mo of age, respectively. Rumen pH was higher in calves that consumed 8L of WM/d than in calves that consumed 4L of WM/d. Whole-milk feeding level did not affect age at first calving or milk-production parameters. These results suggest that enhanced WM feeding improved growth performance until 3mo of age. However, first-lactation results indicated no lactation-performance benefits of increased nutrition and growth performance during the milk-fed period in dairy calves.


Asunto(s)
Bovinos/fisiología , Lactancia/fisiología , Leche/metabolismo , Crianza de Animales Domésticos , Animales , Bovinos/crecimiento & desarrollo , Ingestión de Líquidos , Femenino , Concentración de Iones de Hidrógeno , Distribución Aleatoria , Rumen/metabolismo , Destete
19.
Clin Exp Obstet Gynecol ; 42(5): 580-5, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26524802

RESUMEN

BACKGROUND: These studies were undertaken to determine methamphetamine (METH) and smoking effects on umbilical vascular dynamics and pregnancy outcomes. MATERIALS AND METHODS: Umbilical cords (54) were collected prospectively at birth, washed of blood, and stored at -80°C. Cords were thawed and lysates prepared, then catecholamine levels quantified with enzyme-linked immunosorbent assay (ELISA). RESULTS: Catecholamine levels in umbilical cords were not associated with maternal or gestational age, gravidity, parity, neonatal or placental weight. Neither smoking nor METH affected dopamine or epinephrine. However, smoking (two-fold) and METH (four-fold) decreased norepinephrine and together a 60-fold reduction occurred (p = 0.025). Cesarean section and hypertension were both associated with lower norepinephrine levels (p < 0.001) regardless of drug status. In normotensive pregnancies, smoking and METH significantly decreased norepinephrine levels (two-fold and 3.5-fold each, respectively) with a 40-fold decrease for METH/smoking together. DISCUSSION: Depletion of norephinephrine by METH and smoking likely contributes to pregnancy complications, including the higher incidence of respiratory distress and postpartum hemorrhage in cesarean section.


Asunto(s)
Hipertensión Inducida en el Embarazo/fisiopatología , Metanfetamina/efectos adversos , Norepinefrina/metabolismo , Fumar/efectos adversos , Cordón Umbilical/metabolismo , Cesárea , Ensayo de Inmunoadsorción Enzimática , Femenino , Edad Gestacional , Humanos , Proyectos Piloto , Embarazo , Resultado del Embarazo , Trastornos Relacionados con Sustancias , Cordón Umbilical/irrigación sanguínea
20.
J Undergrad Neurosci Educ ; 13(2): A74-80, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25838805

RESUMEN

Action potentials and the postsynaptic potentials they evoke fill the pages of neuroscience textbooks, but students have relatively few opportunities to record these phenomena on their own. However, the act of making such recordings can be key events in a student's scientific education. The crayfish abdominal slow flexor muscle system is a well-established platform for recording spikes and PSPs. It enables students to see nerves and the muscles they innervate, record spontaneous spikes from several motor axons in these nerves as well as PSPs in their postsynaptic muscle fibers, and interpret these recordings quantitatively. Here we describe an improved method for preparing the slow-flexor system for recording that employs transmitted illumination through the stereo microscope's conventional substage lighting. Oblique transmitted lighting allows students to see the nerve and muscles fibers in each segment clearly and position recording electrodes accurately under visual control. Because students can see the nerves, muscles, and recording electrodes, broken electrode tips are relatively uncommon and the first successful recordings come more quickly. Many kinds of neurons in the CNS have the same pattern of multineuronal, multiterminal innervation that occurs on these muscle fibers. To visualize these innervation patterns on these fibers, we describe an immunohistochemical protocol that labels the GABAergic inhibitory motor axon and all the synaptic vesicles in the synaptic terminals on these muscle fibers. Dual-color images reveal extensive branching of the axons and fields of presynaptic terminals, only some of which are double-labeled for GABA.

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