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BACKGROUND: PT027 is a fixed-dose combination of albuterol (salbutamol) and budesonide in a single pressurized metered-dose inhaler. OBJECTIVE: To evaluate the efficacy and safety of albuterol/budesonide compared with placebo in patients with asthma and exercise-induced bronchoconstriction (EIB). METHODS: In this randomized, double-blind, 2-period, single-dose crossover study, adolescents and adults with asthma and EIB (defined by ≥20% decrease from pre-exercise challenge forced expiratory volume in 1 second [FEV1]) were randomized to albuterol/budesonide (180/160 µg) followed by placebo (n = 29) or the reverse sequence (n = 31). Subjects were stratified by background therapy (as-needed short-acting ß2-agonist alone or low-to-medium dose inhaled corticosteroid plus as-needed short-acting ß2-agonist). FEV1 was measured 5 minutes pre-dose, 30 minutes postdose (5 minutes pre-exercise challenge [baseline]), and 5, 10, 15, 30, and 60 minutes postexercise. The primary end point was maximum percentage fall from baseline in FEV1 up to 60 minutes postexercise challenge. RESULTS: Least squares mean maximum percentage fall in FEV1 up to 60 minutes postexercise challenge was 5.45% with albuterol/budesonide vs 18.97% with placebo (difference, -13.51% [95% confidence interval, -16.94% to -10.09%]; P < .001). More subjects were fully protected (maximum percentage fall in FEV1 post-exercise challenge < 10%) with albuterol/budesonide than with placebo (78.3% vs 28.3%; P < .001). The treatment effect was consistent irrespective of background inhaled corticosteroid therapy, and albuterol/budesonide was well tolerated. CONCLUSION: In adolescents and adults with asthma and EIB, a single dose of albuterol/budesonide 180/160 µg taken approximately 30 minutes before exercise was significantly more effective than placebo in preventing EIB. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04234464.
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Albuterol , Asma , Administração por Inalação , Adolescente , Adulto , Asma/induzido quimicamente , Asma/tratamento farmacológico , Broncoconstrição , Broncodilatadores , Budesonida/uso terapêutico , Estudos Cross-Over , Método Duplo-Cego , Volume Expiratório Forçado , HumanosRESUMO
Even after 30+ years of research, there are still few examples of physically stable transparent nanoemulsions despite their high potential to revolutionise pharmaceutical, personal care, and food products. In this study, we examine how low-energy "microemulsion inspired" (co-solvent/co-surfactant) approaches impact the formation and destabilisation mechanisms of homogenised triglyceride nanoemulsions. The addition of n-alcohol co-solvents and Span 80 co-surfactants had two effects on nanoemulsion droplet diameter; a beneficial one that reduced droplet diameter from 120 to 50 nm and a deleterious one that caused destabilisation. The decrease in nanoemulsion droplet diameter facilitated by n-alcohols is thought to arise from changes in: (i) solvent quality near the interface and (ii) interface spontaneous curvature which dramatically reduce interfacial tension. The strength of this effect was magnified by n-alcohol partitioning behaviour and their tendency to associate with the headgroup of POE surfactants. Addition of an excess of n-alcohol led to nanoemulsion destabilisation, unusually for nanoemulsions, destabilisation was not via Ostwald ripening, instead coalescence was found to be the primary destabilisation mechanism. A rapid increase in nanoemulsion droplet growth rate with increasing n-alcohol content was observed for each n-alcohol. Such rapid changes in nanoemulsion instability with composition are reminiscent of PIC/PIT emulsions in the Winsor III region, whose instability has been described to be a function of the activation energy barrier to coalescence. The microemulsion inspired approaches developed in this work highlight a new general approach to the creation of transparent nanoemulsions, and are particularly advantageous for triglyceride oils which are inherently stable against Ostwald ripening.
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Background: Self-determination, described broadly as experiencing causal agency, is positively associated with quality of life (QoL) and increases through satisfaction of three basic psychological needs: autonomy (feeling able to make choices free from pressure), competence (perceived self-efficacy), and relatedness (social connection). Both unsupportive environments and challenges with social interaction can interfere with satisfaction of psychological needs. Social challenges are a key trait for autism diagnosis, and unsupportive environments are also known to adversely affect QoL for autistic people. Autistic people report, on average, lower self-determination than non-autistic people. Therefore, it is hypothesized that higher levels of autistic traits may reduce opportunities to develop self-determination, affecting QoL. Methods: We tested a parallel indirect effects model where we hypothesized that the relationships between autistic traits and four domains of QoL (psychological, social, physical, and environmental) would be indirectly influenced through self-determination (represented through satisfaction of the basic psychological needs for autonomy, competence, and relatedness). This study drew participants from the general population (N = 262; M AGE = 37.6, standard deviation = 11.92; 1.9% reported an autism diagnosis and 2.7% identified as autistic without a diagnosis). Participants completed an online survey. Results: Higher levels of autistic traits were associated with lower levels of self-determination and lower levels of QoL, and there was a significant indirect effect between autistic traits and QoL via self-determination. More specifically, we found a significant indirect effect between autistic traits and all QoL domains via competence; between autistic traits and the environmental, social, and psychological QoL domains via relatedness; and between autistic traits and the physical and environmental QoL domains through autonomy. Conclusions: Our results suggest that supporting satisfaction of the needs for autonomy, competence, and relatedness may represent an important element in designing effective programs to support the development of self-determination in people with higher levels of autistic traits (potentially including autistic individuals) and also to support these people to improve their QoL.
Why is this an important issue? In this study, we looked at how autistic traits might affect self-determination and quality of life. Quality of life is the way that you feel about your own life circumstances. In this study, we looked at four aspects of quality of lifepsychological (e.g., mental health), social (how you interact with other people), physical (e.g., disability or sickness), and environmental (e.g., where you live). Self-determination is the ability to choose based on your own wants, needs, and interests, without feeling pressured. To be self-determined, you need to meet your needs for autonomy (experiencing free choice), competence (feeling able to do things effectively), and relatedness (feeling connected with others). Meeting these needs is affected by the world around you (e.g., where you live, if you have a job, whether you are disabled) and by the actions and beliefs of the people around you. People with higher autistic traits report, on average, lower quality of life and self-determination than people with lower autistic traits. Because other researchers have found that self-determination influences quality of life, lower levels of self-determination might partly explain lower quality of life. Programs that promote self-determination may reduce the gap in quality of life between autistic and non-autistic people. What was the purpose of this study? We thought that self-determination might partly explain why people with higher autistic traits report lower quality of life than people with lower autistic traits, so we wanted to test this idea. What did the researchers do? We asked people to answer questions about autistic traits, self-determination, and quality of life in an online survey. We statistically analyzed their answers to find out whether autistic traits influenced the levels of self-determination (feelings of autonomy, competence, and relatedness) or quality of life (psychological, social, physical and environmental quality of life). What were the results of this study? Autistic traits did not directly influence psychological, physical, or environmental quality of life but did directly influence social quality of life. In our study, people with higher autistic traits reported less satisfaction of their psychological needs than people with lower autistic traits. People with lower satisfaction of psychological needs also reported lower quality of life. Autistic traits influenced self-determination, which in turn influenced quality of life. What do these findings add to what was already known? To the best of our knowledge, this was the first study to explore relationships between autistic traits, self-determination, and quality of life. Our results showed that people with higher levels of autistic traits may report lower quality of life partly because autistic traits might make it difficult to become self-determined. What are the potential weaknesses in the study? We investigated self-determination and quality of life among one group of people from the general population. We did not compare autistic and non-autistic people. While some studies have shown that people with high levels of autistic traits may be similar to autistic people in some ways, this is not necessarily the case all the time. We cannot assume that results will be the same in other groups, that autistic traits cause lower self-determination, or that lower self-determination causes lower quality of life. We also did not consider all the things that might have influenced self-determination or quality of life (e.g., where people lived, how much money they had, or what their health was like). How will these findings help autistic adults now or in the future? People with higher autistic traits (including autistic adults) may find it harder to be self-determined both because of their autistic traits (e.g., difficulty in social interaction, sensory sensitivities) and also because school, work, and community systems may not be designed to support acceptance of differences. The results from this study suggest that higher autistic traits might make it difficult to meet the psychological needs for autonomy, competence, and relatedness. Research that compares autistic and non-autistic people is needed to determine both personal and environmental factors which may support the development of self-determination in autistic people and empower them to achieve higher quality of life.
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The solubility of milk protein concentrate (MPC) powders was influenced by the method used for preparing the concentrate, drying conditions, and the type of dryer used. Increasing total solids of the ultrafiltered concentrates (23% total solids, TS) by diafiltration to 25% TS or evaporation to 31% TS decreased the solubility of MPC powders (80-83% protein, w/w dry basis), with ultrafiltration followed by evaporation to higher total solids having the greater detrimental effect on solubility. High shear treatment (homogenisation at 350/100 bar, microfluidisation at 800 bar or ultrasonication at 24 kHz, 600 watts) of ultrafiltered and diafiltered milk protein concentrates prior to spray drying increased the nitrogen solubility of MPC powders (82% protein, w/w dry basis). Of the treatments applied, microfluidisation was the most effective for increasing nitrogen solubility of MPC powders after manufacture and during storage. Manufacture of MPC powders (91% protein, w/w dry basis) prepared on two different pilot-scale dryers (single stage or two stage) from milk protein concentrates (20% TS) resulted in powders with different nitrogen solubility and an altered response to the effects of microfluidisation. Microfluidisation (400, 800 and 1200 bar) of the concentrate prior to drying resulted in increased long term solubility of MPC powders that were prepared on a single stage dryer but not those produced on a two stage spray dryer. This work demonstrates that microfluidisation can be used as a physical intervention for improving MPC powder solubility. Interactions between the method of preparation and treatment of concentrate prior to drying, the drying conditions and dryer type all influence MPC solubility characteristics.
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Alimentos em Conserva , Proteínas do Leite/química , Dessecação/métodos , Filtração , Nitrogênio/química , Solubilidade , Sonicação , UltrafiltraçãoRESUMO
BACKGROUND: Wear particles, found at the bone-implant interface surrounding a loose prosthesis, are commonly phagocytosed by macrophages. Wear particles and wear particle-containing macrophages are also found in regional lymph nodes draining arthroplasty tissues. The means by which wear particles are transported from arthroplasty tissues to lymph nodes is uncertain, as the presence or absence of lymphatic vessels in periprosthetic tissues has not been established. METHODS: We determined immunophenotypic expression of LYVE-1 and podoplanin, two highly specific lymphatic endothelial cell markers, in the hip arthroplasty pseudocapsule surrounding the false joint and the bone-implant interface of the femoral and acetabular pseu-domembrane. RESULTS: LYVE-1+/podoplanin+ lymphatic vessels were not identified in the pseudomembrane but were found in the pseudocapsule. Normal bone did not contain lymphatic vessels. INTERPRETATION: Our findings suggest that the wear particles shed at the bone-implant interface are not transported to draining lymph nodes by lymphatics directly from the pseudomembrane, but via the pseudocapsule. The absence of a lymphatic clearance mechanism may contribute to accumulation of wear particles at the bone-implant interface and promote periprosthetic osteolysis through stimulation of osteoclast formation and activity.
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Artroplastia de Quadril/efeitos adversos , Vasos Linfáticos/patologia , Osteólise/etiologia , Falha de Prótese , Acetábulo/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Células Endoteliais/citologia , Feminino , Prótese de Quadril/efeitos adversos , Humanos , Imuno-Histoquímica , Vasos Linfáticos/citologia , Vasos Linfáticos/metabolismo , Masculino , Pessoa de Meia-Idade , Tamanho da PartículaRESUMO
In mood disorder, early stressors including parental separation are vulnerability factors, and hippocampal involvement is prominent. In common marmoset monkeys, daily parental deprivation during infancy produces a prodepressive state of increased basal activity and reactivity in stress systems and mild anhedonia that persists at least to adolescence. Here we examined the expression of eight genes, each implicated in neural plasticity and in the pathophysiology of mood disorder, in the hippocampus of these same adolescent marmosets, relative to their normally reared sibling controls. We also measured hippocampal volume. Early deprivation led to decreases in hippocampal growth-associated protein-43 (GAP-43) mRNA, serotonin 1A receptor (5-HT(1A)R) mRNA and binding ([3H]WAY100635), and to increased vesicular GABA transporter mRNA. Brain-derived neurotrophic factor (BDNF), synaptophysin, vesicular glutamate transporter 1 (VGluT1), microtubule-associated protein-2, and spinophilin transcripts were unchanged. There were some correlations with in vivo biochemical and behavioral indices, including VGluT1 mRNA with reward-seeking behavior, and serotonin 1A receptor mRNA with CSF cortisol. Early deprivation did not affect hippocampal volume. We conclude that early deprivation in a nonhuman primate, in the absence of subsequent stressors, has a long-term effect on the hippocampal expression of genes implicated in synaptic function and plasticity. The reductions in GAP-43 and serotonin 1A receptor expressions are comparable with findings in mood disorder, supporting the possibility that the latter reflect an early developmental contribution to disease vulnerability. Equally, the negative results suggest that other features of mood disorder, such as decreased hippocampal volume and BDNF expression, are related to different aspects of the pathophysiological process.
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Expressão Gênica , Hipocampo/fisiologia , Privação Materna , Transtornos do Humor/genética , Plasticidade Neuronal/genética , Privação Paterna , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Callithrix , Feminino , Proteína GAP-43/metabolismo , Hipocampo/anatomia & histologia , Hidrocortisona/líquido cefalorraquidiano , Masculino , Proteínas dos Microfilamentos/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Transtornos do Humor/fisiopatologia , Proteínas do Tecido Nervoso/metabolismo , RNA Mensageiro/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Recompensa , Transmissão Sináptica , Sinaptofisina/metabolismo , Proteína Vesicular 1 de Transporte de Glutamato/metabolismo , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/metabolismoRESUMO
Axonal pathology in multiple sclerosis (MS) has been described for over a century, but new insights into axonal loss and disability have refocused interest in this area. There is evidence of oxidative damage to mitochondrial DNA in chronic MS plaques, suggesting that mitochondrial failure may play a role in MS pathology. We propose that in the chronic absence of myelin the maintenance of conduction relies partially on an increase in mitochondria to provide energy. This increased energy requirement also promotes reactive oxygen species (ROS), because most intraaxonal ROS are generated by mitochondria. If antioxidant defenses are overwhelmed by an excess of ROS, this may result in damage to the axon. Our aim was to investigate whether a chronic lack of myelin results in adaptive changes involving mitochondria within the axon. We investigated this in the shiverer mouse. This myelin basic protein gene mutant provides a model of how adult central nervous system (CNS) axons cope with the chronic absence of a compact myelin sheath. Cytochrome c histochemistry demonstrated a twofold increase in mitochondrial activity in white matter tracts of shiverer, and electron microscopy confirmed a significantly higher number of mitochondria within the dysmyelinated axons. Our data demonstrate that there are adaptive changes involving mitochondria occurring within CNS axons in shiverer mice in response to a lack of myelin. This work contributes to our understanding of the adaptive changes occurring in response to a lack of myelin in a noninflammatory environment similar to the situation seen in chronically demyelinated MS plaques.