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AIM: To identify the barriers and facilitators for timely detection and optimal management of otitis media (OM) in Aboriginal children in a primary care setting from the perspective of carers of Aboriginal children. METHODS: A qualitative, Aboriginal co-designed, participatory action research study with interviews and focus groups in a large town in the Kimberley, Western Australia. The Consolidated Framework for Implementation Research informed stakeholder group identification and interview framework development. Data underwent thematic analysis using NVivo software. RESULTS: Thirty-two carers of Aboriginal children participated. Key barriers identified for the detection of OM were limited information about OM provided to carers and carers feeling disempowered to express their concerns. Key facilitators identified were the provision of health information through health promotion and the use of culturally secure resources. Having a culturally secure clinical environment was identified as essential, with Aboriginal Health Workers playing a vital role in clinical care. No barriers to management of OM in primary care were reported. Facilitators included health care practitioners (HCPs) emphasising the importance of completing antibiotic course and the clinic providing necessary medications. CONCLUSIONS: A culturally secure health promotion strategy with health promotion teams, campaigns and resources is needed to increase community awareness of OM signs and symptoms and facilitate appropriate health seeking. It is essential that the local Aboriginal community co-lead and co-develop these initiatives to ensure the unique wisdom and knowledge of Aboriginal people are captured. HCPs and the clinic effectively facilitate management of OM by providing medications and emphasising completion of antibiotics.
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Individuals who have Down syndrome (DS) frequently develop early onset Alzheimer's disease (AD), a neurodegenerative condition caused by the buildup of aggregated amyloid-ß (Aß) and tau proteins in the brain. Aß is produced by amyloid precursor protein (APP), a gene located on chromosome 21. People who have DS have three copies of chromosome 21 and thus also an additional copy of APP; this genetic change drives the early development of AD in these individuals. Here we use a combination of next-generation mouse models of DS (Tc1, Dp3Tyb, Dp(10)2Yey and Dp(17)3Yey) and a knockin mouse model of Aß accumulation (AppNL-F ) to determine how chromosome 21 genes, other than APP, modulate APP/Aß in the brain when in three copies. Using both male and female mice, we demonstrate that three copies of other chromosome 21 genes are sufficient to partially ameliorate Aß accumulation in the brain. We go on to identify a subregion of chromosome 21 that contains the gene(s) causing this decrease in Aß accumulation and investigate the role of two lead candidate genes, Dyrk1a and Bace2 Thus, an additional copy of chromosome 21 genes, other than APP, can modulate APP/Aß in the brain under physiological conditions. This work provides critical mechanistic insight into the development of disease and an explanation for the typically later age of onset of dementia in people who have AD in DS, compared with those who have familial AD caused by triplication of APP SIGNIFICANCE STATEMENT Trisomy of chromosome 21 is a commonly occurring genetic risk factor for early-onset Alzheimer's disease (AD), which has been previously attributed to people with Down syndrome having three copies of the amyloid precursor protein (APP) gene, which is encoded on chromosome 21. However, we have shown that an extra copy of other chromosome 21 genes modifies AD-like phenotypes independently of APP copy number (Wiseman et al., 2018; Tosh et al., 2021). Here, we use a mapping approach to narrow down the genetic cause of the modulation of pathology, demonstrating that gene(s) on chromosome 21 decrease Aß accumulation in the brain, independently of alterations to full-length APP or C-terminal fragment abundance and that just 38 genes are sufficient to cause this.
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Doença de Alzheimer , Síndrome de Down , Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/genética , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Síndrome de Down/complicações , Síndrome de Down/genética , Feminino , Humanos , Masculino , CamundongosRESUMO
BACKGROUND: In children, chronic wet cough may be a sign of underlying lung disease, including protracted bacterial bronchitis (PBB) and bronchiectasis. Chronic (> 4 weeks in duration) wet cough (without indicators pointing to alternative causes) that responds to antibiotic treatment is diagnostic of PBB. Timely recognition and management of PBB can prevent disease progression to irreversible bronchiectasis with lifelong consequences. However, detection and management require timely health-seeking by carers and effective management by clinicians. We aim to improve (a) carer health-seeking for chronic wet cough in their child and (b) management of chronic wet cough in children by clinicians. We hypothesise that implementing a culturally integrated program, which is informed by barriers and facilitators identified by carers and health practitioners, will result in improved lung health of First Nations children, and in the future, a reduced the burden of bronchiectasis through the prevention of the progression of protracted bacterial bronchitis to bronchiectasis. METHODS: This study is a multi-centre, pseudorandomised, stepped wedge design. The intervention is the implementation of a program. The program has two components: a knowledge dissemination component and an implementation component. The implementation is adapted to each study site using a combined Aboriginal Participatory Action Research and an Implementation Science approach, guided by the Consolidated Framework of Implementation Research. There are three categories of outcome measures related to (i) health (ii) cost, and (iii) implementation. We will measure health-seeking as the proportion of parents seeking help for their child in a 6-month period before the intervention and the same 6-month period (i.e., the same six calendar months) thereafter. The parent-proxy, Cough-specific Quality of Life (PC-QoL) will be the primary health-related outcome measure. DISCUSSION: We hypothesise that a tailored intervention at each site will result in improved health-seeking for carers of children with a chronic wet cough and improved clinician management of chronic wet cough. In addition, we expect this will result in improved lung health outcomes for children with a chronic wet cough. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry; ACTRN12622000430730 , registered 16 March 2022, Retrospectively registered.
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Infecções Bacterianas , Bronquiectasia , Bronquite Crônica , Bronquite , Criança , Humanos , Tosse/diagnóstico , Qualidade de Vida , Bronquite/diagnóstico , Ciência da Implementação , Austrália , Doença Crônica , Infecções Bacterianas/diagnóstico , Bronquiectasia/complicações , Bronquite Crônica/complicações , Avaliação de Resultados em Cuidados de Saúde , Estudos Multicêntricos como AssuntoRESUMO
AIM: To determine the frequency of protracted bacterial bronchitis (PBB) in children referred to tertiary care with chronic cough and describe management prior to referral. METHODS: A retrospective cohort study of all new patients with a history of ≥4 weeks of cough seen at the only tertiary paediatric outpatient respiratory service in Western Australia between July 2018 and June 2019. Medical records were reviewed until a final diagnosis was documented or otherwise for a period of 18 months. RESULTS: PBB was the most common cause and comprised 37.9% of all children referred to tertiary respiratory care with chronic cough. In children with PBB, the median cough duration at the time of first specialist review was 5.1 months (IQR 2.1-12.0 months). The most common referral source of PBB was primary practice (40.9%) and the most common working diagnosis pre-referral was asthma (15.9%). Seventy-eight percent of children with PBB had an ongoing cough at their first respiratory review, and of these, only 13.5% had been prescribed 4 weeks of antibiotics prior to their respiratory review. Asthma treatment had been prescribed for 34.0% of children with PBB. CONCLUSION: PBB is the most common cause of chronic cough in children referred to tertiary respiratory care and is frequently misdiagnosed and undertreated pre-referral. There is a need to facilitate diagnosis and optimal management of PBB in primary care, which could result in earlier symptom resolution and potentially limit disease progression to bronchiectasis.
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Infecções Bacterianas , Bronquiectasia , Bronquite , Bronquite/diagnóstico , Bronquite/tratamento farmacológico , Bronquite/epidemiologia , Criança , Doença Crônica , Tosse/diagnóstico , Tosse/etiologia , Tosse/terapia , Humanos , Encaminhamento e Consulta , Estudos RetrospectivosRESUMO
AIM: To explore immunisation rates and catch-up delivery to children admitted to hospital before and after an immunisation service was commenced. METHODS: This pre- and post-intervention study examined 300 admissions prior to (cohort 1) and 300 following (cohort 2) the introduction of an immunisation service. Immunisation rates, documentation, catch-up delivery and accuracy of the Australian Immunisation Register (AIR) were examined. RESULTS: On admission, 75% (cohort 1) and 89% (cohort 2) were up-to-date with immunisations. Immunisation history was documented in the medical record in 78% and requirement for catch-up documented in 10%. AIR was incorrect in one-third of cases. By 3 months following discharge, 28% (cohort 1) and 64% (cohort 2) of patients were immunised. CONCLUSIONS: Children admitted to hospital have lower immunisation rates than the national average. Documentation was poor, opportunities for catch-up were missed and AIR is error-prone. Catch-up rates increased following the introduction of an immunisation service.
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Hospitais Pediátricos , Imunização , Austrália , Criança , Documentação , Humanos , Lactente , VacinaçãoRESUMO
Anxiety and depression contribute to a substantial burden of Chronic Obstructive Pulmonary Disease-related morbidity by impairing quality of life and by reducing adherence to treatment. The identification of COPD patients with comorbid depression or anxiety symptoms is vital, as it is estimated that only a third of patients with these co-morbidities are receiving appropriate treatment. The aim of this audit was therefore to identify whether current methods of anxiety and depression screening in elderly patients (over the age of 65) with severe COPD (FEV1 <50% at most recent spirometry reading) are adequate by assessing how frequently anxiety and depression is reported as "discussed with patient" in COPD review appointments across two practices. SystmOne was used to identify a total of 83 patients, and the recording of depression and anxiety discussions in this cohort's review appointments was analysed and compared with the incidence of QOF-coded depression and anxiety in the patient notes. The results show that both the rate and the quality of depression and anxiety reporting in these review appointments is highly heterogeneous, and has led to 'missed' patients suffering from comorbid mental health issues. Additionally, this audit identified a number of patients with depression or anxiety directly related to their COPD, and it highlighted a trend among this cohort towards more frequent appointments with their General Practitioner, and towards related presentations at the Emergency Department. The results of this audit suggest there is room for amelioration of the current practice, such as the implementation of a structured screening tool into System One's COPD review appointment template.
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Ansiedade/complicações , Ansiedade/diagnóstico , Auditoria Clínica , Depressão/complicações , Depressão/diagnóstico , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/psicologia , Idoso , Humanos , Qualidade de VidaRESUMO
Schizophrenic patients have traditionally suffered from high rates of cardiovascular disease and early mortality. NICE guidelines suggest that several physical health measures be monitored regularly in these patients, and particularly those on antipsychotic medication, which has a wide side-effect profile that may potentiate the risk of cardiovascular disease and other comorbidities. This general practice audit aimed to determine the rates of physical health monitoring in primary care in patients on antipsychotic medication for over a year for psychotic symptoms or schizophrenia. The search was conducted in three different general practices in March 2019, yielding 19, 8 and 30 patients respectively, with a total of 57 patients. This audit aims to record and analyse rates of monitoring of a range of physical health measures recommended by NICE guidelines over the past year. The results demonstrated that physical health monitoring was poor amongst all the practices audited, especially that of prolactin and waist circumference. We recommend that these rates of monitoring be improved, through implementing templates or the delivery of targeted education to general practitioners and nurses.
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Antipsicóticos/efeitos adversos , Medicina Geral , Atenção Primária à Saúde , Transtornos Psicóticos/complicações , Transtornos Psicóticos/tratamento farmacológico , Esquizofrenia/complicações , Esquizofrenia/tratamento farmacológico , Antipsicóticos/administração & dosagem , Auditoria Clínica , Humanos , Transtornos Psicóticos/fisiopatologia , Esquizofrenia/fisiopatologiaRESUMO
The chemokine receptors CCR5 and CCR2b share 89% amino acid homology. CCR5 is a co-receptor for HIV and CCR5 antagonists have been investigated as inhibitors of HIV infection. We describe the use of two CCR5 antagonists, Schering-C (SCH-C), which is specific for CCR5, and TAK-779, a dual inhibitor of CCR5 and CCR2b, to probe the CCR5 inhibitor binding site using CCR5/CCR2b chimeric receptors. Compound inhibition in the different chimeras was assessed by inhibition of chemokine-induced calcium flux. SCH-C inhibited RANTES (regulated on activation, normal T cell expressed and secreted) (CCL5)-mediated calcium flux on CCR5 with an IC50 of 22.8 nM but was inactive against monocyte chemoattractant protein-1 (CCL2)-mediated calcium flux on CCR2b. However, SCH-C inhibited CCL2-induced calcium flux against a CCR5/CCR2b chimera consisting of transmembrane domains IV-VI of CCR5 with an IC50 of 55 nM. A sequence comparison of CCR5 and CCR2b identified a divergent amino acid sequence located at the junction of transmembrane domain V and second extracellular loop. Transfer of the CCR5 sequence KNFQTLKIV into CCR2b conferred SCH-C inhibition (IC50 of 122 nM) into the predominantly CCR2b chimera. Furthermore, a single substitution, R206I, conferred partial but significant inhibition (IC50 of 1023 nM) by SCH-C. These results show that a limited amino acid sequence is responsible for SCH-C specificity to CCR5, and we propose a model showing the interaction with CCR5 Ile(198).
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Amidas/química , Antagonistas dos Receptores CCR5/química , Modelos Moleculares , Compostos de Amônio Quaternário/química , Receptores CCR5/química , Sequência de Aminoácidos , Animais , Sinalização do Cálcio , Células HEK293 , Humanos , Isoleucina/química , Isoleucina/genética , Isoleucina/metabolismo , Macaca , Estrutura Terciária de Proteína , Receptores CCR2/antagonistas & inibidores , Receptores CCR2/química , Receptores CCR2/genética , Receptores CCR2/metabolismo , Receptores CCR5/genética , Receptores CCR5/metabolismo , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismoRESUMO
DNA-point accumulation for imaging at nanoscale topography (DNA-PAINT) can image fixed biological specimens with nanometer resolution and absolute stoichiometry. In living systems, however, the usage of DNA-PAINT has been limited due to high salt concentration in the buffer required for specific binding of the imager to the docker attached to the target. Here, we used multiple binding motifs of the docker, from 2 to 16, to accelerate the binding speed of the imager under physiological buffer conditions without compromising spatial resolution and maintaining the basal level homeostasis during the measurement. We imaged endogenous α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) in cultured neurons-critical proteins involved in nerve communication-by DNA-PAINT in 3-dimensions using a monovalent single-chain variable fragment (scFv) to the GluA1 subunit of AMPAR. We found a heterogeneous distribution of synaptic AMPARs: ≈60% are immobile, primarily in nanodomains, defined as AMPARs that are within 0.3 µm of the Homer1 protein in the postsynaptic density; the other â¼40% of AMPARs have restricted mobility and trajectory.
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Neurônios , Receptores de AMPA , Receptores de AMPA/genética , Neurônios/metabolismo , Proteínas de Transporte/metabolismoRESUMO
INTRODUCTION: E-cigarette (EC) and vaping use continue to remain popular amongst teenage and young adult populations, despite several reports of vaping associated lung injury. One of the first compounds that EC aerosols comes into contact within the lungs during a deep inhalation is pulmonary surfactant. Impairment of surfactant's critical surface tension reducing activity can contribute to lung dysfunction. Currently, information on how EC aerosols impacts pulmonary surfactant remains limited. We hypothesized that exposure to EC aerosol impairs the surface tension reducing ability of surfactant. METHODS: Bovine Lipid Extract Surfactant (BLES) was used as a model surfactant in a direct exposure syringe system. BLES (2ml) was placed in a syringe (30ml) attached to an EC. The generated aerosol was drawn into the syringe and then expelled, repeated 30 times. Biophysical analysis after exposure was completed using a constrained drop surfactometer (CDS). RESULTS: Minimum surface tensions increased significantly after exposure to the EC aerosol across 20 compression/expansion cycles. Mixing of non-aerosolized e-liquid did not result in significant changes. Variation in device used, addition of nicotine, or temperature of the aerosol had no additional effect. Two e-liquid flavours, menthol and red wedding, had further detrimental effects, resulting in significantly higher surface tension than the vehicle exposed BLES. Menthol exposed BLES has the highest minimum surface tensions across all 20 compression/expansion cycles. Alteration of surfactant properties through interaction with the produced aerosol was observed with a basic e-liquid vehicle, however additional compounds produced by added flavourings appeared to be able to increase inhibition. CONCLUSION: EC aerosols alter surfactant function through increases in minimum surface tension. This impairment may contribute to lung dysfunction and susceptibility to further injury.
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Sistemas Eletrônicos de Liberação de Nicotina , Surfactantes Pulmonares , Bovinos , Animais , Tensão Superficial , Mentol , Aerossóis e Gotículas Respiratórios , Tensoativos/farmacologiaRESUMO
BACKGROUND: The burden of bronchiectasis is disproportionately high in Aboriginal adults, with early mortality. Bronchiectasis precursors, that is, protracted bacterial bronchitis (PBB) and chronic suppurative lung disease (CSLD), often commence in early childhood. We previously reported a 10% prevalence of PBB in Aboriginal children aged 0 to 7 years, however there are no data on prevalence of chronic lung diseases in older children. Our study aimed to determine the prevalence of PBB, CSLD, bronchiectasis, and asthma in Aboriginal children living in four communities. METHODS: A whole-population cross-sectional community co-designed study of Aboriginal children aged <18-years in four remote communities in Western Australia across two-time points, a month apart. Children were assessed by pediatric respiratory clinicians with spirometry undertaken (when possible) between March-September 2021. Children with respiratory symptoms were followed up via medical record audit from either the local medical clinic or via a respiratory specialist clinic through to March 2022 to establish a final diagnosis. FINDINGS: We recruited 392 (91.6%) of those in the selected communities; median age = 8.4 years (interquartile range [IQR] 5.1-11.5). Seventy children (17.9%) had a chronic respiratory pathology or abnormal spirometry results. PBB was confirmed in 30 (7.7%), CSLD = 13 (3.3%), bronchiectasis = 5 (1.3%) and asthma = 17 (4.3%). The prevalence of chronic wet cough significantly increased with increasing age. INTERPRETATION: The prevalence of PBB, CSLD and bronchiectasis is high in Aboriginal children and chronic wet cough increases with age. This study highlights the high disease burden in Aboriginal children and the urgent need for strategies to address these conditions.
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Asma , Infecções Bacterianas , Bronquiectasia , Pneumopatias , Adulto , Criança , Pré-Escolar , Humanos , Tosse/epidemiologia , Tosse/diagnóstico , Prevalência , Estudos Transversais , Bronquiectasia/diagnóstico , Pneumopatias/diagnóstico , Supuração , Infecções Bacterianas/microbiologia , Doença Crônica , Asma/epidemiologiaRESUMO
The viral resistance of marketed antiviral drugs including the emergence of new viral resistance of the only marketed CCR5 entry inhibitor, maraviroc, makes it necessary to develop new CCR5 allosteric inhibitors. A mutagenesis/modeling approach was used (a) to remove the potential hERG liability in an otherwise very promising series of compounds and (b) to design a new class of compounds with an unique mutant fingerprint profile depending on residues in the N-terminus and the extracellular loop 2. On the basis of residues, which were identified by mutagenesis as key interaction sites, binding modes of compounds were derived and utilized for compound design in a prospective manner. The compounds were then synthesized, and in vitro evaluation not only showed that they had good antiviral potency but also fulfilled the requirement of low hERG inhibition, a criterion necessary because a potential approved drug would be administered chronically. This work utilized an interdisciplinary approach including medicinal chemistry, molecular biology, and computational chemistry merging the structural requirements for potency with the requirements of an acceptable in vitro profile for allosteric CCR5 inhibitors. The obtained mutant fingerprint profiles of CCR5 inhibitors were used to translate the CCR5 allosteric binding site into a general pharmacophore, which can be used for discovering new inhibitors.
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Fármacos Anti-HIV/farmacologia , Desenho de Fármacos , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Leucócitos Mononucleares/efeitos dos fármacos , Ureia/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Antagonistas dos Receptores CCR5 , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Peso Molecular , Mutagênese , Estereoisomerismo , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/químicaRESUMO
A novel series of CCR5 antagonists were identified based on the redesign of Schering C. An SAR was established based on inhibition of CCR5 (RANTES) binding and these compounds exhibited potent inhibition of R5 HIV-1 replication in peripheral blood mononuclear cells.
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Amidas/química , Antagonistas dos Receptores CCR5 , Óxidos N-Cíclicos/química , HIV-1/efeitos dos fármacos , Piperidinas/química , Piridinas/química , Amidas/síntese química , Amidas/farmacocinética , Animais , Cães , Desenho de Fármacos , Humanos , Oximas , Ratos , Receptores CCR5/metabolismo , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
BACKGROUND: To our knowledge, no previous study has examined the inter-relationship between frailty, dysglycaemia, and mortality in frail older adults with type 2 diabetes who are on insulin therapy. We used continuous glucose monitors (CGMs) to profile this patient population and determine the prognostic value of CGM metrics. We hypothesised that incremental frailty was associated with increased hypoglycaemia or time below range (TBR). METHODS: HARE was a multicentre, prospective, observational cohort study with mortality hazard analysis carried out in four hospitals in Hong Kong. Eligible participants were community-living adults aged 70 years and older; had had type 2 diabetes for 5 years or more; were on insulin therapy; were frail; and were not hospitalised at the time of frailty assessment and CGM recording. Glucose control was characterised according to the Advanced Technologies and Treatments for Diabetes 2019 international consensus clinical targets. Frailty index was computed, and comprehensive frailty assessments and targeted serum metabolic profiling were performed. The Jonckheere-Terpstra test for trend was used to analyse frailty index tertiles and variables. Inter-relationships between CGM metrics and frailty, glycated haemoglobin A1c (HbA1c), and serum albumin were characterised using adjusted regression models. Survival analysis and Cox proportional hazard modelling were performed. FINDINGS: Between July 25, 2018, and Sept 27, 2019, 225 participants were recruited, 222 of whom had CGMs fitted and 215 of whom had analysable CGM data (190 were frail, 25 were not frail). Incremental frailty was associated with older age, greater HbA1c, worse renal function, and history of stroke. Eight of 11 CGM metrics were significantly associated with frailty. Decreased time in range (TIR; glucose concentration 3·9-10·0 mmol/L) and increased time above range (TAR) metrics were strongly correlated with increased frailty and hyperglycaemia, whereas TBR metrics were marginally or not different between frailty levels. Glucose-lowering agents did not significantly affect regression estimates. In patients with HbA1c of 7·5% or more, reduced serum albumin was associated with level 2 TAR (glucose concentration >13·9 mmol/L) and dysglycaemia. During a median follow-up of 28·0 months (IQR 25·3-30·4), increased level 2 TAR was predictive of mortality explainable by frailty in the absence of detectable interaction. Each 1% increment of level 2 TAR was associated with 1·9% increase in mortality hazard. INTERPRETATION: In older adults with type 2 diabetes who are on insulin therapy, incremental frailty was associated with increased dysglycaemia and hyperglycaemia rather than hypoglycaemia. Mortality hazard was increased with severe hyperglycaemia. Future clinical studies and trials targeting actionable CGM metrics highlighted in this study could translate into improved care and outcomes. FUNDING: Health and Medical Research Fund, Food and Health Bureau, The Government of the Hong Kong Special Administrative Region of China.
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Diabetes Mellitus Tipo 2 , Fragilidade , Lebres , Hiperglicemia , Hipoglicemia , Idoso , Idoso de 80 Anos ou mais , Animais , Glicemia/análise , Automonitorização da Glicemia , Estudos de Coortes , Diabetes Mellitus Tipo 2/tratamento farmacológico , Fragilidade/epidemiologia , Humanos , Hipoglicemia/induzido quimicamente , Insulina , Insulina Regular Humana , Estudos Prospectivos , Albumina Sérica/análiseRESUMO
Substantial evidence demonstrates that ostracism has powerful negative effects on psychological well-being. However, little is known about how to ameliorate the negative effects of this ubiquitous social experience. A key preliminary strategy for developing effective methods to reduce the negative impact of ostracism is to examine factors that influence the persistence of these effects. Therefore, the authors examined whether the persistence of these negative effects is dependent on the vantage perspective from which an experience of exclusion is recalled. Using a virtual ball-toss game, being ostracized elicited an immediate aversive effect; furthermore, these effects persisted when individuals recalled the experience from an observer perspective compared with a field perspective. This study shows, for the first time, that the persistence of the debilitating effects of ostracism is influenced by how individuals recall that experience. These results have implications for the development of ameliorative strategies to manage the impact of social exclusion.
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Relações Interpessoais , Rememoração Mental , Isolamento Social/psicologia , Adaptação Psicológica , Jogos Experimentais , Humanos , Individualidade , Desejabilidade Social , Estresse Psicológico/psicologiaRESUMO
Tarsal-carpal coalition syndrome is a progressive condition involving synostosis of the wrist, ankle and digits. We describe a mother and her newborn that have this rare inherited condition where the diagnosis was made only after the baby's birth. The baby's condition was suspected on antenatal scanning, and he was born with reduced range of motion of his digits, elbows and ankles. The mother's condition has progressed to involve a fixed flexion deformity of her bilateral elbows, synostoses of her second to fifth digits and extensive coalition of her tarsal and carpal bones. She has required regular osteotomies to improve limb functioning and quality of life.
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Ossos do Carpo/anormalidades , Proteínas de Transporte/genética , Deformidades Congênitas do Pé/diagnóstico por imagem , Deformidades Congênitas do Pé/cirurgia , Deformidades Congênitas da Mão/diagnóstico por imagem , Deformidades Congênitas da Mão/cirurgia , Estribo/anormalidades , Sinostose/diagnóstico por imagem , Sinostose/cirurgia , Ossos do Tarso/anormalidades , Ossos do Carpo/diagnóstico por imagem , Ossos do Carpo/cirurgia , Diagnóstico Precoce , Feminino , Deformidades Congênitas do Pé/genética , Deformidades Congênitas da Mão/genética , Humanos , Recém-Nascido , Masculino , Idade Materna , Osteotomia , Polimorfismo de Nucleotídeo Único , Estribo/diagnóstico por imagem , Sinostose/genética , Ossos do Tarso/diagnóstico por imagem , Ossos do Tarso/cirurgia , Adulto JovemRESUMO
The chemokine receptor CXCR4 is widely expressed on different cell types, is involved in leukocyte chemotaxis, and is a co-receptor for HIV. AMD3100 has been shown to be a CXCR4 receptor antagonist, and to block HIV infection of T-tropic, X4-using, virus in vitro and in vivo. AMD3100 is an effective mobilizer of hematopoietic stem cells and is being investigated in clinical trials in multiple myeloma and non-Hodgkins lymphoma patients. Using the CCRF-CEM T-cell line that constitutively expresses CXCR4 we confirmed that AMD3100 was an antagonist of SDF-1/CXCL12 ligand binding (IC50=651+/-37 nM). We have also shown that AMD3100 inhibits SDF-1 mediated GTP-binding (IC50=27+/-2.2 nM), SDF-1 mediated calcium flux (IC50=572+/-190 nM), and SDF-1 stimulated chemotaxis (IC50=51+/-17 nM). AMD3100 did not inhibit calcium flux against cells expressing CXCR3, CCR1, CCR2b, CCR4, CCR5 or CCR7 when stimulated with their cognate ligands, nor did it inhibit receptor binding of LTB4. AMD3100 did not, on its own, induce a calcium flux in the CCRF-CEM cells, which express multiple GPCRs including CXCR4, CCR4 and CCR7. Furthermore, AMD3100 neither stimulated GTP-binding, an assay for GPCR activation, in CEM cell membranes; nor chemotaxis of CCRF-CEM cells. These data therefore demonstrate that AMD3100 is a specific antagonist of CXCR4, is not cross-reactive with other chemokine receptors, and is not an agonist of CXCR4.
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Compostos Heterocíclicos/farmacologia , Receptores CXCR4/antagonistas & inibidores , Benzilaminas , Cálcio/metabolismo , Linhagem Celular , Quimiocina CXCL12 , Quimiocinas CXC/metabolismo , Quimiotaxia/efeitos dos fármacos , Ciclamos , Humanos , Ligação Proteica , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: Iron deficiency anemia is highly prevalent in patients with chronic kidney disease and is often treated with intravenous iron. There are few trials directly comparing the safety and efficacy of different intravenous iron products. METHODS: This post-hoc analysis pooled data from 767 patients enrolled in two randomized, controlled, open-label trials of similar design comparing the treatment of iron deficiency anemia with ferumoxytol and iron sucrose across patients with all stages of renal function. One trial was conducted in adults with CKD either on or not on dialysis and the second in adults with IDA of any underlying cause and a history of unsatisfactory oral iron therapy or in whom oral iron could not be used who had normal to no worse than moderately impaired renal function. Patients were categorized by chronic kidney disease stage (i.e., estimated glomerular filtration rate), and the primary efficacy endpoint was the mean change in hemoglobin from Baseline to Week 5. RESULTS: The overall incidence of adverse events was numerically lower in ferumoxytol-treated patients compared to those treated with iron sucrose (42.4 vs. 50.2 %, respectively); the incidence of treatment-related adverse events was generally similar between the two treatment groups (13.6 vs. 16.0 %, respectively). Adverse events of Special Interest (i.e., hypotension, hypersensitivity) occurred at lower rates in those treated with ferumoxytol compared to those treated with iron sucrose (2.5 vs. 5.3 %, respectively). Overall, mean hemoglobin increased in both treatment groups, regardless of degree of renal insufficiency, although greater increases were seen among those with less severe kidney damage. Mean increases in hemoglobin from Baseline to Week 5 were significantly greater with ferumoxytol than with iron sucrose treatment in the subgroup with an estimated glomerular filtration rate ≥90 mL/min (Least Squares mean difference = 0.53 g/dL; p < 0.001). There were no other consistent, significant differences in hemoglobin levels between treatment groups for the other chronic kidney disease categories except for isolated instances favoring ferumoxytol. CONCLUSIONS: The efficacy and safety of ferumoxytol is at least comparable to iron sucrose in patients with varying degrees of renal function. TRIAL REGISTRATION: (CKD-201; ClinicalTrials.gov identifier: NCT01052779; registered 15 January, 2010), (IDA-302; ClinicalTrials.gov identifier: NCT01114204; registered 29 April, 2010).
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Chemokine receptors have been implicated in several disease processes such as acute and chronic inflammation, cancer, and allograft rejection and are therefore targets for drug development. The chemokine receptors CCR5 and CXCR4 are of particular interest as they serve as entry cofactors for human immunodeficiency virus. These receptors are members of the G protein-coupled receptor (GPCR) family. In this respect, assessing GPCR activation by GTP binding is an important tool to study the early stage of signal transduction. The assay normally utilizes the non-hydrolysable GTP analogue guanosine 5'-gamma-[35S]thiotriphosphate. In order to avoid the problems involved in working with radioactivity, a new non-radioactive version of the assay was developed using a europium-labeled GTP analogue in which europium-GTP binding can be assayed using time-resolved fluorescence. The assay was optimized for CXCR4 and CCR5 and validated for screening of chemokine antagonists using the small molecule CXCR4 antagonist AMD3100 and CCR5 antagonists.