Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 33
Filtrar
1.
Ophthalmic Plast Reconstr Surg ; 37(4): e143-e145, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33782323

RESUMO

A 91-year-old female with a history of chronic lymphocytic leukemia developed recurrent bouts of bilateral dacryocystitis. She underwent incision and drainage of the lacrimal sac with culture demonstrating the rare bacteria Stenotrophomonas maltophilia. She underwent subsequent dacryocystectomy with biopsy revealing bilateral involvement of chronic lymphocytic leukemia in the lacrimal sac. Stenotrophomonas maltophilia has been associated with immune suppression and is rarely seen in dacryocystitis. Local and/or systemic immune deregulation or suppression may play a role in lacrimal sac infection with this bacterium in some patients.


Assuntos
Dacriocistite , Dacriocistorinostomia , Doenças do Aparelho Lacrimal , Leucemia Linfocítica Crônica de Células B , Ducto Nasolacrimal , Stenotrophomonas maltophilia , Idoso de 80 Anos ou mais , Dacriocistite/diagnóstico , Dacriocistite/cirurgia , Feminino , Humanos , Doenças do Aparelho Lacrimal/cirurgia
3.
Sci Immunol ; 5(52)2020 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-33097591

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease in which airway macrophages (AMs) play a key role. Itaconate has emerged as a mediator of macrophage function, but its role during fibrosis is unknown. Here, we reveal that itaconate is an endogenous antifibrotic factor in the lung. Itaconate levels are reduced in bronchoalveolar lavage, and itaconate-synthesizing cis-aconitate decarboxylase expression (ACOD1) is reduced in AMs from patients with IPF compared with controls. In the murine bleomycin model of pulmonary fibrosis, Acod1-/- mice develop persistent fibrosis, unlike wild-type (WT) littermates. Profibrotic gene expression is increased in Acod1-/- tissue-resident AMs compared with WT, and adoptive transfer of WT monocyte-recruited AMs rescued mice from disease phenotype. Culture of lung fibroblasts with itaconate decreased proliferation and wound healing capacity, and inhaled itaconate was protective in mice in vivo. Collectively, these data identify itaconate as critical for controlling the severity of lung fibrosis, and targeting this pathway may be a viable therapeutic strategy.


Assuntos
Carboxiliases/metabolismo , Fibrose Pulmonar Idiopática/imunologia , Macrófagos Alveolares/imunologia , Succinatos/metabolismo , Administração por Inalação , Transferência Adotiva/métodos , Adulto , Idoso , Animais , Bleomicina/administração & dosagem , Bleomicina/toxicidade , Líquido da Lavagem Broncoalveolar/imunologia , Broncoscopia , Estudos de Casos e Controles , Células Cultivadas , Modelos Animais de Doenças , Feminino , Fibroblastos , Voluntários Saudáveis , Humanos , Hidroliases/genética , Hidroliases/metabolismo , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/terapia , Pulmão/citologia , Pulmão/imunologia , Pulmão/patologia , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/transplante , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Cultura Primária de Células , Índice de Gravidade de Doença , Succinatos/administração & dosagem , Succinatos/imunologia
4.
BMJ Open Respir Res ; 7(1)2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32928787

RESUMO

The SARS-CoV-2 can lead to severe illness with COVID-19. Outcomes of patients requiring mechanical ventilation are poor. Awake proning in COVID-19 improves oxygenation, but on data clinical outcomes is limited. This single-centre retrospective study aimed to assess whether successful awake proning of patients with COVID-19, requiring respiratory support (continuous positive airways pressure (CPAP) or high-flow nasal oxygen (HFNO)) on a respiratory high-dependency unit (HDU), is associated with improved outcomes. HDU care included awake proning by respiratory physiotherapists. Of 565 patients admitted with COVID-19, 71 (12.6%) were managed on the respiratory HDU, with 48 of these (67.6%) requiring respiratory support. Patients managed with CPAP alone 22/48 (45.8%) were significantly less likely to die than patients who required transfer onto HFNO 26/48 (54.2%): CPAP mortality 36.4%; HFNO mortality 69.2%, (p=0.023); however, multivariate analysis demonstrated that increasing age and the inability to awake prone were the only independent predictors of COVID-19 mortality. The mortality of patients with COVID-19 requiring respiratory support is considerable. Data from our cohort managed on HDU show that CPAP and awake proning are possible in a selected population of COVID-19, and may be useful. Further prospective studies are required.


Assuntos
Pressão Positiva Contínua nas Vias Aéreas/métodos , Infecções por Coronavirus/terapia , Oxigenoterapia/métodos , Posicionamento do Paciente/métodos , Pneumonia Viral/terapia , Decúbito Ventral , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus , COVID-19 , Infecções por Coronavirus/mortalidade , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ventilação não Invasiva/métodos , Razão de Chances , Pandemias , Pneumonia Viral/mortalidade , Estudos Retrospectivos , SARS-CoV-2 , Resultado do Tratamento , Reino Unido , Vigília
5.
Respir Res ; 21(1): 75, 2020 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-32216814

RESUMO

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease with poor prognosis and a significant unmet medical need. This study evaluated the safety, pharmacokinetics (PK) and target engagement in the lungs, of GSK3008348, a novel inhaled alpha-v beta-6 (αvß6) integrin inhibitor, in participants with IPF. METHODS: This was a phase 1b, randomised, double-blind (sponsor unblind) study, conducted in the UK (two clinical sites, one imaging unit) between June 2017 and July 2018 (NCT03069989). Participants with a definite or probable diagnosis of IPF received a single nebulised dose of 1000 mcg GSK3008348 or placebo (ratio 5:2) in two dosing periods. In period 1, safety and PK assessments were performed up to 24 h post-dose; in period 2, after a 7-day to 28-day washout, participants underwent a total of three positron emission tomography (PET) scans: baseline, Day 1 (~ 30 min post-dosing) and Day 2 (~ 24 h post-dosing), using a radiolabelled αvß6-specific ligand, [18F]FB-A20FMDV2. The primary endpoint was whole lung volume of distribution (VT), not corrected for air volume, at ~ 30 min post-dose compared with pre-dose. The study success criterion, determined using Bayesian analysis, was a posterior probability (true % reduction in VT > 0%) of ≥80%. RESULTS: Eight participants with IPF were enrolled and seven completed the study. Adjusted posterior median reduction in uncorrected VT at ~ 30 min after GSK3008348 inhalation was 20% (95% CrI: - 9 to 42%). The posterior probability that the true % reduction in VT > 0% was 93%. GSK3008348 was well tolerated with no reports of serious adverse events or clinically significant abnormalities that were attributable to study treatment. PK was successfully characterised showing rapid absorption followed by a multiphasic elimination. CONCLUSIONS: This study demonstrated engagement of the αvß6 integrin target in the lung following nebulised dosing with GSK3008348 to participants with IPF. To the best of our knowledge this is the first time a target-specific PET radioligand has been used to assess target engagement in the lung, not least for an inhaled drug. TRIAL REGISTRATION: clinicaltrials.gov: NCT03069989; date of registration: 3 March 2017.


Assuntos
Butiratos/uso terapêutico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Integrinas/antagonistas & inibidores , Naftiridinas/uso terapêutico , Pirazóis/uso terapêutico , Pirrolidinas/uso terapêutico , Volume de Ventilação Pulmonar/efeitos dos fármacos , Administração por Inalação , Idoso , Antígenos de Neoplasias , Teorema de Bayes , Butiratos/administração & dosagem , Butiratos/farmacocinética , Método Duplo-Cego , Determinação de Ponto Final , Feminino , Humanos , Fibrose Pulmonar Idiopática/diagnóstico por imagem , Masculino , Naftiridinas/administração & dosagem , Naftiridinas/farmacocinética , Nebulizadores e Vaporizadores , Tomografia por Emissão de Pósitrons , Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Pirrolidinas/administração & dosagem , Pirrolidinas/farmacocinética , Resultado do Tratamento
6.
Am J Respir Crit Care Med ; 200(2): 209-219, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31051082

RESUMO

Rationale: Idiopathic pulmonary fibrosis (IPF) is a devastating progressive disease with limited therapeutic options. Airway macrophages (AMs) are key components of the defense of the airways and are implicated in the pathogenesis of IPF. Alterations in iron metabolism have been described during fibrotic lung disease and in murine models of lung fibrosis. However, the role of transferrin receptor 1 (CD71)-expressing AMs in IPF is not known. Objectives: To assess the role of CD71-expressing AMs in the IPF lung. Methods: We used multiparametric flow cytometry, gene expression analysis, and phagocytosis/transferrin uptake assays to delineate the role of AMs expressing or lacking CD71 in the BAL of patients with IPF and of healthy control subjects. Measurements and Main Results: There was a distinct increase in proportions of AMs lacking CD71 in patients with IPF compared with healthy control subjects. Concentrations of BAL transferrin were enhanced in IPF-BAL, and furthermore, CD71- AMs had an impaired ability to sequester transferrin. CD71+ and CD71- AMs were phenotypically, functionally, and transcriptionally distinct, with CD71- AMs characterized by reduced expression of markers of macrophage maturity, impaired phagocytosis, and enhanced expression of profibrotic genes. Importantly, proportions of AMs lacking CD71 were independently associated with worse survival, underlining the importance of this population in IPF and as a potential therapeutic target. Conclusions: Taken together, these data highlight how CD71 delineates AM subsets that play distinct roles in IPF and furthermore show that CD71- AMs may be an important pathogenic component of fibrotic lung disease.


Assuntos
Antígenos CD/metabolismo , Fibrose Pulmonar Idiopática/metabolismo , Macrófagos Alveolares/metabolismo , Fagocitose , Receptores da Transferrina/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Estudos de Casos e Controles , Feminino , Citometria de Fluxo , Perfilação da Expressão Gênica , Humanos , Ferro/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real , Taxa de Sobrevida , Transferrina/metabolismo , Adulto Jovem
7.
Am J Respir Crit Care Med ; 200(2): 199-208, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31034279

RESUMO

Rationale: Several common and rare genetic variants have been associated with idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung. Objectives: To develop an integrated understanding of the rare and common variants located in multiple loci that have been reported to contribute to the risk of disease. Methods: We performed deep targeted resequencing (3.69 Mb of DNA) in cases (n = 3,624) and control subjects (n = 4,442) across genes and regions previously associated with disease. We tested for associations between disease and 1) individual common variants via logistic regression and 2) groups of rare variants via sequence kernel association tests. Measurements and Main Results: Statistically significant common variant association signals occurred in all 10 of the regions chosen based on genome-wide association studies. The strongest risk variant is the MUC5B promoter variant rs35705950, with an odds ratio of 5.45 (95% confidence interval, 4.91-6.06) for one copy of the risk allele and 18.68 (95% confidence interval, 13.34-26.17) for two copies of the risk allele (P = 9.60 × 10-295). In addition to identifying for the first time that rare variation in FAM13A is associated with disease, we confirmed the role of rare variation in the TERT and RTEL1 gene regions in the risk of IPF, and found that the FAM13A and TERT regions have independent common and rare variant signals. Conclusions: A limited number of common and rare variants contribute to the risk of idiopathic pulmonary fibrosis in each of the resequencing regions, and these genetic variants focus on biological mechanisms of host defense and cell senescence.


Assuntos
Senescência Celular/genética , Interações Hospedeiro-Patógeno/genética , Fibrose Pulmonar Idiopática/genética , Transportadores de Cassetes de Ligação de ATP/genética , Estudos de Casos e Controles , DNA Helicases/genética , Exorribonucleases/genética , Feminino , Proteínas Ativadoras de GTPase/genética , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Modelos Logísticos , Masculino , Mucina-5B/genética , Regiões Promotoras Genéticas/genética , Proteína A Associada a Surfactante Pulmonar/genética , Proteína C Associada a Surfactante Pulmonar/genética , RNA/genética , Análise de Sequência de DNA , Telomerase/genética , Proteínas de Ligação a Telômeros/genética
8.
Eur Respir J ; 53(3)2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30765508

RESUMO

Phosphatidylinositol 3-kinases (PI3Ks) and mammalian target of rapamycin (mTOR) play a role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Omipalisib (GSK2126458) is a potent inhibitor of PI3K/mTOR.A randomised, placebo-controlled, double-blind, repeat dose escalation, experimental medicine study of omipalisib in subjects with IPF was conducted (NCT01725139) to test safety, tolerability, pharmacokinetics and pharmacodynamics. Omipalisib was dosed at 0.25 mg, 1 mg and 2 mg twice daily for 8 days in four cohorts of four subjects randomised 3:1 to receive omipalisib or placebo (two cohorts received 2 mg twice daily).17 subjects with IPF were enrolled. The most common adverse event was diarrhoea, which was reported by four participants. Dose-related increases in insulin and glucose were observed. Pharmacokinetic analysis demonstrated that exposure in the blood predicts lung exposure. Exposure-dependent inhibition of phosphatidylinositol 3,4,5 trisphosphate and pAKT confirmed target engagement in blood and lungs. 18F-2-fluoro-2-deoxy-d-glucose(FDG)-positron emission tomography/computed tomography scans revealed an exposure-dependent reduction in 18F-FDG uptake in fibrotic areas of the lung, as measured by target-to-background, ratio thus confirming pharmacodynamic activity.This experimental medicine study demonstrates acceptable tolerability of omipalisib in subjects with IPF at exposures for which target engagement was confirmed both systemically and in the lungs.


Assuntos
Fibrose Pulmonar Idiopática/tratamento farmacológico , Quinolinas/administração & dosagem , Sulfonamidas/administração & dosagem , Administração Oral , Idoso , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Fluordesoxiglucose F18 , Humanos , Fibrose Pulmonar Idiopática/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/metabolismo , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Piridazinas , Serina-Treonina Quinases TOR/metabolismo , Resultado do Tratamento
9.
Lancet Respir Med ; 6(10): 759-770, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30170904

RESUMO

BACKGROUND: In fibrotic interstitial lung diseases, exertional breathlessness is strongly linked to health-related quality of life (HRQOL). Breathlessness is often associated with oxygen desaturation, but few data about the use of ambulatory oxygen in patients with fibrotic interstitial lung disease are available. We aimed to assess the effects of ambulatory oxygen on HRQOL in patients with interstitial lung disease with isolated exertional hypoxia. METHODS: AmbOx was a prospective, open-label, mixed-method, crossover randomised controlled clinical trial done at three centres for interstitial lung disease in the UK. Eligible patients were aged 18 years or older, had fibrotic interstitial lung disease, were not hypoxic at rest but had a fall in transcutaneous arterial oxygen saturation to 88% or less on a screening visit 6-min walk test (6MWT), and had self-reported stable respiratory symptoms in the previous 2 weeks. Participants were randomly assigned (1:1) to either oxygen treatment or no oxygen treatment for 2 weeks, followed by crossover for another 2 weeks. Randomisation was by a computer-generated sequence of treatments randomly permuted in blocks of constant size (fixed size of ten). The primary outcome, which was assessed by intention to treat, was the change in total score on the King's Brief Interstitial Lung Disease questionnaire (K-BILD) after 2 weeks on oxygen compared with 2 weeks of no treatment. General linear models with treatment sequence as a fixed effect were used for analysis. Patient views were explored through semi-structured topic-guided interviews in a subgroup of participants. This study was registered with ClinicalTrials.gov, number NCT02286063, and is closed to new participants with all follow-up completed. FINDINGS: Between Sept 10, 2014, and Oct 5, 2016, 84 patients were randomly assigned, 41 randomised to ambulatory oxygen first and 43 to no oxygen. 76 participants completed the trial. Compared with no oxygen, ambulatory oxygen was associated with significant improvements in total K-BILD scores (mean 55·5 [SD 13·8] on oxygen vs 51·8 [13·6] on no oxygen, mean difference adjusted for order of treatment 3·7 [95% CI 1·8 to 5·6]; p<0·0001), and scores in breathlessness and activity (mean difference 8·6 [95% CI 4·7 to 12·5]; p<0·0001) and chest symptoms (7·6 [1·9 to 13·2]; p=0·009) subdomains. However, the effect on the psychological subdomain was not significant (2·4 [-0·6 to 5·5]; p=0·12). The most common adverse events were upper respiratory tract infections (three in the oxygen group and one in the no-treatment group). Five serious adverse events, including two deaths (one in each group) occurred, but none were considered to be related to treatment. INTERPRETATION: Ambulatory oxygen seemed to be associated with improved HRQOL in patients with interstitial lung disease with isolated exertional hypoxia and could be an effective intervention in this patient group, who have few therapeutic options. However, further studies are needed to confirm this finding. FUNDING: UK National Institute for Health Research.


Assuntos
Doenças Pulmonares Intersticiais/terapia , Oxigenoterapia/métodos , Oxigênio/administração & dosagem , Fibrose Pulmonar/terapia , Qualidade de Vida , Idoso , Estudos Cross-Over , Feminino , Humanos , Análise de Intenção de Tratamento , Modelos Lineares , Doenças Pulmonares Intersticiais/psicologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fibrose Pulmonar/psicologia , Resultado do Tratamento
10.
Theor Biol Forum ; 111(1-2): 105-106, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31089676
12.
Trials ; 18(1): 275, 2017 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-28619061

RESUMO

BACKGROUND: Interstitial lung disease (ILD) frequently complicates systemic autoimmune disorders resulting in considerable morbidity and mortality. The connective tissue diseases (CTDs) most frequently resulting in ILD include: systemic sclerosis, idiopathic inflammatory myositis (including dermatomyositis, polymyositis and anti-synthetase syndrome) and mixed connective tissue disease. Despite the development, over the last two decades, of a range of biological therapies which have resulted in significant improvements in the treatment of the systemic manifestations of CTD, the management of CTD-associated ILD has changed little. At present there are no approved therapies for CTD-ILD. Following trials in scleroderma-ILD, cyclophosphamide is the accepted standard of care for individuals with severe or progressive CTD-related ILD. Observational studies have suggested that the anti-CD20 monoclonal antibody, rituximab, is an effective rescue therapy in the treatment of refractory CTD-ILD. However, before now, there have been no randomised controlled trials assessing the efficacy of rituximab in this treatment population. METHODS/DESIGN: RECITAL is a UK, multicentre, prospective, randomised, double-blind, double-dummy, controlled trial funded by the Efficacy and Mechanism Evaluation Programme of the Medical Research Council and National Institute for Health Research. The trial will compare rituximab 1 g given intravenously, twice at an interval of 2 weeks, with intravenously administered cyclophosphamide given monthly at a dose of 600 mg/m2 body surface area in individuals with ILD due to systemic sclerosis, idiopathic inflammatory myositis (including anti-synthetase syndrome) or mixed connective tissue disease. A total of 116 individuals will be randomised 1:1 to each of the two treatment arms, with stratification based on underlying CTD, and will be followed for a total of 48 weeks from first dose. The primary endpoint for the study will be change in forced vital capacity (FVC) at 24 weeks. Key secondary endpoints include: safety, change in FVC at 48 weeks as well as survival, change in oxygen requirements, total 48-week corticosteroid exposure and utilisation of health care resources. DISCUSSION: This is the first randomised control trial to study the efficacy of rituximab as first-line treatment in CTD-associated ILD. The results generated should provide important information on the treatment of a life-threatening complication affecting a rare group of CTDs. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01862926. Registered on 22 May 2013.


Assuntos
Doenças do Tecido Conjuntivo/tratamento farmacológico , Ciclofosfamida/administração & dosagem , Imunossupressores/administração & dosagem , Doenças Pulmonares Intersticiais/tratamento farmacológico , Pulmão/efeitos dos fármacos , Rituximab/administração & dosagem , Administração Intravenosa , Corticosteroides/administração & dosagem , Protocolos Clínicos , Doenças do Tecido Conjuntivo/diagnóstico , Doenças do Tecido Conjuntivo/imunologia , Doenças do Tecido Conjuntivo/fisiopatologia , Ciclofosfamida/efeitos adversos , Método Duplo-Cego , Esquema de Medicação , Humanos , Imunossupressores/efeitos adversos , Pulmão/imunologia , Pulmão/fisiopatologia , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/fisiopatologia , Oxigenoterapia , Estudos Prospectivos , Recuperação de Função Fisiológica , Projetos de Pesquisa , Rituximab/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Reino Unido , Capacidade Vital
13.
Am J Bioeth ; 17(3): 47-48, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28207359
14.
Theor Biol Forum ; 109(1-2): 123-130, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29513357

RESUMO

DESCRIPTION: Ever since Darwin, there have been challenges to the claim that the natural selection of small random variations is a sufficient explanation of evolution. Even mainstream evolutionists are now beginning to accept that something more is required. The question is whether this will be merely a few add-ons that leave the paradigm unaltered, or whether the whole framework of explanation, including its application to other disciplines, will be changed.


Assuntos
Evolução Biológica , Aptidão Genética , Variação Genética/genética , Seleção Genética/genética , Animais , Biologia/métodos , Biologia/tendências , Genótipo , Humanos , Fenótipo
15.
Arab J Urol ; 12(1): 37-41, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26019921

RESUMO

BACKGROUND: Modern medicine has created a need for innovative methods of training that create safe, proficient specialists with adequate experience, and who are fit for purpose in this new system. Patient safety and patient-focused care are central to current practice and promoted by the use of simulation, human factors, team-based, multidisciplinary and interspecialty training. An acknowledgement that postgraduate training occurs within the work environment underlies the need to create systems that support learning within the workplace. Supervision, protected time for adequate induction and the opportunity to be involved in workplace learning are the key. It is also important that robust mechanisms to assure the quality of postgraduate education are in place. METHODS: Available reports were researched, and the particularities of anaesthetic training were outlined and summarised. Then, in a translational approach, we examined how to apply the lessons learned from anaesthesiological training to surgical training. RESULTS: The trend towards reducing the working hours of junior doctors, whilst still providing excellent training, creates a need for innovative, efficient, concentrated training programmes, where trainers and trainees are engaged in a seamless, constant educational endeavour. CONCLUSION: Within this review we offer the system of anaesthetic training in the UK, and some of its recent changes, as a template to highlight themes in postgraduate education that exemplify this innovation and are transferable not only to surgery but across different specialties.

16.
Adv Child Dev Behav ; 44: 257-84, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23834008

RESUMO

While Darwinism has contributed much to our understanding of the living world, it has not given us an adequate account of why organisms are the way they are and how they came to be that way. For that we will need all of science, not just a single algorithm. The crucial contribution of Darwinism to biology is that it explains how we can have functional physical traits without a creator. This is less important in psychology because no one is surprised when people behave in ways that work to their advantage. Evolutionary psychology nevertheless follows the Darwinian model. It assumes from the outset that the brain is largely modular and that human nature is made up of a very large number of functionally specialized psychological mechanisms that have been constructed over time by natural selection. How much confidence one should have in its conclusions depends very much on how far one accepts its premises.


Assuntos
Evolução Biológica , Epigênese Genética , Psicologia , Biologia de Sistemas , Humanos , Modelos Genéticos
18.
Am J Hematol ; 86(12): 1032-4, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21812020

RESUMO

Clopidogrel is a widely used antiplatelet agent that irreversibly inhibits platelet P2Y12 ADP receptors after conversion to an active metabolite. There are a number of laboratory tests capable of detecting clopidogrel-induced platelet inhibition and published literature correlates suboptimal clopidogrel response to adverse cardiovascular outcomes. Genetic polymorphisms are thought to affect conversion of the prodrug to the active metabolite, and the FDA has recently added a black-box warning to clopidogrel to highlight the effects of these polymorphisms on drug bioavailability and to inform prescribers about the availability of genetic testing. For these reasons, there is growing interest in the use of laboratory tests to monitor patients treated with clopidogrel. This article summarizes the currently available laboratory testing, including platelet function tests and genotyping for CYP2C19 variants.


Assuntos
Plaquetas/efeitos dos fármacos , Monitoramento de Medicamentos/métodos , Inibidores da Agregação Plaquetária/farmacocinética , Inibidores da Agregação Plaquetária/uso terapêutico , Ticlopidina/análogos & derivados , Hidrocarboneto de Aril Hidroxilases/genética , Hidrocarboneto de Aril Hidroxilases/metabolismo , Disponibilidade Biológica , Biotransformação , Clopidogrel , Citocromo P-450 CYP2C19 , Técnicas de Genotipagem , Humanos , Inibidores da Agregação Plaquetária/efeitos adversos , Testes de Função Plaquetária , Pró-Fármacos/efeitos adversos , Pró-Fármacos/farmacocinética , Pró-Fármacos/uso terapêutico , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Receptores Purinérgicos P2Y12/química , Ticlopidina/efeitos adversos , Ticlopidina/farmacocinética , Ticlopidina/uso terapêutico
20.
J Endourol ; 23(10): 1603-6, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19747056

RESUMO

BACKGROUND AND PURPOSE: The prone position is the most commonly used position for percutaneous endourologic procedures. It is usually combined with a general anesthesia. In high-risk patients, this approach can lead to circulatory and respiratory compromises. Operating on such patients in a full lateral position will minimize the hemodynamic and respiratory risks and-if combined with spinal anesthesia-will allow for increased patient comfort and safety. PATIENTS AND METHODS: After rigorous preoperative assessment, 27 medical high-risk patients (12 men) with a mean age of 62 years and an American Society of Anesthesiologists score of 3+ were included in this study. The majority (78%) had regional anesthesia and were fully awake and alert during the operation. The procedures consisted of an initial retrograde renal study/filling with contrast medium with the patient in the lithotomy position to aid kidney puncture. The percutaneous procedure was then performed with the patient in the lateral decubitus position, and access was performed under fluoroscopic and/or ultrasonographic guidance. RESULTS: Twenty-two percutaneous nephrolithotomies (PCNL), 3 anterograde endopyelotomies (AEP), 1 percutaneous resection of renal pelvic transitional-cell carcinoma, and 1 percutaneous renal cyst sclerotization were performed. After PCNL, 11 patients were stone free postoperatively, and a further 8 were stone free after adjuvant shockwave lithotripsy. Two patients needed temporary Double-J stents. One renal access failed. Two procedures were aborted because of hemorrhage. One patient died in the recovery room from uncontrollable renal bleeding. A renal scan after 3 months showed relief of obstruction in the three patients who had undergone AEP. Ultrasonography confirmed complete resolution of the sclerotized renal cyst. Neither of the patients with regional anesthesia needed conversion to general anesthesia. In two patients who experienced moderate pain, a "top-up" with local anesthesia solved the problem. CONCLUSION: The full lateral position-while necessitating expertise and some learning for renal puncture from an unusual angle-is safe in medical high-risk patients. It can be safely performed using regional anesthesia, avoiding the risks of general anesthesia and allowing for patient-anesthetist communication throughout the procedure. Cardiac and respiratory parameters are improved, stable, and easily controlled. As opposed to the supine position, the awake patient is more comfortable, and morbid obesity is not a problem.


Assuntos
Anestesia por Condução , Nefrostomia Percutânea/métodos , Posicionamento do Paciente/métodos , Procedimentos Cirúrgicos Urológicos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Procedimentos Cirúrgicos Urológicos/métodos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...