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1.
Nutr Clin Pract ; 38(1): 157-166, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35788985

RESUMO

BACKGROUND: Preoperative dysphagia screening is rare. The purpose of this study was to assess the prevalence and potential risk factors of preoperative dysphagia risk in adults preparing for surgery. METHODS: The Eating Assessment Tool (EAT-10), Patient-Generated Subjective Global Assessment Short Form (PG-SGA SF), and Sarcopenia Screening Tool (SARC-F) were self-administered in adults preparing for surgery to identify dysphagia, malnutrition, and sarcopenia risk, respectively. Other variables collected include clinical demographics, fall risk, and surgical history associated with increased dysphagia risk. Descriptive summary statistics, univariate analysis, and logistic regression were performed as appropriate. RESULTS: The median age was 69 years and preoperative dysphagia risk was 9.6%. Among 357 patients completing both EAT-10 and PG-SGA SF or SARC-F, 7.3% had preoperative dysphagia and malnutrition risk and 7.2% had preoperative dysphagia and sarcopenia risk. Preoperative dysphagia risk was 2.7 times greater in those with prior surgical history associated with increased risk of dysphagia, 2.2 times higher in women, and almost twice as high in Black patients and patients with fall risk. Logistic regression revealed significant odds ratios (ORs) for prior surgical history associated with increased risk of dysphagia (OR, 2.95; 95% CI, 1.62-5.40) and male sex (OR, 0.52; 95% CI, 0.29-0.94), and a significant relationship between preoperative dysphagia and malnutrition risk (OR, 4.56; 95% CI, 2.02-10.28) when controlling for clinical variables. CONCLUSION: The high prevalence of dysphagia risk alone and in combination with malnutrition and sarcopenia risk in community-dwelling adults underscores the need for standardized preoperative screening and optimization prior to surgery.


Assuntos
Transtornos de Deglutição , Desnutrição , Sarcopenia , Humanos , Masculino , Feminino , Adulto , Idoso , Transtornos de Deglutição/epidemiologia , Transtornos de Deglutição/etiologia , Vida Independente , Avaliação Nutricional , Sarcopenia/etiologia , Sarcopenia/complicações , Prevalência , Desnutrição/diagnóstico , Desnutrição/epidemiologia , Desnutrição/etiologia , Fatores de Risco
2.
Brain Behav Immun ; 102: 312-323, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35259429

RESUMO

BACKGROUND: Systemic inflammation induces acute changes in mood, motivation and cognition that closely resemble those observed in depressed individuals. However, the mechanistic pathways linking peripheral inflammation to depression-like psychopathology via intermediate effects on brain function remain incompletely understood. METHODS: We combined data from 30 patients initiating interferon-α treatment for Hepatitis-C and 20 anti-tumour necrosis factor (TNF) therapy for inflammatory arthritis and used resting-state functional magnetic resonance imaging to investigate acute effects of each treatment on regional global brain connectivity (GBC). We leveraged transcriptomic data from the Allen Human Brain Atlas to uncover potential biological and cellular pathways underpinning regional vulnerability to GBC changes induced by each treatment. RESULTS: Interferon-α and anti-TNF therapies both produced differential small-to-medium sized decreases in regional GBC. However, these were observed within distinct brain regions and the regional patterns of GBC changes induced by each treatment did not correlate suggesting independent underlying processes. Further, the spatial distribution of these differential GBC decreases could be captured by multivariate patterns of constitutive regional expression of genes respectively related to: i) neuroinflammation and glial cells; and ii) glutamatergic neurotransmission and neurons. The extent to which each participant expressed patterns of GBC changes aligning with these patterns of transcriptomic vulnerability also correlated with both acute treatment-induced changes in interleukin-6 (IL-6) and, for Interferon-α, longer-term treatment-associated changes in depressive symptoms. CONCLUSIONS: Together, we present two transcriptomic models separately linking regional vulnerability to the acute effects of interferon-α and anti-TNF treatments on brain function to glial neuroinflammation and glutamatergic neurotransmission. These findings generate hypotheses about two potential brain mechanisms through which bidirectional changes in peripheral inflammation may contribute to the development/resolution of psychopathology.


Assuntos
Transcriptoma , Inibidores do Fator de Necrose Tumoral , Anti-Inflamatórios/farmacologia , Encéfalo , Humanos , Inflamação , Interferon-alfa/efeitos adversos
3.
Med Mycol Case Rep ; 34: 1-4, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34458084

RESUMO

Blastomyces is an endemic fungal pathogen found in regions of North America. It is endemic in the Ohio and Mississippi river valleys, New York, Wisconsin, Colorado, Texas, Kansas, Nebraska, and other regions of the United States. It is common in Canada, mainly Ontario and Manitoba. Here, we report a case of tracheal and pulmonary blastomycosis. Interestingly, this case presented as an unexpected diagnosis as part of a malignancy workup. To our knowledge, this is only the second case of tracheal blastomycosis reported in the literature.

5.
Nat Commun ; 10(1): 3159, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31320635

RESUMO

Plutonium metal undergoes an anomalously large 25% collapse in volume from its largest volume δ phase (δ-Pu) to its low temperature α phase, yet the underlying thermodynamic mechanism has largely remained a mystery. Here we use magnetostriction measurements to isolate a previously hidden yet substantial electronic contribution to the entropy of δ-Pu, which we show to be crucial for the stabilization of this phase. The entropy originates from two competing instabilities of the 5f-electron shell, which we show to drive the volume of Pu in opposing directions, depending on the temperature and volume. Using calorimetry measurements, we establish a robust thermodynamic connection between the two excitation energies, the atomic volume, and the previously reported excess entropy of δ-Pu at elevated temperatures.

6.
Benef Microbes ; 10(4): 473-482, 2019 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-30931589

RESUMO

Effective cultivation methods, total cost, and biomass preservation are key factors that have a significant impact on the commercialisation and effectiveness of probiotics, such as Lactobacillus. Sugar polymers, milk and whey proteins have been suggested as good additives for industrial preparations. Alternative compounds, such as phytophenols, are a more attractive option, given their potential benefits to human health. The overall goal of this study was to determine if the addition of blueberry phytophenols improves the survival of Lactobacillus johnsonii N6.2 during the freeze-drying process. The addition of blueberry aqueous extract (BAE) stimulated the growth of L. johnsonii under aerobic conditions and improved the stationary phase survival of the bacteria. Furthermore, the addition of BAE to the culture media improved the endurance of L. johnsonii N6.2 to freeze-drying stress, as well as to storage at 4 °C for up to 21 weeks. Moreover, blueberry extract performed more effectively as a lyophilising additive compared to skim milk and microencapsulation with whey protein/sodium alginate. In sum, this study demonstrates that BAE is an effective additive to increase the growth and survival of L. johnsonii N6.2 when added to the culture medium and/or used as a lyophilising preservative. Moreover, BAE or other polyphenols sources might likely enhance growth and increase survival of more probiotic lactic acid bacterial strains.


Assuntos
Mirtilos Azuis (Planta) , Aditivos Alimentares , Liofilização , Lactobacillus johnsonii/fisiologia , Probióticos , Aerobiose , Mirtilos Azuis (Planta)/química , Aditivos Alimentares/química , Aditivos Alimentares/farmacologia , Armazenamento de Alimentos , Lactobacillus johnsonii/efeitos dos fármacos , Lactobacillus johnsonii/crescimento & desenvolvimento , Viabilidade Microbiana/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Polifenóis/química , Polifenóis/farmacologia
7.
Dysphagia ; 34(6): 904-915, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-30798360

RESUMO

(1) To examine the association between vocal fold paresis/paralysis (VFP) and poor swallowing outcomes in a thoracic surgery cohort at the population level, and (2) to assess utilization of ENT/speech-language pathology intervention in these cases. The National Inpatient Sample (NIS) represents a 20% stratified sample of discharges from US hospitals. Using ICD-9 codes, discharges undergoing general thoracic surgical procedures between 2008 and 2013 were identified in the NIS. Sub-cohorts of discharges with VFP and those who utilized ENT/SLP services were also identified. Weighted logistic regression models were used to compare binary outcomes such as dysphagia, aspiration pneumonia, and other complications; generalized linear models with generalized estimating equations (GEE) were used to compare total hospital costs and length of stay (LOS). We identified a weighted estimate of 673,940 discharges following general thoracic surgery procedures. The weighted frequency of VFP was 3738 (0.55%). Compared to those without VFP, patients who discharged with VFP had increased odds of dysphagia (6.56, 95% CI 5.07-8.47), aspiration pneumonia (2.54, 95% CI 1.74-3.70), post-operative tracheotomy (3.10, 95% CI 2.16-4.45), and gastrostomy tube requirement (2.46, 95% CI 1.66-3.64). Discharges with VFP also had a longer length of stay and total hospital costs. Of the discharges with VFP, 15.7% received ENT/SLP intervention. VFP after general thoracic procedures is associated with negative swallowing-related health outcomes and higher costs. Despite these negative impacts, most patients with VFP do not receive ENT/SLP intervention, identifying a potential opportunity for improving adverse swallowing-related outcomes.


Assuntos
Transtornos de Deglutição/diagnóstico , Procedimentos Cirúrgicos Torácicos/efeitos adversos , Paralisia das Pregas Vocais/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Transtornos de Deglutição/etiologia , Biomarcadores Ambientais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição de Risco/métodos , Fatores de Risco , Paralisia das Pregas Vocais/etiologia
8.
Laryngoscope ; 128(12): 2815-2822, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30229921

RESUMO

OBJECTIVES/HYPOTHESIS: Vocal fold paralysis/paresis (VFP) is an uncommon but serious complication following esophagectomy. The objectives of this study were to: 1) identify the prevalence of VFP and associated complications after esophagectomy in the United States, and 2) determine the utilization and otolaryngology-head and neck surgery/speech-language pathology (OHNS/SLP) and predictors of such utilization in the management of these patients. STUDY DESIGN: Retrospective database analysis. METHODS: The National Inpatient Sample (NIS) represents a 20% stratified sample of discharges from US hospitals. Using International Classification of Diseases, Ninth Revision, Clinical Modification codes, patients undergoing esophagectomy between 2008 and 2013 were identified in the NIS. Subcohorts of patients with VFP and OHNS/SLP utilization were also identified. Weighted logistic regression models were used to compare binary outcomes such as complications; generalized linear models were used to compare total hospital charges and length of stay (LOS). RESULTS: We studied 10,896 discharges, representing a weighted estimate of 52,610 patients undergoing esophagectomy. The incidence of VFP after esophagectomy was 1.96%. Compared to those without VFP, patients with VFP had a higher incidence of postoperative pneumonia, more medical complications, and were more likely to undergo tracheostomy; hospital charges and LOS were also higher. Of the patients with VFP, 35.0% received OHNS/SLP intervention. CONCLUSIONS: VFP after esophagectomy is associated with postoperative complications, prolonged LOS, and higher hospital costs. OHNS/SLP intervention occurred in roughly one-third of postesophagectomy VFP patients, suggesting there may be opportunities for enhanced evaluation and management of these patients. LEVEL OF EVIDENCE: 4 Laryngoscope, 128:2815-2822, 2018.


Assuntos
Esofagectomia/efeitos adversos , Recursos em Saúde/organização & administração , Complicações Pós-Operatórias , Sistema de Registros , Paralisia das Pregas Vocais/epidemiologia , Prega Vocal/lesões , Idoso , Feminino , Seguimentos , Humanos , Incidência , Masculino , Prevalência , Estudos Retrospectivos , Estados Unidos/epidemiologia , Paralisia das Pregas Vocais/etiologia
9.
Thromb Res ; 140 Suppl 1: S185, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27161712

RESUMO

INTRODUCTION: Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE) are common complications in patients with cancer, affecting up to 18% of patients. VTE risk is increased by surgery and disease progression, whilst chemotherapy further increases risk up to 7-fold compared to patients without cancer. VTE contributes significantly to morbidity and mortality in patients with cancer, and is the second most common cause of death. Lung cancer is well established to be high risk for VTE, with up to a 22-fold increase in VTE risk associated with this malignancy, and 12% incidence in a recent study of patients with lung cancer undergoing chemotherapy. Furthermore, platinum based chemotherapy agents used in treatment of lung cancer are further associated with increased VTE risk. AIM: Current risk assessment tools have little value in predicting VTE risk, but prophylactic anticoagulation of patients with cancer increases bleeding incidence and no overall survival benefit. There is therefore a need for a pragmatic test with which assesses coagulation in patients with cancer, and potentially predict VTE risk, leading to personalised management and targeted treatment. We have previously demonstrated that fractal dimension (df) is sensitive to changes in clot microstructure in patients with lung cancer, assessing global coagulation in these patients. Furthermore, df is significantly different in patients with extensive disease (stages 3&4), which conventional laboratory markers failed to identify. Given the increased risk of VTE associated with chemotherapy, FATCAT will aim to assess changes in df in a larger cohort of patients with lung cancer undergoing chemotherapy, quantifying changes in df and relating these to clinical outcome. MATERIALS AND METHODS: This is a prospective observational cohort study investigating changes in df in patients with lung cancer undergoing chemotherapy. Patients will have a new diagnosis of cytologically or histologically confirmed lung cancer planned for chemotherapy and no history of previous cancer treatment, any thromboembolic / haemostatic disorders or be on anticoagulation. RESULTS: Following a power calculation, 300 patients will be recruited and followed up for 1 year. df, Doppler ultrasonography and standard coagulation markers will be performed on recruitment, at the mid point, and on completion of chemotherapy in line with standard diagnostic procedures i.e. CT scanning. CONCLUSIONS: The primary endpoint of the study will be VTE diagnosis, whilst secondary outcomes will determine the change in df during and after treatment with chemotherapy.

10.
Thromb Res ; 135(6): 1075-80, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25895846

RESUMO

BACKGROUND: Venous thromboembolism (VTE) is common in patients with cancer, contributing significantly to morbidity and mortality Currently, no test reliably identifies patients at increased risk of developing VTE who would therefore benefit from prophylactic intervention. The aim of the current study was to evaluate rotational thromboelastometry (ROTEM) in identifying VTE risk in patients with lung cancer. We also compared parameters of ROTEM in patients with limited and extensive disease. METHODS: Parameters of ROTEM were measured in 67 patients with lung cancer and 72 age-matched healthy controls and compared with conventional markers of haemostasis. Patients were followed up for 12 months and VTE incidence recorded. RESULTS: Lung cancer patients had a reduced clotting time (CT), increased maximum clot firmness (MCF) and increased alpha angle compared with controls. Patients also had significantly higher levels of fibrinogen and PAI-1 than controls and in the former group there was a strong correlation between fibrinogen and both MCF and alpha angle. Six patients developed a VTE during the follow-up period and all had values for MCF at or above the upper limit of normal for EXTEM. CONCLUSIONS: This study demonstrates that several ROTEM parameters are significantly different in lung cancer patients compared to healthy age-matched controls, whereas only one of the parameters measured is significantly different between extensive compared to limited disease. No differences were observed between patients who developed a VTE compared to those who did not, highlighting the limitations of ROTEM use in patients with lung cancer.


Assuntos
Coagulação Sanguínea , Neoplasias Pulmonares/complicações , Tromboelastografia/métodos , Trombofilia/diagnóstico , Tromboembolia Venosa/complicações , Idoso , Anticoagulantes/uso terapêutico , Testes de Coagulação Sanguínea , Estudos de Casos e Controles , Feminino , Fibrinogênio/biossíntese , Hemostasia , Humanos , Neoplasias Pulmonares/sangue , Masculino , Pessoa de Meia-Idade , Inibidor 1 de Ativador de Plasminogênio/biossíntese , Medição de Risco , Trombofilia/sangue , Trombofilia/complicações , Resultado do Tratamento , Tromboembolia Venosa/sangue
11.
Int J Androl ; 34(4 Pt 2): e175-87; discussion e187-8, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21651578

RESUMO

The antigenic profile of human embryonic stem (ES) and embryonal carcinoma (EC) cells has served as a key element of their characterization, with a common panel of surface and intracellular markers now widely used. Such markers have been used to identify cells within the 'undifferentiated state', yet it appears that this categorization may be an oversimplification, because a number of sub-states appear to exist within this state. To increase the resolution of the undifferentiated state, we have generated eight novel monoclonal antibodies, all capable of recognizing undifferentiated human ES and EC cells, and herein describe their characterization. The reactivity of these antibodies against a range of cell lines is reported, as well as their developmental regulation, basic biochemistry and reactivity in immunohistochemistry of testicular germ cell tumours. Our data reveal a range of reactivity for all antibodies against both ES and EC cells, suggesting that these markers will afford recognition of unique sub-states within the undifferentiated stem cell compartment.


Assuntos
Anticorpos Monoclonais/imunologia , Antígenos de Superfície/imunologia , Carcinoma Embrionário/imunologia , Células-Tronco de Carcinoma Embrionário/imunologia , Células-Tronco Embrionárias/imunologia , Neoplasias Embrionárias de Células Germinativas/imunologia , Animais , Anticorpos Monoclonais/metabolismo , Biomarcadores , Diferenciação Celular , Linhagem Celular/imunologia , Citometria de Fluxo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Testiculares/imunologia
12.
Monaldi Arch Chest Dis ; 71(2): 76-80, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19719040

RESUMO

Non-tuberculous mycobacterias (NTMs) have many clinical manifestations in humans, depending on the underlying immunological status. We present a patient with Mycobacterium avium intracellulare pulmonary infection and co-existing, biopsy proven non-granulomatous organising pneumonia in distinct regions within the lungs. Treatment consisting of anti-mycobacterial therapy and corticosteroids led to clinico-radiological resolution. This case represents a potential broader clinico-pathological manifestation of Mycobacterium avium intracellulare.


Assuntos
Infecção por Mycobacterium avium-intracellulare/complicações , Pneumonia/complicações , Broncoscopia , Enfisema/complicações , Etambutol/uso terapêutico , Feminino , Glucocorticoides/uso terapêutico , Humanos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Pessoa de Meia-Idade , Infecção por Mycobacterium avium-intracellulare/diagnóstico , Infecção por Mycobacterium avium-intracellulare/tratamento farmacológico , Pneumonia/diagnóstico , Pneumonia/tratamento farmacológico , Prednisolona/uso terapêutico , Rifampina/uso terapêutico , Tomografia Computadorizada por Raios X
14.
Phys Rev Lett ; 96(7): 077204, 2006 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-16606135

RESUMO

It has recently been suggested that the organic compound NiCl2-4SC(NH2)2 (DTN) undergoes field-induced Bose-Einstein condensation (BEC) of the Ni spin degrees of freedom. The Ni S = 1 spins exhibit three-dimensional XY antiferromagnetism above a critical field H(c1) approximately 2 T. The spin fluid can be described as a gas of hard-core bosons where the field-induced antiferromagnetic transition corresponds to Bose-Einstein condensation. We have determined the spin Hamiltonian of DTN using inelastic neutron diffraction measurements, and we have studied the high-field phase diagram by means of specific heat and magnetocaloric effect measurements. Our results show that the field-temperature phase boundary approaches a power-law H - H(c1) proportional variant T(alpha)(c) near the quantum critical point, with an exponent that is consistent with the 3D BEC universal value of alpha = 1.5.

15.
J Phys Chem B ; 110(16): 8314-9, 2006 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-16623514

RESUMO

Aluminum chloride is used extensively as Lewis acid catalyst in a variety of industrial processes, including Friedel-Crafts and Cl/F exchange reactions. There is a common misconception that pure AlCl3 is itself a Lewis acid. In the current study, we use experimental and computational methods to investigate the surface structure and catalytic properties of solid AlCl3. The catalytic activity of AlCl3 for two halide isomerization reactions is studied and compared with different AlF3 phases. It is shown that pure solid AlCl3 does not catalyze these reactions. The (001) surface of crystalline AlCl(3) is the natural cleavage plane and its structure is predicted via first principles calculations. The chlorine ions in the outermost layer of the material mask the Al3+ ions from the external gas phase. Hence, the experimentally found catalytic properties of pure solid AlCl3 are supported by the predicted surface structure of AlCl3.

17.
Breast ; 13(4): 350-2, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15325673

RESUMO

The key to diagnosis for deformed or scaling nipple is cytology or histology. While scrape cytology and punch biopsy do not provide underlying breast tissue for histology wedge excision requires more time and resource. We present the technique of nipple core biopsy (NCB) in 40 patients with deformed or scaling nipple done as a part of triple assessment yielding both skin and breast tissue for histological examination. Histological diagnosis confirmed eczema in 24, Paget's disease of nipple in 9 and chronic inflammation in 2. Among 5 remaining patients with normal skin histology, underlying breast invasive ductal carcinoma was seen in 3, ductal carcinoma in situ (DCIS) in 1 and adenoma in 1. NCB identified 5(55%) significant breast pathologies in Paget's disease and detected a further 2 invasive cancers in the absence of a palpable mass. The technique also provides additional information in the form of oestrogen receptor, which can have direct impact on patient management.


Assuntos
Neoplasias da Mama/diagnóstico , Carcinoma Ductal de Mama/diagnóstico , Eczema/diagnóstico , Mamilos/patologia , Doença de Paget Mamária/diagnóstico , Idoso , Biópsia por Agulha/métodos , Feminino , Humanos , Receptores de Estrogênio/análise
18.
Breast ; 13(2): 110-4, 2004 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15019690

RESUMO

When mammogramography detects a non-palpable lesion the surgeons may be called upon to establish a diagnosis. Various techniques are currently employed. We describe a technique, which can be used both for diagnostic and for therapeutic procedures. The technique essentially involves localising the tip of a guide-wire, placed under mammographic guidance, with ultrasound scanning. This minimises many of the problems encountered with wire guided excision. We conducted a prospective non-randomised study using our combined image guidance technique (CIG) for patients undergoing diagnostic (n = 24) and therapeutic biopsy (n = 13). We found that significantly smaller diagnostic biopsy weights were achievable using CIG, compared to non-CIG techniques. Reduced biopsy weights are recommended by current guidelines.


Assuntos
Neoplasias da Mama/cirurgia , Cirurgia Assistida por Computador/métodos , Biópsia por Agulha/métodos , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos
19.
J Infect ; 46(4): 246-8, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12799151

RESUMO

A 64-year-old man was referred to chest clinic after presenting initially with painless haematuria. Bladder biopsies showed granulomatous inflammation and subsequent urine cultures grew Mycobacterium bovis. He had been treated empirically for genito-urinary tuberculosis twice previously and on both occasions his haematuria ceased. Although the early hospital notes have been destroyed we believe this represents a very late and recurrent relapse of cystitis due to M. bovis.


Assuntos
Tuberculose Urogenital/diagnóstico , Tuberculose Urogenital/microbiologia , Antituberculosos/uso terapêutico , Quimioterapia Combinada , Humanos , Masculino , Pessoa de Meia-Idade , Mycobacterium bovis/isolamento & purificação , Recidiva , Tuberculose Urogenital/tratamento farmacológico
20.
Neuropharmacology ; 41(8): 952-64, 2001 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11747900

RESUMO

gamma-Aminobutyric acid type A (GABA(A)) receptors are an important target for general anesthetics in the central nervous system. Site-directed mutagenesis techniques have identified amino acid residues that are important for the positive modulation of GABA(A) receptors by general anesthetics. In the present study, we investigate the role of an amino acid residue in transmembrane (TM) domain 3 of the GABA(A) receptor beta(2) subunit for modulation by the general anesthetic 2,6-diisopropylphenol (propofol). Mutation of methionine 286 to tryptophan (M286W) in the beta(2) subunit abolished potentiation of GABA responses by propofol but did not affect direct receptor activation by propofol in the absence of GABA. In contrast, substitution of methionine 286 by alanine, cysteine, glutamate, lysine, phenylalanine, serine, or tyrosine was permissive for potentiation of GABA responses and direct activation by propofol. Using propofol analogs of varying molecular size, we show that the beta(2)(M286W) mutation resulted in a decrease in the 'cut-off' volume for propofol analog molecules to enhance GABA responses at GABA(A) alpha(1)beta(2)gamma(2s) receptors. This suggests that mutation of M286 in the GABA(A) beta(2) subunit alters the dimensions of a 'binding pocket' for propofol and related alkylphenol general anesthetics.


Assuntos
Anestésicos Gerais/metabolismo , Anestésicos Intravenosos/metabolismo , Metionina/genética , Propofol/metabolismo , Receptores de GABA-A/fisiologia , Sequência de Aminoácidos , Substituição de Aminoácidos/genética , Anestésicos Gerais/química , Anestésicos Intravenosos/química , Animais , Sítios de Ligação/efeitos dos fármacos , Sítios de Ligação/genética , Linhagem Celular , Relação Dose-Resposta a Droga , Etomidato/farmacologia , Humanos , Metionina/farmacologia , Metoexital/farmacologia , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Mutação , Propofol/química , Estrutura Terciária de Proteína/genética , Ratos , Receptores de GABA-A/genética , Ácido gama-Aminobutírico/farmacologia
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