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1.
J Orthop ; 54: 148-157, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38586600

RESUMO

Background: Varus deformity is common in medial compartment knee osteoarthritis (OA). This coronal plane malalignment is compensated for by static and dynamic adjustments in the position of the adjacent joints, principally in the hindfoot & ankle. Varus knee OA can be treated in selected patients with high tibial osteotomy (HTO) and stabilised with a fixed angle plate or circular frame, which may reverse these compensatory adjustments. The aim of this systematic review is to determine the evidence available for static and dynamic compensations with the main objectives being to improve deformity planning and optimise patient outcomes. Method: A systematic review with meta-analysis was designed using the PRISMA template to meet the research aims & objectives. Results: A total of 1006 patients (1020 knees) with acombined mean age of 54.5 years, female:male ratio of 0.9:1 were extracted from 19 included studies. The methodologies of the majority of studies were at high risk of bias according to the Newcastle-Ottawa Scale demonstrating significant heterogeneity. The combined mean change in the HKA axis was 7.7°; MPTA 7.4°; TT, 0.21°; TI 4.56° & AJLO 4° valgus. Preoperative hindfoot valgus compensation reverts towards neutral post-HTO. There is limited evidence available for a direct relationship between static alignment and dynamic gait parameters. Conclusions: An inverse relationship between ankle and hindfoot alignment in varus deformity of the knee forms the basis of this compensation theory. In cases with a stiff hindfoot which may not revert postoperatively, the reconstructive orthopaedic surgeon may consider angulation with translation HTO, in order to optimise joint alignment and minimise transference of symptoms to the foot and ankle.

2.
Sensors (Basel) ; 22(16)2022 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-36016032

RESUMO

This proof-of-concept study explores the potential of developing objective pain identification based on the analysis of electroencephalography (EEG) signals. Data were collected from participants living with chronic fibromyalgia pain (n = 4) and from healthy volunteers (n = 7) submitted to experimental pain by the application of capsaicin cream (1%) on the right upper trapezius. This data collection was conducted in two parts: (1) baseline measures including pain intensity and EEG signals, with the participant at rest; (2) active measures collected under the execution of a visuo-motor task, including EEG signals and the task performance index. The main measure for the objective identification of the presence of pain was the coefficient of variation of the upper envelope (CVUE) of the EEG signal from left fronto-central (FC5) and left temporal (T7) electrodes, in alpha (8-12 Hz), beta (12-30 Hz) and gamma (30-43 Hz) frequency bands. The task performance index was also calculated. CVUE (%) was compared between groups: those with chronic fibromyalgia pain, healthy volunteers with "No pain" and healthy volunteers with experimentally-induced pain. The identification of the presence of pain was determined by an increased CVUE in beta (CVUEß) from the EEG signals captured at the left FC5 electrode. More specifically, CVUEß increased up to 20% in the pain condition at rest. In addition, no correlation was found between CVUEß and pain intensity or the task performance index. These results support the objective identification of the presence of pain based on the quantification of the coefficient of variation of the upper envelope of the EEG signal.


Assuntos
Fibromialgia , Eletrodos , Eletroencefalografia/métodos , Fibromialgia/diagnóstico , Humanos , Dor/diagnóstico , Análise e Desempenho de Tarefas
3.
Bone Jt Open ; 2(5): 338-343, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34044581

RESUMO

AIMS: Displaced distal radius fractures were investigated at a level 1 major trauma centre during the COVID-19 2020 lockdown due to the implementation of temporary changes in practice. The primary aim was to establish if follow-up at one week in place of the 72-hour British Orthopaedic Association Standards for Trauma & Orthopaedics (BOAST) guidance was safe following manipulation under anaesthetic. A parallel adaptation during lockdown was the non-expectation of Bier's block. The secondary aim was to compare clinical outcomes with respect to block type. METHODS: Overall, 90 patients were assessed in a cross-sectional cohort study using a mixed, retrospective-prospective approach. Consecutive sampling of 30 patients pre-lockdown (P1), 30 during lockdown (P2), and 30 during post-lockdown (P3) was applied. Type of block, operative status, follow-up, and complications were extracted. Primary endpoints were early complications (≤ one week). Secondary endpoints were later complications including malunion, delayed union or osteotomy. RESULTS: In P1, 86.6% of patients were seen between days one to three, 26.7% in P2, and 56.7% in P3. There were no documented complications from days one to three. Operative rate was 35.5%, which did not vary significantly (p= 0.712). Primary endpoints occurred between day four to seven, and included one patient each period treated for plaster cast pain. Secondary endpoints in P1 included delayed union (one patient). During P2, this included malunion (one patient), a pressure sore (one patient) and ulnar cutaneous nerve symptoms (two patients). In P3, malunion was identified in one patient. Mean follow-up was six months (4 to 9) with union rate 96%. Change in block practice varied significantly (p =<0.05). The risk ratio of complications using regional block (Bier's) over haematoma block was 0.65. CONCLUSION: Follow-up adaptations during lockdown did not adversely affect patient outcomes. Regional anaesthesia is gold standard for manipulation of displaced distal radial fractures. Cite this article: Bone Jt Open 2021;2(5):338-343.

4.
Sci Rep ; 10(1): 19753, 2020 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-33184444

RESUMO

Ecotourism opportunities in the marine environment often rely heavily on provisioning to ensure the viewing of cryptic species by the public. However, intentional feeding of wildlife can impact numerous aspects of an animals' behavior and ecology. Southern stingrays (Hypanus americana) provisioned at Stingray City Sandbar (SCS) in Grand Cayman have altered diel activity patterns and decreased measures of health. This study looked at seasonal changes in stable isotope (SI) and fatty acid (FA) profiles of provisioned stingrays at SCS. Plasma δ15N was higher in male stingrays (11.86 ± 1.71‰) compared to females (10.70 ± 1.71‰). Lower values for δ15N in males and females were measured in October during low tourist season, suggesting stingrays may be forced to rely on native prey items to supplement the decreased amount of provisioned squid available during this time. Plasma FA profiles were significantly different between sexes and across sampling time points, with FAs 22:6n3, 16:0, 20:5n3, 18:1n3C, 18:0 and 18:1n9T contributing to dissimilarity scores between groups. Dietary FAs primarily contributed to differences between males and females lending further evidence to differences in foraging patterns at SCS, likely due to intraspecific competition. Further, canonical analysis of principal coordinates (CAP) analysis of FA profiles suggest similar diets during peak tourist season and differences in diet between males and females during the low season. This study demonstrates alterations in feeding ecology in stingrays at SCS which is of critical importance for effective management of the SCS aggregation.

5.
Mov Ecol ; 8: 21, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32514356

RESUMO

BACKGROUND: The importance of thermal resources to terrestrial ectotherms has been well documented but less often considered in larger-scale analyses of habitat use and selection, such as those routinely conducted using standard habitat features such as vegetation and physical structure. Selection of habitat based on thermal attributes may be of particular importance for ectothermic species, especially in colder climates. In Canada, Western Rattlesnakes (Crotalus oreganus) reach their northern limits, with limited time to conduct annual migratory movements between hibernacula and summer habitat. We radio-tracked 35 male snakes departing from 10 different hibernacula. We examined coarse-scale differences in migratory movements across the region, and then compared the route of each snake with thermal landscapes and ruggedness GIS maps generated for different periods of the animals' active season. RESULTS: We observed dichotomous habitat use (grasslands versus upland forests) throughout most of the species' northern range, reflected in different migratory movements of male snakes emanating from different hibernacula. Snakes utilizing higher-elevation forests moved further during the course of their annual migrations, and these snakes were more likely to use warmer areas of the landscape. CONCLUSION: In addition to thermal benefits, advantages gained from selective migratory patterns may include prey availability and outbreeding. Testing these alternative hypotheses was beyond the scope of this study, and to collect the data to do so will require overcoming certain challenges. Still, insight into migratory differences between rattlesnake populations and the causal mechanism(s) of migrations will improve our ability to assess the implications of landscape change, management, and efficacy of conservation planning. Our findings suggest that such assessments may need to be tailored to individual dens and the migration strategies of their inhabitants. Additionally, local and landscape-scale migration patterns, as detected in this study, will have repercussions for snakes under climate-induced shifts in ecosystem boundaries and thermal regimes.

6.
J Public Health (Oxf) ; 42(3): 480-482, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32478853

RESUMO

The author aims to depict the current COVID-19 pandemic and personal protective equipment (PPE) crisis in the UK. The current situation is put into context exploring the history of global outbreaks of infectious disease and what has been learnt. These lessons are then applied and weighed against the recent response to coronavirus. An in depth interview with a UK biomedical SME based in Shanghai, China is reported in order to inform future procurement of PPE. It is hoped that an appreciation of the dynamic nature of the market will allow adaptations to be made in order to secure reliable supply chains moving forwards.


Assuntos
Infecções por Coronavirus , Pandemias , Equipamento de Proteção Individual , Pneumonia Viral , Betacoronavirus , COVID-19 , China , Humanos , SARS-CoV-2
7.
Dev Med Child Neurol ; 62(1): 48-56, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31313290

RESUMO

AIM: To give evidence-based recommendations on the application of ketogenic diet parenteral nutrition (KD-PN) in emergency situations. METHOD: An international group of experts (n=14) researched the literature and distributed a survey among 150 expert centers. International accepted guidelines (European Society for Clinical Nutrition and Metabolism/European Society for Paediatric Gastroenterology Hepatology and Nutrition and the American Society for Parenteral and Enteral Nutrition) and handbooks for parenteral nutrition were considered general standards of care. RESULTS: In the literature, we identified 35 reports of patients treated by KD-PN. International guidelines and handbooks provided some conflicting information. Twenty-four expert teams from nine countries responded to the survey, reflecting the limited clinical experience. INTERPRETATION: This paper highlights 23 consensus-based recommendations for safe and effective KD-PN (e.g. diet initiation, calculation, application, monitoring, and evaluation) based on the best evidence available and expert opinions. WHAT THIS PAPER ADDS: In acute settings, ketogenic diet therapy (KDT) can be administered parenterally. Parenteral administration of KDT should be started only at the intensive care unit. Initiate ketogenic parenteral nutrition stepwise to the highest ratio possible with the lowest level of complications. Evaluate the risk-benefit ratio of parenteral administration continuously. Restart enteral feeding as soon as appropriate.


MANEJO CLÍNICO ÓPTIMO DE LOS NIÑOS QUE RECIBEN NUTRICIÓN PARENTERAL CETOGÉNICA: UNA GUÍA DE PRÁCTICA CLÍNICA: OBJETIVO: Dar recomendaciones basadas en evidencia sobre la aplicación de dieta cetogénica en la nutrición parenteral (DC-NP) en situaciones de emergencia. MÉTODO: Un grupo de expertos (n=14) investigó la literatura y distribuyó una encuesta en 150 centros especializados. Considerando como estándares de manejo las guías aceptadas internacionalmente (Sociedad Europea para la Nutrición Clínica y Metabolismo/Sociedad Europea de Gastroenterología Pediátrica, Hepatología y Nutrición, y la Sociedad Americana para Nutrición Enteral y Parenteral) y los manuales para la nutrición parenteral. RESULTADOS: En la literatura se identificaron 35 informes de pacientes tratados por DC-NP. Las directrices y manuales internacionales proporcionaron alguna información contradictoria. Veinticuatro equipos de expertos de nueve países respondieron a la encuesta, reflejando la limitada experiencia clínica. INTERPRETACIÓN: Este documento destaca 23 recomendaciones basadas en consensos para una DC-NP segura y eficaz (por ejemplo; iniciación de la dieta, cálculo, aplicación, monitoreo y evaluación) basada en la mejor evidencia disponible y las opiniones de expertos.


MANEJO CLÍNICO ÓTIMO DE CRIANÇAS RECEBENDO NUTRIÇÃO CETOGÊNICA PARENTERAL: UM GUIA PARA A PRÁTICA CLÍNICA: OBJETIVO: Oferecer recomendações baseadas em evidências da aplicação de dieta cetogênica por nutrição parenteral (DC-NP) em situações de emergência. MÉTODO: Um grupo internacional de especialistas (n=14) pesquisou a literatura e distribuiu um questionário em 150 centros especializados. Diretrizes internacioansi aceitas (Sociedade Européia de Nutrição Clínica e Metabolismo/ Sociedade Européia de Gastroenterologia, Hepatologia e Nutrição Pediátrica, e a Sociedade Americana de Nutrição Enteral e Parenteral) e livros sobre nutrição parenteral foram considerados padrão geral de atenção. RESULTADOS: Na literatura, identificamos 35 relados de pacientes tratados por DC-NP. As diretrizes internacionais e os livros forneceram informações conflitantes. Vinte e quatro equips de especialistas de nove países responderam ao questionário, refletindo a experiência clínica limitada. INTERPRETAÇÃO: Este artigo destaca 23 recomendações baseadas em consenso para DC-NP segura e efetiva (ex: início da dieta, cálculo, aplicação, monitoramento e avaliação) com base na melhor evidência disponível e opiniões de especialistas.


Assuntos
Doença Aguda/terapia , Cuidados Críticos/normas , Dieta Cetogênica/normas , Nutrição Parenteral/normas , Guias de Prática Clínica como Assunto/normas , Criança , Humanos
8.
Front Mol Neurosci ; 12: 139, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31293383

RESUMO

Neural crest cells arise in the embryo from the neural plate border and migrate throughout the body, giving rise to many different tissue types such as bones and cartilage of the face, smooth muscles, neurons, and melanocytes. While studied extensively in animal models, neural crest development and disease have been poorly described in humans due to the challenges in accessing embryonic tissues. In recent years, patient-derived human induced pluripotent stem cells (hiPSCs) have become easier to generate, and several streamlined protocols have enabled robust differentiation of hiPSCs to the neural crest lineage. Thus, a unique opportunity is offered for modeling neurocristopathies using patient specific stem cell lines. In this work, we make use of hiPSCs derived from patients affected by the Bardet-Biedl Syndrome (BBS) ciliopathy. BBS patients often exhibit subclinical craniofacial dysmorphisms that are likely to be associated with the neural crest-derived facial skeleton. We focus on hiPSCs carrying variants in the BBS10 gene, which encodes a protein forming part of a chaperonin-like complex associated with the cilium. Here, we establish a pipeline for profiling hiPSCs during differentiation toward the neural crest stem cell fate. This can be used to characterize the differentiation properties of the neural crest-like cells. Two different BBS10 mutant lines showed a reduction in expression of the characteristic neural crest gene expression profile. Further analysis of both BBS10 mutant lines highlighted the inability of these mutant lines to differentiate toward a neural crest fate, which was also characterized by a decreased WNT and BMP response. Altogether, our study suggests a requirement for wild-type BBS10 in human neural crest development. In the long term, approaches such as the one we describe will allow direct comparison of disease-specific cell lines. This will provide valuable insights into the relationships between genetic background and heterogeneity in cellular models. The possibility of integrating laboratory data with clinical phenotypes will move us toward precision medicine approaches.

10.
PeerJ ; 6: e5540, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30221091

RESUMO

BACKGROUND: Functional magnetic resonance imaging (fMRI) is a popular method for examining pharmacological effects on the brain; however, the BOLD response is dependent on intact neurovascular coupling, and potentially modulated by a number of physiological factors. Pharmacological fMRI is therefore vulnerable to confounding effects of pharmacological probes on general physiology or neurovascular coupling. Controlling for such non-specific effects in pharmacological fMRI studies is therefore an important consideration, and there is an additional need for well-validated fMRI task paradigms that could be used to control for such effects, or for general testing purposes. METHODS: We have developed two variants of a standardized control task that are short (5 minutes duration) simple (for both the subject and experimenter), widely applicable, and yield a number of readouts in a spatially diverse set of brain networks. The tasks consist of four functionally discrete three-second trial types (plus additional null trials) and contain visual, auditory, motor and cognitive (eye-movements, and working memory tasks in the two task variants) stimuli. Performance of the tasks was assessed in a group of 15 subjects scanned on two separate occasions, with test-retest reliability explicitly assessed using intra-class correlation coefficients. RESULTS: Both tasks produced robust patterns of brain activation in the expected brain regions, and region of interest-derived reliability coefficients for the tasks were generally high, with four out of eight task conditions rated as 'excellent' or 'good', and only one out of eight rated as 'poor'. Median values in the voxel-wise reliability measures were also >0.7 for all task conditions, and therefore classed as 'excellent' or 'good'. The spatial concordance between the most highly activated voxels and those with the highest reliability coefficients was greater for the sensory (auditory, visual) conditions than the other (motor, cognitive) conditions. DISCUSSION: Either of the two task variants would be suitable for use as a control task in future pharmacological fMRI studies or for any other investigation where a short, reliable, basic task paradigm is required. Stimulus code is available online for re-use by the scientific community.

11.
Epilepsy Res ; 144: 1-6, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29727818

RESUMO

PURPOSE: To describe the efficacy and safety of ketogenic diet (KD) for convulsive refractory status epilepticus (RSE). METHODS: RSE patients treated with KD at the 6/11 participating institutions of the pediatric Status Epilepticus Research Group from January-2011 to December-2016 were included. Patients receiving KD prior to the index RSE episode were excluded. RSE was defined as failure of ≥2 anti-seizure medications, including at least one non-benzodiazepine drug. Ketosis was defined as serum beta-hydroxybutyrate levels >20 mg/dl (1.9 mmol/l). Outcomes included proportion of patients with electrographic (EEG) seizure resolution within 7 days of starting KD, defined as absence of seizures and ≥50% suppression below 10 µV on longitudinal bipolar montage (suppression-burst ratio ≥50%); time to start KD after onset of RSE; time to achieve ketosis after starting KD; and the proportion of patients weaned off continuous infusions 2 weeks after KD initiation. Treatment-emergent adverse effects (TEAEs) were also recorded. RESULTS: Fourteen patients received KD for treatment of RSE (median age 4.7 years, interquartile range [IQR] 5.6). KD was started via enteral route in 11/14 (78.6%) patients. KD was initiated a median of 13 days (IQR 12.5) after the onset of RSE, at 4:1 ratio in 8/14 (57.1%) patients. Ketosis was achieved within a median of 2 days (IQR 2.0) after starting KD. EEG seizure resolution was achieved within 7 days of starting KD in 10/14 (71.4%) patients. Also, 11/14 (78.6%) patients were weaned off their continuous infusions within 2 weeks of starting KD. TEAEs, potentially attributable to KD, occurred in 3/14 (21.4%) patients, including gastro-intestinal paresis and hypertriglyceridemia. Three month outcomes were available for 12/14 (85.7%) patients, with 4 patients being seizure-free, and 3 others with decreased seizure frequency compared to pre-RSE baseline. CONCLUSIONS: This series suggests efficacy and safety of KD for treatment of pediatric RSE.


Assuntos
Dieta Cetogênica/métodos , Epilepsia Resistente a Medicamentos/dietoterapia , Estado Epiléptico/dietoterapia , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Eletroencefalografia , Feminino , Humanos , Lactente , Masculino , Resultado do Tratamento , Adulto Jovem
12.
Adv Synth Catal ; 359(18): 3261-3269, 2017 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-30100832

RESUMO

5-Phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-ones react under palladium- and visible light photoredox catalysis, in refluxing methanol, with aryldiazonium salts to afford the respective 5-(2-arylphenyl) analogues. With 2- or 4-fluorobenzenediazonium derivatives, both fluoroaryl- and methoxyaryl- products were obtained, the latter resulting from a SNAr on the fluorobenzenediazonium salt ("nuisance effect"). A computational DFT analysis of the palladium-catalysed and the palladium/ruthenium-photocalysed mechanism for the functionalization of benzodiazepines indicated that, in the presence of the photocatalyst, the reaction proceeds via a low-energy SET pathway avoiding the high-energy oxidative addition step in the palladium-only catalysed reaction pathway.

13.
J Adolesc ; 37(2): 185-96, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24439624

RESUMO

This study hypothesized that frequent exposure to and attention to music with substance-use references would be indirectly related to alcohol, cigarette, or marijuana use through pro-substance-use beliefs (e.g., norms, outcome expectancies, and refusal efficacy). Parent-child communication, however, would attenuate such associations, which would differ by ethnicity. Multigroup mediation and moderation analyses were conducted, using cross-sectional survey data from 253 Latino and 308 European American 6th-8th grades students. For Latino and European American early adolescents, best-friend-injunctive norms and weak refusal efficacy were significant mediators, but not positive outcome expectancies. Descriptive norms were a significant mediator, but only for European American early adolescents. Although targeted parent-child communication and parental mediation did not moderate the associations between the music-exposure variables and the pro-substance-use beliefs variables, targeted parent-child communication attenuated the association between listening to favorite songs and alcohol consumption. Parental mediation attenuated the association between attention to music and alcohol consumption.


Assuntos
Comportamento do Adolescente/etnologia , Comunicação , Hispânico ou Latino , Música , Relações Pais-Filho , Transtornos Relacionados ao Uso de Substâncias , População Branca , Adolescente , Criança , Feminino , Humanos , Masculino , Teoria Psicológica , Transtornos Relacionados ao Uso de Substâncias/etnologia , Estados Unidos
14.
Methods Mol Biol ; 995: 43-54, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23494371

RESUMO

Calcium signaling plays a major role in the function of cells. Measurement of intracellular calcium mobilization is a robust assay that can be performed in a high-throughput manner to study the effect of compounds on potential drug targets. Pharmaceutical companies frequently use calcium signaling assays to screen compound libraries on G-protein-coupled receptors (GPCRs). In this chapter we describe the application of FLIPR technology to the evaluation of GPCR-induced calcium mobilization. We also include the implications of GPCR hetero-oligomerization and the identification of heteromeric receptors as novel drug targets on high-throughput calcium screening.


Assuntos
Compostos de Benzilideno/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , D-Penicilina (2,5)-Encefalina/farmacologia , Ensaios de Triagem em Larga Escala/métodos , Naltrexona/análogos & derivados , Receptores Opioides delta/agonistas , Sinalização do Cálcio , Técnicas de Cultura de Células , Células HEK293 , Humanos , Naltrexona/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/biossíntese , Receptores Opioides delta/antagonistas & inibidores , Receptores Opioides delta/biossíntese , Proteínas Recombinantes/agonistas , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/biossíntese , Espectrometria de Fluorescência , Transfecção
15.
J Pharmacol Exp Ther ; 344(1): 179-88, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23097213

RESUMO

Drugs targeting G-protein-coupled receptors (GPCRs) make up more than 25% of all prescribed medicines. The ability of GPCRs to form heteromers with unique signaling properties suggests an entirely new and unexplored pool of drug targets. However, current in vitro assays are ill equipped to detect heteromer-selective compounds. We have successfully adapted an approach, using fusion proteins of GPCRs and chimeric G proteins, to create an in vitro screening assay (in human embryonic kidney cells) in which only activated heteromers are detectable. Here we show that this assay can demonstrate heteromer-selective G-protein bias as well as measure transinhibition. Using this assay, we reveal that the δ-opioid receptor agonist ADL5859, which is currently in clinical trials, has a 10-fold higher potency against δ-opioid receptor homomers than δ/µ-opioid receptor heteromers (pEC(50) = 6.7 ± 0.1 versus 5.8 ± 0.2). The assay enables the screening of large compound libraries to identify heteromer-selective compounds that could then be used in vivo to determine the functional role of heteromers and develop potential therapeutic agents.


Assuntos
Receptores Acoplados a Proteínas G/fisiologia , Transdução de Sinais/efeitos dos fármacos , Sequência de Aminoácidos , Benzamidas/farmacologia , Cálcio/metabolismo , Sinalização do Cálcio , Clonagem Molecular , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Encefalina Leucina/farmacologia , Ensaio de Imunoadsorção Enzimática , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/efeitos dos fármacos , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Subunidades alfa Gs de Proteínas de Ligação ao GTP/efeitos dos fármacos , Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo , Células HEK293 , Humanos , Microscopia de Fluorescência , Dados de Sequência Molecular , Proteínas Mutantes Quiméricas/química , Proteínas Mutantes Quiméricas/genética , Piperazinas/farmacologia , Reação em Cadeia da Polimerase , Receptores Acoplados a Proteínas G/genética , Receptores Opioides delta/efeitos dos fármacos , Receptores Opioides delta/genética , Proteínas Recombinantes de Fusão
16.
J Am Chem Soc ; 134(25): 10321-4, 2012 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-22671299

RESUMO

The bioconjugation of organometallic complexes with peptides has proven to be a novel approach for drug discovery. We report the facile and chemoselective reaction of tyrosine-containing G-protein-coupled receptor (GPCR) peptides with [Cp*Rh(H(2)O)(3)](OTf)(2), in water, at room temperature, and at pH 5-6. We have focused on three important GPCR peptides; namely, [Tyr(1)]-leu-enkephalin, [Tyr(4)]-neurotensin(8-13), and [Tyr(3)]-octreotide, each of which has a different position for the tyrosine residue, together with competing functionalities. Importantly, all other functional groups present, i.e., amino, carboxyl, disulfide, phenyl, and indole, were not prominent sites of reactivity by the Cp*Rh tris aqua complex. Furthermore, the influence of the Cp*Rh moiety on the structure of [Tyr(3)]-octreotide was characterized by 2D NMR, resulting in the first representative structure of an organometallic-peptide complex. The biological consequences of these Cp*Rh-peptide complexes, with respect to GPCR binding and growth inhibition of MCF7 and HT29 cancer cells, will be presented for [(η(6)-Cp*Rh-Tyr(1))-leu-enkephalin](OTf)(2) and [(η(6)-Cp*Rh-Tyr(3))-octreotide](OTf)(2).


Assuntos
Modelos Moleculares , Compostos Organometálicos/química , Peptídeos/química , Receptores Acoplados a Proteínas G/química , Ródio/química , Tirosina/química , Ligação Competitiva , Neoplasias da Mama/tratamento farmacológico , Feminino , Células HT29 , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Compostos Organometálicos/farmacologia , Ligação Proteica/efeitos dos fármacos , Estrutura Terciária de Proteína , Receptores Acoplados a Proteínas G/metabolismo
17.
ACS Med Chem Lett ; 3(8): 640-644, 2012 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-23585918

RESUMO

Opioid receptors, including the mu and delta opioid receptors (MOR and DOR) are important targets for the treatment of pain. Although there is mounting evidence that these receptors form heteromers, the functional role of the MOR/DOR heteromer remains unresolved. We have designed and synthesized bivalent ligands as tools to elucidate the functional role of the MOR/DOR heteromer. Our ligands (L2 and L4) are comprised of a compound with low affinity at the DOR tethered to a compound with high affinity at the MOR, with the goal of producing ligands with "tuned affinity" at MOR/DOR heteromers compared to DOR homomers. Here we show that both L2 and L4 demonstrate enhanced affinity at MOR/DOR heteromers compared to DOR homomers, thereby providing unique pharmacological tools to dissect the role of the MOR/DOR heteromer in pain.

18.
J Adv Nurs ; 63(5): 440-50, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18727745

RESUMO

AIM: This paper is a report of a systematic review to examine the effectiveness of preventive interventions to reduce congenital cytomegalovirus transmission and infection among women of childbearing age. BACKGROUND: Congenital cytomegalovirus has been identified as the leading infectious cause of damage to the growing fetus in developed countries, including Down syndrome, fetal alcohol syndrome and spina bifida. Despite the prevalence and consequences of this infection, it has a low profile and pregnant mothers are often unaware of the risks and protective behaviours related to its transmission. Women with children in daycare and nurses working with children are particularly at risk of acquiring the virus. DATA SOURCES: A computerized literature search for articles up to 1 December 2007 was performed using MEDLINE (from 1950); EMBASE (from 1980) and CINAHL (from 1982). REVIEW METHODS: Both authors independently reviewed studies that met inclusion criteria and assigned a quality rating determined by the number of validity criteria met. Differences were discussed until consensus was reached. FINDINGS: Differences in hygiene behaviour changes were most statistically significant for pregnant, seronegative women. Although the methodological quality of the three included studies was not strong, seroconversion rates consistently decreased as cytomegalovirus education and support increased. CONCLUSION: Nurses can act as preventive agents for cytomegalovirus infection through education about hygiene precautions during antenatal care and through preventive measures in the workplace. The review findings suggest educational interventions in hygiene practices have the potential to be a feasible, large-scale, primary prevention strategy.


Assuntos
Infecções por Citomegalovirus/prevenção & controle , Higiene , Complicações Infecciosas na Gravidez/prevenção & controle , Prevenção Primária/métodos , Adulto , Infecções por Citomegalovirus/enfermagem , Infecções por Citomegalovirus/transmissão , Educação em Enfermagem , Feminino , Humanos , Exposição Ocupacional/efeitos adversos , Educação de Pacientes como Assunto , Gravidez , Complicações Infecciosas na Gravidez/enfermagem
20.
Phys Rev Lett ; 99(3): 038301, 2007 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-17678335

RESUMO

We have observed reversible light-induced mechanical switching for individual organic molecules bound to a metal surface. Scanning tunneling microscopy (STM) was used to image the features of individual azobenzene molecules on Au(111) before and after reversibly cycling their mechanical structure between trans and cis states using light. Azobenzene molecules were engineered to increase their surface photomechanical activity by attaching varying numbers of tert-butyl (TB) ligands ("legs") to the azobenzene phenyl rings. STM images show that increasing the number of TB legs "lifts" the azobenzene molecules from the substrate, thereby increasing molecular photomechanical activity by decreasing molecule-surface coupling.

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