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1.
Br J Anaesth ; 125(5): 779-801, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32798067

RESUMO

BACKGROUND: Despite common use, the benefit of adding steroids to local anaesthetics (SLA) for chronic non-cancer pain (CNCP) injections is uncertain. We performed a systematic review and meta-analysis of English-language RCTs to assess the benefit and safety of adding steroids to local anaesthetics (LA) for CNCP. METHODS: We searched MEDLINE, EMBASE, and CENTRAL databases from inception to May 2019. Trial selection and data extraction were performed in duplicate. Outcomes were guided by the Initiative in Methods, Measurements, and Pain Assessment in Clinical Trials (IMMPACT) statement with pain improvement as the primary outcome and pooled using random effects model and reported as relative risks (RR) or mean differences (MD) with 95% confidence intervals (CIs). RESULTS: Among 5097 abstracts, 73 trials were eligible. Although SLA increased the rate of success (42 trials, 3592 patients; RR=1.14; 95% CI, 1.03-1.25; number needed to treat [NNT], 13), the effect size decreased by nearly 50% (NNT, 22) with the removal of two intrathecal injection studies. The differences in pain scores with SLA were not clinically meaningful (54 trials, 4416 patients, MD=0.44 units; 95% CI, 0.24-0.65). No differences were observed in other outcomes or adverse events. No subgroup effects were detected based on clinical categories. Meta-regression showed no significant association with steroid dose or length of follow-up and pain relief. CONCLUSIONS: Addition of cortico steroids to local anaesthetic has only small benefits and a potential for harm. Injection of local anaesthetic alone could be therapeutic, beyond being diagnostic. A shared decision based on patient preferences should be considered. If used, one must avoid high doses and series of steroid injections. CLINICAL TRIAL REGISTRATION: PROSPERO #: CRD42015020614.


Assuntos
Corticosteroides/uso terapêutico , Anestésicos Locais/uso terapêutico , Dor Crônica/tratamento farmacológico , Manejo da Dor/métodos , Corticosteroides/efeitos adversos , Anestésicos Locais/efeitos adversos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
2.
J Mol Graph Model ; 89: 234-241, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30921557

RESUMO

In drug discovery, structural knowledge of a target enables structure-based design approaches and thereby reduces the time and labor required to develop a therapy. Whilst molecular graphics frameworks coupled with computational analysis are now ubiquitous tools for the structural and computational biologist, sharing the detailed visualization and derived structural information with non-expert users still presents a challenge. Here we describe an intuitive virtual world for viewing, manipulating, and modifying chemical and macromolecular structures in a fully immersive and collaborative 3D environment. By reducing the barriers to viewing and interacting with structural data, structural analysis can be democratized to a general scientist, which in turn fosters novel collaboration, ideas, and findings in structural biology and structure-based drug discovery.


Assuntos
Descoberta de Drogas , Relação Quantitativa Estrutura-Atividade , Realidade Virtual , Sítios de Ligação , Biologia Computacional , Desenho de Fármacos , Humanos , Ligantes , Ligação Proteica , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/antagonistas & inibidores , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/química , Software , Interface Usuário-Computador
3.
Opt Lett ; 43(21): 5255-5258, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30382981

RESUMO

Optical beam steering has broad applications in lidar, optical communications, optical interconnects, and spatially resolved optical sensors. For high-speed applications, phased-array-based beam-steering methods are favored over mechanical methods, as they are unconstrained by inertia and can inherently operate at a higher speed. However, phased-array systems exhibit a tradeoff between angular range and beam divergence, making it difficult to achieve both a large steering angle and a narrow beam divergence. Here, we present a beam-steering method based on wavefront shaping through a disorder-engineered metasurface that circumvents this range-resolution tradeoff. We experimentally demonstrate that, through this technique, one can continuously steer an optical beam within a range of 160° (80° from normal incidence) with an angular resolution of about 0.01° at the cost of beam throughput.

4.
Opt Express ; 25(4): 3935-3945, 2017 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-28241603

RESUMO

Optical microscopy in complex, inhomogeneous media is challenging due to the presence of multiply scattered light that limits the depths at which diffraction-limited resolution can be achieved. One way to circumvent the degradation in resolution is to use speckle- correlation-based imaging (SCI) techniques, which permit imaging of objects inside scattering media at diffraction-limited resolution. However, SCI methods are currently limited to imaging sparsely tagged objects in a dark-field scenario. In this work, we demonstrate the ability to image hidden, moving objects in a bright-field scenario. By using a deterministic phase modulator to generate a spatially incoherent light source, the background contribution can be kept constant between acquisitions and subtracted out. In this way, the signal arising from the object can be isolated, and the object can be reconstructed with high fidelity. With the ability to effectively isolate the object signal, our work is not limited to imaging bright objects in the dark-field case, but also works in bright-field scenarios, with non-emitting objects.

5.
Protein Sci ; 25(4): 877-86, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26833751

RESUMO

Two putative haloalkane dehalogenases (HLDs) of the HLD-I subfamily, DccA from Caulobacter crescentus and DsaA from Saccharomonospora azurea, have been identified based on sequence comparisons with functionally characterized HLD enzymes. The two genes were synthesized, functionally expressed in E. coli and shown to have activity toward a panel of haloalkane substrates. DsaA has a moderate activity level and a preference for long (greater than 3 carbons) brominated substrates, but little activity toward chlorinated alkanes. DccA shows high activity with both long brominated and chlorinated alkanes. The structure of DccA was determined by X-ray crystallography and was refined to 1.5 Å resolution. The enzyme has a large and open binding pocket with two well-defined access tunnels. A structural alignment of HLD-I subfamily members suggests a possible basis for substrate specificity is due to access tunnel size.


Assuntos
Actinobacteria/enzimologia , Caulobacter crescentus/enzimologia , Hidrolases/química , Hidrolases/metabolismo , Actinobacteria/química , Actinobacteria/genética , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Caulobacter crescentus/química , Caulobacter crescentus/genética , Cristalografia por Raios X , Hidrolases/genética , Modelos Moleculares , Conformação Proteica , Homologia Estrutural de Proteína , Especificidade por Substrato
6.
Optica ; 3(10): 1107-1113, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28713849

RESUMO

Imaging of a weak target hidden behind a scattering medium can be significantly confounded by glare. We report a method, termed coherence gated negation (CGN), that uses destructive optical interference to suppress glare and allow improved imaging of a weak target. As a demonstration, we show that by permuting through a set range of amplitude and phase values for a reference beam interfering with the optical field from the glare and target reflection, we can suppress glare by an order of magnitude, even when the optical wavefront is highly disordered. This strategy significantly departs from conventional coherence gating methods in that CGN actively "gates out" the unwanted optical contributions while conventional methods "gate in" the target optical signal. We further show that the CGN method can outperform conventional coherence gating image quality in certain scenarios by more effectively rejecting unwanted optical contributions.

7.
Optica ; 2(8): 728-735, 2015 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-26677458

RESUMO

Digital optical phase conjugation (DOPC) is a new technique employed in wavefront shaping and phase conjugation for focusing light through or within scattering media such as biological tissues. DOPC is particularly attractive as it intrinsically achieves a high fluence reflectivity in comparison to nonlinear optical approaches. However, the slow refresh rate of liquid crystal spatial light modulators and limitations imposed by computer data transfer speeds have thus far made it difficult for DOPC to achieve a playback latency of shorter than ~200 ms and, therefore, prevented DOPC from being practically applied to thick living samples. In this paper, we report a novel DOPC system that is capable of 5.3 ms playback latency. This speed improvement of almost 2 orders of magnitude is achieved by using a digital micromirror device, field programmable gate array (FPGA) processing, and a single-shot binary phase retrieval technique. With this system, we are able to focus through 2.3 mm living mouse skin with blood flowing through it (decorrelation time ~30 ms) and demonstrate that the focus can be maintained indefinitely-an important technological milestone that has not been previously reported, to the best of our knowledge.

8.
Neurobiol Dis ; 80: 93-103, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25986728

RESUMO

BACKGROUND: Whether L-NAT, a cytochrome c release inhibitor and an antagonist of NK-1R, provides protection in ALS is not known. RESULTS: L-NAT delays disease onset and mortality in mSOD1(G93A) ALS mice by inhibiting mitochondrial cell death pathways, inflammation, and NK-1R downregulation. CONCLUSION: L-NAT offers protection in a mouse model of ALS. SIGNIFICANCE: Data suggest the potential of L-NAT as a novel therapeutic strategy for ALS and provide insight into its action mechanisms. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, while inflammation has been implicated in its pathogenesis. Both inhibitors of cytochrome c release and antagonists of the neurokinin 1 receptor (NK-1R) have been reported to provide neuroprotection in ALS and/or other neurodegenerative diseases by us and other researchers. However, whether N-acetyl-L-tryptophan (L-NAT), an inhibitor of cytochrome c release and an antagonist of NK-1R, provides neuroprotection in ALS remains unknown. Here we demonstrate that the administration of L-NAT delayed disease onset, extended survival, and ameliorated deteriorations in motor performance in mSOD1(G93A) ALS transgenic mice. Our data showed that L-NAT reached the spinal cord, skeletal muscle, and brain. In addition, we demonstrate that L-NAT reduced the release of cytochrome c/smac/AIF, increased Bcl-xL levels, and inhibited the activation of caspase-3. L-NAT also ameliorated motor neuron loss and gross atrophy, and suppressed inflammation, as shown by decreased GFAP and Iba1 levels. Furthermore, we found gradually reduced NK-1R levels in the spinal cords of mSOD1(G93A) mice, while L-NAT treatment restored NK-1R levels. We propose the use of L-NAT as a potential therapeutic invention against ALS.


Assuntos
Esclerose Amiotrófica Lateral/prevenção & controle , Triptofano/análogos & derivados , Esclerose Amiotrófica Lateral/mortalidade , Esclerose Amiotrófica Lateral/patologia , Animais , Apoptose/efeitos dos fármacos , Masculino , Camundongos , Camundongos Transgênicos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/patologia , Neuroglia/efeitos dos fármacos , Receptores da Neurocinina-1/metabolismo , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Superóxido Dismutase/genética , Análise de Sobrevida , Triptofano/administração & dosagem
9.
Drug Discov Today ; 20(1): 65-75, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25205348

RESUMO

Amyotrophic lateral sclerosis (ALS) is a debilitating disease characterized by progressive loss of voluntary motor neurons leading to muscle atrophy, weight loss and respiratory failure. Evidence suggests that inflammation, oxidative stress, mitochondrial dysfunction, apoptosis, glutamate excitotoxicity and proteasomal dysfunction are all responsible for ALS pathogenesis. We review neuroprotective agents with the ability to reduce ALS-related bodyweight loss, summarize the various therapies tested on animal models targeting the proposed molecular mechanisms, compare their effects on bodyweight loss, muscle damage, disease onset, duration and survival, and analyze their structure-activity relationships, with the overall goal of creating a screening strategy for further clinical application.


Assuntos
Esclerose Amiotrófica Lateral/tratamento farmacológico , Atrofia Muscular/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Animais , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Relação Estrutura-Atividade , Perda de Peso/efeitos dos fármacos
10.
EMBO J ; 34(2): 184-99, 2015 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-25425577

RESUMO

Acetylation of transcriptional regulators is normally dynamically regulated by nutrient status but is often persistently elevated in nutrient-excessive obesity conditions. We investigated the functional consequences of such aberrantly elevated acetylation of the nuclear receptor FXR as a model. Proteomic studies identified K217 as the FXR acetylation site in diet-induced obese mice. In vivo studies utilizing acetylation-mimic and acetylation-defective K217 mutants and gene expression profiling revealed that FXR acetylation increased proinflammatory gene expression, macrophage infiltration, and liver cytokine and triglyceride levels, impaired insulin signaling, and increased glucose intolerance. Mechanistically, acetylation of FXR blocked its interaction with the SUMO ligase PIASy and inhibited SUMO2 modification at K277, resulting in activation of inflammatory genes. SUMOylation of agonist-activated FXR increased its interaction with NF-κB but blocked that with RXRα, so that SUMO2-modified FXR was selectively recruited to and trans-repressed inflammatory genes without affecting FXR/RXRα target genes. A dysregulated acetyl/SUMO switch of FXR in obesity may serve as a general mechanism for diminished anti-inflammatory response of other transcriptional regulators and provide potential therapeutic and diagnostic targets for obesity-related metabolic disorders.


Assuntos
Regulação da Expressão Gênica , Inflamação/patologia , Hepatopatias/patologia , Obesidade/complicações , Receptores Citoplasmáticos e Nucleares/metabolismo , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/metabolismo , Acetilação , Sequência de Aminoácidos , Animais , Western Blotting , Citocinas/genética , Citocinas/metabolismo , Ensaio de Desvio de Mobilidade Eletroforética , Perfilação da Expressão Gênica , Técnicas Imunoenzimáticas , Imunoprecipitação , Inflamação/etiologia , Inflamação/metabolismo , Hepatopatias/etiologia , Hepatopatias/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Dados de Sequência Molecular , NF-kappa B/genética , NF-kappa B/metabolismo , Obesidade/fisiopatologia , Conformação Proteica , Processamento de Proteína Pós-Traducional , Proteômica , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores Citoplasmáticos e Nucleares/química , Receptores Citoplasmáticos e Nucleares/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Homologia de Sequência de Aminoácidos , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/química , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/genética , Sumoilação , Espectrometria de Massas em Tandem
11.
Protein Eng Des Sel ; 28(2): 29-35, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25538307

RESUMO

The l-alanine dehydrogenase (AlaDH) has a natural history that suggests it would not be a promising candidate for expansion of substrate specificity by protein engineering: it is the only amino acid dehydrogenase in its fold family, it has no sequence or structural similarity to any known amino acid dehydrogenase, and it has a strong preference for l-alanine over all other substrates. By contrast, engineering of the amino acid dehydrogenase superfamily members has produced catalysts with expanded substrate specificity; yet, this enzyme family already contains members that accept a broad range of substrates. To test whether the natural history of an enzyme is a predictor of its innate evolvability, directed evolution was carried out on AlaDH. A single mutation identified through molecular modeling, F94S, introduced into the AlaDH from Mycobacterium tuberculosis (MtAlaDH) completely alters its substrate specificity pattern, enabling activity toward a range of larger amino acids. Saturation mutagenesis libraries in this mutant background additionally identified a double mutant (F94S/Y117L) showing improved activity toward hydrophobic amino acids. The catalytic efficiencies achieved in AlaDH are comparable with those that resulted from similar efforts in the amino acid dehydrogenase superfamily and demonstrate the evolvability of MtAlaDH specificity toward other amino acid substrates.


Assuntos
Alanina Desidrogenase/química , Substituição de Aminoácidos , Proteínas de Bactérias/química , Modelos Moleculares , Mutação de Sentido Incorreto , Mycobacterium tuberculosis/enzimologia , Alanina Desidrogenase/genética , Alanina Desidrogenase/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Mycobacterium tuberculosis/genética , Especificidade por Substrato/genética
12.
Optica ; 1(4): 227-232, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25621302

RESUMO

Focusing light through scattering media has been a longstanding goal of biomedical optics. While wavefront shaping and optical time-reversal techniques can in principle be used to focus light across scattering media, achieving this within a scattering medium with a noninvasive and efficient reference beacon, or guide star, remains an important challenge. Here, we show optical time-reversal focusing using a new technique termed Time Reversal by Analysis of Changing wavefronts from Kinetic targets (TRACK). By taking the difference between time-varying scattering fields caused by a moving object and applying optical time reversal, light can be focused back to the location previously occupied by the object. We demonstrate this approach with discretely moved objects as well as with particles in an aqueous flow, and obtain a focal peak-to-background strength of 204 in our demonstration experiments. We further demonstrate that the generated focus can be used to noninvasively count particles in a flow-cytometry configuration-even when the particles are hidden behind a strong diffuser. By achieving optical time reversal and focusing noninvasively without any external guide stars, using just the intrinsic characteristics of the sample, this work paves the way to a range of scattering media imaging applications, including underwater and atmospheric focusing as well as noninvasive in vivo flow cytometry.

13.
Cent Nerv Syst Agents Med Chem ; 12(1): 15-27, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22283698

RESUMO

Various molecular mechanisms including apoptosis, inflammation, oxidative stress, mitochondrial dysfunction and excitotoxicity have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), though the exact mechanisms have yet to be specified. Furthermore, the underlying restorative molecular mechanisms resulting in neuronal and/or non-neuronal regeneration have to be yet elucidated. Therapeutic agents targeting one or more of these mechanisms to combat either initiation or progression of the disease are under research. Novel treatments including stem cell therapy, growth factors, and gene therapy might prolong survival and delay progression of symptoms. Harnessing the regenerative potential of the central nervous system would be a novel approach for the treatment of motor neuron death resulting from ALS. Endogenous neural replacement, if augmented with administration of exogenous growth factors or with pharmaceuticals that increase the rate of neural progenitor formation, neural migration, and neural maturation could slow the rate of cell loss enough to result in clinical improvement. In this review, we discuss the impact of therapeutic treatment involving stem cell therapy, growth factors, gene therapy, and combination therapy on disease onset and progression of ALS. In addition, we summarize human clinical trials of stem cell therapy, growth factor therapy, and gene therapy in individuals with ALS.


Assuntos
Esclerose Amiotrófica Lateral/terapia , Terapia Genética/métodos , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Fármacos Neuroprotetores/administração & dosagem , Transplante de Células-Tronco/métodos , Células-Tronco/fisiologia , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/metabolismo , Animais , Terapia Genética/tendências , Humanos , Fármacos Neuroprotetores/química , Transplante de Células-Tronco/tendências
14.
Acta Crystallogr D Biol Crystallogr ; 58(Pt 8): 1343-5, 2002 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12136150

RESUMO

EcoRII, a type IIe restriction endonuclease, has been crystallized in space group P2(1), with unit-cell parameters a = 58.3, b = 127.8, c = 59.9 A, beta = 91.4 degrees. There are two monomers in the asymmetric unit and the solvent content is estimated to be 49% by volume. The crystals diffract to 2.8 A resolution, which is much higher than that of the previously reported cubic crystal form, which diffracted to 4 A resolution.


Assuntos
Desoxirribonucleases de Sítio Específico do Tipo II/química , Cristalização , Cristalografia por Raios X , Desoxirribonucleases de Sítio Específico do Tipo II/isolamento & purificação , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação
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