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Collagen is the most abundant protein in mammals. A unique feature of collagen is its triple-helical structure formed by the Gly-Xaa-Yaa repeats. Three single chains of procollagen make a trimer, and the triple-helical structure is then folded in the endoplasmic reticulum (ER). This unique structure is essential for collagen's functions in vivo, including imparting bone strength, allowing signal transduction, and forming basement membranes. The triple-helical structure of procollagen is stabilized by posttranslational modifications and intermolecular interactions, but collagen is labile even at normal body temperature. Heat shock protein 47 (Hsp47) is a collagen-specific molecular chaperone residing in the ER that plays a pivotal role in collagen biosynthesis and quality control of procollagen in the ER. Mutations that affect the triple-helical structure or result in loss of Hsp47 activity cause the destabilization of procollagen, which is then degraded by autophagy. In this review, we present the current state of the field regarding quality control of procollagen.
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Colágeno/química , Fibrose/metabolismo , Proteínas de Choque Térmico HSP47/metabolismo , Pró-Colágeno/química , Pró-Colágeno/metabolismo , Animais , Colágeno/metabolismo , Retículo Endoplasmático/metabolismo , Fibrose/genética , Proteínas de Choque Térmico HSP47/química , Proteínas de Choque Térmico HSP47/genética , Humanos , Hidroxilação , Chaperonas Moleculares/metabolismo , Prolina/química , Prolina/metabolismo , Conformação Proteica , Dobramento de Proteína , Processamento de Proteína Pós-TraducionalRESUMO
Maintenance of endoplasmic reticulum (ER) proteostasis is controlled by a dynamic signaling network known as the unfolded protein response (UPR). IRE1α is a major UPR transducer, determining cell fate under ER stress. We used an interactome screening to unveil several regulators of the UPR, highlighting the ER chaperone Hsp47 as the major hit. Cellular and biochemical analysis indicated that Hsp47 instigates IRE1α signaling through a physical interaction. Hsp47 directly binds to the ER luminal domain of IRE1α with high affinity, displacing the negative regulator BiP from the complex to facilitate IRE1α oligomerization. The regulation of IRE1α signaling by Hsp47 is evolutionarily conserved as validated using fly and mouse models of ER stress. Hsp47 deficiency sensitized cells and animals to experimental ER stress, revealing the significance of Hsp47 to global proteostasis maintenance. We conclude that Hsp47 adjusts IRE1α signaling by fine-tuning the threshold to engage an adaptive UPR.
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Endorribonucleases/metabolismo , Proteínas de Choque Térmico HSP47/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Células COS , Chlorocebus aethiops , Proteínas de Ligação a DNA/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Proteínas de Choque Térmico HSP47/fisiologia , Humanos , Camundongos , Chaperonas Moleculares/metabolismo , Transdução de Sinais , Estresse Fisiológico , Fatores de Transcrição/metabolismo , Resposta a Proteínas não DobradasRESUMO
OBJECTIVE: To describe characteristics of published research on the safety and efficacy of vitamin K antagonists (VKA) for pregnant patients with antiphospholipid antibodies (aPLs), including their methodological characteristics and knowledge gaps. METHODS: This study followed the Joanna Briggs Institute Methodology for Scoping Reviews (JBI) methodology and utilized the PRISMA-ScR protocol system. Studies were primarily identified through searching electronic databases including MEDLINE, EMBASE, Web of Science and the Cochrane Central Register of Controlled Trials. Study characteristics and outcomes were reported and described using customized charting tables. RESULTS: Of 1,528 publications, 17 remained in the final analysis. These reported up to 190VKA-treated aPL-positive pregnancies diagnosed as antiphospholipid syndrome (APS), where pregnancies were likely overlapping cases in some publications. In the 17 reports, there were 723 individuals in comparison groups, including healthy, pre-treatment pregnancies or APS women treated with standard therapies without VKA. However, only 4 (23.5%) of the 17 publications stated a study objective focusing on VKA use, of which only one was a full-length article. In addition, information on VKA doses, disease diagnostic criteria and the long-term outcome of the offspring were largely absent. CONCLUSION: The current evidence is insufficient to assess VKA efficacy and safety profiles in aPL-positive pregnant patients. Studies with a defined focus on VKA use in this population are lacking, and reporting of key information is not consistent. The relative lack of the knowledge of VKA use in pregnant women with APS is concerning, and the efficacy and safety questions remain open.
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BACKGROUND: Patients with heart failure (HF) experience a wide variety of symptoms. Appropriate recognition of symptoms is important in HF care. The Heart Failure Somatic Perception Scale (HFSPS) measures the presence of HF symptoms and the degree to which physical symptoms are bothersome. OBJECTIVE: The aim of this study was to assess the validity and reliability of the Japanese version of the HFSPS. METHODS: Confirmatory factor analysis was used to assess structural validity. Construct validity was assessed using Spearman's rank correlation coefficient to evaluate the association between HFSPS total and subscale scores and global physical health on the Patient-Reported Outcomes Measurement Information System. Internal consistency was assessed using the model-based internal consistency for the HFSPS as a whole and Cronbach α for the subscales. RESULTS: Participants were 315 Japanese outpatients (72.1% male), with a mean age of 72.9 ± 12.9 years. The result of confirmatory factor analysis was an adequate model fit by adding error correlations. Construct validity was significant for the correlation with global physical health of the Patient-Reported Outcomes Measurement Information System. The model-based internal consistency was 0.95. Cronbach αs for each subscale were 0.88 for dyspnea, 0.60 for chest discomfort, 0.77 for early and subtle symptoms, and 0.77 for edema. CONCLUSIONS: The findings support the use of the HFSPS in a more diverse population, suggesting that it is a reliable and valid instrument in Japanese patients with HF. The HFSPS may provide an accurate assessment of the symptoms experienced by patients with HF in daily life in future educational intervention studies to improve symptom perception and coping behaviors.
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BACKGROUND AND OBJECTIVES: To examine the reliability and validity of the Japanese version of the Dutch Eating Behavior Questionnaire (DEBQ-J) for patients with mental illness, and to determine the characteristics of eating behavior among these patients when compared with healthy controls. METHODS AND STUDY DESIGN: In May 2018, 120 outpatients with mental illness and 132 healthy controls were surveyed. First, exploratory factor analysis was conducted on the DEBQ-J statement responses for both patients and healthy controls. Next, reliability coefficients were calculated for the eating behavior scale scores (emotional, restrained, and external eating) extracted from the factor analysis. The association between BMI and eating behavior was examined using Student's t-test and Pearson's correlation coefficient. RESULTS: The DEBQ-J had a similar factor structure to that of the original DEBQ for healthy controls, with a cumulative contribution of 52.4% for the three factors, and alpha coefficients ranging from 0.87 to 0.91. For patients, factor analysis showed that four statements classified as emotional eating items in the original DEBQ were recategorized as external eating items, and the percentage of patients with obesity (BMI≥25) was 57.5%, compared with only 25.4% among the healthy controls. The patients with obesity tended to score higher on the external eating scale than did those with BMI<25. CONCLUSIONS: Patients tended to blur the distinction between emotional feelings of mental irritability or anxiety and feelings in response to external stimuli. Monitoring of the DEBQ-J external eating score and appropriate intervention among patients living with mental illness may help to prevent obesity.
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Comportamento Alimentar , Transtornos Mentais , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Massa Corporal , Estudos de Casos e Controles , População do Leste Asiático , Comportamento Alimentar/psicologia , Japão , Transtornos Mentais/psicologia , Reprodutibilidade dos Testes , Inquéritos e QuestionáriosRESUMO
The Hodgkin-Huxley model of action potential generation and propagation, published in the Journal of Physiology in 1952, initiated the field of biophysically detailed computational modelling in neuroscience, which has expanded to encompass a variety of species and components of the nervous system. Here we review the developments in this area with a focus on efforts in the community towards modelling the mammalian neocortex using spatially extended conductance-based neuronal models. The Hodgkin-Huxley formalism and related foundational contributions, such as Rall's cable theory, remain widely used in these efforts to the current day. We argue that at present the field is undergoing a qualitative change due to new very rich datasets describing the composition, connectivity and functional activity of cortical circuits, which are being integrated systematically into large-scale network models. This trend, combined with the accelerating development of convenient software tools supporting such complex modelling projects, is giving rise to highly detailed models of the cortex that are extensively constrained by the data, enabling computational investigation of a multitude of questions about cortical structure and function.
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Neocórtex , Neurônios , Animais , Neurônios/fisiologia , Potenciais de Ação/fisiologia , Simulação por Computador , Modelos Neurológicos , MamíferosRESUMO
Sensory information from different modalities is processed in parallel, and then integrated in associative brain areas to improve object identification and the interpretation of sensory experiences. The Superior Colliculus (SC) is a midbrain structure that plays a critical role in integrating visual, auditory, and somatosensory input to assess saliency and promote action. Although the response properties of the individual SC neurons to visuoauditory stimuli have been characterized, little is known about the spatial and temporal dynamics of the integration at the population level. Here we recorded the response properties of SC neurons to spatially restricted visual and auditory stimuli using large-scale electrophysiology. We then created a general, population-level model that explains the spatial, temporal, and intensity requirements of stimuli needed for sensory integration. We found that the mouse SC contains topographically organized visual and auditory neurons that exhibit nonlinear multisensory integration. We show that nonlinear integration depends on properties of auditory but not visual stimuli. We also find that a heuristically derived nonlinear modulation function reveals conditions required for sensory integration that are consistent with previously proposed models of sensory integration such as spatial matching and the principle of inverse effectiveness.
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Modelos Neurológicos , Colículos Superiores/fisiologia , Estimulação Acústica , Animais , Percepção Auditiva/fisiologia , Mapeamento Encefálico/estatística & dados numéricos , Biologia Computacional , Fenômenos Eletrofisiológicos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos CBA , Modelos Psicológicos , Neurônios/fisiologia , Dinâmica não Linear , Estimulação Luminosa , Sensação/fisiologia , Colículos Superiores/citologia , Percepção Visual/fisiologiaRESUMO
More than half of women take medications during breastfeeding, predisposing their infants to medication exposure via breast milk. As a result, adverse drug reactions may emerge in the infant, although they are rarely reported. Disposition of maternal drugs in breast milk is described with several key parameters, which include relative infant dose (RID): infant drug intake via milk (weight- and time-adjusted) expressed as a percentage of the similarly adjusted mother's dose. Most drugs show RID values of <10%, indicating that drug concentrations in infant serum do not reach a level known to be therapeutic in adults unless drug clearance is markedly lower than the adult level on a weight basis. RID is a function of milk-to-(maternal) plasma drug concentration ratio (MP ratio) and maternal drug clearance. Therefore, MP ratio between drugs must be interpreted not by itself but with maternal drug clearance of each drug. This is why some drugs such as phenobarbital show an MP ratio of <1 but an RID as high as 50-70%, while morphine shows an MP ratio of 2 but an RID in the range of 5%. Using RID, we interpreted case reports of infant adverse outcomes, and we observed cases with relatively low infant serum concentrations of drug, consistent with low RID, as well as those with near- or above-adult therapeutic serum concentrations, with or without increased drug intake (i.e. high RID). It is important to consider both pharmacokinetic and pharmacodynamic factors in interpreting adverse outcomes in infants breastfed by a mother taking medications.
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Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Leite Humano , Adulto , Aleitamento Materno/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Feminino , Humanos , Lactente , LactaçãoRESUMO
OBJECTIVES: The purpose of this study was to evaluate the influence of augmented renal clearance (ARC) on vancomycin clearance and provide dosage recommendations for paediatric patients with febrile neutropenia following HSCT. METHODS: A population pharmacokinetic analysis was performed based on a two-compartment model structure using a non-linear mixed-effect modelling approach. Monte Carlo simulations were conducted as a target attainment analysis of AUC between 400 mg·h/L and 650 mg·h/L for MRSA at an MIC of 1 mg/L. RESULTS: A total of 165 paediatric patients and 276 vancomycin serum concentrations were analysed in this study. Age, body weight, estimated glomerular filtration rate (eGFR) and fever (≥38.0°C) were identified as factors that significantly influenced vancomycin clearance. The median eGFR of the population was 143 mL/min/1.73 m2 and 34% of patients showed an eGFR ≥160 mL/min/1.73 m2, which may be classified as ARC. Our simulations showed that current dosing recommendations result in poor target attainment. In particular, children aged 6 months old to 6 years old with ARC require an initial vancomycin dose up to 35%-65% higher than the current dosing guidelines. CONCLUSIONS: ARC is frequently observed in paediatric patients with post-HSCT febrile neutropenia, resulting in a significant increase in vancomycin clearance. We propose a vancomycin dosing strategy for children with febrile neutropenia following HSCT based on eGFR, age, weight and body temperature.
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Neutropenia Febril , Vancomicina , Antibacterianos , Criança , Neutropenia Febril/tratamento farmacológico , Taxa de Filtração Glomerular , Humanos , Lactente , Método de Monte CarloRESUMO
BACKGROUND: With high survival rates for pediatric acute lymphoblastic leukemia (ALL), long-term quality of life is a prominent consideration in treatment. We concurrently evaluated cognition, behavior, and quality of life in child and adolescent ALL survivors and determined associations between them. METHODS: The sample included 83 controls (mean age: 12.5 years) and 71 ALL survivors (mean age: 11.9 years, mean age at diagnosis: 3.8 years). Participants completed measures of general intellectual abilities, math achievement, and fine motor skills. Parents and teachers completed a survey assessing child participants' cognitive, behavioral, and emotional function. Parents additionally completed a survey about their child's quality of life. RESULTS: Survivors had lower scores on measures of working memory, processing speed, timed math, and fine motor skills (effect size 0.5-1, p < 0.001). Parents identified more problems with executive function and learning in survivors than controls (effect size > 0.7, p < 0.001), and indicated a lower quality of life in all categories evaluated (effect size > 0.7, p < 10-4). Reduced quality of life was associated with lower math achievement scores and with inattention and executive function problems. CONCLUSIONS: ALL survivors experience diffuse cognitive, behavioral, and motor impairments, which are associated with reduced quality of life. These findings underscore the need to address these challenges in ALL survivors. IMPACT: Compared with cancer-free peers, parents of childhood acute lymphoblastic leukemia survivors treated with chemotherapy only reported reduced quality of life. Math difficulties and behavioral problems increased the risk for reduced quality of life. Reduced quality of life is associated with mild cognitive and behavioral difficulties, suggesting that even relatively mild impairments have broad implications for ALL survivors. Screening and early intervention targeting cognitive and behavioral function may enhance quality of life for ALL survivors.
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Comportamento do Adolescente , Desenvolvimento do Adolescente , Sobreviventes de Câncer/psicologia , Comportamento Infantil , Desenvolvimento Infantil , Cognição , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Qualidade de Vida , Adolescente , Fatores Etários , Estudos de Casos e Controles , Criança , Pré-Escolar , Emoções , Função Executiva , Feminino , Humanos , Inteligência , Masculino , Memória de Curto Prazo , Destreza Motora , Medição de Risco , Fatores de RiscoRESUMO
OBJECTIVES: The CNAP system is a noninvasive monitor that provides a continuous arterial pressure waveform using an inflatable finger cuff. The authors hypothesized that dramatic changes in systemic vascular resistance index during abdominal aortic aneurysm (AAA) surgery might affect the accuracy of noninvasive pulse contour monitors. The aim of this study was to evaluate the accuracy and trending ability of cardiac index derived by the CNAP system (CICN) in patients undergoing AAA surgery. DESIGN: Prospective clinical study. SETTING: Cardiac surgery operating room in a single cardiovascular center. PARTICIPANTS: Twenty patients who underwent elective AAA surgery. INTERVENTIONS: CICN and cardiac index measured using 3-dimensional images (CI3D) were determined simultaneously at 8 points during the surgery. At aortic clamping and unclamping, the authors tested the trending ability of CICN using 4-quadrant plot analysis and polar plot analysis. MEASUREMENTS AND MAIN RESULTS: The authors found a wide limit of agreement between CICN and CI3D (percentage error: 85.0%). The cubic splines, which show the relationship between systemic vascular resistance index and percentage CI discrepancy [(CICN-CI3D)/CI3D], were sloped positively. Four-quadrant plot analysis showed poor trending ability for CICN at both aortic clamping and unclamping (concordance rate: 29.4% and 57.9%, respectively). In the polar plot analysis, the concordance rates at aortic clamping and unclamping were 15.0% and 35.0%, respectively. CONCLUSIONS: CICN is not interchangeable with CI3D in patients undergoing AAA surgery. The trending ability for CICN at aortic clamping and unclamping was below the acceptable limit. These inaccuracies might be secondary to the high systemic vascular resistance index during AAA surgery.
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Aneurisma da Aorta Abdominal , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/cirurgia , Pressão Arterial , Débito Cardíaco , Humanos , Monitorização Fisiológica , Estudos Prospectivos , TermodiluiçãoRESUMO
On March 19, 2019, Brexanolone (Zulresso ™) was released as the first-ever FDA-approved medication specifically for the treatment of postpartum depression by Sage Therapeutics, Inc. Unfortunately, its use in breastfeeding mothers was not evaluated and is being restricted. An efficacious drug for postpartum depression stands to benefit many families. However, the lack of guidance for breastfeeding patients, and the resultant restrictions on breastfeeding by insurance companies is deeply troubling. Conversely, withholding this medication from a lactating mother is ethically problematic. From a public health perspective, we aim to foster continuous breastfeeding among depressed women while they are being treated for depression. We therefore aim to address concerns about Brexanolone's effects on the breastfed child, as exposed through breastmilk, as well as the impact this medication may have on lactation.
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Aleitamento Materno , Depressão Pós-Parto , Leite Humano/química , Depressão Pós-Parto/tratamento farmacológico , Combinação de Medicamentos , Feminino , Humanos , Lactação , Período Pós-Parto , Pregnanolona , beta-CiclodextrinasRESUMO
Heat shock protein 47 (Hsp47) is an endoplasmic reticulum (ER)-resident molecular chaperone essential for correct folding of procollagen in mammalian cells. In this Review, we discuss the role and function of Hsp47 in vertebrate cells and its role in connective tissue disorders. Hsp47 binds to collagenous (Gly-Xaa-Arg) repeats within triple-helical procollagen in the ER and can prevent its local unfolding or aggregate formation, resulting in accelerating triple-helix formation of procollagen. Hsp47 pH-dependently dissociates from procollagen in the cis-Golgi or ER-Golgi intermediate compartment and is then transported back to the ER. Although Hsp47 belongs to the serine protease inhibitor (serpin) superfamily, it does not possess serine protease inhibitory activity. Whereas general molecular chaperones such as Hsp70 and Hsp90 exhibit broad substrate specificity, Hsp47 has narrower specificity mainly for procollagens. However, other Hsp47-interacting proteins have been recently reported, suggesting a much broader role for Hsp47 in the cell that warrants further investigation. Other ER-resident stress proteins, such as binding immunoglobulin protein (BiP), are induced by ER stress, whereas Hsp47 is induced only by heat shock. Constitutive expression of Hsp47 is always correlated with expression of various collagen types, and disruption of the Hsp47 gene in mice causes embryonic lethality due to impaired basement membrane and collagen fibril formation. Increased Hsp47 expression is associated with collagen-related disorders such as fibrosis, characterized by abnormal collagen accumulation, highlighting Hsp47's potential as a clinically relevant therapeutic target.
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Colágeno/biossíntese , Perda do Embrião/metabolismo , Estresse do Retículo Endoplasmático , Proteínas de Choque Térmico HSP47/metabolismo , Animais , Colágeno/genética , Perda do Embrião/genética , Perda do Embrião/patologia , Fibrose , Proteínas de Choque Térmico HSP47/genética , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Choque Térmico HSP90/genética , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Camundongos , Estrutura Secundária de Proteína , Sequências Repetitivas de AminoácidosRESUMO
Molecular chaperones perform pivotal roles in proteostasis by engaging in protein-protein interactions (PPIs). The collagen-specific molecular chaperone Hsp47 (heat shock protein 47) interacts with procollagen in the endoplasmic reticulum (ER) and plays crucial roles in collagen synthesis. PPIs between Hsp47 and collagen could offer a therapeutic target for fibrosis, which is characterized by abnormal collagen accumulation in the extracellular matrix of fibrotic organs. Herein, we established a bioluminescence resonance energy transfer (BRET) system for assessing Hsp47-collagen interaction dynamics within the ER. After optimization and validation of the method, we could demonstrate inhibition of the interaction between Hsp47 and collagen by a small molecule (Col003) in the ER. Using the BRET system, we also found that Hsp47 interacts not only with the Gly-Pro-Arg motif but also weakly with Gly-Pro-Hyp motifs of triple-helical collagen in cells. Moreover, we found that the serpin loop of Hsp47 (SerpinH1) contributes to its binding to collagen. We propose that the method developed here can provide valuable information on PPIs between Hsp47 and collagen and on the effects of PPI inhibitors important for the management of fibrotic disorders.
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Colágeno/metabolismo , Proteínas de Choque Térmico HSP47/metabolismo , Sítios de Ligação , Técnicas de Transferência de Energia por Ressonância de Bioluminescência/métodos , Colágeno/química , Retículo Endoplasmático/metabolismo , Células HEK293 , Proteínas de Choque Térmico HSP47/antagonistas & inibidores , Proteínas de Choque Térmico HSP47/química , Humanos , Ligação ProteicaRESUMO
Detecting synaptic connections using large-scale extracellular spike recordings presents a statistical challenge. Although previous methods often treat the detection of each putative connection as a separate hypothesis test, here we develop a modeling approach that infers synaptic connections while incorporating circuit properties learned from the whole network. We use an extension of the generalized linear model framework to describe the cross-correlograms between pairs of neurons and separate correlograms into two parts: a slowly varying effect due to background fluctuations and a fast, transient effect due to the synapse. We then use the observations from all putative connections in the recording to estimate two network properties: the presynaptic neuron type (excitatory or inhibitory) and the relationship between synaptic latency and distance between neurons. Constraining the presynaptic neuron's type, synaptic latencies, and time constants improves synapse detection. In data from simulated networks, this model outperforms two previously developed synapse detection methods, especially on the weak connections. We also apply our model to in vitro multielectrode array recordings from the mouse somatosensory cortex. Here, our model automatically recovers plausible connections from hundreds of neurons, and the properties of the putative connections are largely consistent with previous research.NEW & NOTEWORTHY Detecting synaptic connections using large-scale extracellular spike recordings is a difficult statistical problem. Here, we develop an extension of a generalized linear model that explicitly separates fast synaptic effects and slow background fluctuations in cross-correlograms between pairs of neurons while incorporating circuit properties learned from the whole network. This model outperforms two previously developed synapse detection methods in the simulated networks and recovers plausible connections from hundreds of neurons in in vitro multielectrode array data.
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Potenciais de Ação/fisiologia , Modelos Teóricos , Rede Nervosa/fisiologia , Neurônios/fisiologia , Córtex Somatossensorial/fisiologia , Sinapses/fisiologia , Transmissão Sináptica/fisiologia , Animais , Camundongos , Redes Neurais de ComputaçãoRESUMO
Studies on the effect of cytochrome P450 2C9 (CYP2C9), vitamin K epoxide reductase complex subunit 1 (VKORC1), and cytochrome P450 4F2 (CYP4F2) polymorphisms on warfarin maintenance dose in children are conflicting. We conducted a systematic review and meta-analysis to evaluate the effect of these polymorphisms on warfarin maintenance dose in children. We searched relevant literature using the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trial libraries without any language restrictions from their inception to 23 July 2017. Dose differences are expressed as standardized mean difference (SMD) or mean difference (MD) with 95% confidence intervals (CI). This review was registered in the PROSPERO prospective register of systematic reviews (CRD42015016172). We included a total of nine studies (745 participants) in the meta-analysis. Patients with CYP2C9 *1/*2, *1/*3, *2/*2, *2/*3, or *3/*3 required a lower warfarin maintenance dose compared with patients with CYP2C9 *1/*1 (SMD = -0.610, 95% CI: -0.802 to -0.419, I2 = 0%). Patients with VKORC1-1639GA or AA required a lower warfarin maintenance dose compared with patients with VKORC1-1639GG (SMD = -0.666, 95% CI: -0.887 to -0.445, I2 = 33%). However, no associations were observed between CYP4F2 polymorphisms and warfarin maintenance dose (MD = 0.005 mg/kg/day, 95% CI: -0.006 to 0.015, I2 = 0%). These results were not affected by a sensitivity analysis. Our meta-analysis provides evidence that CYP2C9 and VKORC1 variant statuses affect warfarin maintenance dose in children, but not CYP4F2.
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Anticoagulantes/administração & dosagem , Citocromo P-450 CYP2C9/genética , Família 4 do Citocromo P450/genética , Polimorfismo de Nucleotídeo Único/genética , Vitamina K Epóxido Redutases/genética , Varfarina/administração & dosagem , Criança , Estudos Transversais/métodos , Humanos , Quimioterapia de Manutenção/métodos , Estudos Observacionais como Assunto/métodosRESUMO
OBJECTIVES: Before a clinician decides whether treatment with TNF inhibition in children with JIA has failed, one should ensure adequate systemic exposure has been achieved. Therapeutic drug monitoring might allow for improved treatment outcome with lower treatment-associated costs. However, this requires understanding of the pharmacokinetic (PK) characteristics, and the pharmacokinetic/pharmacodynamic (PK/PD) relationship for children with JIA. We performed a scoping review to summarize the available literature and identify areas for future research. METHODS: A systematic search was conducted of the Medline, EMBASE, Web of Science and Cochrane databases as well as the clinicaltrials.gov registry. In total, 3959 records were screened and 130 publications were selected for full text assessment. RESULTS: Twenty publications were included and divided into three categories: PK (n = 9), PK/PD (n = 3) and anti-drug antibodies (n = 13). Industry involvement was significant in 14 publications. Although data are limited, systemic exposure to TNF inhibitors is generally lower in younger children but meta-analysis is not possible. The PK/PD relationship has had limited study but there is partial evidence for infliximab. Anti-drug antibodies are common, and are related to impaired clinical outcome with adalimumab and infliximab therapy. CONCLUSION: The current knowledge about the PK and PK/PD of TNF inhibitors in the treatment of children with JIA is limited, which prevents the introduction of TDM. Re-analysis of available data from previous trials, incorporation of pharmacologic assessments into existing biorepository studies as well as new prospective PK and PK/PD trials are required to obtain this knowledge.
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Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Monitoramento de Medicamentos , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Antirreumáticos/efeitos adversos , Criança , Humanos , Inibidores do Fator de Necrose Tumoral/efeitos adversosRESUMO
Paclitaxel, a mitotic inhibitor with anti-cancer effects, is dissolved in Cremophor EL (CrEL). However, peripheral neuropathy is a known side effect. As one of the mechanisms of the neuropathy, mitochondrial dysfunction has been proposed, while peroxidation products are involved in the cause of CrEL-induced neurotoxicity. Riboflavin is an essential nutrient required for ATP production in mitochondria and has an antioxidant role as a coenzyme for glutathione. Therefore, riboflavin transporters might play a key role to mitigate neuropathy. However, it is unclear whether paclitaxel and CrEL affect these transporters. In this study, human riboflavin transporter SLC52A2 was used to analyze the effects of paclitaxel and CrEL. CrEL, but not paclitaxel, inhibited uptake of riboflavin in human embryonic kidney 293 cells transfected with the SLC52A2 expression vector, suggesting that altered riboflavin disposition may be involved in the pathogenesis of paclitaxel/CrEL toxicity.
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Antineoplásicos Fitogênicos/farmacologia , Glicerol/análogos & derivados , Paclitaxel/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Riboflavina/metabolismo , Glicerol/farmacologia , Células HEK293 , Humanos , Receptores Acoplados a Proteínas G/genética , Riboflavina/antagonistas & inibidoresRESUMO
OBJECTIVES: To investigate the accuracy and trending ability of ClearSight (Edwards Lifesciences, Irvine, CA) in patients with reduced ejection fraction (<55%) undergoing off-pump coronary artery bypass graft (CABG) surgery by comparing the ClearSight-derived cardiac index (CICS) with the cardiac index measured with thermodilution using a pulmonary artery catheter. In addition, the accuracy and trending ability of ClearSight for blood pressure measurement was investigated by comparing the mean arterial pressure (MAP) derived by ClearSight (MAPcs) with invasive intra-arterial pressure. DESIGN: Prospective clinical study. DESIGN: Cardiac surgery operating room in a single cardiovascular center. PARTICIPANTS: The study comprised 20 patients who underwent elective CABG surgery. INTERVENTIONS: MAP and cardiac index were measured simultaneously at 6 time points intraoperatively. Trending ability was investigated at the following 2 points: (1) before and after placing the patient in the Trendelenburg position and (2) before and after atrial pacing with a targeted heart rate increase of 20%. MEASUREMENTS AND MAIN RESULTS: Bland-Altman analysis showed that the percentage error between CICS and the cardiac index measured with thermodilution was 40.2% and the percentage error between MAPcs and MAP was 24.6%. Four-quadrant plot analysis showed that the tracking ability of CICS with the Trendelenburg position and atrial pacing was below the good trending ability cutoff (92%). However, the concordance rate of the 4-quadrant plot analysis showed a good trending ability for MAPcs. The polar plot analysis showed the same trend. CONCLUSIONS: CICS was not sufficiently accurate in patients with reduced ejection fraction undergoing off-pump CABG surgery. However, ClearSight was clinically acceptable for MAP regarding its accuracy and trending ability in patients with reduced ejection fraction.
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Monitorização Intraoperatória , Termodiluição , Pressão Sanguínea , Débito Cardíaco , Humanos , Estudos Prospectivos , Reprodutibilidade dos Testes , Volume SistólicoRESUMO
This study demonstrates the structure-activity relationship of Col-003, a potent collagen-heat-shock protein 47 (Hsp47) interaction inhibitor. Col-003 analogues were successfully synthesized by Pd(0)-catalyzed cross-coupling reactions of 5-bromosalicylaldehyde derivatives with alkyl-metal species, and the inhibitory activities of the synthetic analogues were evaluated using surface plasmon resonance analysis (BIAcore). We succeeded in discovering two potent inhibitors that showed 85 and 81% inhibition at a concentration of 1.9 µM against the collagen-Hsp47 interaction. This indicates that elongation of an alkyl linker between two aromatic rings could considerably improve inhibitory activity due to the adjustment of a pendant phenyl moiety to an appropriate position, in addition to the hydrophobic interaction with an alkyl linker moiety.