RESUMO
Sickle cell disease is a single point mutation disease that is known to alter the coagulation system, leading to hypercoagulable plasma conditions. These hypercoagulable conditions can lead to complications in the vasculature, caused by fibrin clots that form undesirably. There is a need to understand the morphology and structure of fibrin clots from patients with sickle cell disease, as this could lead to further discovery of treatments and life-saving therapies. In this work, a computational imaging analysis method is presented to evaluate fibrin agglomeration in the presence of erythrocytes (RBCs) homozygous for the sickle cell mutation (SS). Numerical algorithms were used to determine agglomeration of fibrin fibers within a matrix with SS RBCs to test the hypothesis that fibrin matrices with the inclusion of SS RBCs possess a more agglomerated structure than native fibrin matrices with AA RBCs. The numerical results showed that fibrin structures with SS RBCs displayed an overall higher degree of agglomeration as compared to native fibrin structures. The computational algorithm was also used to evaluate fibrin fiber overlap (aggregation) and anisotropy (orientation) in normal fibrin matrices compared to fibrin matrices polymerized around SS RBCs; however, there was no statistical difference. Ultrasound measurements of stiffness revealed rigid RBCs in the case of samples derived from homozygous SS blood, and densely evolving matrices, when compared to normal fibrin with the inclusion of AA RBCs. An agglomeration model is suggested to quantify the fibrin aggregation/clustering near RBCs for both normal fibrin matrices and for the altered structures. The results of this work are important in the sense that the understanding of aggregation and morphology in fibrin clots with incorporation of RBCs from persons living with sickle cell anemia may elucidate the complexities of comorbidities and other disease complications.
Assuntos
Anemia Falciforme/sangue , Eritrócitos/metabolismo , Fibrina/ultraestrutura , Imageamento Tridimensional/métodos , Microscopia Confocal/métodos , Algoritmos , Anemia Falciforme/genética , Agregação Eritrocítica/genética , Fibrina/metabolismo , Homozigoto , Humanos , Agregados ProteicosRESUMO
This study describes general synthesis aspects of fragments for FBDD, as illustrated by the dihydroisoquinolones 1-3. Previous Rh(III) methodology is extended to incorporate amines, heteroatoms (N and S), and substituents (halogen, ester) as potential binding groups and/or synthetic growth points for fragment-to-lead elaboration.
Assuntos
Descoberta de Drogas , Isoquinolinas/síntese química , Desenho de Fármacos , Isoquinolinas/química , Estrutura MolecularRESUMO
Compensating for biodiversity losses in 1 location by conserving or restoring biodiversity elsewhere (i.e., biodiversity offsetting) is being used increasingly to compensate for biodiversity losses resulting from development. We considered whether a form of biodiversity offsetting, enhancement offsetting (i.e., enhancing the quality of degraded natural habitats through intensive ecological management), can realistically secure additional funding to control biological invaders at a scale and duration that results in enhanced biodiversity outcomes. We suggest that biodiversity offsetting has the potential to enhance biodiversity values through funding of invasive species control, but it needs to meet 7 key conditions: be technically possible to reduce invasive species to levels that enhance native biodiversity; be affordable; be sufficiently large to compensate for the impact; be adaptable to accommodate new strategic and tactical developments while not compromising biodiversity outcomes; acknowledge uncertainties associated with managing pests; be based on an explicit risk assessment that identifies the cost of not achieving target outcomes; and include financial mechanisms to provide for in-perpetuity funding. The challenge then for conservation practitioners, advocates, and policy makers is to develop frameworks that allow for durable and effective partnerships with developers to realize the full potential of enhancement offsets, which will require a shift away from traditional preservation-focused approaches to biodiversity management.
Assuntos
Biodiversidade , Conservação dos Recursos Naturais/economia , Conservação dos Recursos Naturais/métodos , Espécies Introduzidas , Mamíferos/fisiologia , Controle de Pragas/economia , Controle de Pragas/métodos , Animais , Nova ZelândiaRESUMO
Poor sleep and subsequent decline in mental health often occur during times of prolonged stress, such as a pandemic. Self-compassion is linked with improved sleep and better mental health, while self-criticism is linked with poorer sleep and psychological distress. Given there is little evidence of the interrelationships of these constructs, we examined whether higher self-compassion or lower levels of self-criticism can reduce psychological distress directly and indirectly via sleep during times of prolonged stress. Structural equation modelling was used to analyse two samples (N = 722, Study 1, and N = 622, Replication Study) of university students during different stages of the pandemic. An aggregate psychological distress construct was calculated using depression, anxiety and stress measures. We created models that showed insomnia symptoms mediated the relationship between self-compassion/self-criticism and psychological distress. Sleep partially mediated both relationships, and this was the strongest effect in both samples. This suggests that improving self-compassion and reducing self-criticism will improve sleep, leading to reduced psychological distress. As our findings are robust and held at two time points, future research should investigate broader demographics and differing stress responses.
Assuntos
Angústia Psicológica , Transtornos do Sono-Vigília , Humanos , Autoavaliação (Psicologia) , Depressão/psicologia , Autocompaixão , Empatia , Sono , Estresse Psicológico/psicologiaRESUMO
The dynamic equilibrium model of species diversity predicts that ecosystem productivity interacts with disturbance to determine how many species coexist. However, a robust test of this model requires manipulations of productivity and disturbance over a sufficient timescale to allow competitive exclusion, and such long-term experimental tests of this hypothesis are rare. Here we use long-term (27 years), large-scale (8 × 50-m plots), factorial manipulations of soil resource availability and sheep grazing intensity (disturbance) in grasslands to test the dynamic equilibrium model. As predicted by the model, increased productivity not only reduced plant species richness, but also moderated the effects of grazing intensity, shifting them from negative to neutral with increasing productivity. Reductions in species richness with productivity were associated with dominance by faster growing (i.e. high specific leaf area) and taller plants. Conversely, grazing favoured shorter plants and this effect became stronger with greater productivity, consistent with the view that grazing can lead to weaker asymmetric competition for light. Our study shows that the dynamic equilibrium model can help to explain changes in plant species richness following long-term increases in soil resource availability and grazing pressure, two fundamental drivers of change in grasslands worldwide.
Assuntos
Biodiversidade , Ecossistema , Modelos Teóricos , Plantas , Animais , Comportamento Alimentar , Herbivoria , Ovinos , SoloRESUMO
The Tonle Sap is the largest wetland in Southeast Asia and one of the world's most productive inland fisheries. The Mekong River inundates the Tonle Sap every year, shaping a mosaic of natural and agricultural habitats. Ongoing hydropower development, however, will dampen the flood pulse that maintains the Tonle Sap. This study established the current underlying relationship among hydrology, vegetation, and human use. We found that vegetation is strongly influenced by flood duration; however, this relationship was heavily distorted by fire, grazing, and rice cultivation. The expected flood pulse alteration will result in higher water levels during the dry season, permanently inundating existing forests. The reduction of the maximum flood extent will facilitate agricultural expansion into natural habitats. This study is the most comprehensive field survey of the Tonle Sap to date, and it provides fundamental knowledge needed to understand the underlying processes that maintain this important wetland.
Assuntos
Agricultura , Pesqueiros , Inundações , Áreas Alagadas , Conservação dos Recursos Naturais , Humanos , Vale do MecomRESUMO
A series of α7 nicotinic acetylcholine receptor full-agonists with a 1,3,4-oxadiazol-2-amine core has been discovered. Systematic exploration of the structure-activity relationships for both α7 potency and selectivity with respect to interaction with the hERG channel are described. Further profiling led to the identification of compound 22, a potent full agonist showing efficacy in the novel object recognition model of cognition enhancement.
Assuntos
Cognição/efeitos dos fármacos , Agonistas Nicotínicos/farmacologia , Receptores Nicotínicos/efeitos dos fármacos , Animais , Cães , Agonistas Nicotínicos/química , Receptor Nicotínico de Acetilcolina alfa7RESUMO
A series of α7 nicotinic acetylcholine receptor full agonists with a 1,3,4-oxadiazol-2-amine core has been discovered. Early lead 1 was found to have a limited therapeutic index with respect to its potential for cardiovascular side effects. Further optimisation of this series led to the identification of 22 a potent full agonist showing efficacy at a dose of 0.1mg/kg in the novel object recognition model of cognition enhancement. Comparison of 1 with 22 demonstrated the latter to have an improved oral pharmacokinetic profile and cardiovascular therapeutic index.
Assuntos
Cognição/efeitos dos fármacos , Agonistas Nicotínicos/farmacologia , Receptores Nicotínicos/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Coelhos , Receptores Nicotínicos/química , Receptor Nicotínico de Acetilcolina alfa7RESUMO
ADAM10, a member of a disintegrin and metalloprotease family, is an alpha-secretase capable of anti-amyloidogenic proteolysis of the amyloid precursor protein. Here, we present evidence for genetic association of ADAM10 with Alzheimer's disease (AD) as well as two rare potentially disease-associated non-synonymous mutations, Q170H and R181G, in the ADAM10 prodomain. These mutations were found in 11 of 16 affected individuals (average onset age 69.5 years) from seven late-onset AD families. Each mutation was also found in one unaffected subject implying incomplete penetrance. Functionally, both mutations significantly attenuated alpha-secretase activity of ADAM10 (>70% decrease), and elevated Abeta levels (1.5-3.5-fold) in cell-based studies. In summary, we provide the first evidence of ADAM10 as a candidate AD susceptibility gene, and report two potentially pathogenic mutations with incomplete penetrance for late-onset familial AD.
Assuntos
Proteínas ADAM/genética , Proteínas ADAM/metabolismo , Doença de Alzheimer/enzimologia , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Mutação , Proteína ADAM10 , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Animais , Células CHO , Cricetinae , Cricetulus , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Polimorfismo de Nucleotídeo ÚnicoRESUMO
The prevalence of the biaryl structural motif in biologically interesting and synthetically important molecules has inspired considerable interest in the development of methods for aryl-aryl bond formation. Herein we describe a novel strategy for this process involving the fluoride-free, palladium-catalysed cross-coupling of readily accessible aryldisiloxanes and aryl bromides. Using a statistical-based optimisation process, preparatively useful reaction conditions were formulated to allow the cross-coupling of a wide range of different substrates. This methodology represents an attractive, cost-efficient, flexible and robust alternative to the traditional transition-metal-catalysed routes typically used to generate molecules containing the privileged biaryl scaffold.
Assuntos
Reagentes de Ligações Cruzadas/química , Fluoretos/química , Hidrocarbonetos Bromados/química , Paládio/química , Siloxanas/química , Catálise , Estrutura MolecularRESUMO
The NRF2-mediated cytoprotective response is central to cellular homoeostasis, and there is increasing interest in developing small-molecule activators of this pathway as therapeutics for diseases involving chronic oxidative stress. The protein KEAP1, which regulates NRF2, is a key point for pharmacological intervention, and we recently described the use of fragment-based drug discovery to develop a tool compound that directly disrupts the protein-protein interaction between NRF2 and KEAP1. We now present the identification of a second, chemically distinct series of KEAP1 inhibitors, which provided an alternative chemotype for lead optimization. Pharmacophoric information from our original fragment screen was used to identify new hit matter through database searching and to evolve this into a new lead with high target affinity and cell-based activity. We highlight how knowledge obtained from fragment-based approaches can be used to focus additional screening campaigns in order to de-risk projects through the rapid identification of novel chemical series.
Assuntos
Ácidos Carboxílicos/farmacologia , Descoberta de Drogas , Proteína 1 Associada a ECH Semelhante a Kelch/antagonistas & inibidores , Animais , Ácidos Carboxílicos/química , Linhagem Celular , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/metabolismo , Ligação Proteica , Pirazóis , Relação Estrutura-AtividadeRESUMO
The MAPK signaling pathway is commonly upregulated in human cancers. As the primary downstream effector of the MAPK pathway, ERK is an attractive therapeutic target for the treatment of MAPK-activated cancers and for overcoming resistance to upstream inhibition. ASTX029 is a highly potent and selective dual-mechanism ERK inhibitor, discovered using fragment-based drug design. Because of its distinctive ERK-binding mode, ASTX029 inhibits both ERK catalytic activity and the phosphorylation of ERK itself by MEK, despite not directly inhibiting MEK activity. This dual mechanism was demonstrated in cell-free systems, as well as cell lines and xenograft tumor tissue, where the phosphorylation of both ERK and its substrate, ribosomal S6 kinase (RSK), were modulated on treatment with ASTX029. Markers of sensitivity were highlighted in a large cell panel, where ASTX029 preferentially inhibited the proliferation of MAPK-activated cell lines, including those with BRAF or RAS mutations. In vivo, significant antitumor activity was observed in MAPK-activated tumor xenograft models following oral treatment. ASTX029 also demonstrated activity in both in vitro and in vivo models of acquired resistance to MAPK pathway inhibitors. Overall, these findings highlight the therapeutic potential of a dual-mechanism ERK inhibitor such as ASTX029 for the treatment of MAPK-activated cancers, including those which have acquired resistance to inhibitors of upstream components of the MAPK pathway. ASTX029 is currently being evaluated in a first in human phase I-II clinical trial in patients with advanced solid tumors (NCT03520075).
Assuntos
Neoplasias do Colo/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Indóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Animais , Apoptose , Ciclo Celular , Movimento Celular , Proliferação de Células , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fosforilação , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Aberrant activation of the mitogen-activated protein kinase pathway frequently drives tumor growth, and the ERK1/2 kinases are positioned at a key node in this pathway, making them important targets for therapeutic intervention. Recently, a number of ERK1/2 inhibitors have been advanced to investigational clinical trials in patients with activating mutations in B-Raf proto-oncogene or Ras. Here, we describe the discovery of the clinical candidate ASTX029 (15) through structure-guided optimization of our previously published isoindolinone lead (7). The medicinal chemistry campaign focused on addressing CYP3A4-mediated metabolism and maintaining favorable physicochemical properties. These efforts led to the identification of ASTX029, which showed the desired pharmacological profile combining ERK1/2 inhibition with suppression of phospho-ERK1/2 (pERK) levels, and in addition, it possesses suitable preclinical pharmacokinetic properties predictive of once daily dosing in humans. ASTX029 is currently in a phase I-II clinical trial in patients with advanced solid tumors.
Assuntos
Antineoplásicos/uso terapêutico , Indóis/uso terapêutico , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Cristalografia por Raios X , Cães , Humanos , Indóis/síntese química , Indóis/metabolismo , Indóis/farmacocinética , Masculino , Camundongos Endogâmicos BALB C , Proteína Quinase 1 Ativada por Mitógeno/química , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Estrutura Molecular , Fosforilação/efeitos dos fármacos , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Proto-Oncogene Mas , Pirimidinas/síntese química , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Ratos Sprague-Dawley , Ratos Wistar , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Some anesthetics have been suggested to induce neurotoxicity, including promotion of Alzheimer's disease neuropathogenesis. Nitrous oxide and isoflurane are common anesthetics. The authors set out to assess the effects of nitrous oxide and/or isoflurane on apoptosis and beta-amyloid (Abeta) levels in H4 human neuroglioma cells and primary neurons from naïve mice. METHODS: The cells or neurons were exposed to 70% nitrous oxide and/or 1% isoflurane for 6 h. The cells or neurons and conditioned media were harvested at the end of the treatment. Caspase-3 activation, apoptosis, processing of amyloid precursor protein, and Abeta levels were determined. RESULTS: Treatment with a combination of 70% nitrous oxide and 1% isoflurane for 6 h induced caspase-3 activation and apoptosis in H4 naïve cells and primary neurons from naïve mice. The 70% nitrous oxide plus 1% isoflurane, but neither alone, for 6 h induced caspase-3 activation and apoptosis, and increased levels of beta-site amyloid precursor protein-cleaving enzyme and Abeta in H4-amyloid precursor protein cells. In addition, the nitrous oxide plus isoflurane-induced Abeta generation was reduced by a broad caspase inhibitor, Z-VAD. Finally, the nitrous oxide plus isoflurane-induced caspase-3 activation was attenuated by gamma-secretase inhibitor L-685,458, but potentiated by exogenously added Abeta. CONCLUSION: These results suggest that the common anesthetics nitrous oxide plus isoflurane may promote neurotoxicity by inducing apoptosis and increasing Abeta levels. The generated Abeta may further potentiate apoptosis to form another round of apoptosis and Abeta generation. More studies, especially the in vivo confirmation of these in vitro findings, are needed.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Anestésicos Inalatórios/toxicidade , Apoptose/efeitos dos fármacos , Isoflurano/toxicidade , Óxido Nitroso/toxicidade , Actinas/metabolismo , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Western Blotting , Carbamatos/farmacologia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Dipeptídeos/farmacologia , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Ensaio de Imunoadsorção Enzimática , Humanos , Marcação In Situ das Extremidades Cortadas , Camundongos , Neurônios/efeitos dos fármacosRESUMO
Vinyldisiloxanes equilibrate with the corresponding silanolates under basic conditions and subsequently undergo palladium catalysed cross coupling with aryl/heteroaryl iodides and bromides.
Assuntos
Siloxanas/química , Catálise , Hidrocarbonetos Bromados/química , Hidrocarbonetos Iodados/química , Estrutura Molecular , Paládio/química , Estereoisomerismo , Estilbenos/síntese química , Estilbenos/químicaRESUMO
Biodiversity offsets are increasingly being used for securing biodiversity conservation outcomes as part of sustainable economic development to compensate for the residual unavoidable impacts of projects. Two recent New Zealand examples of biodiversity offsets are reviewed-while both are positive for biodiversity conservation, the process by which they were developed and approved was based more on the precautionary principal than on any formal framework. Based on this review and the broader offset literature, an environmental framework for developing and approving biodiversity offsets, comprising six principles, is outlined: (1) biodiversity offsets should only be used as part of an hierarchy of actions that first seeks to avoid impacts and then minimizes the impacts that do occur; (2) a guarantee is provided that the offset proposed will occur; (3) biodiversity offsets are inappropriate for certain ecosystem (or habitat) types because of their rarity or the presence of threatened species within them; (4) offsets most often involve the creation of new habitat, but can include protection of existing habitat where there is currently no protection; (5) a clear currency is required that allows transparent quantification of values to be lost and gained in order to ensure ecological equivalency between cleared and offset areas; (6) offsets must take into account both the uncertainty involved in obtaining the desired outcome for the offset area and the time-lag that is involved in reaching that point.
Assuntos
Biodiversidade , Monitoramento Ambiental/métodos , Nova ZelândiaRESUMO
BACKGROUND: In patients with right iliac fossa pain, the need for surgery is largely determined by the likelihood of appendicitis. Patients often undergo ultrasound scanning despite a low diagnostic accuracy for appendicitis. This study aimed to determine the feasibility of a larger trial of computed tomography in the evaluation of patients with atypical right iliac fossa pain. MATERIALS AND METHODS: A single-centre, unblinded, parallel randomised controlled trial of computed tomography in the assessment of patients with atypical right iliac fossa pain. After a retrospective evaluation, standard care was defined as serial examination with or without ultrasound. Atypical right iliac fossa pain was defined as no firm diagnosis after initial senior review. Simple descriptions of the risks and benefits of computed tomography were devised for patients to consider. Primary objectives were to assess feasibility and acceptability of the study procedures. RESULTS: A total of 71 patients were invited to participate and 68 were randomised. Final analysis included 31 participants in the standard care arm and 33 in the computed tomography arm, with comparable demographics. Computed tomography was associated with superior diagnostic accuracy, with 100% positive and negative predictive value. The proportion of scans that positively influenced management was 73% for computed tomography and 0% for ultrasound. In the computed tomography arm, there was a trend towards a shorter length of stay (2.3 vs 3.1 days) and a lower negative laparoscopy rate (2 of 11 vs 4 of 9). CONCLUSION: A large randomised trial to evaluate the use of unenhanced computed tomography in atypical right iliac fossa pain appears feasible and justified.
Assuntos
Abdome Agudo/diagnóstico por imagem , Apendicite/diagnóstico por imagem , Adulto , Estudos de Viabilidade , Feminino , Humanos , Ílio , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Tomografia Computadorizada por Raios X , Ultrassonografia , Adulto JovemRESUMO
The KEAP1-NRF2-mediated cytoprotective response plays a key role in cellular homoeostasis. Insufficient NRF2 signaling during chronic oxidative stress may be associated with the pathophysiology of several diseases with an inflammatory component, and pathway activation through direct modulation of the KEAP1-NRF2 protein-protein interaction is being increasingly explored as a potential therapeutic strategy. Nevertheless, the physicochemical nature of the KEAP1-NRF2 interface suggests that achieving high affinity for a cell-penetrant druglike inhibitor might be challenging. We recently reported the discovery of a highly potent tool compound which was used to probe the biology associated with directly disrupting the interaction of NRF2 with the KEAP1 Kelch domain. We now present a detailed account of the medicinal chemistry campaign leading to this molecule, which included exploration and optimization of protein-ligand interactions in three energetic "hot spots" identified by fragment screening. In particular, we also discuss how consideration of ligand conformational stabilization was important to its development and present evidence for preorganization of the lead compound which may contribute to its high affinity and cellular activity.
Assuntos
Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Propionatos/metabolismo , Ligação Proteica/efeitos dos fármacos , Sítios de Ligação , Linhagem Celular , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/química , Conformação Molecular , Fator 2 Relacionado a NF-E2/química , Propionatos/síntese química , Propionatos/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
We describe an experimental closed bioreactor device for studying novel tissue engineered peripheral nerve conduits in vitro. The system integrates a closed loop system consisting of one, two, or three experimental nerve conduits connected in series or parallel, with the ability to study novel scaffolds within guidance conduits. The system was established using aligned synthetic microfiber scaffolds of viscose rayon and electrospun polystyrene. Schwann cells were seeded directly into conduits varying from 10 to 80 mm in length and allowed to adhere under 0 flow for 1 h, before being cultured for 4 days under static or continuous flow conditions. In situ viability measurements showed the distribution of live Schwann cells within each conduit and enabled quantification thereafter. Under static culture viable cells only existed in short conduit scaffolds (10 mm) or at the ends of longer conduits (20-80 mm) with a variation in viable cell distribution. Surface modification of scaffold fibers with type-1 collagen or acrylic acid increased cell number by 17% and 30%, respectively. However, a continuous medium flow of 0.8 mL/h was found to increase total cell number by 2.5-fold verses static culture. Importantly, under these conditions parallel viability measurements revealed a ninefold increase compared to static culture. Fluorescence microscopy of scaffolds showed cellular adhesion and alignment on the longitudinal axis. We suggest that such a system will enable a rigorous and controlled approach for evaluating novel conduits for peripheral nerve repair, in particular using hydrolysable materials for the parallel organization of nerve support cells, prior to in vivo study.
Assuntos
Reatores Biológicos , Nervos Periféricos/citologia , Células de Schwann/citologia , Resinas Acrílicas , Animais , Contagem de Células , Linhagem Celular , Sobrevivência Celular , Celulose , Regeneração Nervosa , Poliestirenos , Ratos , Engenharia Tecidual , Alicerces TeciduaisRESUMO
The feasibility and effectiveness of a distance-based quality improvement model were examined in a cohort of Pediatric Research in Office Settings (PROS) practices, with the goal of improving immunization rates and practitioner behaviors and attitudes. Of an initially assessed 82 practices, 29 with baseline rates of < or =88% for children 8 to 15 months of age were randomized into year-long paper-based education or distance-based quality improvement intervention groups. Outcomes were utility/helpfulness of quality improvement modalities, immunization rate change, and behavior/attitude change. Quality improvement participants attended approximately 75% of monthly conference calls but used the quality improvement Listserv and Web site infrequently (mean 1.09 and 0.92 uses, respectively). Helpfulness ratings of quality improvement modalities mirrored usage. Analyses revealed a 4.9% increase in quality improvement group immunization rates (P = .061), a 0.8% education group increase (P = .752), and a 4.1% difference between groups (P = .261). More quality improvement practices adopted systems identifying children behind in immunizations. A distance-based quality improvement model is feasible and may improve immunization rates.