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Intraspecific interactions within predator populations can affect predator-prey dynamics and community structure, highlighting the need to better understand how these interactions respond to anthropogenic change. To this end, we used a half-century (1969-2018) of abundance and size-at-age data from Lake Erie's walleye (Sander vitreus) population to determine how anthropogenic alterations have influenced intraspecific interactions. Before the 1980s, the length-at-age of younger walleye (ages 1 and 2) negatively correlated with older (age 3 +) walleye abundance, signaling a 'density feedback' in which intraspecific competition limited growth. However, after the early 1980s this signal of intraspecific competition disappeared. This decoupling of the density feedback was related to multiple anthropogenic changes, including a larger walleye population resulting from better fisheries management, planned nutrient reductions to improve water quality and transparency, warmer water temperatures, and the proliferation of a non-native fish with novel traits (white perch, Morone americana). We argue that these changes may have reduced competitive interactions by reducing the spatial overlap between older and younger walleye and by introducing novel prey. Our findings illustrate the potential for anthropogenic change to diminish density dependent intraspecific interactions within top predator populations, which has important ramifications for predicting predator dynamics and managing natural resources.
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Bass , Percas , Animais , Retroalimentação , Lagos , Temperatura , Comportamento PredatórioRESUMO
Methane (CH4) produced by ruminants is a significant source of greenhouse gases from agriculture in the United Kingdom (UK), accounting for approximately 50% of the emissions in this sector. Ration modification is linked to changes in rumen fermentation and can be an effective means of CH4 abatement. In temperate climate countries, forage silage represents a major feed component for cattle during the housing period. The objective of this study was, therefore, to compare enteric CH4 emission from cattle offered silage produced from different types of grassland. Beef cattle, steers (n = 89) and heifers (n = 88) with average liveweight (LW) of 328 ± 57.1 kg were evaluated during two housing seasons (2016-2017 and 2017-2018) from November to April, at the Rothamsted Research North Wyke Farm Platform (UK). The treatments corresponded to three diet types, comprising silage harvested from three different pastures: MRG, monoculture of perennial ryegrass (PRG, Lolium perenne L.cv. AberMagic), bred to express the high-sugar phenotype; RG-WC, a mixed sward comprised of the same perennial ryegrass cultivar with white clover (Trifolium repens L.) with a target clover proportion of 30% as land cover; and permanent pasture (PP) dominated by PRG and a small number of non-introduced species. MRG and PP received 160-200 kg N/ha/year. Cattle were weighed every 30 days, and the enteric CH4 emission was determined using GreenFeed automated systems. No significant differences in enteric CH4 emission per head or per kg LW were observed between treatments. However, emission expressed per average daily gain (ADG) in LW was greater (P < 0.001) for MRG compared with RG-WC and PP, at 270, 248 and 235 g CH4/kg ADG, respectively. This related to a lower ADG (P = 0.041) for the animals fed MRG silage compared with RG-WC and PP which were similar, with respective values of 0.67, 0.71 and 0.74 kg/day. The forages compared in this study showed little or no potential to reduce enteric CH4 emission when fed as silage to growing beef cattle during the winter housing period.
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Lolium , Trifolium , Bovinos , Animais , Feminino , Silagem/análise , Dieta/veterinária , Metano , Habitação , Melhoramento Vegetal , Ruminantes , Rúmen , Ração Animal/análiseRESUMO
OBJECTIVES: Wnt pathway upregulation contributes to knee osteoarthritis (OA) through osteoblast differentiation, increased catabolic enzymes, and inflammation. The small-molecule Wnt pathway inhibitor, lorecivivint (SM04690), which previously demonstrated chondrogenesis and cartilage protection in an animal OA model, was evaluated to elucidate its mechanism of action. DESIGN: Biochemical assays measured kinase activity. Western blots measured protein phosphorylation in human mesenchymal stem cells (hMSCs), chondrocytes, and synovial fibroblasts. siRNA knockdown effects in hMSCs and BEAS-2B cells on Wnt pathway, chondrogenic genes, and LPS-induced inflammatory cytokines was measured by qPCR. In vivo anti-inflammation, pain, and function were evaluated following single intra-articular (IA) lorecivivint or vehicle injection in the monosodium iodoacetate (MIA)-induced rat OA model. RESULTS: Lorecivivint inhibited intranuclear kinases CDC-like kinase 2 (CLK2) and dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). Lorecivivint inhibited CLK2-mediated phosphorylation of serine/arginine-rich (SR) splicing factors and DYRK1A-mediated phosphorylation of SIRT1 and FOXO1. siRNA knockdowns identified a role for CLK2 and DYRK1A in Wnt pathway modulation without affecting ß-catenin with CLK2 inhibition inducing early chondrogenesis and DYRK1A inhibition enhancing mature chondrocyte function. NF-κB and STAT3 inhibition by lorecivivint reduced inflammation. DYRK1A knockdown was sufficient for anti-inflammatory effects, while combined DYRK1A/CLK2 knockdown enhanced this effect. In the MIA model, lorecivivint inhibited production of inflammatory cytokines and cartilage degradative enzymes, resulting in increased joint cartilage, decreased pain, and improved weight-bearing function. CONCLUSIONS: Lorecivivint inhibition of CLK2 and DYRK1A suggested a novel mechanism for Wnt pathway inhibition, enhancing chondrogenesis, chondrocyte function, and anti-inflammation. Lorecivivint shows potential to modify structure and improve symptoms of knee OA.
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Anti-Inflamatórios/uso terapêutico , Imidazóis/uso terapêutico , Indazóis/uso terapêutico , Osteoartrite do Joelho/tratamento farmacológico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Piridinas/uso terapêutico , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Western Blotting , Células Cultivadas , Modelos Animais de Doenças , Humanos , Reação em Cadeia da Polimerase , Ratos , Quinases DyrkRESUMO
BACKGROUND: As one strategy to improve the health and survival of people who inject drugs, the King County Heroin & Opioid Addiction Task Force recommended the establishment of supervised injection facilities (SIF) where people can inject drugs in a safe and hygienic environment with clinical supervision. Analyses for other sites have found them to be cost-effective, but it is not clear whether these findings are transferable to other settings. METHODS: We utilized local estimates and other data sources deemed appropriate for our setting to implement a mathematical model that assesses the impact of a hypothetical SIF on overdose deaths, non-fatal overdose health service utilization, skin and soft tissue infections, bacterial infections, viral infections, and enrollment in medication assisted treatment (MAT). We estimated the costs and savings that would occur on an annual basis for a small-scale pilot site given current overdose rates, as well as three other scenarios of varying scale and underlying overdose rates. RESULTS: Assuming current overdose rates, a hypothetical Seattle SIF in a pilot phase is projected to annually reverse 167 overdoses and prevent 6 overdose deaths, 45 hospitalizations, 90 emergency department visits, and 92 emergency medical service deployments. Additionally, the site would facilitate the enrollment of 41 SIF clients in medication assisted treatment programs. These health benefits correspond to a monetary value of $5,156,019. The annual estimated cost of running the SIF is $1,222,332. The corresponding cost-benefit ratio suggests that the pilot SIF would generate $4.22 for every dollar spent on SIF operational costs. The pilot SIF is projected to save the healthcare system $534,453. If Seattle experienced elevated overdose rates and Seattle SIF program were scaled up, the health benefits and financial value would be considerably greater. CONCLUSION: This analysis suggests that a SIF program in Seattle would save lives and result in considerable health benefits and cost savings.
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Redução de Custos/estatística & dados numéricos , Análise Custo-Benefício/estatística & dados numéricos , Programas de Troca de Agulhas/economia , Abuso de Substâncias por Via Intravenosa/economia , Overdose de Drogas/mortalidade , Overdose de Drogas/prevenção & controle , Infecções por HIV/prevenção & controle , Redução do Dano , Humanos , Modelos Teóricos , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , WashingtonRESUMO
Chemical reactions typically proceed via stochastic encounters between reactants. Going beyond this paradigm, we combined exactly two atoms in a single, controlled reaction. The experimental apparatus traps two individual laser-cooled atoms [one sodium (Na) and one cesium (Cs)] in separate optical tweezers and then merges them into one optical dipole trap. Subsequently, photoassociation forms an excited-state NaCs molecule. The discovery of previously unseen resonances near the molecular dissociation threshold and measurement of collision rates are enabled by the tightly trapped ultracold sample of atoms. As laser-cooling and trapping capabilities are extended to more elements, the technique will enable the study of more diverse, and eventually more complex, molecules in an isolated environment, as well as synthesis of designer molecules for qubits.
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OBJECTIVES: Osteoarthritis (OA) is a degenerative disease characterized by loss of cartilage and increased subchondral bone within synovial joints. Wnt signaling affects the pathogenesis of OA as this pathway modulates both the differentiation of osteoblasts and chondrocytes, and production of catabolic proteases. A novel small-molecule Wnt pathway inhibitor, SM04690, was evaluated in a series of in vitro and in vivo animal studies to determine its effects on chondrogenesis, cartilage protection and synovial-lined joint pathology. DESIGN: A high-throughput screen was performed using a cell-based reporter assay for Wnt pathway activity to develop a small molecule designated SM04690. Its properties were evaluated in bone-marrow-derived human mesenchymal stem cells (hMSCs) to assess chondrocyte differentiation and effects on cartilage catabolism by immunocytochemistry and gene expression, and glycosaminoglycan breakdown. In vivo effects of SM04690 on Wnt signaling, cartilage regeneration and protection were measured using biochemical and histopathological techniques in a rodent acute cruciate ligament tear and partial medial meniscectomy (ACLT + pMMx) OA model. RESULTS: SM04690 induced hMSC differentiation into mature, functional chondrocytes and decreased cartilage catabolic marker levels compared to vehicle. A single SM04690 intra-articular (IA) injection was efficacious in a rodent OA model, with increased cartilage thickness, evidence for cartilage regeneration, and protection from cartilage catabolism observed, resulting in significantly improved Osteoarthritis Research Society International (OARSI) histology scores and biomarkers, compared to vehicle. CONCLUSIONS: SM04690 induced chondrogenesis and appeared to inhibit joint destruction in a rat OA model, and is a candidate for a potential disease modifying therapy for OA.
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Anti-Inflamatórios/farmacologia , Imidazóis/farmacologia , Indazóis/farmacologia , Osteoartrite do Joelho/tratamento farmacológico , Piridinas/farmacologia , Animais , Anti-Inflamatórios/farmacocinética , Cartilagem Articular/fisiologia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Condrócitos/citologia , Condrócitos/efeitos dos fármacos , Dimetil Sulfóxido/farmacologia , Imidazóis/farmacocinética , Indazóis/farmacocinética , Masculino , Piridinas/farmacocinética , Ratos Sprague-Dawley , Regeneração/efeitos dos fármacos , Solventes/farmacologia , Via de Sinalização Wnt/efeitos dos fármacosRESUMO
OBJECTIVE: To assess the safety, pharmacokinetics, and exploratory efficacy of SM04690, a novel Wnt pathway inhibitor, as a potential disease modifying treatment for knee osteoarthritis (OA). DESIGN: Subjects with Kellgren-Lawrence grade 2-3 knee OA were randomized in successive dose-escalation cohorts to receive a knee intra-articular (IA) injection with 0.03, 0.07, or 0.23 mg SM04690, or placebo (PBO) (4:1 ratio). Safety, pharmacokinetics, efficacy (WOMAC Total/Function/Pain, Pain VAS, Physician Global Assessment [MDGA], and OMERACT-OARSI Response), OA-related biomarker (P1NP, ß-CTX, and cartilage oligomeric matrix protein [COMP]), and radiographic/imaging data were collected at baseline and during 24-week follow-up. RESULTS: 61 subjects (SM04690 n = 50; PBO n = 11) enrolled. Two dose limiting toxicities (DLTs), increased pain following injection and paroxysmal tachycardia (also the single serious AE), were reported in the 0.07 mg cohort. A total of 72 AEs were reported; Sixteen (occurring in eight subjects) were considered related to study medication. There were three discontinuations; one due to an AE (0.03 mg cohort). Bone marrow edema (BME) remained constant for most subjects. No doses were excluded from further study due to DLT criteria. Plasma levels of SM04690 were below the limit of detection at all time points. At Week 24, improvements from baseline were seen in all cohorts for the exploratory measures WOMAC Total, WOMAC Function, WOMAC Pain, MDGA, Pain VAS, and OMERACT-OARSI response. Joint space width (JSW) improvement was observed in the 0.07 mg cohort (P = 0.02 vs PBO). CONCLUSION: SM04690 appeared safe and well tolerated, with no evidence of systemic exposure. Exploratory efficacy analyses suggested positive trends for measurements of OA pain, function and disease-modifying osteoarthritis drug (DMOAD) properties. CLINICALTRIALS. GOV REGISTRATION: NCT02095548.
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Antirreumáticos/efeitos adversos , Antirreumáticos/farmacocinética , Imidazóis/efeitos adversos , Imidazóis/farmacocinética , Indazóis/efeitos adversos , Indazóis/farmacocinética , Osteoartrite do Joelho/tratamento farmacológico , Piridinas/efeitos adversos , Piridinas/farmacocinética , Via de Sinalização Wnt/efeitos dos fármacos , Idoso , Antirreumáticos/administração & dosagem , Antirreumáticos/uso terapêutico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Imidazóis/administração & dosagem , Imidazóis/uso terapêutico , Indazóis/administração & dosagem , Indazóis/uso terapêutico , Injeções Intra-Articulares , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/diagnóstico por imagem , Medição da Dor/métodos , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Radiografia , Índice de Gravidade de DoençaRESUMO
Microbially mediated mechanisms of human decomposition begin immediately after death, and are a driving force for the conversion of a once living organism to a resource of energy and nutrients. Little is known about post-mortem microbiology in cadavers, particularly the community structure of microflora residing within the cadaver and the dynamics of these communities during decomposition. Recent work suggests these bacterial communities undergo taxa turnover and shifts in community composition throughout the post-mortem interval. In this paper we describe how the microbiome of a living host changes and transmigrates within the body after death thus linking the microbiome of a living individual to post-mortem microbiome changes. These differences in the human post-mortem from the ante-mortem microbiome have demonstrated promise as evidence in death investigations. We investigated the post-mortem structure and function dynamics of Staphylococcus aureus and Clostridium perfringens after intranasal inoculation in the animal model Mus musculus L. (mouse) to identify how transmigration of bacterial species can potentially aid in post-mortem interval estimations. S. aureus was tracked using in vivo and in vitro imaging to determine colonization routes associated with different physiological events of host decomposition, while C. perfringens was tracked using culture-based techniques. Samples were collected at discrete time intervals associated with various physiological events and host decomposition beginning at 1h and ending at 60 days post-mortem. Results suggest that S. aureus reaches its highest concentration at 5-7 days post-mortem then begins to rapidly decrease and is undetectable by culture on day 30. The ability to track these organisms as they move in to once considered sterile space may be useful for sampling during autopsy to aid in determining post-mortem interval range estimations, cause of death, and origins associated with the geographic location of human remains during death investigations.
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Translocação Bacteriana/fisiologia , Clostridium perfringens/fisiologia , Mudanças Depois da Morte , Staphylococcus aureus/fisiologia , Animais , Contagem de Colônia Microbiana , Fluorescência , Patologia Legal , Camundongos Pelados , Modelos Animais , Imagem Corporal TotalRESUMO
Introduction Preoperative anaemia remains undertreated in the UK despite advice from national agencies to implement blood conservation measures. A local retrospective audit of 717 primary hip/knee replacements in 2008-2009 revealed 25% of patients were anaemic preoperatively. These patients experienced significantly increased transfusion requirements and length of stay. We report the results of a simple and pragmatic blood management protocol in a district general hospital. Methods Since 2010 patients at our institution who are found to be anaemic when listed for hip/knee replacement have been offered iron supplementation and/or erythropoietin depending on haemoglobin and ferritin levels. In this study, postoperative blood transfusions, length of stay and readmissions were assessed retrospectively for all patients undergoing elective primary hip/knee replacement in 2014 and compared with the baseline findings. Results During the 12-month study period, 406 patients were eligible for inclusion and none were excluded. Eighty-nine patients (22%) were anaemic preoperatively and sixty-five received treatment. The transfusion rate fell from the baseline levels of 23.0% and 6.7% to 4.3% and 0.5% for hip and knee replacements respectively (p<0.001). The median length of stay reduced from 6 to 3 days (p<0.001) for both hip and knee replacements. The rate for readmissions within 90 days fell from 13.5% to 8.9% (p<0.05). Conclusions Preoperative anaemia is common in patients listed for hip/knee replacement and it is associated strongly with increased blood transfusion. The introduction of a blood management protocol has led to significant reductions in transfusion and length of stay, sustained over a four-year period. This suggests that improved patient outcomes, conservation of blood stocks and cost savings can be achieved.
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Anemia/tratamento farmacológico , Artroplastia de Quadril , Artroplastia do Joelho , Transfusão de Sangue/estatística & dados numéricos , Protocolos Clínicos , Cuidados Pré-Operatórios , Epoetina alfa/uso terapêutico , Compostos Férricos/uso terapêutico , Ferritinas/sangue , Hematínicos/uso terapêutico , Hemoglobinas/análise , Hospitais Gerais , Humanos , Tempo de Internação/estatística & dados numéricos , Maltose/análogos & derivados , Maltose/uso terapêutico , Readmissão do Paciente/estatística & dados numéricos , Complicações Pós-Operatórias/prevenção & controle , Estudos Retrospectivos , Reino UnidoRESUMO
We report observations of superradiance for atoms trapped in the near field of a photonic crystal waveguide (PCW). By fabricating the PCW with a band edge near the D(1) transition of atomic cesium, strong interaction is achieved between trapped atoms and guided-mode photons. Following short-pulse excitation, we record the decay of guided-mode emission and find a superradiant emission rate scaling as ΓÌ (SR)âNÌ Γ(1D) for average atom number 0.19â²NÌ â²2.6 atoms, where Γ(1D)/Γ'=1.0±0.1 is the peak single-atom radiative decay rate into the PCW guided mode, and Γ' is the radiative decay rate into all the other channels. These advances provide new tools for investigations of photon-mediated atom-atom interactions in the many-body regime.
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The integration of nanophotonics and atomic physics has been a long-sought goal that would open new frontiers for optical physics, including novel quantum transport and many-body phenomena with photon-mediated atomic interactions. Reaching this goal requires surmounting diverse challenges in nanofabrication and atomic manipulation. Here we report the development of a novel integrated optical circuit with a photonic crystal capable of both localizing and interfacing atoms with guided photons. Optical bands of a photonic crystal waveguide are aligned with selected atomic transitions. From reflection spectra measured with average atom number N=1.1+/-0.4, we infer that atoms are localized within the waveguide by optical dipole forces. The fraction of single-atom radiative decay into the waveguide is Γ1D/Γ'≃(0.32±0.08), where Γ1D is the rate of emission into the guided mode and Γ' is the decay rate into all other channels. Γ1D/Γ' is unprecedented in all current atom-photon interfaces.
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AIMS: To assess the utility of flexible sigmoidoscopy (FS) and minimal preparation CT (MPCT) in investigating lower gastrointestinal (LGI) symptoms in elderly patients who are too frail to undergo colonoscopy or spiral CT. METHODS: All FS examinations performed in patients aged over 70 between 1 January and 31 December 2008 were analysed. Predictors of usefulness were determined using multivariable analysis. In patients who also underwent MPCT, we analyzed the correlation between FS and MPCT. RESULTS: 426 FS were performed. Bowel preparation was inadequate in 24% of procedures. Indications in which FS was useful were: radiological abnormality (odds ratio [OR] 9.32), history of polyps (OR 4.54) and rectal bleeding (OR 1.73). Indications for which FS was least useful were: change in bowel habit (OR 0.22), diarrhoea (OR 0.46) and constipation (OR 0.38). CONCLUSIONS: LGI investigation in frail elderly patients can be rationalised according to indication. Performing FS and MPCT together is not always necessary.
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Doenças do Colo/diagnóstico , Idoso Fragilizado , Satisfação do Paciente , Melhoria de Qualidade , Sigmoidoscopia/métodos , Tomografia Computadorizada Espiral/métodos , Idoso , Feminino , Humanos , Masculino , Estudos RetrospectivosRESUMO
The quality factor of a mechanical resonator is an important figure of merit for various sensing applications and for observing quantum behavior. Here, we demonstrate a technique to push the quality factor of a micromechanical resonator beyond conventional material and fabrication limits by using an optical field to stiffen or trap a particular motional mode. Optical forces increase the oscillation frequency by storing most of the mechanical energy in a nearly lossless optical potential, thereby strongly diluting the effect of material dissipation. By placing a 130 nm thick SiO2 pendulum in an optical standing wave, we achieve an increase in the pendulum center-of-mass frequency from 6.2 to 145 kHz. The corresponding quality factor increases 50-fold from its intrinsic value to a final value of Q=5.8(1.1)×10(5), representing more than an order of magnitude improvement over the conventional limits of SiO2 for this geometry. Our technique may enable new opportunities for mechanical sensing and facilitate observations of quantum behavior in this class of mechanical systems.
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A variety of assays were utilized to determine the effects of Leptospermum petersonii essential oil on both Candida albicans and Aspergillus fumigatus. Hyphal morphology, susceptibility of spheroplasts and uptake of propidium iodide following exposure to the oil suggest that the mode of action of L. petersonii essential oil is through direct disturbance of the fungal cell membrane. Data also confirms that the volatile component of the oil is highly antifungal, independent of direct contact between the liquid oil and the fungal membrane. The degree of inhibition was greater when fungi were directly exposed to oil volatiles compared to pre-inoculation exposure of oil volatiles into the agar. It is likely that the essential oil volatiles are acting both directly and indirectly on the fungi to produce growth inhibition.
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Antifúngicos/farmacologia , Aspergillus fumigatus/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Leptospermum/química , Óleos Voláteis/farmacologia , Óleos de Plantas/farmacologia , Aspergillus fumigatus/crescimento & desenvolvimento , Candida albicans/crescimento & desenvolvimento , Humanos , Hifas/efeitos dos fármacos , Testes de Sensibilidade MicrobianaRESUMO
An investigation is currently underway to explore and control an outbreak of Bacillus anthracis among drug users (mainly injecting) in Scotland. Contaminated heroin or a contaminated cutting agent mixed with the heroin is considered to be the most likely source and vehicle of infection. Heroin users have been advised of the risk. The risk to the general public is regarded as very low.
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Antraz/etiologia , Bacillus anthracis/isolamento & purificação , Surtos de Doenças , Abuso de Substâncias por Via Intravenosa/microbiologia , Adulto , Feminino , Heroína/administração & dosagem , Heroína/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Vigilância da População , Escócia/epidemiologiaRESUMO
OBJECTIVES: This study investigates the volatile (vapour) component of an essential oil derived from the Australian native Leptospermum petersonii as a potential treatment for aspergillosis. METHODS: The in vitro antifungal effects of the volatiles were assayed by a variety of methods. In vitro mammalian cell toxicity of the oil and the oil volatiles was also determined prior to animal testing. Efficacy of the volatiles in vivo was assessed using a murine model. RESULTS: L. petersonii oil volatiles were found to be potent inhibitors of fungal growth in vitro, with fungicidal activity displayed following short exposure times (< or =1 h). No significant mammalian cell toxicity was found to be associated with the volatiles. In the absence of treatment, Aspergillus fumigatus infection of animals resulted in an increase in inflammatory cell counts and high fungal burden within the lung tissue. Chitin levels in treated animals were significantly reduced compared with control animals. No viable fungi could be recovered from animals that had completed the treatment regimen. CONCLUSIONS: The significant reduction in fungal burden in the lungs of infected animals by the volatiles of L. petersonii oil was larger than that reported for conventional antifungal drugs of choice.
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Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Aspergilose/tratamento farmacológico , Aspergillus fumigatus/efeitos dos fármacos , Leptospermum/química , Óleos Voláteis/farmacologia , Óleos Voláteis/uso terapêutico , Animais , Antifúngicos/isolamento & purificação , Antifúngicos/toxicidade , Linhagem Celular , Quitina/análise , Contagem de Colônia Microbiana , Modelos Animais de Doenças , Humanos , Pulmão/química , Pulmão/imunologia , Pulmão/microbiologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Viabilidade Microbiana/efeitos dos fármacos , Neutrófilos/imunologia , Óleos Voláteis/isolamento & purificação , Óleos Voláteis/toxicidadeRESUMO
Chronic myelogenous leukemia (CML) patients treated with imatinib mesylate (IM) become drug resistant by mutations within the kinase domain of Bcr-Abl, and by other changes that cause progression to advanced stage (blast crisis) and increased expression of the Lyn tyrosine kinase, the regulation of which is not understood yet. In Bcr-Abl+ cells inhibition of Jak2, a downstream target of Bcr-Abl, by either Jak2 inhibitors or Jak2-specific short interfering RNA (siRNA) reduced the level of the SET protein, and increased PP2A Ser/Thr phosphatase and Shp1 tyrosine phosphatase activities, which led to decreased levels of activated Lyn. Activation of PP2A combined with Jak2 inhibition enhanced the reduction of activated Lyn kinase compared with Jak2 inhibition alone. In contrast, inhibition of either PP2A or Shp1 combined with Jak2 inhibition interfered with the loss of Lyn kinase activation more so than Jak2 inhibition alone, indicating the involvement of PP2A and Shp1 in the inactivation of the Lyn kinase caused by Jak2 inhibition. Inhibition of Jak2 induced apoptosis and reduced colony formation in IM-sensitive and -resistant Bcr-Abl mutant cell lines. Jak2 inhibition also induced apoptosis in CML cells from blast crisis patients but not in normal hematopoietic cells. These results indicate that Lyn is downstream of Jak2, and Jak2 maintains activated Lyn kinase in CML through the SET-PP2A-Shp1 pathway.
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Apoptose/efeitos dos fármacos , Proteínas Cromossômicas não Histona/fisiologia , Janus Quinase 2/antagonistas & inibidores , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Proteína Fosfatase 2/fisiologia , Proteína Tirosina Fosfatase não Receptora Tipo 6/fisiologia , Fatores de Transcrição/fisiologia , Quinases da Família src/metabolismo , Animais , Benzamidas , Cicloexanos/farmacologia , Proteínas de Ligação a DNA , Resistencia a Medicamentos Antineoplásicos , Chaperonas de Histonas , Humanos , Mesilato de Imatinib , Janus Quinase 2/fisiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Camundongos , Fosforilação , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirimidinas/farmacologia , Tirfostinas/farmacologiaRESUMO
Statistical process control (SPC) charts have previously been advocated for infection control quality improvement. To determine their effectiveness, a multicentre randomised controlled trial was undertaken to explore whether monthly SPC feedback from infection control nurses (ICNs) to healthcare workers of ward-acquired meticillin-resistant Staphylococcus aureus (WA-MRSA) colonisation or infection rates would produce any reductions in incidence. Seventy-five wards in 24 hospitals in the UK were randomised into three arms: (1) wards receiving SPC chart feedback; (2) wards receiving SPC chart feedback in conjunction with structured diagnostic tools; and (3) control wards receiving neither type of feedback. Twenty-five months of pre-intervention WA-MRSA data were compared with 24 months of post-intervention data. Statistically significant and sustained decreases in WA-MRSA rates were identified in all three arms (P<0.001; P=0.015; P<0.001). The mean percentage reduction was 32.3% for wards receiving SPC feedback, 19.6% for wards receiving SPC and diagnostic feedback, and 23.1% for control wards, but with no significant difference between the control and intervention arms (P=0.23). There were significantly more post-intervention 'out-of-control' episodes (P=0.021) in the control arm (averages of 0.60, 0.28, and 0.28 for Control, SPC and SPC+Tools wards, respectively). Participants identified SPC charts as an effective communication tool and valuable for disseminating WA-MRSA data.
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Infecção Hospitalar , Controle de Infecções/estatística & dados numéricos , Resistência a Meticilina , Modelos Estatísticos , Infecções Estafilocócicas , Staphylococcus aureus , Infecção Hospitalar/diagnóstico , Infecção Hospitalar/epidemiologia , Infecção Hospitalar/prevenção & controle , Interpretação Estatística de Dados , Pessoal de Saúde , Unidades Hospitalares/estatística & dados numéricos , Hospitais/estatística & dados numéricos , Humanos , Incidência , Controle de Infecções/organização & administração , Controle de Infecções/normas , Infecções Estafilocócicas/diagnóstico , Infecções Estafilocócicas/epidemiologia , Infecções Estafilocócicas/prevenção & controle , Staphylococcus aureus/efeitos dos fármacos , Reino Unido/epidemiologiaAssuntos
Células Eritroides/patologia , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/genética , Pirrolidinas/farmacologia , Sulfonamidas/farmacologia , Proliferação de Células/efeitos dos fármacos , Humanos , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/genética , Mutação , Transtornos Mieloproliferativos/patologia , Receptores de Trombopoetina/genética , Células Tumorais CultivadasRESUMO
BACKGROUND: Open abdominal aortic aneurysm (AAA) repair is associated with cardiac and respiratory complications and an overall mortality rate of 2 to 8%. We hypothesised that excessive fluid administration during the perioperative period contributes to complications and poor outcome after AAA repair. METHODS: This was a retrospective cohort study. Medical records were analysed for fluid balance and complications in 100 consecutive patients treated by open AAA repair at a single centre between 2002-2005. Mortality and all major adverse events (MAE) such as myocardial infarction (MI), cardiac arrhythmia (Arr), pulmonary oedema (PO), pulmonary infection (PI), and acute renal failure (ARF) were included in the analysis. Level of care and hospital stay, were also recorded. RESULTS: There were no in-hospital deaths. MAE occurred in 40/100 (40%): MI (6%); Arr (14%); PO (14%); PI (25%); ARF (8%). Complications were not predicted by preoperative cardiovascular risk factors, operative and clamp time, or blood loss. Patients with complications had significantly greater cumulative positive fluid balance on postoperative day 0 (p<0.01), day 1 (p<0.05), day 2 (p<0.03) and day 3 (p<0.04). This relationship also existed for individual complications such as MI, and pulmonary oedema. These patients had significantly longer ICU/HDU (p<0.002) and hospital stay (p<0.0001). CONCLUSIONS: Serious complications are common after elective open AAA repair, and we have shown that positive fluid balance is predictive of major adverse events increased HDU/ICU and overall hospital stay.