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1.
Sharon R. Weeks Xun Luo Lindsey Toman Ahmet O. Gurakar Fizza F. Naqvi Saleh A. Alqahtani Benjamin Philosophe Andrew M. Cameron Niraj M. Desai Shane E. Ottmann Dorry L. Segev Jacqueline Garonzik-Wang 《Clinical transplantation》2020,34(10):e14036
Optimization of maintenance immunosuppression (mIS) regimens in the transplant recipient requires a balance between sufficient potency to prevent rejection and avoidance of excessive immunosuppression to prevent toxicities and complications. The optimal regimen after simultaneous liver-kidney (SLK) transplantation remains unclear, but small single-center reports have shown success with steroid-sparing regimens. We studied 4184 adult SLK recipients using the Scientific Registry of Transplant Recipients, from March 1, 2002, to February 28, 2017, on tacrolimus-based regimens at 1 year post-transplant. We determined the association between mIS regimen and mortality and graft failure using Cox proportional hazard models. The use of steroid-sparing regimens increased post-transplant, from 16.1% at discharge to 88.0% at 5 years. Using multi-level logistic regression modeling, we found center-level variation to be the major contributor to choice of mIS regimen (ICC 44.5%; 95% CI: 36.2%-53.0%). In multivariate analysis, use of a steroid-sparing regimen at 1 year was associated with a 21% decreased risk of mortality compared to steroid-containing regimens (aHR 0.79, P = .01) and 20% decreased risk of liver graft failure (aHR 0.80, P = .01), without differences in kidney graft loss risk (aHR 0.92, P = .6). Among SLK recipients, the use of a steroid-sparing regimen appears to be safe and effective without adverse effects on patient or graft survival. 相似文献
2.
John Weeks Albert P. Li Utkarsh Doshi Karla Johanning Patrick D. Guiney 《Journal of applied toxicology : JAT》2020,40(10):1421-1434
In vitro metabolic stability of nine fragrance chemicals: p-tolyl acetate, cashmeran, ethylene brassylate, celestolide, galaxolide, traseolide, ambretone, tonalide and pentadecanolide, was evaluated in trout and human hepatocytes. The compounds were incubated with trout hepatocytes at 12°C and human hepatocytes at 37°C. Quantification of compound disappearance with time was performed using gas chromatography/mass spectrometry. in vivo hepatic intrinsic clearance values were calculated from the in vitro data. Significant metabolism was observed with trout hepatocytes for five of the nine fragrance chemicals, while all nine were metabolized significantly with human hepatocytes. Previously published models were used to examine expected bioaccumulation and persistence in whole organisms. Calculated half-lives due to metabolism of the nine chemicals are significantly shorter for humans than trout: <1 hour and <1 day, respectively. For all chemicals with demonstrated hepatic metabolism, the models indicate a lack of accumulation. For those where metabolism was demonstrated in trout, calculated bioconcentration factors would not be classified as bioaccumulative under prevailing regulatory systems. 相似文献
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An inhibitor persistently decreased enteric methane emission from dairy cows with no negative effect on milk production 总被引:2,自引:0,他引:2
Alexander N. Hristov Joonpyo Oh Fabio Giallongo Tyler W. Frederick Michael T. Harper Holley L. Weeks Antonio F. Branco Peter J. Moate Matthew H. Deighton S. Richard O. Williams Maik Kindermann Stephane Duval 《Proceedings of the National Academy of Sciences of the United States of America》2015,112(34):10663-10668
A quarter of all anthropogenic methane emissions in the United States are from enteric fermentation, primarily from ruminant livestock. This study was undertaken to test the effect of a methane inhibitor, 3-nitrooxypropanol (3NOP), on enteric methane emission in lactating Holstein cows. An experiment was conducted using 48 cows in a randomized block design with a 2-wk covariate period and a 12-wk data collection period. Feed intake, milk production, and fiber digestibility were not affected by the inhibitor. Milk protein and lactose yields were increased by 3NOP. Rumen methane emission was linearly decreased by 3NOP, averaging about 30% lower than the control. Methane emission per unit of feed dry matter intake or per unit of energy-corrected milk were also about 30% less for the 3NOP-treated cows. On average, the body weight gain of 3NOP-treated cows was 80% greater than control cows during the 12-wk experiment. The experiment demonstrated that the methane inhibitor 3NOP, applied at 40 to 80 mg/kg feed dry matter, decreased methane emissions from high-producing dairy cows by 30% and increased body weight gain without negatively affecting feed intake or milk production and composition. The inhibitory effect persisted over 12 wk of treatment, thus offering an effective methane mitigation practice for the livestock industries.The livestock sector is a significant source of greenhouse gas (GHG) emissions in the United States and globally (1, 2). In the United States, enteric fermentation of feed by ruminants is the largest source of anthropogenic methane emissions (0.14 Gt of CO2 Eq. in 2012; or 25% of the total methane emissions; ref. 3). Globally, according to the most recent Intergovernmental Panel on Climate Change (IPCC) report, GHG emissions from agriculture represent around 10–12% (5.0–5.8 Gt CO2 Eq/yr) of the total anthropogenic GHG emissions (1). In this report, livestock contribution to the global anthropogenic GHG emissions was estimated at 6.3%, with GHG emissions from enteric fermentation accounting for 2.1 Gt CO2 Eq/yr and manure management accounting for 0.99 Gt CO2 Eq/yr (1). The relative contribution of emissions from enteric fermentation to the total agricultural GHG emissions will vary by region depending on the structure of agricultural production and type of livestock production systems. For example, GHG from enteric fermentation were estimated at 57% for New Zealand, a country with a large, pasture-based livestock sector (4). Extensive research in recent years has provided a number of viable enteric methane mitigation practices, such as alternative electron receptors, methane inhibitors, dietary lipids, and increased animal productive efficiency (5). Methane emission in the reticulo-rumen is an evolutionary adaptation that enables the rumen ecosystem to dispose of hydrogen, a fermentation product and an important energy substrate for the methanogenic archaea (6), which may otherwise accumulate and inhibit carbohydrate fermentation and fiber degradation (7, 8). Some compounds may be effective in decreasing methane emission, but they may also decrease feed intake, fiber degradability, and animal productivity (5), or the rumen archaea may adapt to them (9). Therefore, it is important to evaluate methane mitigation strategies in long-term experiments, which for livestock experimentation requires treatment periods considerably longer than the 21–28 d, common for crossover designs. In addition, due to a variety of constraints and confounding factors of batch or continuous culture in vitro systems (5, 10), mitigation compounds, including methane inhibitors, have to be tested in vivo using animals with similar productivity to those on commercial farms. An example of the limitations of in vitro systems is a series of experiments with garlic oil. In continuous rumen culture, garlic oil was very effective in inhibiting rumen methane emission (11), but it failed to produce an effect in sheep (12). The nutrient requirements of high-producing dairy cows are much greater than those of nonlactating or low-producing cows (13) and hence any reduction in feed intake caused by a methane mitigation compound or practice would likely result in decreased productivity, which may not be evident in low-producing cows.Methane inhibitors are chemical compounds with inhibitory effects on rumen archaea. Compounds such as bromochloromethane, 2-bromoethane sulfonate, chloroform, and cyclodextrin have been tested, some successfully, in various ruminant species (5). Inhibition of methanogenesis by these compounds in vivo can be up to 60% with the effect of bromochloromethane shown to persist in long-term experiments (5, 14). However, the viability of these compounds as mitigation agents has been questioned due to concerns for animal health, food safety, or environmental impact. Bromochloromethane, for example, is an ozone-depleting agent and is banned in many countries.Among the efficacious methane inhibitors identified is 3-nitrooxypropanol (3NOP; ref. 15). This compound was part of a developmental program designing specific small molecule inhibitors for methyl coenzyme-M (CoM) reductase, the enzyme that catalyzes the last step of methanogenesis, the reduction of methyl CoM and coenzyme-B (CoB) into methane and a CoM–CoB complex (16). A continuous in vitro culture study (11) was followed by in vivo experiments in sheep (17), beef (18), and dairy cattle (19, 20), which demonstrated that 3NOP is an effective methane inhibitor. However, these experiments were conducted using nonlactating animals (17), or were short-term (<35 d; refs. 19 and 20). The rumen microorganisms have the ability to adapt to foreign agents or changes in the feeding regimen and, therefore, short-term responses are not representative of the effect of a given mitigation compound or practice in real farm conditions. McIntosh et al. (21), for example, showed that the MIC50 of essential oils doubled or tripled for a number of important rumen bacteria (Butyrivibrio fibrisolvens, Prevotella bryantii, Ruminococcus albus, Ruminobacter amylophilus), if they were adapted to the treatment for a period of 10 d. Thus, it is critically important for the success of GHG mitigation efforts to substantiate the mitigation potential of a given compound in long-term animal experiments before considering it for adoption by the livestock industries. 相似文献
5.
Melanie Kistler-Fischbacher Jedidah S Yong Benjamin K Weeks Belinda R Beck 《Journal of bone and mineral research》2021,36(9):1680-1693
The goal of the MEDEX-OP trial was to compare the efficacy of a known effective high-intensity resistance and impact training (HiRIT) with a low-intensity exercise control (Buff Bones® [BB]), alone or in combination with antiresorptive bone medication, on indices of fracture risk (bone mass, body composition, muscle strength, functional performance), compliance, and safety. Primary study outcomes were 8-month change in lumbar spine (LS) and total hip (TH) bone mineral density (BMD). Healthy postmenopausal women with low bone mass (T-score ≤ −1.0) on or off stable doses (≥12 months) of antiresorptive medication were recruited. A total of 115 women (aged 63.6 ± 0.7 years; body mass index [BMI] 25.5 kg/m2; femoral neck [FN] T-score −1.8 ± 0.1) were randomly allocated to 8-month, twice-weekly, 40-minute HiRIT (5 sets of 5 repetitions, >80% to 85% 1 repetition maximum) or BB (low-intensity, Pilates-based training), stratified by medication intake, resulting in four groups: HiRIT (n = 42), BB (n = 44), HiRIT-med (n = 15), BB-med (n = 14). HiRIT improved LS BMD (1.9 ± 0.3% versus 0.1 ± 0.4%, p < 0.001) and stature (0.2 ± 0.1 cm versus −0.0 ± 0.1 cm, p = 0.004) more than BB. Both programs improved functional performance, but HiRIT effects were larger for leg and back muscle strength and the five times sit-to-stand test (p < 0.05). There was a positive relationship between maximum weight lifted and changes in LS BMD and muscle strength in the HiRIT groups. Exploratory analyses suggest antiresorptive medication may enhance exercise efficacy at the proximal femur and lumbar spine. Exercise compliance was good (82.4 ± 1.3%) and both programs were well tolerated (7 adverse events: HiRIT 4; BB 3). HiRIT improved indices of fracture risk significantly more than Buff Bones®. More trials combining bone medication and bone-targeted exercise are needed. © 2021 American Society for Bone and Mineral Research (ASBMR). 相似文献
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Angela L. Palmer-Wackerly Heather L. Voorhees Sarah D’Souza Edward Weeks 《Patient education and counseling》2019,102(4):804-809
Objective
To identify how and why infertility patients’ communication with health care providers relates to their continuity of care within infertility treatment.Method
A grounded theory analysis was conducted for 25 in-depth interviews across three coding phases, where we remained open to all themes present in the data, narrowed to most prominent themes, and found the connections between the themes.Results
Based on our identified themes, we created a conceptual model that explains why infertility patients (dis)continued care with one or more clinician. Through this model, we describe two infertility identity transitions for patients: Transition 1: “Infertility as Temporary” to “Infertility as Enduring”; and Transition 2: “Infertility as Enduring” to “Infertility as Integrated.”Conclusion
The study explains how and why patients’ view of their infertility affects their communication, and thus their continuity of care, with clinicians.Practice implications
To provide patient-centered care within infertility treatment, providers can recognize how patients’ view of their infertility, and thus their needs, goals, and expectations, shift throughout their infertility experience. 相似文献8.
l‐Methionine anti‐biofilm activity against Pseudomonas aeruginosa is enhanced by the cystic fibrosis transmembrane conductance regulator potentiator,ivacaftor 下载免费PDF全文
Calvin Mackey BS Christopher G. Weeks BS Jaime A. Peña Garcia BS Daniel Skinner BS Jessica W. Grayson MD Harrison S. Hill BS David K. Alexander Shaoyan Zhang PhD Bradford A. Woodworth MD 《International forum of allergy & rhinology》2018,8(5):577-583
Background
Biofilms may contribute to refractory chronic rhinosinusitis (CRS), as they lead to antibiotic resistance and failure of effective clinical treatment. l ‐Methionine is an amino acid with reported biofilm‐inhibiting properties. Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator with mild antimicrobial activity via inhibition of bacterial DNA gyrase and topoisomerase IV. The objective of this study was to evaluate whether co‐treatment with ivacaftor and l ‐methionine can reduce the formation of Pseudomonas aeruginosa biofilms.Methods
P aeruginosa (PAO‐1 strain) biofilms were studied in the presence of l ‐methionine and/or ivacaftor. For static biofilm assays, PAO‐1 was cultured in a 48‐well plate for 72 hours with stepwise combinations of these agents. Relative biofilm inhibitions were measured according to optical density of crystal violet stain at 590 nm. Live/dead assays (BacTiter‐Glo? assay, Promega) were imaged with laser scanning confocal microscopy. An agar diffusion test was used to confirm antibacterial effects of the drugs.Results
l ‐Methionine (0.5 μM) significantly reduced PAO‐1 biofilm mass (32.4 ± 18.0%; n = 4; p < 0.001) compared with controls. Low doses of ivacaftor alone (4, 8, and 12 μg/mL) had no effect on biofilm formation. When combined with ivacaftor (4 μg/mL), a synergistic anti‐biofilm effect was noted at 0.05 μM and 0.5 μM of l ‐methionine (two‐way analysis of variane, p = 0.0415) compared with corresponding concentrations of l ‐methionine alone.Conclusion
Ivacaftor enhanced the anti‐biofilm activity of l ‐methionine against the PAO‐1 strain of P aeruginosa. Further studies evaluating the efficacy of ivacaftor/l ‐methionine combinations for P aeruginosa sinusitis are planned.9.
Convergent,incremental, and criterion‐related validity of multi‐informant assessments of adolescents' fears of negative and positive evaluation 下载免费PDF全文
10.
IntroductionThe p53 tumour suppressor protein plays a pivotal role in the response of mammalian cells to DNA damage. It regulates cell cycle progression, apoptosis and DNA repair mechanisms and is therefore likely to influence response to targeted radionuclide therapy. This study investigated the role of p53 in the cellular response to the Auger-emitting radionuclide indium-111.MethodsTwo stable clones of a HT1080 fibrosarcoma cell line, differing only in p53 status due to RNAi-mediated knockdown of p53 expression, were incubated for 1 h with [111In]-oxinate (0–10 MBq/ml). Radiopharmaceutical uptake into HT1080 cells was measured in situ using a non-contact phosphorimager method. Cellular sensitivity and DNA damage were measured by, respectively, clonogenic survival analysis and the single cell gel electrophoresis (Comet) assay.ResultsMean uptake of [111In]-oxinate in HT1080 cells was unaffected by p53 status, reaching a maximum of 9 Bq/cell. [111In]-oxinate-induced cytotoxicity was also identical in both clones, as measured by IC50 (0.68 MBq/ml). However the formation of DNA damage, measured immediately after treatment with [111In]-oxinate, was found to be up to 2.5-fold higher in the p53-deficient HT1080 clone.ConclusionsThe increased DNA damage induced in p53-deficient HT1080 cells suggests an early deficiency in the repair of DNA damage during the treatment period. However, the similarity in cellular sensitivity, irrespective of p53 status, suggests that reduced p53 leads to a concomitant reduction in p53-dependent cytotoxicity despite the persistence of DNA damage. The results may provide insight into how tumours that differ in p53 status respond to therapeutic radionuclides. 相似文献