Hypersecretion of central corticotropin-releasing hormone (CRH) has been implicated in the pathophysiology of affective disorders. Both, basic and clinical studies suggested that disrupting CRH ...signaling through CRH type 1 receptors (CRH-R1) can ameliorate stress-related clinical conditions. To study the effects of CRH-R1 blockade upon CRH-elicited behavioral and neurochemical changes we created different mouse lines overexpressing CRH in distinct spatially restricted patterns. CRH overexpression in the entire central nervous system, but not when overexpressed in specific forebrain regions, resulted in stress-induced hypersecretion of stress hormones and increased active stress-coping behavior reflected by reduced immobility in the forced swim test and tail suspension test. These changes were related to acute effects of overexpressed CRH as they were normalized by CRH-R1 antagonist treatment and recapitulated the effect of stress-induced activation of the endogenous CRH system. Moreover, we identified enhanced noradrenergic activity as potential molecular mechanism underlying increased active stress-coping behavior observed in these animals. Thus, these transgenic mouse lines may serve as animal models for stress-elicited pathologies and treatments that target the central CRH system.
Background
The CRTH2 antagonist OC000459 has previously been demonstrated to reduce airway inflammation and improve lung function in moderate persistent asthma. A study was conducted to determine the ...effect of lower once daily doses of OC000459 and to define the phenotype of subjects most responsive to treatment.
Methods
Adult subjects (percentage of predicted forced expiratory volume in 1 s (FEV1) 60–85%) were randomized to OC000459 at three dose levels (25 mg once daily, 200 mg once daily or 100 mg twice daily) or placebo for 12 weeks (n = 117–125 per group, full analysis set). The primary endpoint was the change from baseline in prebronchodilator FEV1, and secondary endpoints included Asthma Control Questionnaire (ACQ) and Standardised Asthma Quality of Life Questionnaire AQLQ(S), and incidence of exacerbations and respiratory tract infections.
Results
OC459 caused a significant improvement in FEV1 compared with placebo at a dose of 25 mg once daily (P = 0.028). A similar increase was observed in the other dose groups, and the mean change in FEV1 in the pooled dose groups at endpoint was 95 ml greater than placebo (P = 0.024). In a post hoc analysis of atopic eosinophilic subjects with uncontrolled asthma, a mean increase in FEV1 of 220 ml was observed compared with placebo (P = 0.005). The mean increase in FEV1 was more marked in younger subjects in this group: for subjects aged ≤40 years, there was a mean increase of 355 ml compared with placebo (P = 0.007). Improvements in ACQ and AQLQ(S) were observed in both the full analysis set and the atopic eosinophilic subgroup. There was a lower incidence of exacerbations and respiratory infections in subjects treated with OC000459. There were no drug‐related serious adverse events.
Conclusions
OC000459 is a safe and effective oral anti‐inflammatory agent, which achieved clinically meaningful improvements in lung function and asthma control in allergic asthmatics with an eosinophil‐dominant form of the disease. A dose of 25 mg given once daily was as effective as the higher doses studied.
Background Descriptive epidemiology of total joint replacement procedures is limited to annual procedure volumes (incidence). The prevalence of the growing number of individuals living with a total ...hip or total knee replacement is currently unknown. Our objective was to estimate the prevalence of total hip and total knee replacement in the United States. Methods Prevalence was estimated using the counting method by combining historical incidence data from the National Hospital Discharge Survey and the Healthcare Cost and Utilization Project (HCUP) State Inpatient Databases from 1969 to 2010 with general population census and mortality counts. We accounted for relative differences in mortality rates between those who have had total hip or knee replacement and the general population. Results The 2010 prevalence of total hip and total knee replacement in the total U.S. population was 0.83% and 1.52%, respectively. Prevalence was higher among women than among men and increased with age, reaching 5.26% for total hip replacement and 10.38% for total knee replacement at eighty years. These estimates corresponded to 2.5 million individuals (1.4 million women and 1.1 million men) with total hip replacement and 4.7 million individuals (3.0 million women and 1.7 million men) with total knee replacement in 2010. Secular trends indicated a substantial rise in prevalence over time and a shift to younger ages. Conclusions Around 7 million Americans are living with a hip or knee replacement, and consequently, in most cases, are mobile, despite advanced arthritis. These numbers underscore the substantial public health impact of total hip and knee arthroplasties.
Kisspeptin (Kiss1) and neurokinin B (NKB) (encoded by the Kiss1 and Tac2 genes, respectively) are indispensable for reproduction. In the female of many species, Kiss1 neurons in the arcuate nucleus ...(ARC) coexpress dynorphin A and NKB. Such cells have been termed Kiss1/NKB/Dynorphin (KNDy) neurons, which are thought to mediate the negative feedback regulation of GnRH/LH secretion by 17β-estradiol. However, we have less knowledge about the molecular physiology and regulation of Kiss1/Kiss1-expressing neurons in the ARC of the male. Our work focused on the adult male mouse, where we sought evidence for coexpression of these neuropeptides in cells in the ARC, assessed the role of Kiss1 neurons in negative feedback regulation of GnRH/LH secretion by testosterone (T), and investigated the action of NKB on KNDy and GnRH neurons. Results showed that 1) the mRNA encoding Kiss1, NKB, and dynorphin are coexpressed in neurons located in the ARC; 2) Kiss1 and dynorphin A mRNA are regulated by T through estrogen and androgen receptor-dependent pathways; 3) senktide, an agonist for the NKB receptor (neurokinin 3 receptor, encoded by Tacr3), stimulates gonadotropin secretion; 4) KNDy neurons express Tacr3, whereas GnRH neurons do not; and 5) senktide activates KNDy neurons but has no discernable effect on GnRH neurons. These observations corroborate the putative role for KNDy neurons in mediating the negative feedback effects of T on GnRH/LH secretion and provide evidence that NKB released from KNDy neurons is part of an auto-feedback loop that generates the pulsatile secretion of Kiss1 and GnRH in the male.
Phenotypic plasticity is ubiquitous and generally regarded as a key mechanism for enabling organisms to survive in the face of environmental change. Because no organism is infinitely or ideally ...plastic, theory suggests that there must be limits (for example, the lack of ability to produce an optimal trait) to the evolution of phenotypic plasticity, or that plasticity may have inherent significant costs. Yet numerous experimental studies have not detected widespread costs. Explicitly differentiating plasticity costs from phenotype costs, we re-evaluate fundamental questions of the limits to the evolution of plasticity and of generalists vs specialists. We advocate for the view that relaxed selection and variable selection intensities are likely more important constraints to the evolution of plasticity than the costs of plasticity. Some forms of plasticity, such as learning, may be inherently costly. In addition, we examine opportunities to offset costs of phenotypes through ontogeny, amelioration of phenotypic costs across environments, and the condition-dependent hypothesis. We propose avenues of further inquiry in the limits of plasticity using new and classic methods of ecological parameterization, phylogenetics and omics in the context of answering questions on the constraints of plasticity. Given plasticity's key role in coping with environmental change, approaches spanning the spectrum from applied to basic will greatly enrich our understanding of the evolution of plasticity and resolve our understanding of limits.
Live donor kidney transplantation is the best treatment option for most patients with late‐stage chronic kidney disease; however, the rate of living kidney donation has declined in the United States. ...A consensus conference was held June 5–6, 2014 to identify best practices and knowledge gaps pertaining to live donor kidney transplantation and living kidney donation. Transplant professionals, patients, and other key stakeholders discussed processes for educating transplant candidates and potential living donors about living kidney donation; efficiencies in the living donor evaluation process; disparities in living donation; and financial and systemic barriers to living donation. We summarize the consensus recommendations for best practices in these educational and clinical domains, future research priorities, and possible public policy initiatives to remove barriers to living kidney donation.
This article summarizes the proceedings of the June 2014 Consensus Conference on Best Practices in Live Kidney Donation, which include recommendations for educating transplant candidates and potential living donors, improving efficiencies in the living donor evaluation process, reducing disparities in living kidney donation, and steering future research and policy priorities to remove barriers to donation.
Sustainable intensification is an emerging model for agriculture designed to reconcile accelerating global demand for agricultural products with long-term environmental stewardship. Defined here as ...increasing agricultural production while maintaining or improving environmental quality, sustainable intensification hinges upon decision-making by agricultural producers, consumers, and policy-makers. The Long-Term Agroecosystem Research (LTAR) network was established to inform these decisions. Here we introduce the LTAR Common Experiment, through which scientists and partnering producers in US croplands, rangelands, and pasturelands are conducting 21 independent but coordinated experiments. Each local effort compares the outcomes of a predominant, conventional production system in the region ('business as usual') with a system hypothesized to advance sustainable intensification ('aspirational'). Following the logic of a conceptual model of interactions between agriculture, economics, society, and the environment, we identified commonalities among the 21 experiments in terms of (a) concerns about business-as-usual production, (b) 'aspirational outcomes' motivating research into alternatives, (c) strategies for achieving the outcomes, (d) practices that support the strategies, and (e) relationships between practice outreach and adoption. Network-wide, concerns about business as usual include the costs of inputs, opportunities lost to uniform management approaches, and vulnerability to accelerating environmental changes. Motivated by environmental, economic, and societal outcomes, scientists and partnering producers are investigating 15 practices in aspirational treatments to sustainably intensify agriculture, from crop diversification to ecological restoration. Collectively, the aspirational treatments reveal four general strategies for sustainable intensification: (1) reducing reliance on inputs through ecological intensification, (2) diversifying management to match land and economic potential, (3) building adaptive capacity to accelerating environmental changes, and (4) managing agricultural landscapes for multiple ecosystem services. Key to understanding the potential of these practices and strategies are informational, economic, and social factors-and trade-offs among them-that limit their adoption. LTAR is evaluating several actions for overcoming these barriers, including finding financial mechanisms to make aspirational production systems more profitable, resolving uncertainties about trade-offs, and building collaborative capacity among agricultural producers, stakeholders, and scientists from a broad range of disciplines.
Agriculture in the United States must respond to escalating demands for productivity and efficiency, as well as pressures to improve its stewardship of natural resources. Growing global population ...and changing diets, combined with a greater societal awareness of agriculture's role in delivering ecosystem services beyond food, feed, fiber, and energy production, require a comprehensive perspective on where and how US agriculture can be sustainably intensified, that is, made more productive without exacerbating local and off‐site environmental concerns. The USDA's Long‐Term Agroecosystem Research (LTAR) network is composed of 18 locations distributed across the contiguous United States working together to integrate national and local agricultural priorities and advance the sustainable intensification of US agriculture. We explore here the concept of sustainable intensification as a framework for defining strategies to enhance production, environmental, and rural prosperity outcomes from agricultural systems. We also elucidate the diversity of factors that have shaped the past and present conditions of cropland, rangeland, and pastureland agroecosystems represented by the LTAR network and identify priorities for research in the areas of production, resource conservation and environmental quality, and rural prosperity. Ultimately, integrated long‐term research on sustainable intensification at the national scale is critical to developing practices and programs that can anticipate and address challenges before they become crises.
Core Ideas
The LTAR network was established to enhance the sustainability of US agriculture.
The LTAR “common experiment” compares business as usual with aspirational management.
LTAR sites contribute research observations to the network's database.
LTAR network research will support sustainable intensification strategies.
The sensitivity of the Deep Underground Neutrino Experiment (DUNE) to neutrino oscillation is determined, based on a full simulation, reconstruction, and event selection of the far detector and a ...full simulation and parameterized analysis of the near detector. Detailed uncertainties due to the flux prediction, neutrino interaction model, and detector effects are included. DUNE will resolve the neutrino mass ordering to a precision of 5
σ
, for all
δ
CP
values, after 2 years of running with the nominal detector design and beam configuration. It has the potential to observe charge-parity violation in the neutrino sector to a precision of 3
σ
(5
σ
) after an exposure of 5 (10) years, for 50% of all
δ
CP
values. It will also make precise measurements of other parameters governing long-baseline neutrino oscillation, and after an exposure of 15 years will achieve a similar sensitivity to
sin
2
2
θ
13
to current reactor experiments.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
ABSTRACT PURPOSE Lower continuity of care has been associated with higher rates of adverse outcomes for persons with multiple chronic medical conditions. It is unclear, however, whether this ...relationship also exists within integrated systems that offer high levels of informational continuity through shared electronic health records. METHODS We conducted a retrospective cohort study of 12,200 seniors with 3 or more chronic conditions within an integrated delivery system. Continuity of care was calculated using the Continuity of Care Index, which reflects visit concentration with individual clinicians. Using Cox proportional hazards regression permitting continuity to vary monthly until the outcome or censoring event, we separately assessed inpatient admissions and emergency department visits as a function of primary care continuity and specialty care continuity. RESULTS After adjusting for covariates (demographics; baseline, primary, and specialty care visits; baseline outcomes; and morbidity burden), greater primary care continuity and greater specialty care continuity were each associated with a lower risk of inpatient admission (respective hazard ratios (95% CIs) = 0.97 (0.96, 0.99) and 0.95 (0.93, 0.98)) and a lower risk of emergency department visits (respective hazard ratios = 0.97 (0.96, 0.98) and 0.98 (0.96, 1.00)). For the subgroup with 3 or more primary care and 3 or more specialty care visits, specialty care continuity (but not primary care continuity) was independently associated with a decreased risk of inpatient admissions (hazard ratio = 0.94 (0.92, 0.97)), and primary care continuity (but not specialty care continuity) was associated with a decreased risk of emergency department visits (hazard ratio = 0.98 (0.96, 1.00)). CONCLUSIONS In an integrated delivery system with high informational continuity, greater continuity of care is independently associated with lower hospital utilization for seniors with multiple chronic medical conditions. Different subgroups of patients will benefit from continuity with primary and specialty care clinicians depending on their care needs.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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