Summary Objective Microgliosis, the activation of microglial cells, is thought to contribute to synaptic transmission in the dorsal horn and thereby promote chronic pain. The primary aim of this ...study was to document the temporal profile of dorsal horn microgliosis after destabilization of the medial meniscus (DMM) in wild type (WT) and Adamts5 null mice. Since neuronal fractalkine (CX3CL1) contributes to microgliosis, we assessed its release from dorsal root ganglia (DRG) cultures after DMM. Design DMM or sham surgery was performed in the right knee of 10-week old male WT, CX3CR1-GFP, or Adamts5 null C57BL/6 mice. Hind paw mechanical allodynia was monitored using von Frey fibers. L4 dorsal horn microgliosis was assessed 4, 8 and 16 weeks after surgery, based on the morphology of Iba1-immunoreactive microglia. DRG cells (L3–L5) were cultured and supernatants collected for fractalkine (FKN) ELISA. Results In WT mice, numbers of activated microglia were increased 8 and 16 weeks, but not 4 weeks, after DMM but not sham surgery. DRG cultures showed increased basal FKN release at 8 and 16 weeks. Adamts5 null mice did not develop mechanical allodynia up to 16 weeks after DMM. Accordingly, DRG cultures from these mice did not exhibit increased FKN release and dorsal horn microgliosis did not occur. Conclusion DMM surgery leads to late stage dorsal horn microgliosis. The temporal correlation with DRG FKN release suggests it may contribute to microgliosis. Reduced microgliosis in Adamts5 null mice, which are protected from joint damage and associated mechanical allodynia after DMM, suggests that microgliosis is associated with joint damage and accompanying persistent pain.
Postnatal Depression (PND) is a mood disorder that steals motherhood and affects the health and development of a newborn. While the impact of PND on motherhood and newborn in developed countries are ...well described, its epidemiology and health consequences in infant is not well known in middle-and low-income countries. The objective of this review was to determine the burden and association of PND with adverse infant health outcomes in low-and middle- income countries.
We searched observational studies written in the English language and conducted in middle-and low-income countries between December 1st, 2007, and December 31st, 2017. The CINHAL, MEDLINE, Emcare, PubMed, Psych Info, and Scopus databases were searched for the following search terms: PND, acute respiratory infection, pneumonia, diarrhea, exclusive breastfeeding, common infant illnesses, and malnutrition. We excluded studies in which the primary outcomes were not measured following a standardized approach. We have meta-analyzed the estimates from primary studies by adjusting for possible publication bias and heterogeneity. The analysis was conducted in Stata 14. The study was registered in PROSPERO protocol number CRD42017082624.
Fifty-eight studies on PND prevalence (among 63,293 women) and 17 studies (among 32,454 infants) on infant health outcomes were included. PND prevalence was higher in the low-income countries (Pooled prevalence (PP) = 25.8%; 95%CI: 17.9-33.8%) than in the middle-income countries (PP = 20.8%; 95%CI: 18.4-23.1%) and reached its peak in five to ten weeks after birth. Poor obstetric history and social support, low economic and educational status, and history of exposure to violence were associated with an increased risk of PND. The risk of having adverse infant health outcomes was 31% higher among depressed compared to non-depressed postnatal mothers (Pooled relative risk (PRR) = 1.31; 95%CI: 1.17-1.48). Malnutrition (1.39; 1.21-1.61), non-exclusive breastfeeding (1.55; 1.39-1.74), and common infant illnesses (2.55; 1.41-4.61) were the main adverse health outcomes identified.
One in four and one in five postnatal mothers were depressed in low and middle-income countries, respectively. Causes of depression could be explained by social, maternal, and psychological constructs. High risk of adverse infant health outcomes was associated with PND. Timely screening of PND and evidence-based interventions were a pressing need in low and middle-income countries.
Mycorrhizal phenotypes arise from interactions among plant and fungal genotypes and the environment. Differences in the stoichiometry and uptake capacity of fungi and plants make arbuscular ...mycorrhizal (AM) fungi inherently more nitrogen (N) limited and less phosphorus (P) limited than their host plants. Mutualistic phenotypes are most likely in P‐limited systems and commensal or parasitic phenotypes in N‐limited systems. Carbon (C) limitation is expected to cause phenotypes to shift from mutualism to commensalism and even parasitism. Two experiments compared the influence of fertilizer and shade on mycorrhizas in Andropogon gerardii across three naturally N‐limited or P‐limited grasslands. A third experiment examined the interactive effects of N and P enrichment and shade on A. gerardii mycorrhizas. Our experiments generated the full spectrum of mycorrhizal phenotypes. These findings support the hypothesis that mutualism is likely in P‐limited systems and commensalism or parasitism is likely in N‐limited systems. Furthermore, shade decreased C‐assimilation and generated less mutualistic mycorrhizal phenotypes with reduced plant and fungal biomass. Soil fertility is a key controller of mycorrhizal costs and benefits and the Law of the Minimum is a useful predictor of mycorrhizal phenotype. In our experimental grasslands arbuscular mycorrhizas can ameliorate P‐limitation but not N‐limitation.
The pace of transmission of domesticated cereals, including millet from China as well as wheat and barley from southwest Asia, throughout the vast pastoralist landscapes of the Eurasian Steppe (ES) ...is unclear. The rich monumental record of the ES preserves abundant human remains that provide a temporally deep and spatially broad record of pastoralist dietary intake. Calibration of human δ
C and δ
N values against isotope ratios derived from co-occurring livestock distinguish pastoralist consumption of millet from the products of livestock and, in some regions, identify a considerable reliance by pastoralists on C
crops. We suggest that the adoption of millet was initially sporadic and consumed at low intensities during the Bronze Age, with the low-level consumption of millet possibly taking place in the Minusinsk Basin perhaps as early as the late third millennium cal BC. Starting in the mid-second millennium cal BC, millet consumption intensified dramatically throughout the ES with the exception of both the Mongolian steppe where millet uptake was strongly delayed until the end of first millennium cal BC and the Trans-Urals where instead barley or wheat gained dietary prominence. The emergence of complex, trans-regional political networks likely facilitated the rapid transfer of cultivars across the steppe during the transition to the Iron Age.
OBJECTIVETo review the literature systematically and perform meta-analyses to address these questions1) Is there evidence that self-measured blood pressure (BP) without other augmentation is superior ...to office-based measurement of BP for achieving better BP control or for preventing adverse clinical outcomes that are related to elevated BP? 2) What is the optimal target for BP lowering during antihypertensive therapy in adults? 3) In adults with hypertension, how do various antihypertensive drug classes differ in their benefits and harms compared with each other as first-line therapy?
METHODSElectronic literature searches were performed by Doctor Evidence, a global medical evidence software and services company, across PubMed and EMBASE from 1966 to 2015 using key words and relevant subject headings for randomized controlled trials that met eligibility criteria defined for each question. We performed analyses using traditional frequentist statistical and Bayesian approaches, including random-effects Bayesian network meta-analyses.
RESULTSOur results suggest that1) There is a modest but significant improvement in systolic BP in randomized controlled trials of self-measured BP versus usual care at 6 but not 12 months, and for selected patients and their providers self-measured BP may be a helpful adjunct to routine office care. 2) systolic BP lowering to a target of <130 mm Hg may reduce the risk of several important outcomes including risk of myocardial infarction, stroke, heart failure, and major cardiovascular events. No class of medications (ie, angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, calcium channel blockers, or beta blockers) was significantly better than thiazides and thiazide-like diuretics as a first-line therapy for any outcome.
Following destabilization of the medial meniscus (DMM), mice develop experimental osteoarthritis (OA) and associated pain behaviors that are dependent on the stage of disease. We aimed to describe ...changes in gene expression in knee-innervating dorsal root ganglia (DRG) after surgery, in order to identify molecular pathways associated with three pre-defined pain phenotypes: “post-surgical pain”, “early-stage OA pain”, and “persistent OA pain”.
We performed DMM or sham surgery in 10-week old male C57BL/6 mice and harvested L3-L5 DRG 4, 8, and 16 weeks after surgery or from age-matched naïve mice (n = 3/group). RNA was extracted and an Affymetrix Mouse Transcriptome Array 1.0 was performed. Three pain phenotypes were defined: “post-surgical pain” (sham and DMM 4-week vs 14-week old naïve), “early OA pain” (DMM 4-week vs sham 4-week), and “persistent OA pain” (DMM 8- and 16-week vs naïve and sham 8- and 16-week). ‘Top hit’ genes were defined as P < 0.001. Pathway analysis (Ingenuity Pathway Analysis) was conducted using differentially expressed genes defined as P < 0.05. In addition, we performed qPCR for Ngf and immunohistochemistry for F4/80+ macrophages in the DRG.
For each phenotype, top hit genes identified a small number of differentially expressed genes, some of which have been previously associated with pain (7/67 for “post-surgical pain”; 2/14 for “early OA pain”; 8/37 for “persistent OA pain”). Overlap between groups was limited, with 8 genes differentially regulated (P < 0.05) in all three phenotypes. Pathway analysis showed that in the persistent OA pain phase many of the functions of differentially regulated genes are related to immune cell recruitment and activation. Genes previously linked to OA pain (CX3CL1, CCL2, TLR1, and NGF) were upregulated in this phenotype and contributed to activation of the neuroinflammation canonical pathway. In separate sets of mice, we confirmed that Ngf was elevated in the DRG 8 weeks after DMM (P = 0.03), and numbers of F4/80+ macrophages were increased 16 weeks after DMM (P = 0.002 vs Sham).
These transcriptomics findings support the idea that distinct molecular pathways discriminate early from persistent OA pain. Pathway analysis suggests neuroimmune interactions in the DRG contribute to initiation and maintenance of pain in OA.
Toxic cyanobacterial blooms threaten freshwaters worldwide but have proven difficult to predict because the mechanisms of bloom formation and toxin production are unknown, especially on weekly time ...scales. Water quality management continues to focus on aggregated metrics, such as chlorophyll and total nutrients, which may not be sufficient to explain complex community changes and functions such as toxin production. For example, nitrogen (N) speciation and cycling play an important role, on daily time scales, in shaping cyanobacterial communities because declining N has been shown to select for N fixers. In addition, subsequent N pulses from N(2) fixation may stimulate and sustain toxic cyanobacterial growth. Herein, we describe how rapid early summer declines in N followed by bursts of N fixation have shaped cyanobacterial communities in a eutrophic lake (Lake Mendota, Wisconsin, USA), possibly driving toxic Microcystis blooms throughout the growing season. On weekly time scales in 2010 and 2011, we monitored the cyanobacterial community in a eutrophic lake using the phycocyanin intergenic spacer (PC-IGS) region to determine population dynamics. In parallel, we measured microcystin concentrations, N(2) fixation rates, and potential environmental drivers that contribute to structuring the community. In both years, cyanobacterial community change was strongly correlated with dissolved inorganic nitrogen (DIN) concentrations, and Aphanizomenon and Microcystis alternated dominance throughout the pre-toxic, toxic, and post-toxic phases of the lake. Microcystin concentrations increased a few days after the first significant N(2) fixation rates were observed. Then, following large early summer N(2) fixation events, Microcystis increased and became most abundant. Maximum microcystin concentrations coincided with Microcystis dominance. In both years, DIN concentrations dropped again in late summer, and N(2) fixation rates and Aphanizomenon abundance increased before the lake mixed in the fall. Estimated N inputs from N(2) fixation were large enough to supplement, or even support, the toxic Microcystis blooms.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We introduce a liquid application method for time-resolved analyses (LAMA), an in situ mixing approach for serial crystallography. Picoliter-sized droplets are shot onto chip-mounted protein ...crystals, achieving near-full ligand occupancy within theoretical diffusion times. We demonstrate proof-of-principle binding of GlcNac to lysozyme, and resolve glucose binding and subsequent ring opening in a time-resolved study of xylose isomerase.
During the 1980s, the free radical, nitric oxide (NO), was discovered to be a crucial signalling molecule, with wide‐ranging functions in the cardiovascular, nervous and immune systems. Aside from ...providing a credible explanation for the actions of organic nitrates and sodium nitroprusside that have long been used in the treatment of angina and hypertensive crises respectively, the discovery generated great hopes for new NO‐based treatments for a wide variety of ailments. Decades later, however, we are still awaiting novel licensed agents in this arena, despite an enormous research effort to this end. This review explores some of the most promising recent advances in NO donor drug development and addresses the challenges associated with NO as a therapeutic agent.
British Journal of Pharmacology (2007) 151, 305–321; doi:10.1038/sj.bjp.0707224
In observational studies, increased vitamin C intake, vitamin C supplementation, and higher blood concentrations of vitamin C are associated with lower blood pressure (BP). However, evidence for ...blood pressure-lowering effects of vitamin C in clinical trials is inconsistent.
The objective was to conduct a systematic review and meta-analysis of clinical trials that examined the effects of vitamin C supplementation on BP.
We searched Medline, EMBASE, and Central databases from 1966 to 2011. Prespecified inclusion criteria were as follows: 1) use of a randomized controlled trial design; 2) trial reported effects on systolic BP (SBP) or diastolic BP (DBP) or both; 3) trial used oral vitamin C and concurrent control groups; and 4) trial had a minimum duration of 2 wk. BP effects were pooled by random-effects models, with trials weighted by inverse variance.
Twenty-nine trials met eligibility criteria for the primary analysis. The median dose was 500 mg/d, the median duration was 8 wk, and trial sizes ranged from 10 to 120 participants. The pooled changes in SBP and DBP were -3.84 mm Hg (95% CI: -5.29, -2.38 mm Hg; P < 0.01) and -1.48 mm Hg (95% CI: -2.86, -0.10 mm Hg; P = 0.04), respectively. In trials in hypertensive participants, corresponding reductions in SBP and DBP were -4.85 mm Hg (P < 0.01) and -1.67 mm Hg (P = 0.17). After the inclusion of 9 trials with imputed BP effects, BP effects were attenuated but remained significant.
In short-term trials, vitamin C supplementation reduced SBP and DBP. Long-term trials on the effects of vitamin C supplementation on BP and clinical events are needed.
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