Abstract Background Obesity and atrial fibrillation (AF) are public health issues with significant consequences. Objectives This study sought to delineate the development of global ...electrophysiological and structural substrate for AF in sustained obesity. Methods Ten sheep fed ad libitum calorie-dense diet to induce obesity over 36 weeks were maintained in this state for another 36 weeks; 10 lean sheep with carefully controlled weight served as controls. All sheep underwent electrophysiological and electroanatomic mapping; hemodynamic and imaging assessment (echocardiography and dual-energy x-ray absorptiometry); and histology and molecular evaluation. Evaluation included atrial voltage, conduction velocity (CV), and refractoriness (7 sites, 2 cycle lengths), vulnerability for AF, fatty infiltration, atrial fibrosis, and atrial transforming growth factor (TGF)-β1 expression. Results Compared with age-matched controls, chronically obese sheep demonstrated greater total body fat (p < 0.001); LA volume (p < 0.001); LA pressure (p < 0.001), and PA pressures (p < 0.001); reduced atrial CV (LA p < 0.001) with increased conduction heterogeneity (p < 0.001); increased fractionated electrograms (p < 0.001); decreased posterior LA voltage (p < 0.001) and increased voltage heterogeneity (p < 0.001); no change in the effective refractory period (ERP) (p > 0.8) or ERP heterogeneity (p > 0.3). Obesity was associated with more episodes (p = 0.02), prolongation (p = 0.01), and greater cumulative duration (p = 0.02) of AF. Epicardial fat infiltrated the posterior LA in the obese group (p < 0.001), consistent with reduced endocardial voltage in this region. Atrial fibrosis (p = 0.03) and TGF-β1 protein (p = 0.002) were increased in the obese group. Conclusions Sustained obesity results in global biatrial endocardial remodeling characterized by LA enlargement, conduction abnormalities, fractionated electrograms, increased profibrotic TGF-β1 expression, interstitial atrial fibrosis, and increased propensity for AF. Obesity was associated with reduced posterior LA endocardial voltage and infiltration of contiguous posterior LA muscle by epicardial fat, representing a unique substrate for AF.
The neurodegenerative disease glaucoma is characterised by the progressive death of retinal ganglion cells (RGCs) and structural damage to the optic nerve (ON). New insights have been gained into the ...pathogenesis of glaucoma through the use of rodent models; however, a coherent picture of the early pathology remains elusive. Here, we use a validated, experimentally induced rat glaucoma model to address fundamental issues relating to the spatio-temporal pattern of RGC injury. The earliest indication of RGC damage was accumulation of proteins, transported by orthograde fast axonal transport within axons in the optic nerve head (ONH), which occurred as soon as 8 h after induction of glaucoma and was maximal by 24 h. Axonal cytoskeletal abnormalities were first observed in the ONH at 24 h. In contrast to the ONH, no axonal cytoskeletal damage was detected in the entire myelinated ON and tract until 3 days, with progressively greater damage at later time points. Likewise, down-regulation of RGC-specific mRNAs, which are sensitive indicators of RGC viability, occurred subsequent to axonal changes at the ONH and later than in retinas subjected to NMDA-induced somatic excitotoxicity. After 1 week, surviving, but injured, RGCs had initiated a regenerative-like response, as delineated by Gap43 immunolabelling, in a response similar to that seen after ON crush. The data presented here provide robust support for the hypothesis that the ONH is the pivotal site of RGC injury following moderate elevation of IOP, with the resulting anterograde degeneration of axons and retrograde injury and death of somas.
IMPORTANCE: Triglycerides and cholesterol are both carried in plasma by apolipoprotein B (ApoB)–containing lipoprotein particles. It is unknown whether lowering plasma triglyceride levels reduces the ...risk of cardiovascular events to the same extent as lowering low-density lipoprotein cholesterol (LDL-C) levels. OBJECTIVE: To compare the association of triglyceride-lowering variants in the lipoprotein lipase (LPL) gene and LDL-C–lowering variants in the LDL receptor gene (LDLR) with the risk of cardiovascular disease per unit change in ApoB. DESIGN, SETTING, AND PARTICIPANTS: Mendelian randomization analyses evaluating the associations of genetic scores composed of triglyceride-lowering variants in the LPL gene and LDL-C–lowering variants in the LDLR gene, respectively, with the risk of cardiovascular events among participants enrolled in 63 cohort or case-control studies conducted in North America or Europe between 1948 and 2017. EXPOSURES: Differences in plasma triglyceride, LDL-C, and ApoB levels associated with the LPL and LDLR genetic scores. MAIN OUTCOMES AND MEASURES: Odds ratio (OR) for coronary heart disease (CHD)—defined as coronary death, myocardial infarction, or coronary revascularization—per 10-mg/dL lower concentration of ApoB-containing lipoproteins. RESULTS: A total of 654 783 participants, including 91 129 cases of CHD, were included (mean age, 62.7 years; 51.4% women). For each 10-mg/dL lower level of ApoB-containing lipoproteins, the LPL score was associated with 69.9-mg/dL (95% CI, 68.1-71.6; P = 7.1 × 10−1363) lower triglyceride levels and 0.7-mg/dL (95% CI, 0.03-1.4; P = .04) higher LDL-C levels; while the LDLR score was associated with 14.2-mg/dL (95% CI, 13.6-14.8; P = 1.4 × 10−465) lower LDL-C and 1.9-mg/dL (95% CI, 0.1-3.9; P = .04) lower triglyceride levels. Despite these differences in associated lipid levels, the LPL and LDLR scores were associated with similar lower risk of CHD per 10-mg/dL lower level of ApoB-containing lipoproteins (OR, 0.771 95% CI, 0.741-0.802, P = 3.9 × 10−38 and OR, 0.773 95% CI, 0.747-0.801, P = 1.1 × 10−46, respectively). In multivariable mendelian randomization analyses, the associations between triglyceride and LDL-C levels with the risk of CHD became null after adjusting for differences in ApoB (triglycerides: OR, 1.014 95% CI, 0.965-1.065, P = .19; LDL-C: OR, 1.010 95% CI, 0.967-1.055, P = .19; ApoB: OR, 0.761 95% CI, 0.723-0.798, P = 7.51 × 10−20). CONCLUSIONS AND RELEVANCE: Triglyceride-lowering LPL variants and LDL-C–lowering LDLR variants were associated with similar lower risk of CHD per unit difference in ApoB. Therefore, the clinical benefit of lowering triglyceride and LDL-C levels may be proportional to the absolute change in ApoB.
Retinitis pigmentosa (RP) is an inherited condition that features degeneration of rod and cone photoreceptors. In all forms of RP, the genetic mutation is expressed exclusively in rods; however, ...cones die too. The secondary death of cones in RP remains somewhat mysterious. A better understanding of the mechanisms that cause cone degeneration in RP could lead to novel treatments that preserve cones. There are a number of prevailing theories that attempt to explain cone degeneration in RP. One concept is that cone survival is dependent on trophic factors produced by rods. Another hypothesis is that cones suffer from a nutrient shortage after rods have been lost. Additionally, oxidative stress and pro‐inflammatory microglial activation have also been suggested to play a role in cone death. The present review evaluates the evidence supporting these theories and provides an update on the mechanisms of cone degeneration in RP.
Nitrous oxide (N₂O) has a global warming potential that is 300 times that of carbon dioxide on a 100-y timescale, and is of major importance for stratospheric ozone depletion. The climate sensitivity ...of N₂O emissions is poorly known, which makes it difficult to project how changing fertilizer use and climate will impact radiative forcing and the ozone layer. Analysis of 6 y of hourly N₂O mixing ratios from a very tall tower within the US Corn Belt—one of the most intensive agricultural regions of the world—combined with inverse modeling, shows large interannual variability in N₂O emissions (316 Gg N₂O-N·y−1 to 585 Gg N₂O-N·y−1). This implies that the regional emission factor is highly sensitive to climate. In the warmest year and spring (2012) of the observational period, the emission factor was 7.5%, nearly double that of previous reports. Indirect emissions associated with runoff and leaching dominated the interannual variability of total emissions. Under current trends in climate and anthropogenic N use, we project a strong positive feedback to warmer and wetter conditions and unabated growth of regional N₂O emissions that will exceed 600 Gg N₂O-N·y−1, on average, by 2050. This increasing emission trend in the US Corn Belt may represent a harbinger of intensifying N₂O emissions from other agricultural regions. Such feedbacks will pose a major challenge to the Paris Agreement, which requires large N₂O emission mitigation efforts to achieve its goals.
Intraocular pressure-sensitive retinal ganglion cell degeneration is a hallmark of glaucoma, the leading cause of irreversible blindness. Here, we used RNA-sequencing and metabolomics to examine ...early glaucoma in DBA/2J mice. We demonstrate gene expression changes that significantly impact pathways mediating the metabolism and transport of glucose and pyruvate. Subsequent metabolic studies characterized an intraocular pressure (IOP)-dependent decline in retinal pyruvate levels coupled to dysregulated glucose metabolism prior to detectable optic nerve degeneration. Remarkably, retinal glucose levels were elevated 50-fold, consistent with decreased glycolysis but possibly including glycogen mobilization and other metabolic changes. Oral supplementation of the glycolytic product pyruvate strongly protected from neurodegeneration in both rat and mouse models of glaucoma. Investigating further, we detected mTOR activation at the mechanistic nexus of neurodegeneration and metabolism. Rapamycin-induced inhibition of mTOR robustly prevented glaucomatous neurodegeneration, supporting a damaging role for IOP-induced mTOR activation in perturbing metabolism and promoting glaucoma. Together, these findings support the use of treatments that limit metabolic disturbances and provide bioenergetic support. Such treatments provide a readily translatable strategy that warrants investigation in clinical trials.
1. Changes in agricultural practice across Europe and North America have been associated with range contractions and a decline in the abundance of wild bees. Concerns at these declines have led to ...the development of flower-rich agri-environment schemes as a way to enhance bee diversity and abundance. Whilst the effect of these schemes on bumblebee species (Bombus spp.) has been well studied, their impact on the wider bee community is poorly understood. 2. We used direct observations of foraging bees and pollen load analysis to quantify the relative contribution that sown flowers (i.e. those included in agri-environment scheme seed mixes) make to the pollen diets of wild solitary bees on Higher Level Stewardship farms (HLS) implementing pollinator-focused schemes and on Entry Level Stewardship farms (ELS) without such schemes in southern England, UK. 3. HLS management significantly increased floral abundance, and as the abundance of sown flowers increased, these sown plants were utilized for pollen by a greater proportion of the solitary bee species present. However, the overall proportion of pollen collected from sown plants was low for both direct observations (27.0%) and pollen load analysis (23.3%). 4. At most only 25 of the 72 observed species of solitary bee (34.7%) were recorded utilizing sown plants to a meaningful degree. The majority of solitary bee species did not collect pollen from flower species sown for pollinators. 5. Total bee species richness was significantly associated with plant species richness, but there was no difference in the total species richness of either bee or flowering plant species between HLS and ELS farms. 6. Synthesis and applications. Our results show that the majority of solitary bee species present on farmland in the south-east of England collect most of their pollen from plants that persist unaided in the wider environment, and not from those included in agri-environment schemes focused on pollinators. If diverse bee communities are to be maintained on farmland, existing schemes should contain an increased number of flowering plant species and additional schemes that increase the diversity of flowering plants in complementary habitats should be studied and trialled.
Glaucoma is a term describing a group of ocular disorders with multi‐factorial etiology united by a clinically characteristic intraocular pressure‐associated optic neuropathy. It is not a single ...entity and is sometimes referred to in the plural as the glaucomas. All forms are potentially progressive and can lead to blindness. The diverse conditions that comprise glaucoma are united by a clinically characteristic optic neuropathy: glaucomatous optic neuropathy (GON). Evidence suggests that the primary site of neurological injury is at the optic nerve head. This fact enables the conditions to be grouped, irrespective of the causal mechanism(s). The term experimental glaucoma implies model resemblance to the human condition. We propose that ‘experimental glaucoma’ be restricted to animal models with demonstrable features of GON and/or evidence of a primary axonopathy at the optic nerve head. A fundamental inadequacy in this framework is any reference to the pathogenesis of GON, which remains unclear.
This randomized, noninferiority (NI), global, phase 3 study evaluated the efficacy and safety of bendamustine plus rituximab (BR) vs a standard rituximab-chemotherapy regimen (rituximab plus ...cyclophosphamide, doxorubicin, vincristine, and prednisone R-CHOP or rituximab plus cyclophosphamide, vincristine, and prednisone R-CVP) for treatment-naive patients with indolent non-Hodgkin's lymphoma or mantle cell lymphoma. Investigators preassigned the standard treatment regimen they considered most appropriate for each patient; patients were randomized to receive BR (n = 224) or standard therapy (R-CHOP/R-CVP, n = 223) for 6 cycles; 2 additional cycles were permitted at investigator discretion. Response was assessed by a blinded independent review committee. BR was noninferior to R-CHOP/R-CVP, as assessed by the primary end point of complete response rate (31% vs 25%, respectively; P = .0225 for NI 0.88 margin). The overall response rates for BR and R-CHOP/R-CVP were 97% and 91%, respectively (P = .0102). Incidences of vomiting and drug-hypersensitivity reactions were significantly higher in patients treated with BR (P < .05), and incidences of peripheral neuropathy/paresthesia and alopecia were significantly higher in patients treated with standard-therapy regimens (P < .05). These data indicate BR is noninferior to standard therapy with regard to clinical response with an acceptable safety profile. This trial was registered at www.clinicaltrials.gov as #NCT00877006.
•The complete response rate for first-line bendamustine/rituximab was statistically noninferior to R-CHOP or R-CVP in indolent NHL or MCL.•The safety profile of bendamustine/rituximab is distinct from that of R-CHOP/R-CVP.
PDF
