A Volumetric Method for Quantifying Atherosclerosis in Mice by Using MicroCT: Comparison to En Face

Precise quantification of atherosclerotic plaque in preclinical models of atherosclerosis requires the volumetric assessment of the lesion(s) while maintaining in situ architecture. Here we use micro-computed tomography (microCT) to detect ex vivo aortic plaque established in three dyslipidemic mouse models of atherosclerosis. All three models lack the low-density lipoprotein receptor (Ldlr−/−), each differing in plaque severity, allowing the evaluation of different plaque volumes using microCT technology. From clearly identified lesions in the thoracic aorta from each model, we were able to determine plaque volume (0.04–3.1 mm3), intimal surface area (0.5–30 mm2), and maximum plaque (intimal-medial) thickness (0.1–0.7 mm). Further, quantification of aortic volume allowed calculation of vessel occlusion by the plaque. To validate microCT for future preclinical studies, we compared microCT data to intimal surface area (by using en face methodology). Both plaque surface area and plaque volume were in excellent correlation between microCT assessment and en face surface area (r2 = 0.99, p<0.0001 and r2 = 0.95, p<0.0001, respectively). MicroCT also identified internal characteristics of the lipid core and fibrous cap, which were confirmed pathologically as Stary type III-V lesions. These data validate the use of microCT technology to provide a more exact empirical measure of ex vivo plaque volume throughout the entire intact aorta in situ for the quantification of atherosclerosis in preclinical models

In search of the authentic nation: landscape and national identity in Canada and Switzerland

While the study of nationalism and national identity has flourished in the last decade, little attention has been devoted to the conditions under which natural environments acquire significance in definitions of nationhood. This article examines the identity-forming role of landscape depictions in two polyethnic nation-states: Canada and Switzerland. Two types of geographical national identity are identified. The first – what we call the ‘nationalisation of nature’– portrays zarticular landscapes as expressions of national authenticity. The second pattern – what we refer to as the ‘naturalisation of the nation’– rests upon a notion of geographical determinism that depicts specific landscapes as forces capable of determining national identity. The authors offer two reasons why the second pattern came to prevail in the cases under consideration: (1) the affinity between wild landscape and the Romantic ideal of pure, rugged nature, and (2) a divergence between the nationalist ideal of ethnic homogeneity and the polyethnic composition of the two societies under consideration

MPA in Labor: Securing the Pearl Cays of Nicaragua

Implementation of Marine Protected Areas (MPAs) has always a step-zero, i.e., an initial phase when the idea is incepted, communicated and negotiated among stakeholders. What happens during this phase is likely to have an impact later on. If not done right, the management of the MPA may encounter problems at later stage that will be difficult to correct. Inspired by this working theory, this article describes the effort to establish the Pearl Cays off the Caribbean coast of Nicaragua as a protected area. This case-study illustrates the critical actions to be taken during step-zero, i.e., what needs to be considered and done before an MPA is formally declared. The area investigated consists of a number of small islands (cays) and coral reefs, fishing grounds and marine turtle nesting areas. Throughout history, the cays have played an important role in sustaining livelihoods of nearby communities. Although the idea of an MPA was originally conservation, the communities saw it as an opportunity to regain ownership and control of the cays. By Nicaraguan law, in order to establish protected areas, consultation and approval from local people is required. In the case of the Pearl Cays, this has proved difficult. The article demonstrates how MPA initiatives must sometimes relate to already ongoing complex social processes in the area where they are to be instigated

Impact of Optimized Breastfeeding on the Costs of Necrotizing Enterocolitis in Extremely Low Birthweight Infants

To estimate risk of NEC for ELBW infants as a function of preterm formula and maternal milk (MM) intake and calculate the impact of suboptimal feeding on NEC incidence and costs

The evolving systemic biomarker milieu in obese ZSF1 rat model of human cardiometabolic syndrome: Characterization of the model and cardioprotective effect of GDF15.

Cardiometabolic syndrome has become a global health issue. Heart failure is a common comorbidity of cardiometabolic syndrome. Successful drug development to prevent cardiometabolic syndrome and associated comorbidities requires preclinical models predictive of human conditions. To characterize the heart failure component of cardiometabolic syndrome, cardiometabolic, metabolic, and renal biomarkers were evaluated in lean and obese ZSF1 19- to 32-week-old male rats. Histopathological assessment of kidneys and hearts was performed. Cardiac function, exercise capacity, and left ventricular gene expression were also analyzed. Obese ZSF1 rats exhibited multiple features of human cardiometabolic syndrome by pathological changes in systemic renal, metabolic, and cardiovascular disease circulating biomarkers. Hemodynamic assessment, echocardiography, and decreased exercise capacity confirmed heart failure with preserved ejection fraction. RNA-seq results demonstrated changes in left ventricular gene expression associated with fatty acid and branched chain amino acid metabolism, cardiomyopathy, cardiac hypertrophy, and heart failure. Twelve weeks of growth differentiation factor 15 (GDF15) treatment significantly decreased body weight, food intake, blood glucose, and triglycerides and improved exercise capacity in obese ZSF1 males. Systemic cardiovascular injury markers were significantly lower in GDF15-treated obese ZSF1 rats. Obese ZSF1 male rats represent a preclinical model for human cardiometabolic syndrome with established heart failure with preserved ejection fraction. GDF15 treatment mediated dietary response and demonstrated a cardioprotective effect in obese ZSF1 rats

FGF21 Promotes Metabolic Homeostasis via White Adipose and Leptin in Mice

<div><p>Fibroblast growth factor 21 (FGF21) is a potent metabolic regulator, and pharmacological administration elicits glucose and lipid lowering responses in mammals. To delineate if adipose tissue is the predominant organ responsible for anti<b>-</b>diabetic effects of FGF21, we treated mice with reduced body fat (lipodystrophy mice with adipose specific expression of active sterol regulatory element binding protein 1c; Tg) with recombinant murine FGF21 (rmuFGF21). Unlike wildtype (WT) mice, Tg mice were refractory to the beneficial effects of rmuFGF21 on body weight, adipose mass, plasma insulin and glucose tolerance. To determine if adipose mass was critical for these effects, we transplanted WT white adipose tissue (WAT) into Tg mice and treated the mice with rmuFGF21. After transplantation, FGF21 responsiveness was completely restored in WAT transplanted Tg mice compared to sham Tg mice. Further, leptin treatment alone was sufficient to restore the anti-diabetic effects of rmuFGF21 in Tg mice. Molecular analyses of Tg mice revealed normal adipose expression of <em>Fgfr1</em>, <em>Klb</em> and an 8-fold over-expression of <em>Fgf21</em>. Impaired FGF21-induced signaling indicated that residual adipose tissue of Tg mice was resistant to FGF21, whilst normal FGF21 signaling was observed in Tg livers. Together these data suggest that adipose tissue is required for the triglyceride and glucose, but not the cholesterol lowering efficacy of FGF21, and that leptin and FGF21 exert additive anti-diabetic effects in Tg mice.</p> </div

Lipodystrophy mice are resistant to anti-diabetic effects of recombinant FGF21 treatment.

<p>Recombinant muFGF21 (1 or 10 mg/kg, pink and red symbols respectively) or vehicle (green symbols) was injected BID in wildtype (WT - open bars) and aP2-nSrebp1c lipodystrophy (Tg - hatched bars) male mice as described in Animal Study Design I (Methodology). (A–B) Body weight was monitored daily. Dramatic drop in body weight on day 17 was caused by the 12 h fast for GTT. (C–D) Adipose and lean mass was recorded in WT and Tg mice at 0, 7 and 14 days of treatment. (E–F) Fed blood glucose (OneTouch Basic glucometer) and plasma insulin were measured in WT and Tg mice at the start (PRE) and the end (POST) of the treatment. (G–H) Glucose tolerance was measured on day 18 of treatment (OneTouch Basic glucometer). (I) Area under the curve (AUC) was calculated in WT and Tg mice. (J–L) Plasma lipids (cholesterol, triglycerides, NEFA – non-esterified fatty acids) were measured in WT and Tg mice at the start (PRE) and the end (POST) of the treatment. WT groups N = 8; Tg vehicle group N = 8; Tg FGF21 treatment group N = 7. * <i>P</i><0.05, ** <i>P</i><0.01, *** <i>P</i><0.001 <i>vs.</i> vehicle-treated genotype-matched mice at same time point, ns – not statistically significant. ++ <i>P</i><0.01, +++ <i>P</i><0.001 <i>vs.</i> WT mice (T-Test).</p