The evolution of social philopatry in female primates

The transition from solitary life to sociality is considered one of the major transitions in evolution. In primates, this transition is currently not well understood. Traditional verbal models appear insufficient to unravel the complex interplay of environmental and demographic factors involved in the evolution of primate sociality, and recent phylogenetic reconstructions have produced conflicting results. We therefore analyze a theoretical model for the evolution of female social philopatry that sheds new light on the question why most primates live in groups. In individual-based simulations, we study the evolution of dispersal strategies of both resident females and their offspring. The model reveals that social philopatry can evolve through kin selection, even if retention of offspring is costly in terms of within-group resource competition and provides no direct benefits. Our model supports the role of predator avoidance as a selective pressure for group-living in primates, but it also suggests that a second benefit of group-living, communal resource defense, might be required to trigger the evolution of sizable groups. Lastly, our model reveals that seemingly small differences in demographic parameters can have profound effects on primate social evolution

Capture the fracture: a best practice framework and global campaign to break the fragility fracture cycle

Summary The International Osteoporosis Foundation (IOF) Capture the Fracture Campaign aims to support implementation of Fracture Liaison Services (FLS) throughout the world. Introduction FLS have been shown to close the ubiquitous secondary fracture prevention care gap, ensuring that fragility fracture sufferers receive appropriate assessment and intervention to reduce future fracture risk. Methods Capture the Fracture has developed internationally endorsed standards for best practice, will facilitate change at the national level to drive adoption of FLS and increase awareness of the challenges and opportunities presented by secondary fracture prevention to key stakeholders. The Best Practice Framework (BPF) sets an international benchmark for FLS, which defines essential and aspirational elements of service delivery. Results The BPF has been reviewed by leading experts from many countries and subject to beta-testing to ensure that it is internationally relevant and fit-for-purpose. The BPF will also serve as a measurement tool for IOF to award ‘Capture the Fracture Best Practice Recognition’ to celebrate successful FLS worldwide and drive service development in areas of unmet need. The Capture the Fracture website will provide a suite of resources related to FLS and secondary fracture prevention, which will be updated as new materials become available. A mentoring programme will enable those in the early stages of development of FLS to learn from colleagues elsewhere that have achieved Best Practice Recognition. A grant programme is in development to aid clinical systems which require financial assistance to establish FLS in their localities. Conclusion Nearly half a billion people will reach retirement age during the next 20 years. IOF has developed Capture the Fracture because this is the single most important thing that can be done to directly improve patient care, of both women and men, and reduce the spiralling fracture-related care costs worldwide.</p

Development of a robust protocol for vulnerable plaque characterization by using two peptide-functionalized USPIO derivaties

Purpose: Rupture of atherosclerotic plaque is the primary cause of sudden cardiac death mainly in the industrialized countries. The term 'plaque rupture' defines a structural defect in the fibrous cap that separates a necrotic core from the lumen resulting in its exposure to the blood via a gap in the cap (Schwartz SM et al, Arterioscler Thromb Vasc Biol, 2007, 27, 705). In most patients, acute ischemic events are caused by the disruption of type IV and Va lipid-rich lesions, which are often not angiographically visible (Frank H, Am Heart J, 2001, 141, S45). ApoE-KO mouse model of atherosclerosis is characterized, in certain circumstances, by human-like plaque rupture events (Johnson JL & Jackson CL, Atherosclerosis, 2001, 154, 399). VCAM-1 and apoptotic cell-targeted peptides identified and validated during our previous work (Burtea C et al, J Med Chem, 2009, 52, 4725; Burtea C et al, Mol Pharm, 2009, 6, 1903) were now conjugated to USPIO (USPIO-R832 for VCAM-1 targeting; USPIO-R826 for apoptosis targeting) and assessed by MRI on ApoE-KO mice. The results were then correlated with several biomarkers of plaque vulnerability which were evaluated by immunohistochemistry. Materials and Methods: Female ApoE-KO mice injected with 100 µmol Fe/kg were imaged on a 4.7 T Bruker MRI at the level of abdominal aorta with RARE (TR/TE = 3000/20 ms, spatial resolution = 90 µm) and FLASH (TR/TE = 175/1.88 ms, flip angle = 90°, spatial resolution = 172 µm) imaging protocols. After MRI investigations, aortic samples were examined by histochemistry for the binding of contrast agent (Perl's staining protocol), the presence of collagen and thrombus (Masson's trichrome staining), of angiogenic blood vessels (VCAM-1 and PECAM-1 staining), apoptotic cells (caspase-3), macrophages (Mac 1), cholesterol (Sudan IV), and smooth muscle cells (?-actin staining). The MR images and histological pictures were then analyzed with ImageJ software. Results: Both USPIO-R832 and USPIO-R826 produced a maximum negative contrast 30 min after administration (Fig. 1), being constant until the end of MRI studies (90 min). The plaque surface was measured on images and it was correlated to the level of plaque enhancement and to the histological observations. USPIO-R826 has mainly enhanced lipid-rich plaques, while this parameter did not seem to influence the binding of USPIO-R832 which enhanced fibrous plaques as well. Conclusion: Our VCAM-1 and apoptotic cell targeted USPIO derivatives seem to be highly promising tools for atherosclerosis imaging contributing to the detection of vulnerable plaques. They are able to attain their target in low doses and as fast as 30 min after administration

Development and validation of a peptide-vectorized superparamagnetic imaging probe designed for detection of inflammation in atherosclerotic plaque

Introduction Atherosclerosis develops in response to vascular injury and involves inflammation and vessel remodeling. VCAM-1 is an important biomarker of various inflammatory disorders having a particular relevance for the pathological process of atherosclerotic disease. Molecularly targeted imaging probes have gained great popularity during the last decade in the context of theranostic strategies. The imaging of VCAM-1 expression has thus been approached with antibodies or peptides conjugated to nuclear, magnetooptical, or ultrasound probes. However, the size of most atherosclerotic lesions is below the spatial resolution of nuclear or ultrasound imaging systems. MRI is the only clinical imaging technique able to attain a spatial resolution in the order of micrometers. Nevertheless, the low sensitivity achieved with magnetic probes constitutes a real challenge for molecular targeting by MRI. Owing to their large NMR efficacy, iron oxide nanoparticles may represent an attractive probe alternative [1, 2]. During our previous work [3], we have identified and validated a VCAM-1-targeted cyclic heptapeptide which was able to detect specifically this adhesion molecule both in a mouse a model of T cell mediated hepatitis, and in atherosclerotic plaque of ApoE-KO mice. In the present work, this peptide was conjugated to USPIO (USPIO-R832), and VCAM-1 binding was first confirmed on HUVEC stimulated with TNF-alpha. Subsequently, USPIO-R832 was evaluated by MRI at 4.7T on ApoE-KO mice, by using T2 and T2*-weighted imaging sequences. The ability to bind to atherosclerotic plaque of this molecular imaging probe was furthermore corroborated by histochemistry. The control imaging probe was represented by USPIO vectorized by a non-specific peptide (USPIO-NSP). Materials and methods The peptides were conjugated to USPIO as previously described [4]. The size of functionalized USPIO was of ~30 nm, while their r2 at 60 MHz and 37°C was of 86 s-1 mM-1 for USPIO-R832 and of 90 s-1 mM-1 for USPIO-NSP. Female C57Bl ApoEtm1unc mice received a Western diet (0.21% cholesterol) for 3 months prior to the MRI studies. The contrast agents were assessed blindly on 6 mice each at a dose of 100 µmol Fe/kg. Images were acquired (4.7 T Bruker imaging system, Bruker, Ettlingen, Germany) at the level of abdominal aorta with a T2-weighted RARE sequence (TR/TE = 3000/20 ms, RARE factor = 4, NEX = 4, matrix = 256x256, FOV = 2.3 cm, slice thickness 1 mm, 20 axial slices, spatial resolution = 90 µm) and a T2*-weighted FLASH imaging protocol (TR/TE = 175/1.88 ms, flip angle = 90°, NEX = 8, matrix = 128x128, FOV = 2.5 cm, slice thickness 1.25 mm, 15 axial slices, spatial resolution = 172 µm). A 3D-TOF sequence (TR/TE = 10/2 ms, flip angle = 20°, NEX = 2, FOV = 4x2x4 cm, matrix = 256x128x64, slice thickness = 1 mm, 60 axial slices, spatial resolution = 156x156x625 µm) was used with the aim to confirm the anatomical location of the aorta in the image slice. SI values for each time point were measured within ROIs drawn manually by using the ImageJ image analysis software in the arterial wall of the abdominal aorta. The standard deviation (SD) of noise was also measured in a region situated out of the animal's image. SI enhancement (%SNR) was then calculated. VCAM-1 expression in atherosclerotic aorta was confirmed by immunohistochemistry, while contrast agents were stained on aortic samples by Perl's Prussian blue staining protocol. Results The maximum negative contrast produced by USPIO-R832 on RARE images occurred between ~30 min and 94 min post-injection, probably depending on the level of plaque neovascularization, which influences the diffusion of the contrast agent. This could also be a sign of plaque vulnerability. The plaque surface was measured on images and it was correlated to the level of the plaque enhancement and to the histological observations. In the case of FLASH images, the maximum negative contrast occurred between ~40 min and 80 min post-injection. With the exception of one mouse, the negative contrast was almost absent in the case of USPIO-NSP both on RARE and FLASH images. The histochemistry studies confirmed the MRI results and have shown an extensive VCAM-1 expression, as well as the presence of capillary-like structures that could be of angiogenic nature. Conclusions Our peptide-vectorized, VCAM-1-targeted, superparamagnetic imaging probe seems to be a highly promising tool for atherosclerosis imaging, by considering its ability to attain its target in lower doses and as fast as 30 min after administration. This represents an important progress in comparison with previously developed superparamagnetic agents designed for the same purpose. The lower immunogenic potential and the cost-effectiveness when compared with antibody-conjugated contrast agents represent supplementary arguments for a possible implementation in the clinical practice. Bibliography 1. Kelly KA, Allport JR, Tsurkas A, Shinde-Patil VR, Josephson L, Weissleder R, Circ Res, 96, 2005, 327-336. 2. McAteer MA, Schneider JE, Ali ZA, Warrick N, Bursill CA, von zur Muhlen C, Greaves DR, Neubauer S, Channon KM, Choudhury RP, Arterioscler Thromb Vasc Biol, 28, 2008, 77-83. 3. Burtea C, Laurent S, Port M, Lancelot E, Ballet S, Rousseaux O, Toubeau G, Vander Elst L, Corot C, Muller RN, J Med Chem, 52, 2009, 4725-4742. 4. Port M, Corot C, Raynal I, Rousseaux O, US Patent 2004/0253181 A1

Recombinant human erythropoietin α modulates the effects of radiotherapy on colorectal cancer microvessels

Recent data suggest that recombinant human erythropoietin (rhEPO) modulates tumour growth and therapy response. The purpose of the present study was to examine the modulation of radiotherapy (RT) effects on tumour microvessels by rhEPO in a rat colorectal cancer model. Before and after 5 × 5 Gy of RT, dynamic contrast-enhanced -magnetic resonance imaging was performed and endothelial permeability surface product (PS), plasma flow (F), and blood volume (V) were modelled. Imaging was combined with pO2 measurements, analysis of microvessel density, microvessel diameter, microvessel fractal dimension, and expression of vascular endothelial growth factor (VEGF), hypoxia-inducible factor-1 α (HIF-1α), Bax, and Bcl-2. We found that RT significantly reduced PS and V in control rats, but not in rhEPO-treated rats, whereas F was unaffected by RT. Oxygenation was significantly better in rhEPO-treated animals, and RT induced a heterogeneous reoxygenation in both groups. Microvessel diameter was significantly larger in rhEPO animals, whereas VEGF expression was significantly lower in the rhEPO group. No differences were observed in HIF-1α, Bax, or Bcl-2 expression. We conclude that rhEPO results in spatially heterogeneous modulation of RT effects on tumour microvessels. Direct effects of rhEPO on neoplastic endothelium are likely to explain these findings in addition to indirect effects induced by increased oxygenation

Axillary sentinel lymph node biopsy after mastectomy: a case report

<p>Abstract</p> <p>Background</p> <p>Sentinel lymph node biopsy has been established as the preferred method for staging early breast cancer. A prior history of mastectomy is felt to be a contraindication.</p> <p>Case presentation</p> <p>A patient with recurrent breast cancer in her skin flap was discovered to have positive axillary sentinel nodes by sentinel lymph node biopsy five years after mastectomy for ductal carcinoma in situ.</p> <p>Conclusion</p> <p>A prior history of mastectomy may not be an absolute contraindication to sentinel lymph node biopsy.</p