Mechanostability of the Fibrinogen Bridge between Staphylococcal Surface Protein ClfA and Endothelial Cell Integrin αVβ3

Binding of the Staphylococcus aureus surface protein clumping factor A (ClfA) to endothelial cell integrin αVβ3 plays a crucial role during sepsis, by causing endothelial cell apoptosis and loss of barrier integrity. ClfA uses the blood plasma protein fibrinogen (Fg) to bind to αVβ3 but how this is achieved at the molecular level is not known. Here we investigate the mechanical strength of the three-component ClfA-Fg-αVβ3 interaction on living bacteria, by means of single-molecule experiments. We find that the ClfA-Fg-αVβ3 ternary complex is extremely stable, being able to sustain forces (∼800 pN) that are much stronger than those of classical bonds between integrins and the Arg-Gly-Asp (RGD) tripeptide sequence (∼100 pN). Adhesion forces between single bacteria and αVβ3 are strongly inhibited by an anti-αVβ3 antibody, the RGD peptide, and the cyclic RGD peptide cilengitide, showing that formation of the complex involves RGD-dependent binding sites and can be efficiently inhibited by αVβ3 blockers. Collectively, our experiments favor a binding mechanism involving the extraordinary elasticity of Fg. In the absence of mechanical stress, RGD572-574 sequences in the Aα chains mediate weak binding to αVβ3, whereas under high mechanical stress exposure of cryptic Aα chain RGD95-97 sequences leads to extremely strong binding to the integrin. Our results identify an unexpected and previously undescribed force-dependent binding mechanism between ClfA and αVβ3 on endothelial cells, which could represent a potential target to fight staphylococcal bloodstream infections

Early Carotid Endarterectomy after Ischemic Stroke: The Results of a Prospective Multicenter Italian Study

ObjectivesTo evaluate safety of early carotid endarterectomy (CEA) in patients with acute brain ischemia presenting to the emergency department stroke units (EDSU).MethodsThe neurologists, neuroradiologists and vascular surgeons on duty in emergency departments enrolled 96 patients who underwent very early CEA according to a predefined protocol within two years. The protocol included evaluation of neurological status by National Institute of Health Stroke Scale (NIHSS), neuroimaging assessment, ultrasound of the carotid arteries and Transcranial Doppler. Patients with NIHSS>22 or whose neuroimaging showed brain infarct >2/3 of the middle cerebral artery territory were excluded. All eligible patients underwent CEA as soon as possible. Primary end points of the study were mortality, neurological morbidity by NIHSS and postoperative hemorrhagic conversion on neuroimaging. Statistical analysis was performed by univariate analysis.ResultsThe mean time elapsing between the onset of stroke and endarterectomy was 1.5 days (±2 days). The overall 30-day morbidity mortality rate was 7.3% (7/96). No neurological mortality occurred. On hospital discharge, three patients (3%) experienced worsening of the neurological deficit (NIHSS score 1 to 2, 1 to 3 and 9 to 10 respectively). Postoperative CT demonstrated there were no new cerebral infarcts nor hemorrhagic transformation. At hospital discharge 9/96 patients (9%) had no improvement in NHISS scores, 37 were asymptomatic and 45 showed a median decrease of 4.5 NIHSS points (range 1–18). By univariate analysis none of the considered variables influenced the clinical outcome.ConclusionOur protocol selected patients who can safely undergo very early (<1.5 days) surgery after acute brain ischemia. Large randomized multicenter prospective trials are warranted to compare very early CEA versus best medical therapy

Unification of gravity, gauge fields, and Higgs bosons

We consider a diffeomorphism invariant theory of a gauge field valued in a Lie algebra that breaks spontaneously to the direct sum of the spacetime Lorentz algebra, a Yang-Mills algebra, and their complement. Beginning with a fully gauge invariant action -- an extension of the Plebanski action for general relativity -- we recover the action for gravity, Yang-Mills, and Higgs fields. The low-energy coupling constants, obtained after symmetry breaking, are all functions of the single parameter present in the initial action and the vacuum expectation value of the Higgs.Comment: 12 pages, no figures. v2 minor correction

On the perturbative expansion of a quantum field theory around a topological sector

The idea of treating general relativistic theories in a perturbative expansion around a topological theory has been recently put forward in the quantum gravity literature. Here we investigate the viability of this idea, by applying it to conventional Yang--Mills theory on flat spacetime. We find that the expansion around the topological theory coincides with the usual expansion around the abelian theory, though the equivalence is non-trivial. In this context, the technique appears therefore to be viable, but not to bring particularly new insights. Some implications for gravity are discussed.Comment: 7 page

Coupling gauge theory to spinfoam 3d quantum gravity

We construct a spinfoam model for Yang-Mills theory coupled to quantum gravity in three dimensional riemannian spacetime. We define the partition function of the coupled system as a power series in g_0^2 G that can be evaluated order by order using grasping rules and the recoupling theory. With respect to previous attempts in the literature, this model assigns the dynamical variables of gravity and Yang-Mills theory to the same simplices of the spinfoam, and it thus provides transition amplitudes for the spin network states of the canonical theory. For SU(2) Yang-Mills theory we show explicitly that the partition function has a semiclassical limit given by the Regge discretization of the classical Yang-Mills action.Comment: 18 page

Graviton propagator in loop quantum gravity

We compute some components of the graviton propagator in loop quantum gravity, using the spinfoam formalism, up to some second order terms in the expansion parameter.Comment: 41 pages, 6 figure

Association of Primary Varicose Veins with Dysregulated Vein Wall Apoptosis

BACKGROUND: Disordered programmed cell death may play a role in the development of superficial venous incompetence. We have determined the number of cells in apoptosis, and the mediators regulating the intrinsic and extrinsic pathways in specimens of varicose vein. METHODS: Venous segments were obtained from 46 patients undergoing surgical treatment for primary varicose veins. Controls samples were obtained from 20 patients undergoing distal arterial bypass grafting surgery. Segments of the distal and proximal saphenous trunk as well as tributaries were studied. Cell apoptoses and mediators of the mitochondrial and trans membrane pathway were evaluated with peroxidase in situ apoptosis detection, Bax and Fas detection, caspase-9 and 8 detection in the medial layer. RESULTS: Disorganised histological architecture was observed in varicose veins. Primary varicose veins also contained fewer peroxidase in situ-positive cells than control veins (2.6% S.D. 0.2% versus 12% S.D. 0.93%, P=.0001, Mann-Whitney u test), fewer Bax positive cells (2.1.% S.D. 0.3% versus 13% S.D. 0.9%, P=.0001) and fewer Caspase 9 positive cells (3.2% S.D. 1% versus 12% S.D. 1.3%, P=.0001). Similar findings were observed in saphenous trunk, main tributaries and accessory veins. In patients with recurrent varicose veins in whom the saphenous trunk had been preserved showed similar findings to primary varicose veins. Residual varicose veins contained fewer peroxidase in situ-positive cells than healthy veins (3.2% S.D. 0.6% versus 11% S.D. 2%, P=.0001), fewer Bax positive cells (2.2% S.D. 0.3% versus 12% S.D. 0.7%, P=.0001) and fewer Caspase 9 positive cells (2.6% S.D. 0.6% versus 12% S.D. 1%, P=.0001). Immunohistochemical detection for Fas and caspase 8 remained equal was the same in the varicose vein and control groups. CONCLUSION: Apoptosis is down regulated in the medial layer of varicose veins. This dysregulation is attributable to a disorder of the intrinsic pathway and involves the great saphenous vein trunk, major tributaries and accessory veins. This process may be among the causes of primary varicose veins

Aneurysm of the Pancreaticoduodenal Arteries Associated with a Cœliac Artery Lesion

IntroductionA ruptured aneurysm of the pancreaticoduodenalarteries without acute or chronic pancreatitis butassociated with a median arcuate ligament divisionis an exceptional event described in only 11 cases. Thecase of a ruptured pancreaticoduodenal artery aneur-ysm, associated with a cœliac artery lesion which wedescribe, illustrates the difficulty in diagnosing theserare events promptly and in instituting urgent treat-ment to arrest the bleeding followed by an electiveprocedure to prevent recurrence.Case ReportA 54-year-old man with no history of vascular diseasewas admitted to a district hospital for investigation ofvague abdominal pain mainly affecting the rightabdomen, hypotension corrected by infusion ofcrystalloid and no fever. Laboratory blood chemicalfindings including a normal hemoglobin, raisedleukocyte count and high C-reactive protein concen-tration. This presentation raised the suspicion of a gallbladder infection and the patient was kept under closeobservation overnight. The next day, hypotensiondeveloped and the patient complained of pain in theright iliac quadrant. An abdominal ultrasound scanshowed a large iliac fluid collection, but no lesionsinvolving the gall bladder or liver. Appendicitis wasdiagnosed and the patient underwent a McBurneyoperation. During surgery blood was found in theabdomen. An exploratory laparotomy revealed a largeretroperitoneal hematoma. The patient was trans-ferred to our vascular surgery unit. A CT scan aftercontrast injection revealed an intact retroperitonealhematoma (16 £ 9 £ 15 cm), with no bleeding from theaorta or the visceral arteries, and a median arcuateligament division that compressed the origin of thecœliac trunk. Because these findings suggested aruptured pancreaticoduodenal artery aneurysm arter-iography was planned to confirm the diagnosis andtreat the aneurysm by embolization. The patient, whowas by now haemodynamically stable, was kept underobservation in the ITU and transferred to the vascularsurgical unit. On day 1, a CT scan showed that thehematoma had enlarged. The patient was kept undersurveillance in the vascular unit and arteriographywas planned for the following day. During the night,the patient collapsed but responded to more IVcrystalloid and was immediately transferred to theradiological unit. While the patient was being pre-pared for arteriography, a new CT scan showed thehematoma had now increased in size and had spreadto the intraperitoneal space, filling the peri-hepaticand peri-splenic areas as well as the pelvis.The patient underwent selective arteriography tovisualize the stenosis caused by compression of thecœliac axis, to localize the bleeding pancreaticoduo-denal artery aneurysm and to proceed to treatment byembolization. Under local anesthesia, a 5-F introduce

Second-order amplitudes in loop quantum gravity

We explore some second-order amplitudes in loop quantum gravity. In particular, we compute some second-order contributions to diagonal components of the graviton propagator in the large distance limit, using the old version of the Barrett-Crane vertex amplitude. We illustrate the geometry associated to these terms. We find some peculiar phenomena in the large distance behavior of these amplitudes, related with the geometry of the generalized triangulations dual to the Feynman graphs of the corresponding group field theory. In particular, we point out a possible further difficulty with the old Barrett-Crane vertex: it appears to lead to flatness instead of Ricci-flatness, at least in some situations. The observation raises the question whether this difficulty remains with the new version of the vertex.Comment: 22 pages, 18 figure