Prognostic EEG patterns in patients resuscitated from cardiac arrest with particular focus on Generalized Periodic Epileptiform Discharges (GPEDs).

STUDY AIMS: We assessed clinical and early electrophysiological characteristics, in particular Generalized Periodic Epileptiform Discharges (GPEDs) patterns, of consecutive patients during a 1-year period, hospitalized in the Intensive Care Unit (ICU) after resuscitation following cardiac arrest (CA). PATIENTS AND METHODS: Consecutive patients resuscitated from cardiac arrest (CA) with first EEG recordings within 48hours were included. Clinical data were collected from hospital records, in particular therapeutic hypothermia. Electroencephalograms (EEGs) were re-analyzed retrospectively. RESULTS: Sixty-two patients were included. Forty-two patients (68%) were treated with therapeutic hypothermia according to international guidelines. Global mortality was 74% but not significantly different between patients who benefited from therapeutic hypothermia compared to those who did not. All the patients who did not have an initial background activity (36/62; 58%) died. By contrast, initial background activity was present in 26/62 (42%) and among these patients, 16/26 (61%) survived. Electroencephalography demonstrated GPEDs patterns in 5 patients, all treated by therapeutic hypothermia and antiepileptic drugs. One of these survived and showed persistent background activity with responsiveness to benzodiazepine intravenous injection. CONCLUSION: Patients presenting suppressed background activity, even when treated by hypothermia, have a high probability of poor outcome. Thorough analysis of EEG patterns might help to identify patients with a better chance of survival.

[Genic and cellular therapy for peripheral arterial diseases]. / Thérapie génique et cellulaire dans le traitement des pathologies ischémiques des membres inférieurs.

Late evolution of peripheral arterial disease consists in the apparition of critical limb ischemia. Surgical treatments allow to treat these patients during long time; however, in most patients, especially the diabetic ones, there a very few options and the clinical evolution is rapidly dramatic. For these reasons, the critical limb ischemia is one of the first diseases treated by genic or cellular therapies aiming to improve blood flow perfusion in the lower-limbs. In this short review, we describe the main clinical trials of genic therapy; most of them have been abandoned because serious side effects, modest effects and major risks. Different types of stem cells are now used for cell therapy: endothelial progenitor cells, early or late, activated or not, mesenchymal stem cells, embryonic stem cells and human induced pluripotent stem cells. Problems of characterization are described and the results of the most important clinical trials are reported.

[Nerve and muscle imaging in peripheral neuropathy associated to electroneuromyography: the ideal couple?]. / L'imagerie du nerf et du muscle dans les atteintes nerveuses périphériques associée à l'électroneuromyographie : le couple idéal ?

Electroneuromyography (ENMG) is the gold standard tool in evaluating peripheral neuropathies, and it is essential to the diagnosis and the location of the involvement, as well as the assessment of the severity and the prognosis of the lesion. However, it has also limitations. It is highly examiner dependant and because it is unpleasant, the assessment of some nerves and muscles is limited. The evaluation of proximal nerve and deep muscles is difficult to perform. Magnetic resonance imaging and echography represent a fast growing field in demyelinating and motor neuropathy assessment, while these imaging procedures are now well validated in myopathies. In this article, we discuss sensitivity, specificity and prognostic data brought up by these new imaging tools compared to ENMG and the significant future prospects they offer.

Blood pressure rise following angiogenesis inhibition by bevacizumab. A crucial role for microcirculation.

Arterial hypertension (HT) has been reported in all studies involving bevacizumab, an antiangiogenic agent designed to target vascular endothelial growth factor (VEGF). The mechanism underlying bevacizumab-related HT is not yet clearly understood. As far as endothelial dysfunction and microvascular rarefaction are hallmarks in all forms of HT, we tested the hypothesis that anti-VEGF therapy could alter the microcirculation in nontumor tissues and, thus, result in an increase in blood pressure (BP). We used intravital video microscopy to measure dermal capillary densities in the dorsum of the fingers. Microvascular endothelial function was assessed by laser Doppler flowmetry combined with iontophoresis of pilocarpine (acetylcholine analogue). All measurements were carried out in 18 patients before and after a 6-month treatment with bevacizumab (mean cumulative dose: 3.16 +/- 0.90 g). Mean BP was increased after 6 months of therapy compared with baseline, from 129 +/- 13/75 +/- 7 mmHg to 145 +/- 17/82 +/- 7 mmHg for systolic BP and diastolic BP, respectively (P < 0.0001). Compared with the baseline, mean dermal capillary density at 6 months was significantly lower (75 +/- 12 versus 83 +/- 13/mm(2); P < 0.0001), as well as pilocarpine-induced vasodilation (P < 0.05). Thus, bevacizumab treatment resulted in endothelial dysfunction and capillary rarefaction; both changes are closely associated and could be responsible for the rise in BP observed in most patients.

Murine models of myocardial and limb ischemia: diagnostic end-points and relevance to clinical problems.

Ischemic disease represents the new epidemic worldwide. Animal models of ischemic disease are useful because they can help us to understand the underlying pathogenetic mechanisms and develop new therapies. The present review article summarizes the results of a consensus conference on the status and future development of experimentation in the field of cardiovascular medicine using murine models of peripheral and myocardial ischemia. The starting point was to recognize the limits of the approach, which mainly derive from species- and disease-related differences in cardiovascular physiology. For instance, the mouse heart beats at a rate 10 times faster than the human heart. Furthermore, healing processes are more rapid in animals, as they rely on mechanisms that may have lost relevance in man. The main objective of the authors was to propose general guidelines, diagnostic end points and relevance to clinical problems.

[Diabetes and peripheral arterial occlusive disease: therapeutic potential and pro-angiogenic strategies]. / Diabète et ischémie des membres inférieurs: bénéfice potentiel des stratégies d'angiogenèse thérapeutique.

Cardiovascular complications are the leading cause of morbidity and mortality in patients with diabetes mellitus; up to 80% of deaths in patients with diabetes are closely associated with vascular disease. The ability of the organism to form a collateral network of blood vessels constitutes an important response to vascular occlusive disease and determines to a large part the clinical consequences and severity of tissue ischemia. The development of new vessels is significantly reduced in diabetic patients with coronary or peripheral artery disease. This probably contributes to the severe course of limb ischemia in diabetic patients, in which peripheral artery disease often results in foot ulceration and lower extremity amputation. Diabetic retinopathy remains one of the major causes of acquired blindness in developed nations. This is true despite the development of laser treatment, which can prevent blindness in the majority of those who develop macular edema or proliferative diabetic retinopathy. The hallmark of diabetic retinopathy is the lack of microvessels in the macula, leading to hypoxia, associated with peripheral retinal neovascularization that may ultimately cause severe vitreous cavity bleeding and/or retinal detachment. The factors that stimulate retinal blood vessel growth have not been fully defined, but there is accumulating evidence that the renin-angiotensin-bradykinin system may be involved in a number of retinal vascular disorders, including retinopathy of prematurity and proliferative diabetic retinopathy. Only a few studies have specifically evaluated the effect of diabetes on angiogenesis in ischemic vascular disease and in the retina. Moreover, the mechanisms by which diabetes could both limit the formation of new blood vessels in most organs and simultaneously induce proliferative diabetic retinopathy remain largely undefined. In the present review, we aimed to briefly describe the main molecular mechanisms involved in the ischemia-induced angiogenesis, and their alterations in diabetes. Possible therapeutic strategies to restore angiogenesis in diabetic patients are also listed.

Systolodiastolic variations of blood flow during central retinal vein occlusion: exploration by dynamic angiography.

BACKGROUND/AIM: In patients with acute central retinal vein occlusion (CRVO), dynamic angiography may reveal the presence of pulsatile flow (termed here pulsatile venular outflow, PVO) within first order veins (that is, the large veins). The main goal of this study was to investigate the mechanism underlying PVO. METHODS: 10 patients with CRVO and PVO were included. Quantitative and qualitative analysis of venous flow on dynamic angiograms allowed the correlation, temporally, of second and first order vein flow on the one hand, and venous flow and systolic cycle on the other. RESULTS: Analysis of the time-velocity curve showed that (1) the onset of arterial systole preceded the onset of PVO by less than 0.08 seconds (n = 5); (2) PVO onset was simultaneous to the time of onset of minimal flow (Vmin) in first order veins (n = 10); (3) the time of onset of maximal flow (Vmax) in first order veins occurred 0.20-0.44 seconds after the onset of PVO (n = 6). CONCLUSIONS: During CRVO with severe reduction in blood flow, the presence of PVO is the result of the existence of a distinct haemodynamic regimen in first and second order veins. These data support the hypothesis that second order veins flow is synchronous with the arterial flow, while the delayed peak flow in first order veins may reflect the consequences of the delayed IOP curve and/or of intermittent venous compression.

Understanding angiogenesis: a clue for understanding vascular malformations.

Vasculogenesis is defined by the differentiation of mesodermal precursors into endothelial cells, and angiogenesis by the formation of new vessels from preexisting vessels. Growth factors initiate cellular differentiation but also induce endothelial migration and proliferation; extracellular proteolysis is essential for disassembly and reassembly of endothelial cells to their environmental matrix and allow their migration to elongate the arterial tree. The coagulation and fibrinolysis system, metalloproteinases and adhesion molecules are critical during this step. The balance between pro- and antiangiogenic factors regulates angiogenesis. Ongoing studies dissecting angiogenesis mechanisms offer a new perspective to our understanding of vascular malformations.

[Neurosurgical embryology. Part 8: Post-natal angiogenesis and remodeling]. / Angiogenèse post-natale et remodelage. Un stimulus majeur: les contraintes hémodynamiques.

Post-natal angiogenesis (microvascular proliferation) and remodeling (modifications of diameter and wall thickness) occur in various physiological circumstances including adaptation to exercise or wound healing. The formation of a new vessel is submitted to the combinative action of growth factors. New endothelial cells migrate, proliferate, differentiate and attract pericytes and future smooth muscle cells to create the new vessel. Powerful stimuli leading to remodeling and to the creation of new vessels are mainly represented by hemodynamic forces generated by pressure and blood flow, and by hypoxia. Our purpose is to overview the molecular mechanisms and the stimuli giving rise to these processes.

[Vasculogenesis and angiogenesis: molecular and cellular controls. part I: growth factors]. / Vasculogenèse et angiogenèse: contrôles moléculaires et cellulaires. lère Partie: les facteurs de croissance.

Angiogenesis characterizes embryonic development, but occurs also in adulthood, under physiological circumstances like adaptation to muscular exercise or in pathology like cancers. Knowledge of these mechanisms has step forward partly due to knock-out mice that have allowed to devoid an exact role to the different growth factors that are involved. Interestingly, the same growth factors and their receptors are equally involved during development and adulthood. We have detailed here their respective role and how interactions between them leads to a newly formed vessel.

[Vasculogenesis and angiogenesis: molecular and cellular controls. II. The interactions between the cell and its environment]. / Vasculogenèse et angiogenèse: contrôles moléculaires et cellulaires. 2e Partie: les interactions entre la cellule et son environnement.

Angiogenesis defined as a new blood vessel formation from a preexisting vessel is initiated by angiogenic growth factors and their receptors, that induce endothelial cells migration and proliferation. Extracellular proteolysis is essential for deassembly et reassembly of endothelial cells to their environmental matrix. The aim of this review is to update data upon the role of the coagulation and fibrinolysis system, metalloproteinases and adhesion molecules during this step of angiogenesis.

Doppler sonograpy with dynamic testing in a case of aortic dissection extending to the innominate and right common carotid arteries.

A 50-year-old woman with Marfan's syndrome was admitted for an aortic dissection with an intimal flap extending from the sinus of Valsalva to the descending aorta and aortic valve incompetence. Ultrasonography revealed a double lumen in the innominate and right common carotid (RCCA) arteries. The false lumen extended from the aortic arch to the distal RCCA and compressed and nearly occluded the true lumen in the innominate artery. At the end of the RCCA was a large tear allowing communication between the false and true lumens. Colour-coded Doppler sonography showed blood passing from the false lumen into the true lumen and antegrade flow in the false lumen but reverse flow in the true channel. A dynamic test, as used in accessing for subclavian steal syndrome, producing reactive hyperaemia, showed the retrograde flow in the true channel to be markedly increased, supplying the subclavian artery. We emphasie the importance of functional description of an abnormal haemodynamic situation, which in this case helped to avoid unnecessary surgery to the supra-aortic arteries.

Vasculogenesis and angiogenesis: molecular and cellular controls. Part 1: growth factors.

SUMMARY: Angiogenesis characterizes embryonic development, but also occurs in adulthood in physiological situations such as adaptation to muscle exercise, and in pathological conditions like cancer. Major advances have been made in understanding the molecular mechanisms responsible for vasculogenesis and angiogenesis, largely due to the use of "knock-out mice", i.e. mice in which the gene coding for the protein under investigation has been inactivated. Interestingly, the same growth factors and their receptors are equally involved in the different aspects of vasculogenesis and angiogenesis during development and in adulthood. This review aims to describe in detail their respective roles and how interactions between them lead to a newly formed vessel.

Vasculogenesis and Angiogenesis: Molecular and Cellular Controls. Part 2: Interactions between Cell and Extracellular Environment.

SUMMARY: Angiogenesis, defined as a new blood vessel formation from a pre-existing vessel, is initiated by angiogenic growth factors and their receptors that induce endothelial cell migration and proliferation. Extracellular proteolysis is essential for deassembly and reassembly of endothelial cells to their environmental matrix. The aim of this review is to update data on the role of the coagulation and fibrinolysis system, metalloproteinases and adhesion molecules during this step of angiogenesis.

Angiogenesis therapy in ischemic disease.

The ability of organisms to spontaneously develop collateral vessels represents an important response to vascular occlusive diseases that determines the severity of residual tissue ischemia. Neovascularization of ischemic cardiac or skeletal muscle may be sufficient to preserve tissue integrity and/or function, and may thus be considered to be therapeutic. Innovative gene technologies and advances in animal modeling have enabled research scientists to develop therapeutic angiogenesis strategies applied in animal models of limb or myocardial ischemia and in treatment of patients with peripheral vascular obstruction or coronary artery diseases. Several therapeutic strategies have been proposed and tested even at the clinical level. Recent studies have established the feasibility of using recombinant angiogenic growth factors (mainly VEGF and FGF) to enhance angiogenesis in patients with limb or myocardial ischemia. Angiogenesis therapies using cells as a support for growth factor delivery or using endothelial progenitor cells which may directly participate in the angiogenic process have also been developed. Finally, one potential alternative strategy may be the use of drugs with pro-angiogenic activity, available in an oral formulation and which are currently administered to patients for treatment of different pathologies. All strategies of angiogenesis therapy currently being tested have the potential to be effective in the treatment of ischemic disease. However, such strategies may cause harmful side effects which emphasize the need to be aware of the biological effects of each angiogenic agent proposed for clinical studies.

Increased ischemia-induced angiogenesis in the staggerer mouse, a mutant of the nuclear receptor Roralpha.

Ror alpha is an orphan nuclear receptor. In homozygous staggerer mutant mice (Ror alpha(sg/sg)), a deletion within the Ror alpha gene leads to an overexpression of inflammatory cytokines. Because inflammation and hypoxia are 2 key stimuli of ischemia-induced angiogenesis, we studied the role of Ror alpha in this setting. Ischemia was induced by ligation of the right femoral artery in C57BL/6 Ror alpha(+/+) and Ror alpha(sg/sg) mice. After 3 and 28 days, angiogenesis was evaluated by microangiography, measurement of capillary density using immunohistochemistry (anti-CD31), and measurement of blood flow by laser Doppler imaging. At day 3, angiographic score and blood flow were similar in Ror alpha(sg/sg) mice and in Ror alpha(+/+) littermates. Conversely, at day 28, Ror alpha(sg/sg) mice showed a significant 2-fold increase in angiographic score and a 3-fold increase in capillary density within the ischemic hindlimb compared with control. Functionally, this coincided with a significant rise in leg perfusion in Ror alpha(sg/sg) mice (0.83+/-0.05 for ischemic/nonischemic leg perfusion ratio) compared with Ror(+/+) mice (0.66+/-0.04, P<0.05). In addition, more extensive angiogenesis in Ror alpha(sg/sg) mice correlated with an increased expression of eNOS protein by 83+/-12% and 71+/-24% at 3 and 28 days, respectively (P<0.05), whereas the level of the antiangiogenic cytokine IL-12 was significantly reduced by 38+/-10% at day 28 (P<0.05). Conversely, no changes in VEGF expression were observed. Our study identifies for the first time a new role for Ror alpha as a potent negative regulator of ischemia-induced angiogenesis.

Physiological and pathophysiological functions of the AT(2) subtype receptor of angiotensin II: from large arteries to the microcirculation.

Angiotensin II exerts a potent role in the control of hemodynamic and renal homeostasis. Angiotensin II is also a local and biologically active mediator involved in both endothelial and smooth muscle cell function acting on 2 receptor subtypes: type 1 (AT(1)R) and type 2 (AT(2)R). Whereas the key role of AT(2)R in the development of the embryo has been extensively studied, the role of AT(2)R in the adult remains more questionable, especially in humans. In vitro studies in cultured cells and in isolated segments of aorta have shown that AT(2)R stimulation could lead to the production of vasoactive substances, among which NO is certainly the most cited, suggesting that acute AT(2)R stimulation will produce vasodilation. However, in different organs or in small arteries isolated from different type of tissues, other vasoactive substances may also mediate AT(2)R-dependent dilation. Sometimes, such as in large renal arteries, AT(2)R stimulation may lead to vasoconstriction, although it is not always seen. In isolated arteries submitted to physiological conditions of pressure and flow, AT(2)R stimulation may also have a role in shear stress-induced dilation through a endothelial production of NO. Thus, when acutely stimulated, the most probable response expected from AT(2)R stimulation will be a vasodilation. Therefore, in the perspective of a chronic AT(1)R blockade in patients, overstimulation of AT(2)R might be beneficial, given their potential vasodilator effect. Concerning the possible role of AT(2)R in cardiovascular remodeling, the situation is more controversial. In vitro AT(2)R stimulation clearly inhibits cardiac and vascular smooth muscle growth and proliferation, stimulates apoptosis, and promotes extra cellular matrix synthesis. In vivo, the situation might be less beneficial if not deleterious; indeed, if chronic AT(2)R overstimulation would lead to cardiovascular hypertrophy and fibrosis, then the long-term consequences of chronic AT(1)R blockade, and thus AT(2)R overstimulation, require more in-depth analysis.