Excitotoxicity-induced endocytosis confers drug targeting in cerebral ischemia.

OBJECTIVE: Targeting neuroprotectants specifically to the cells that need them is a major goal in biomedical research. Many peptidic protectants contain an active sequence linked to a carrier such as the transactivator of transcription (TAT) transduction sequence, and here we test the hypothesis that TAT-linked peptides are selectively endocytosed into neurons stressed by excitotoxicity and focal cerebral ischemia. METHODS: In vivo experiments involved intracerebroventricular injection of TAT peptides or conventional tracers (peroxidase, fluorescein isothiocyanate-dextran) in young rats exposed to occlusion of the middle cerebral artery at postnatal day 12. Cellular mechanisms of uptake were analyzed in dissociated cortical neuronal cultures. RESULTS: In both models, all tracers were taken up selectively into stressed neurons by endocytosis. In the in vivo model, this was neuron specific and limited to the ischemic area, where the neurons displayed enhanced immunolabeling for early endosomal antigen-1 and clathrin. The highly efficient uptake of TAT peptides occurred by the same selective mechanism as for conventional tracers. All tracers were targeted to the nucleus and cytoplasm of neurons that appeared viable, although ultimately destined to die. In dissociated cortical neuronal cultures, an excitotoxic dose of N-methyl-D-aspartate induced a similar endocytosis. It was 100 times more efficient with TAT peptides than with dextran, because the former bound to heparan sulfate proteoglycans at the cell surface, but it depended on dynamin and clathrin in both cases. INTERPRETATION: Excitotoxicity-induced endocytosis is the main entry route for protective TAT peptides and targets selectively the neurons that need to be protected.

CT angiography helps to differentiate acute from chronic carotid occlusion: "carotid ring sign".

INTRODUCTION: Currently, there is no reliable method to differentiate acute from chronic carotid occlusion. We propose a novel CTA-based method to differentiate acute from chronic carotid occlusions that could potentially aid clinical management of patients. METHODS: We examined 72 patients with 89 spontaneously occluded extracranial internal carotids with CT angiography (CTA). All occlusions were confirmed by another imaging modality and classified as acute (imaging <1 week of presumed occlusion) orchronic (imaging >4 weeks), based on circumstantial clinical and radiological evidence. A neuroradiologist and a neurologist blinded to clinical information determined the site of occlusion on axial sections of CTA. They also looked for (a) hypodensity in the carotid artery (thrombus), (b) contrast within the carotid wall (vasa vasorum), (c) the site of the occluded carotid, and (d) the "carotid ring sign" (defined as presence of a and/or b). RESULTS: Of 89 occluded carotids, 24 were excluded because of insufficient circumstantial evidence to determine timing of occlusion, 4 because of insufficient image quality, and 3 because of subacute timing of occlusion. Among the remaining 45 acute and 13 chronic occlusions, inter-rater agreement (kappa) for the site of proximal occlusion was 0.88, 0.45 for distal occlusion, 0.78 for luminal hypodensity, 0.82 for wall contrast, and 0.90 for carotid ring sign. The carotid ring sign had 88.9% sensitivity, 69.2% specificity, and 84.5% accuracy to diagnose acute occlusion. CONCLUSION: The carotid ring sign helps to differentiate acute from chronic carotid occlusion. If further confirmed, this information may be helpful in studying ischemic symptoms and selecting treatment strategies in patients with carotid occlusions.

Prise en charge des sténoses carotidiennes [Management of the carotid artery stenosis].

In the western world, the carotid-artery stenosis is one of the major causes of ischemic stroke in elderly people. The principal therapeutic indication is a symptomatic stenosis > 50% in the first two weeks and the surgical approach has shown the best results. Despite inferior results to carotid endarterectomy in terms of post-operative rate of stroke and/or death, except for young patients, carotid stenting remains the best choice in patients at high surgical risk. The best medical treatment, consisting in correction of cardiovascular risk factors, statin therapy and anti-aggregation led to a drastic reduction in the annual rate of stroke associated to carotid stenosis and thus limited the surgical intervention in asymptomatic patient to men with a life expectancy of at least 5 years and a stenosis > 70%.

Neurologie [Therapeutic advances in neurology].

The neurology field has been greatly improved in 2008. The therapeutic window of intravenous thrombolysis for acute ischemic stoke is extended to 4 h 30. New studies show that the clinical progression of Parkinson's disease might be slowed by some medication. Deep brain stimulation may be beneficial early in the course of the disease. Tysabri and Fingolimod in multiple sclerosis are discussed. The pharmacopoeia for epilepsy is in constant development with new products recently released in Switzerland. CGRP receptor antagonists are about to be launched as a promising acute migraine treatment. The pharmacological approach in amyotrophic lateral sclerosis patients might be improved according to research results.

Prediction of Recanalization Trumps Prediction of Tissue Fate: The Penumbra: A Dual-edged Sword.

BACKGROUND AND PURPOSE: To determine whether infarct core or penumbra is the more significant predictor of outcome in acute ischemic stroke, and whether the results are affected by the statistical method used. METHODS: Clinical and imaging data were collected in 165 patients with acute ischemic stroke. We reviewed the noncontrast head computed tomography (CT) to determine the Alberta Score Program Early CT score and assess for hyperdense middle cerebral artery. We reviewed CT-angiogram for site of occlusion and collateral flow score. From perfusion-CT, we calculated the volumes of infarct core and ischemic penumbra. Recanalization status was assessed on early follow-up imaging. Clinical data included age, several time points, National Institutes of Health Stroke Scale at admission, treatment type, and modified Rankin score at 90 days. Two multivariate regression analyses were conducted to determine which variables predicted outcome best. In the first analysis, we did not include recanalization status among the potential predicting variables. In the second, we included recanalization status and its interaction between perfusion-CT variables. RESULTS: Among the 165 study patients, 76 had a good outcome (modified Rankin score ≤2) and 89 had a poor outcome (modified Rankin score >2). In our first analysis, the most important predictors were age (P<0.001) and National Institutes of Health Stroke Scale at admission (P=0.001). The imaging variables were not important predictors of outcome (P>0.05). In the second analysis, when the recanalization status and its interaction with perfusion-CT variables were included, recanalization status and perfusion-CT penumbra volume became the significant predictors (P<0.001). CONCLUSIONS: Imaging prediction of tissue fate, more specifically imaging of the ischemic penumbra, matters only if recanalization can also be predicted.

Traitement médicamenteux de l'artériopathie périphérique [Medical therapy in peripheral arterial occlusive disease]

Atherosclerotic peripheral arterial disease (PAD) is often asymptomatic. If symptomatic, patients present intermittent claudication, ischemic rest pain or tissue necrosis. The prevalence of PAD increases with age and affects about 2% of patients at 60 years. Patients with PAD have an increased risk of coronary or cerebro-vascular events. Measure of the ankle-brachial index (ABI) allows early detection of asymptomatic patients, and allows early preventive interventions, in order to reduce their cardio-vascular risk. The most important interventions are smoking cessation, normalisation of blood pressure and lipid levels, and introduction of an antiplatelet agent, such as aspirin 75 to 160 mg/d.

Critical single proximal left arterial descending coronary artery stenosis to mimic chronic myocardial ischemia: a new model induced by minimal invasive technology.

BACKGROUND/AIMS: The present report examines a new pig model for progressive induction of high-grade stenosis, for the study of chronic myocardial ischemia and the dynamics of collateral vessel growth. METHODS: Thirty-nine Landrace pigs were instrumented with a novel experimental stent (GVD stent) in the left anterior descending coronary artery. Eight animals underwent transthoracic echocardiography at rest and under low-dose dobutamine. Seven animals were examined by nuclear PET and SPECT analysis. Epi-, mid- and endocardial fibrosis and the numbers of arterial vessels were examined by histology. RESULTS: Functional analysis showed a significant decrease in global left ventricular ejection fraction (24.5 +/- 1.6%) 3 weeks after implantation. There was a trend to increased left ventricular ejection fraction after low-dose dobutamine stress (36.0 +/- 6.6%) and a significant improvement of the impaired regional anterior wall motion. PET and SPECT imaging documented chronic hibernation. Myocardial fibrosis increased significantly in the ischemic area with a gradient from epi- to endocardial. The number of arterial vessels in the ischemic area increased and coronary angiography showed abundant collateral vessels of Rentrop class 1. CONCLUSION: The presented experimental model mimics the clinical situation of chronic myocardial ischemia secondary to 1-vessel coronary disease.

Diagnostic contribution of cardiac magnetic resonance in patients with acute coronary syndrome and culprit-free angiograms.

BACKGROUND: In spite of robust knowledge about underlying ischemic myocardial damage, acute coronary syndromes (ACS) with culprit-free angiograms raise diagnostic concerns. The present study aimed to evaluate the additional value of cardiac magnetic resonance (CMR) over commonly available non-CMR standard tests, for the differentiation of myocardial injury in patients with ACS and non-obstructed coronary arteries. MATERIAL/METHODS: Patients with ACS, elevated hs-TnT, and a culprit-free angiogram were prospectively enrolled into the study between January 2009 and July 2013. After initial evaluation with standard tests (ECG, echocardiography, hs-TnT) and provisional exclusion of acute myocardial infarction (AMI) in coronary angiogram, patients were referred for CMR with the suspicion of myocarditis or Takotsubo cardiomyopathy (TTC). According to the result of CMR, patients were reclassified as having myocarditis, AMI, TTC, or non-injured myocardium as assessed by late gadolinium enhancement. RESULTS: Out of 5110 patients admitted with ACS, 75 had normal coronary angiograms and entered the study; 69 of them (92%) were suspected for myocarditis and 6 (8%) for TTC. After CMR, 49 patients were finally diagnosed with myocarditis (65%), 3 with TTC (4%), 7 with AMI (9%), and 16 (21%) with non-injured myocardium. The provisional diagnosis was changed or excluded in 23 patients (31%), with a 9% rate of unrecognized AMI. CONCLUSIONS: The study results suggest that the evaluation of patients with ACS and culprit-free angiogram should be complemented by a CMR examination, if available, because the initial work-up with non-CMR tests leads to a significant proportion of misdiagnosed AMI.

Calcium-mediated activation of pyruvate dehydrogenase in severely injured postischemic myocardium.

Indirect evidence suggests that activity of pyruvate dehydrogenase (PDH) influences recovery of the myocardium after transient ischemia. The present study examined the relationship between postischemic injury and activity of PDH and the role of mitochondrial calcium uptake for observed changes in PDH activity. Isovolumically beating isolated rat hearts perfused with erythrocyte-enriched buffer containing glucose, palmitate, and insulin were submitted to either 20 or 35 min of no-flow ischemia. After 20 min of no-flow ischemia, hearts exhibited complete recovery of developed left ventricular pressure (DLVP). The proportion of myocardial PDH in the active state was modestly increased to 38% (compared with 13% in control hearts) without a change in glucose oxidation. In contrast, in hearts subjected to 35 min of no-flow ischemia (which exhibited poor recovery of DLVP), there was marked stimulation of glucose oxidation (+460%; P < 0.01) and pronounced increase in the active fraction of PDH to 72% (P < 0.01). Glycolytic flux was not significantly altered. Ruthenium red (6 microM) completely abolished the activation of PDH and the increase in glucose oxidation. The results indicate that variable stimulation of glucose oxidation during reperfusion is related to different degrees of activation of PDH, which depends on the severity of the ischemic injury. Activation of PDH seems to be mediated by myocardial calcium uptake.

Indications, perspectives et limites de la stimulation électrique épidurale en cas d'artériopathie périphérique ou coronarienne [Indications, limits and future of epidural spinal cord electrical stimulation for coronary and peripheral artery disease]

The electrical stimulation of the dorsal columns of the spinal cord exerts a dual analgesic and vasodilatory effect on ischemic tissues. It is increasingly considered a valuable method to treat severe and otherwise intractable coronary and peripheral artery disease. The quality of the results depends from both a strict selection of the patients by vascular specialists and the frequency and quality of the follow-up controls. However the indications, limits, mode of action and results of spinal cord stimulation are still poorly understood. This article, based on a personal experience of 164 implantations for peripheral and coronary artery disease, aims to draw attention to this technique and to provide information on recent and future developments.

Lactate and the injured brain: friend or foe?

PURPOSE OF REVIEW: Energy metabolism is increasingly recognized as a key factor in the pathogenesis of acute brain injury (ABI). We review the role of cerebral lactate metabolism and summarize evidence showing that lactate may act as supplemental fuel after ABI. RECENT FINDINGS: The role of cerebral lactate has shifted from a waste product to a potentially preferential fuel and signaling molecule. According to the astrocyte-neuron lactate shuttle model, glycolytic lactate might act as glucose-sparing substrate. Lactate also is emerging as a key signal to regulate cerebral blood flow (CBF) and a neuroprotective agent after experimental ABI. Clinical investigation using cerebral microdialysis shows the existence of two main lactate patterns, ischemic - from anaerobic metabolism - and nonischemic, from activated glycolysis, whereby lactate can be used as supplemental energy fuel. Preliminary clinical data suggests hypertonic lactate solutions improve cerebral energy metabolism and are an effective treatment for elevated intracranial pressure (ICP) after ABI. SUMMARY: Lactate can be a supplemental fuel for the injured brain and is important to regulate glucose metabolism and CBF. Exogenous lactate supplementation may be neuroprotective after experimental ABI. Recent clinical data from ABI patients suggest hypertonic lactate solutions may be a valid therapeutic option for secondary energy dysfunction and elevated ICP.

Appropriateness of colonoscopy in Europe (EPAGE II). Iron-deficiency anemia and hematochezia.

BACKGROUND AND STUDY AIMS: To summarize the published literature on assessment of appropriateness of colonoscopy for the investigation of iron-deficiency anemia (IDA) and hematochezia, and report appropriateness criteria developed by an expert panel, the 2008 European Panel on the Appropriateness of Gastrointestinal Endoscopy, EPAGE II. METHODS: A systematic search of guidelines, systematic reviews and primary studies regarding the evaluation and management of IDA and hematochezia was performed. The RAND/UCLA Appropriateness Method was applied to develop appropriateness criteria for colonoscopy for these conditions. RESULTS: IDA occurs in 2 %-5 % of adult men and postmenopausal women. Examination of both the upper and lower gastrointestinal tract is recommended in patients with iron deficiency. Colonoscopy for IDA yields one colorectal cancer (CRC) in every 9-13 colonoscopies. Hematochezia is a well-recognized alarm symptom and such patients are likely to be referred for colonoscopy. Colonoscopy is unanimously recommended in patients aged > or = 50. Diverticulosis, vascular ectasias, and ischemic colitis are common causes of acute lower gastrointestinal bleeding (LGIB); CRC is found in 0.2 %-11 % of the colonoscopies performed for LGIB. Most patients with scant hematochezia have an anorectal or a distal source of bleeding. The expert panel considered most clinical indications for colonoscopy as appropriate in the presence of IDA (58 %) or hematochezia (83 %). CONCLUSION: Despite the limitations of the published studies, guidelines unanimously recommend colonoscopy for the investigation of IDA and hematochezia in patients aged > or = 50 years. These indications were also considered appropriate by EPAGE II, as were indications in patients at low risk for CRC with no obvious cause of bleeding found during adequate previous investigations.

Differential impact of lacunes and microvascular lesions on poststroke depression.

BACKGROUND AND PURPOSE: Previous studies have postulated that poststroke depression (PSD) might be related to cumulative vascular brain pathology rather than to the location and severity of a single macroinfarct. We performed a detailed analysis of all types of microvascular lesions and lacunes in 41 prospectively documented and consecutively autopsied stroke cases. METHODS: Only cases with first-onset depression <2 years after stroke were considered as PSD in the present series. Diagnosis of depression was established prospectively using DSM-IV criteria for major depression. Neuropathological evaluation included bilateral semiquantitative assessment of microvascular ischemic pathology and lacunes; statistical analysis included Fisher exact test, Mann-Whitney U test, and regression models. RESULTS: Macroinfarct site was not related to the occurrence of PSD for any of the locations studied. Thalamic and basal ganglia lacunes occurred significantly more often in PSD cases. Higher lacune scores in basal ganglia, thalamus, and deep white matter were associated with an increased PSD risk. In contrast, microinfarct and diffuse or periventricular demyelination scores were not increased in PSD. The combined lacune score (thalamic plus basal ganglia plus deep white matter) explained 25% of the variability of PSD occurrence. CONCLUSIONS: The cumulative vascular burden resulting from chronic accumulation of lacunar infarcts within the thalamus, basal ganglia, and deep white matter may be more important than single infarcts in the prediction of PSD.

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Ischaemic heart disease as the result of impaired blood supply is currently the leading cause of failure and death. Ischaemic heart disease refers to a group of clinicopathological symptoms including angina pectoris, acute myocardial infection, chronic ischemic heart disease, as well as heart failure and sudden cardiac death. Coronary artery ischemic heart disease, as well as heart failure and sudden cardiac death. Coronary artery thrombosis is the most common cause of acute myocardial infarction and sudden cardiac death. A thrombotic event is the result of two different processes: plaque disruption and endothelial erosion. The morphology of a "vulnerable plaque" is more clinically indicative than the plaque volume and the degree of luminal stenosis. However, identification of patients with vulnerable plaques remains very challenging and demands the development of new methods of coronary plaque imaging. Sudden death resulting from ventricular fibrillation or AV block frequently complicates coronary thrombosis, accounting for up to 50% of mortality.If a coronary artery is occluded for more than 20 min, irreversible damage to the pericardium occurs. Timely coronary recanalization and myocardial reperfusion limit the extent of myocardial necrosis, but may induce "reperfusion injuries", stunned myocardium, or reperfused myocardial hemorrhagic infarcts, all of which are related to infarct siz and coronary occlusion time. Reperfusion injuries have been described after cardiac surgery, percutaneous transluminal coronary angioplasty, and fibrinolysis. A prolonged imbalance between the supply of and demand for myocardial oxygen and nutrition leads to a subacute, acute, or chronic state (aka hibernating myocardium) of myocardial ischemia. Ischemic heart disease is bwelieved to be the underlying cause of heart failure in approximately two-thirds of patients, resulting from acute and/or chronic injury to the heart.