Anterior Segment Angiography in Strabismus Surgery

Background: Anterior ciliary arteries travelling along recti muscles provide anterior segment vascularization, which can be compromised by surgery involving more than 2 muscles.Patients and Methods: We studied retrospectively the files of 10 patients in whom a fluorescein angiography of the iris had been performed as a pre-operative assessment prior to a second or third oculomotor surgery.Results: The median age of the patients was 47.5 years (range 15 to 73 years). Relative iris ischemia was present in 4 patients following multiple surgeries, none of them presenting any general cardiovascular risk. The initial surgical protocol was modified according to angiographic results in these 4 patients.Conclusion: When further surgery has to be performed on previously multi-operated patients, anterior segment angiography can be useful in the planning of surgery in order to minimize the risks of anterior segment ischemia.

Blockade of the Renin-Angiotensin system in hypertensive patients with atherosclerotic renal artery stenosis.

Renin angiotensin system (RAS) blockers are generally considered as contraindicated when an atheromatous renal artery stenosis (ARAS) is diagnosed. The main reason is the fear of inducing renal ischemia and, hence, accelerating renal fibrosis and the progression towards end stage renal disease, albeit RAS blocker have been shown to be highly effective in controlling blood pressure. Part of the solution came by the development of the revascularization. There is now growing evidence showing no superiority of angioplasty over medical treatment on cardiovascular events and mortality, renal function and blood pressure control. Hence, RAS blockers resurfaced based on their proven beneficial effects on blood pressure control and cardiovascular prevention in high risk atherosclerotic patients. Thus, RAS blockers belong today to the standard treatment of hypertensive patients with ARAS. However they were not systematically prescribed in trials focusing on ARAS. The ongoing CORAL trial will give us further information on the place of this class of antihypertensive drugs in patients with ARAS.

Thrombin-receptor antagonist vorapaxar in acute coronary syndromes

Background: Vorapaxar is a new oral protease-activatedreceptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet activation. Methods: In this multinational, double-blind, randomized trial, we compared vorapaxar with placebo in 12,944 patients who had acute coronary syndromes without ST-segment elevation. The primary end point was a composite of death from cardiovascular causes, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization. RESULTS: Follow-up in the trial was terminated early after a safety review. After a median follow-up of 502 days (interquartile range, 349 to 667), the primary end point occurred in 1031 of 6473 patients receiving vorapaxar versus 1102 of 6471 patients receiving placebo (KaplanMeier 2-year rate, 18.5% vs. 19.9%; hazard ratio, 0.92; 95% confidence interval [CI], 0.85 to 1.01; P = 0.07). A composite of death from cardiovascular causes, myocardial infarction, or stroke occurred in 822 patients in the vorapaxar group versus 910 in the placebo group (14.7% and 16.4%, respectively; hazard ratio, 0.89; 95% CI, 0.81 to 0.98; P = 0.02). Rates of moderate and severe bleeding were 7.2% in the vorapaxar group and 5.2% in the placebo group (hazard ratio, 1.35; 95% CI, 1.16 to 1.58; P<0.001). Intracranial hemorrhage rates were 1.1% and 0.2%, respectively (hazard ratio, 3.39; 95% CI, 1.78 to 6.45; P<0.001). Rates of nonhemorrhagic adverse events were similar in the two groups. Conclusions: In patients with acute coronary syndromes, the addition of vorapaxar to standard therapy did not significantly reduce the primary composite end point but significantly increased the risk of major bleeding, including intracranial hemorrhage. (Funded by Merck; TRACER ClinicalTrials.gov number, NCT00527943.)

Transcranial Doppler ultrasound in the acute phase of aneurysmal subarachnoid hemorrhage.

BACKGROUND: Angiographic studies suggest that acute vasospasm within 48 h of aneurysmal subarachnoid hemorrhage (SAH) predicts symptomatic vasospasm. However, the value of transcranial Doppler within 48 h of SAH is unknown. METHODS: We analyzed 199 patients who had at least 1 middle cerebral artery (MCA) transcranial Doppler examination within 48 h of SAH onset. Abnormal MCA mean blood flow velocity (mBFV) was defined as >90 cm/s. Delayed cerebral ischemia (DCI) was defined as clinical deterioration or radiological evidence of infarction due to vasospasm. RESULTS: Seventy-six patients (38%) had an elevation of MCA mBFV >90 cm/s within 48 h of SAH onset. The predictors of elevated mBFV included younger age (OR = 0.97 per year of age, p = 0.002), admission angiographic vasospasm (OR = 5.4, p = 0.009) and elevated white blood cell count (OR = 1.1 per 1,000 white blood cells, p = 0.003). Patients with elevated mBFV were more likely to experience a 10 cm/s fall in velocity at the first follow-up than those with normal baseline velocities (24 vs. 10%, p < 0.01), suggestive of resolving spasm. DCI developed in 19% of the patients. An elevated admission mBFV >90 cm/s during the first 48 h (adjusted OR = 2.7, p = 0.007) and a poor clinical grade (Hunt-Hess score 4 or 5, OR = 3.2, p = 0.002) were associated with a significant increase in the risk of DCI. CONCLUSION: Early elevations of mBFV correlate with acute angiographic vasospasm and are associated with a significantly increased risk of DCI. Transcranial Doppler ultrasound may be an early useful tool to identify patients at higher risk to develop DCI after SAH.

L'agrégation toxique des protéines: une forme de "delinquance moléculaire" activement combattue dans la cellule par les chaperones moléculaires et les protéases [The toxic aggregation of proteins: a kind of "molecular delinquency" actively fought in the cell by molecular chaperones and proteases]

Under various stresses, mutation-sensitised proteins may spontaneously convert into inactive, aggregation-prone structures, which may be cytotoxic and infectious. In the cell, this new kind of "molecular criminality" is actively fought against by a network of molecular chaperones that can specifically identify, isolate and unfold damaged (delinquent) proteins and favour their subsequent native refolding. Irreversibly damaged molecules unable to natively refold are preferentially "executed" and recycled by proteases. Failing that, they are "imprisoned" within compact amyloids, or "evicted" from the cell. Thus, striking parallels, although of questionable ethical value, exist between protein and human criminality, and between the cellular and social responses to these different types of criminality. Fundamental differences also exist. Whereas programmed death (apoptosis) is the preferred solution chosen by aged and aggregation-stressed cells, collective suicide is seldom an option chosen by lawless human societies. More significantly, there is no clear cellular equivalent for the role of the family and the education system, which are so essential to the proper shaping of functional individuals in the society, and give rise to humanism, that favours crime prevention, reeducation and reinsertion programs over capital punishment. To the cardiologist and transplantation surgeon, the interest of molecular chaperones, in particular of Hsp70, Hsp90 and Hsp27, lays in their ability to inhibit the signalling pathway of programmed cell death. Their induction before and during ischemia, by various treatments and drugs could significantly reduce damages from the post ischemic reperfusion of organs.

Transmyocardial laser revascularisation in acutely ischaemic myocardium.

OBJECTIVE: Although recent experience suggests that transmyocardial laser revascularisation (TMLR) relieves angina, its mechanism of action remains undefined. We examined its functional effects and analysed its morphological features in an animal model of acute ischaemia. METHODS: A total of 15 pigs were randomised to ligation of left marginal arteries (infarction group, n = 5), to TMLR of the left lateral wall using a holmium:yttrium-aluminium garnet (Ho:YAG) laser (laser group, n = 5), and to both (laser-infarction group, n = 5). All the animals were sacrificed 1 month after the procedure. Haemodynamics and echocardiography with segmental wall motion score were carried out at both time intervals (scale 0-3: 0, normal; 1, hypokinesia; 2, akinesia; 3, dyskinesia). Histology of the involved area was analysed. RESULTS: Laser group showed no change of the segmental wall motion score of the involved area 30 min after the laser channels were made (score: 0 +/- 0). Infarction and laser infarction groups both showed a persistent and definitive increase of the segmental wall motion score (at 30 min: 1.6 +/- 0.3 and 2 +/- 0, respectively; at 1 month: 1.8 +/- 0.2 and 1.8 +/- 0.4, respectively). These increases were all statistically significant in comparison with baseline values (P < 0.5), however comparison between infarction and laser-infarction groups showed no significant difference. On macroscopic examination of the endocardial surface, no channel was opened. On histology, there were signs of neovascularisation around the channels in the laser group, whereas in the laser-infarction group the channels were embedded in the infarction scar. CONCLUSIONS: In this acute pig model, TMLR did not provide improvement of contractility of the ischaemic myocardium. To the degree that the present study pertains to the clinical setting, the results suggest that mechanisms other than blood flow through the channels should be considered, such as a laser-induced triggering of neovascularisation or neural destruction.

Enhanced-reality video fluorescence: a real-time assessment of intestinal viability.

OBJECTIVE: Our aim was to evaluate a fluorescence-based enhanced-reality system to assess intestinal viability in a laparoscopic mesenteric ischemia model. MATERIALS AND METHODS: A small bowel loop was exposed, and 3 to 4 mesenteric vessels were clipped in 6 pigs. Indocyanine green (ICG) was administered intravenously 15 minutes later. The bowel was illuminated with an incoherent light source laparoscope (D-light-P, KarlStorz). The ICG fluorescence signal was analyzed with Ad Hoc imaging software (VR-RENDER), which provides a digital perfusion cartography that was superimposed to the intraoperative laparoscopic image [augmented reality (AR) synthesis]. Five regions of interest (ROIs) were marked under AR guidance (1, 2a-2b, 3a-3b corresponding to the ischemic, marginal, and vascularized zones, respectively). One hour later, capillary blood samples were obtained by puncturing the bowel serosa at the identified ROIs and lactates were measured using the EDGE analyzer. A surgical biopsy of each intestinal ROI was sent for mitochondrial respiratory rate assessment and for metabolites quantification. RESULTS: Mean capillary lactate levels were 3.98 (SD = 1.91) versus 1.05 (SD = 0.46) versus 0.74 (SD = 0.34) mmol/L at ROI 1 versus 2a-2b (P = 0.0001) versus 3a-3b (P = 0.0001), respectively. Mean maximal mitochondrial respiratory rate was 104.4 (±21.58) pmolO2/second/mg at the ROI 1 versus 191.1 ± 14.48 (2b, P = 0.03) versus 180.4 ± 16.71 (3a, P = 0.02) versus 199.2 ± 25.21 (3b, P = 0.02). Alanine, choline, ethanolamine, glucose, lactate, myoinositol, phosphocholine, sylloinositol, and valine showed statistically significant different concentrations between ischemic and nonischemic segments. CONCLUSIONS: Fluorescence-based AR may effectively detect the boundary between the ischemic and the vascularized zones in this experimental model.

Impact of the phosphatidylinositide 3-kinase signaling pathway on the cardioprotection induced by intermittent hypoxia.

BACKGROUND: Exposure to intermittent hypoxia (IH) may enhance cardiac function and protects heart against ischemia-reperfusion (I/R) injury. To elucidate the underlying mechanisms, we developed a cardioprotective IH model that was characterized at hemodynamic, biochemical and molecular levels. METHODS: Mice were exposed to 4 daily IH cycles (each composed of 2-min at 6-8% O2 followed by 3-min reoxygenation for 5 times) for 14 days, with normoxic mice as controls. Mice were then anesthetized and subdivided in various subgroups for analysis of contractility (pressure-volume loop), morphology, biochemistry or resistance to I/R (30-min occlusion of the left anterior descending coronary artery (LAD) followed by reperfusion and measurement of the area at risk and infarct size). In some mice, the phosphatidylinositide 3-kinase (PI3K) inhibitor wortmannin was administered (24 µg/kg ip) 15 min before LAD. RESULTS: We found that IH did not induce myocardial hypertrophy; rather both contractility and cardiac function improved with greater number of capillaries per unit volume and greater expression of VEGF-R2, but not of VEGF. Besides increasing the phosphorylation of protein kinase B (Akt) and the endothelial isoform of NO synthase with respect to control, IH reduced the infarct size and post-LAD proteins carbonylation, index of oxidative damage. Administration of wortmannin reduced the level of Akt phosphorylation and worsened the infarct size. CONCLUSION: We conclude that the PI3K/Akt pathway is crucial for IH-induced cardioprotection and may represent a viable target to reduce myocardial I/R injury.

Cell death and autophagy after severe hypoxic-ischemic encephalopathy in term newborns

Introduction: Various studies from hypoxic-ischemic animals haveinvestigated neuroprotection by targeting necrosis and apoptosis with inconclusive results. Three types of cell death have been described: apoptosis, necrosis and more recently, autophagic cell death. While autophagy is a physiological process of degradation of cellular components, excessive autophagy may be involved in cell death. Recent studies showed that inhibition of autophagy is neuroprotective in rodent neonatal models of cerebral ischemia. Furthermore, neonatal hypoxia-ischemia strongly increased neuronal autophagic flux which is linked to cell death in a rat model of perinatal asphyxia. Following our observations in animals, the aim of the present study was to characterize the different neuronal death phenotypes and to clarify whether autophagic cell death could be also involved in neuronal death in the human newborns after perinatal asphyxia. Methods: we selected retrospectively and anonymously all newborns who died in our unit of neonatology between 2004 and 2009, with the following criteria: gestational age >36 weeks, diagnosis of perinatal asphyxia (Apgar <5 at 5 minutes, arterial pH <7.0 at 1 hour of life and encephalopathy Sarnat III) and performed autopsy. The brain of 6 cases in asphyxia group and 6 control cases matching gestational age who died of pulmonary or other malformations were selected. On histological sections of thalamus, frontal cortex and hippocampus, different markers of apoptosis (caspase 3, TUNEL), autophagosomes (LC3-II) and lysosomes (LAMP1, Cathepsin D) were tested by immunohistochemistry. Results: Preliminary studies on markers of apoptosis (TUNEL, caspase 3) and of autophagy (Cathepsin D, LC3II, LAMP1) showed an expected increase of apoptosis, but also an increase of neuronal autophagic flux in the selected areas. The distribution seems to be region specific. Conclusion: This is the first time that autophagic flux linked with cell death is shown in brain of human babies, in association with hypoxicischemic encephalopathy. This work leads to a better understanding of the mechanisms associated with neuronal death following perinatal asphyxia and determines whether autophagy could be a promising therapeutic target.

14.1T magnetic resonance spectroscopic evaluation of metabolic changes in the mouse striatum following transient middle cerebral artery occlusion

Magnetic resonance imaging (MRI) and spectroscopy (MRS) allow establishing theanatomical evolution and neurochemical profiles of ischemic lesions. However onlylimited MRS studies have been reported to-date in mice due to the challenges ofMRS in small organs. The aim of the current work was to study the neurochemicaland imaging sequelae of ischemic stroke in a mouse model in a horizontal bore14.1 Tesla system.ICR-CD1 mice were subjected to 30 minute transient middle cerebral artery occlusion.The extent of the lesion was determined by MRI. The neurochemical profileconsisting of the concentrations of 22 metabolites was measured longitudinallyfollowing the recovery from ischemia at 3, 8 and 24h in the striatum.Our model produced very reproducible striatal lesions which began to appear onT2-weighted images 8h after ischemia. At 24h, they were well established andtheir size correlated with lesions measured by histology. Profound changes couldbe observed in the neurochemical profiles of the core of the striatal lesions as earlyas 3h post-ischemia, in particular, we observed elevated lactate levels, decreases inthe putative neuronal marker N-acetyl-aspartate and in glutamate, and a transienttwo-fold glutamine increase, likely linked to excitotoxic release of glutamate andconversion to glutamine. With further ischemia evolution, other changes appearedat later time-points, mainly decreases of metabolites, consistent with disruption ofcellular function. It is interesting to note that glutamine tended to return to basallevels at 24h.We conclude that early changes in markers of energy metabolism, glutamate excitotoxicityand neuronal viability can be detected with high precision non-invasively inmice following stroke. Such investigations should lead to a better understanding andinsight into the sequential early changes in the brain parenchyma after ischemia,which could be used e.g. for identifying new targets for neuroprotection.

STAT3α interacts with nuclear GSK3beta and cytoplasmic RISK pathway and stabilizes rhythm in the anoxic-reoxygenated embryonic heart.

Activation of the Janus Kinase 2/Signal Transducer and Activator of Transcription 3 (JAK2/STAT3) pathway is known to play a key role in cardiogenesis and to afford cardioprotection against ischemia-reperfusion in adult. However, involvement of JAK2/STAT3 pathway and its interaction with other signaling pathways in developing heart transiently submitted to anoxia remains to be explored. Hearts isolated from 4-day-old chick embryos were submitted to anoxia (30 min) and reoxygenation (80 min) with or without the antioxidant MPG, the JAK2/STAT3 inhibitor AG490 or the PhosphoInositide-3-Kinase (PI3K)/Akt inhibitor LY-294002. Time course of phosphorylation of STAT3α(tyrosine705) and Reperfusion Injury Salvage Kinase (RISK) proteins [PI3K, Akt, Glycogen Synthase Kinase 3beta (GSK3beta), Extracellular signal-Regulated Kinase 2 (ERK2)] was determined in homogenate and in enriched nuclear and cytoplasmic fractions of the ventricle. STAT3 DNA-binding was determined. The chrono-, dromo- and inotropic disturbances were also investigated by electrocardiogram and mechanical recordings. Phosphorylation of STAT3α(tyr705) was increased by reoxygenation, reduced (~50%) by MPG or AG490 but not affected by LY-294002. STAT3 and GSK3beta were detected both in nuclear and cytoplasmic fractions while PI3K, Akt and ERK2 were restricted to cytoplasm. Reoxygenation led to nuclear accumulation of STAT3 but unexpectedly without DNA-binding. AG490 decreased the reoxygenation-induced phosphorylation of Akt and ERK2 and phosphorylation/inhibition of GSK3beta in the nucleus, exclusively. Inhibition of JAK2/STAT3 delayed recovery of atrial rate, worsened variability of cardiac cycle length and prolonged arrhythmias as compared to control hearts. Thus, besides its nuclear translocation without transcriptional activity, oxyradicals-activated STAT3α can rapidly interact with RISK proteins present in nucleus and cytoplasm, without dual interaction, and reduce the anoxia-reoxygenation-induced arrhythmias in the embryonic heart.

Outcomes of optic nerve sheath decompression for nonarteritic ischemic optic neuropathy.

Efficacy of optic nerve sheath decompression (ONSD) in treating non-arteritic ischemic optic neuropathy (NAION) is not clear. We retrospectively analyzed the records of 91 patients with NAION, who were examined during a two-year period, and compared the final Snellen visual acuities of eyes treated with ONSD with those of eyes that did not have surgery. Seven of 18 eyes with ONSD (39%) demonstrated increased visual acuity of two or more lines; whereas 23 of 71 eyes without surgery (32%) had increased acuity. The ONSD group and no surgery group were further subdivided into eyes with progressive visual loss and nonprogressive visual loss. No statistically significant differences in visual outcome between groups were found. We did not find the high frequency of visual improvement that has been reported in some studies of ONSD for NAION.

Postmortem chemistry update part II.

As a continuation of "Postmortem Chemistry Update Part I," Part II deals with molecules linked to liver and cardiac functions, alcohol intake and alcohol misuse, myocardial ischemia, inflammation, sepsis, anaphylaxis, and hormonal disturbances. A very important array of new material concerning these situations had appeared in the forensic literature over the last two decades. Some molecules, such as procalcitonin and C-reactive protein, are currently researched in cases of suspected sepsis and inflammation, whereas many other analytes are not integrated into routine casework. As in part I, a literature review concerning a large panel of molecules of forensic interest is presented, as well as the results of our own observations, where possible.

Enteral nutrition and cardiovascular failure: from myths to clinical practice.

Cardiovascular failure and low flow states may arise in very different conditions from both cardiac and noncardiac causes. Systemic hemodynamic failure inevitably alters splanchnic blood flow but in an unpredictable way. Prolonged low splanchnic blood flow causes intestinal ischemia, increased mucosal permeability, endotoxemia, and distant organ failure. Mortality associated with intestinal ischemia is high. Why would enteral nutrition (EN) be desirable in these complex patients when parenteral nutrition could easily cover energy and substrate requirements? Metabolic, immune, and practical reasons justify the use of EN. In addition, continuous enteral feeding minimizes systemic and myocardial oxygen consumption in patients with congestive heart failure. Further, early feeding in critically ill mechanically ventilated patients has been shown to reduce mortality, particularly in the sickest patients. In a series of cardiac surgery patients with compromised hemodynamics, absorption has been maintained, and 1000-1200 kcal/d could be delivered by enteral feeding. Therefore, early EN in stabilized patients should be attempted, and can be carried out safely under close clinical monitoring, looking for signs of incipient intestinal ischemia. Energy delivery and balance should be monitored, and combined feeding considered when enteral feeds cannot be advanced to target within 4-6 days.