Amyloid-beta aggregates cause alterations of astrocytic metabolic phenotype: impact on neuronal viability.

Amyloid-beta (Abeta) peptides play a key role in the pathogenesis of Alzheimer's disease and exert various toxic effects on neurons; however, relatively little is known about their influence on glial cells. Astrocytes play a pivotal role in brain homeostasis, contributing to the regulation of local energy metabolism and oxidative stress defense, two aspects of importance for neuronal viability and function. In the present study, we explored the effects of Abeta peptides on glucose metabolism in cultured astrocytes. Following Abeta(25-35) exposure, we observed an increase in glucose uptake and its various metabolic fates, i.e., glycolysis (coupled to lactate release), tricarboxylic acid cycle, pentose phosphate pathway, and incorporation into glycogen. Abeta increased hydrogen peroxide production as well as glutathione release into the extracellular space without affecting intracellular glutathione content. A causal link between the effects of Abeta on glucose metabolism and its aggregation and internalization into astrocytes through binding to members of the class A scavenger receptor family could be demonstrated. Using astrocyte-neuron cocultures, we observed that the overall modifications of astrocyte metabolism induced by Abeta impair neuronal viability. The effects of the Abeta(25-35) fragment were reproduced by Abeta(1-42) but not by Abeta(1-40). Finally, the phosphoinositide 3-kinase (PI3-kinase) pathway appears to be crucial in these events since both the changes in glucose utilization and the decrease in neuronal viability are prevented by LY294002, a PI3-kinase inhibitor. This set of observations indicates that Abeta aggregation and internalization into astrocytes profoundly alter their metabolic phenotype with deleterious consequences for neuronal viability.

Atypical Kawasaki disease with peripheral gangrene and myocardial infarction: therapeutic implications.

We describe a 2-month-old girl with atypical Kawasaki disease (KD) complicated by peripheral gangrene and myocardial infarction. Peripheral ischaemia leading to gangrene is a rare but serious complication of KD in infants younger than 7 months of age. Treatment has been targeted at reducing arterial inflammation, arteriospasm and thrombosis. We report the first patient with incomplete KD and peripheral ischaemia in whom therapy with prostaglandin E1 (PGE1) as vasodilating and antithrombotic agent appeared successful, restoring hand and foot perfusion without significant long-term sequelae. However, PGE1 could have supported development of myocardial infarction by shunting blood away from ischaemic areas distal to a giant coronary artery aneurysm with beginning thrombosis. CONCLUSION. Atypical KD with peripheral gangrene appears to react favourably to treatment with PGE1, but needs careful monitoring to detect early signs of cardiac ischaemia.

Automated identification of minimal myocardial motion for improved image quality on MR angiography at 3 T

OBJECTIVE: Imaging during a period of minimal myocardial motion is of paramount importance for coronary MR angiography (MRA). The objective of our study was to evaluate the utility of FREEZE, a custom-built automated tool for the identification of the period of minimal myocardial motion, in both a moving phantom at 1.5 T and 10 healthy adults (nine men, one woman; mean age, 24.9 years; age range, 21-32 years) at 3 T. CONCLUSION: Quantitative analysis of the moving phantom showed that dimension measurements approached those obtained in the static phantom when using FREEZE. In vitro, vessel sharpness, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) were significantly improved when coronary MRA was performed during the software-prescribed period of minimal myocardial motion (p < 0.05). Consistent with these objective findings, image quality assessments by consensus review also improved significantly when using the automated prescription of the period of minimal myocardial motion. The use of FREEZE improves image quality of coronary MRA. Simultaneously, operator dependence can be minimized while the ease of use is improved.

Cardiac repair with allogeneic mesenchymal stem cells after myocardial infarction.

Over the past decade, use of autologous bone marrow-derived mononuclear cells (BMCs) has proven to be safe in phase-I/II studies in patients with myocardial infarction (MI). Taken as a whole, results support a modest yet significant improvement in cardiac function in cell-treated patients. Skeletal myoblasts, adipose-derived stem cells, and bone marrow-derived mesenchymal stem cells (MSCs) have also been tested in clinical studies. MSCs expand rapidly in vitro and have a potential for multilineage differentiation. However, their regenerative capacity decreases with aging, limiting efficacy in old patients. Allogeneic MSCs offer several advantages over autologous BMCs; however, immune rejection of allogeneic cells remains a key issue. As human MSCs do not express the human leukocyte antigen (HLA) class II under normal conditions, and because they modulate T-cell-mediated responses, it has been proposed that allogeneic MSCs may escape immunosurveillance. However, recent data suggest that allogeneic MSCs may switch immune states in vivo to express HLA class II, present alloantigen and induce immune rejection. Allogeneic MSCs, unlike syngeneic ones, were eliminated from rat hearts by 5 weeks, with a loss of functional benefit. Allogeneic MSCs have also been tested in initial clinical studies in cardiology patients. Intravenous allogeneic MSC infusion has proven to be safe in a phase-I trial in patients with acute MI. Endoventricular allogeneic MSC injection has been associated with reduced adverse cardiac events in a phase-II trial in patients with chronic heart failure. The long-term safety and efficacy of allogeneic MSCs for cardiac repair remain to be established. Ongoing phase-II trials are addressing these issues.

Cell viability and noninvasive in vivo MRI tracking of 3D cell encapsulating self-assembled microcontainers.

Several molecular therapies require the implantation of cells that secrete biotherapeutic molecules and imaging the location and microenvironment of the cellular implant to ascertain its function. We demonstrate noninvasive in vivo magnetic resonance imaging (MRI) of self-assembled microcontainers that are capable of cell encapsulation. Negative contrast was obtained to discern the microcontainer with MRI; positive contrast was obtained in the complete absence of background signal. MRI on a clinical scanner highlights the translational nature of this research. The microcontainers were loaded with cells that were dispersed in an extracellular matrix, and implanted both subcutaneously and in human tumor xenografts in SCID mice. MRI was performed on the implants, and microcontainers retrieved postimplantation showed cell viability both within and proximal to the implant. The microcontainers are characterized by their small size, three dimensionality, controlled porosity, ease of parallel fabrication, chemical and mechanical stability, and noninvasive traceability in vivo.

The region makes the difference: disparities in management of acute myocardial infaction within Switzerland

Purpose: To assess geographical differences within Switzerland regarding management and revascularization procedures for acute myocardial infarction (AMI). Methods: Swiss hospital discharge database for period 2007-2008. The main inclusion criterion was AMI as a primary discharge diagnosis. AMI revascularization procedures were identified and seven Swiss regions (Leman, Mittelland, Northwest, Zurich, Central, Eastern and Ticino) were analyzed. Results: Data from 25,674 AMI discharges were analyzed. Almost half (53.6%) of them were managed in a single hospital, the values ranging from 63.1% (Leman) to 31.4% (Ticino) see table. Relative to the total number of discharges, the highest Intensive Care Unit admission rate was in Leman (69.7%), the lowest (16.4%) in Ticino (Swiss average: 35.8%). Intracoronary revascularization rates were highest in Leman (51.6%) and lowest (30.8%) in Central Switzerland (Swiss average: 41.4%). Bare (non-drug-eluting) stents use was highest in Leman (33.1%) and lowest (7.0%) in Ticino (Swiss average: 15.8%), while drug eluting stent use was highest (32.8%) in Ticino and lowest (13.9%) in Central Switzerland (Swiss average: 24.0%). Coronary artery bypass graft rates were highest (4.6%) in Ticino and lowest (0.4%) in Eastern Switzerland (Swiss average: 2.6%). Mechanical circulatory assistance rates were highest (4.1%) in Zurich and lowest (0.4%) in Ticino (Swiss average: 1.7%). The differences in revascularization procedures remained after adjusting for age, single or multiple hospital management and gender. Conclusion: In Switzerland, significant geographical differences in management and revascularization procedures for AMI were found.

Cilengitide modulates attachment and viability of human glioma cells, but not sensitivity to irradiation or temozolomide in vitro.

Cilengitide is a cyclic peptide antagonist of integrins alphavbeta3 and alphavbeta5 that is currently being evaluated as a novel therapeutic agent for recurrent and newly diagnosed glioblastoma. Its mode of action is thought to be mainly antiangiogenic but may include direct effects on tumor cells, notably on attachment, migration, invasion, and viability. In this study we found that, at clinically relevant concentrations, cilengitide (1-100 microM) induces detachment in some but not all glioma cell lines, while the effect on cell viability is modest. Detachment induced by cilengitide could not be predicted by the level of expression of the cilengitide target molecules, alphavbeta3 and alphavbeta5, at the cell surface. Glioma cell death induced by cilengitide was associated with the generation of caspase activity, but caspase activity was not required for cell death since ectopic expression of cytokine response modifier (crm)-A or coexposure to the broad-spectrum caspase inhibitor zVAD-fmk was not protective. Moreover, forced expression of the antiapoptotic protein marker Bcl-X(L) or altering the p53 status did not modulate cilengitide-induced cell death. No consistent effects of cilengitide on glioma cell migration or invasiveness were observed in vitro. Preliminary clinical results indicate a preferential benefit from cilengitide added to temozolomide-based radiochemotherapy in patients with O(6)-methylguanine DNA methyltransferase (MGMT) gene promoter methylation. Accordingly, we also examined whether the MGMT status determines glioma cell responses to cilengitide alone or in combination with temozolomide. Neither ectopic expression of MGMT in MGMT-negative cells nor silencing the MGMT gene in MGMT-positive cells altered glioma cell responses to cilengitide alone or to cilengitide in combination with temozolomide. These data suggest that the beneficial clinical effects derived from cilengitide in vivo may arise from altered perfusion, which promotes temozolomide delivery to glioma cells.

Anisoylated plasminogen streptokinase activator complex versus streptokinase in acute myocardial infarction. Preliminary results of a randomised study.

25 patients with acute myocardial infarction pain lasting more than 20 minutes which was not relieved by nitrates, whose ECGs showed ST segment elevations of 1 mm or more in 2 or more ECG leads, and who presented less than 3 hours after onset of their symptoms were randomly assigned to one of 2 thrombolytic treatment groups: a single intravenous bolus of anisoylated plasminogen streptokinase activator complex (APSAC) 30U in 5 minutes or an intravenous infusion of streptokinase 1,500,000U over 60 minutes. 3 to 4 hours after the administration of the thrombolytic agent, all patients received intravenous heparin at full dosage for 24 hours. The patency of the infarct-related coronary vessels was assessed by angiography 1 to 4 hours after administration of the thrombolytic agent. Clinical signs, ECGs, pulse, blood pressure and temperature were monitored regularly for 24 hours after treatment or as clinically appropriate. APSAC seemed to be at least as effective as streptokinase in terms of patency of the infarct-related vessel (92% vs 63%, respectively). The adverse events were similar and none was life-threatening. APSAC and streptokinase caused similar falls in blood fibrinogen levels. APSAC, given as a bolus injection over 5 minutes, was easier to administer than streptokinase, which was given as an infusion during 60 minutes.

HBV or HCV coinfections and risk of myocardial infarction in HIV-infected individuals: the D:A:D Cohort Study.

BACKGROUND: Data on a link between HCV or HBV infection and the development of cardiovascular disease among HIV-negative and HIV-positive individuals are conflicting. We sought to investigate the association between HBV or HCV infection and myocardial infarction in HIV-infected individuals. METHODS: The prospective observational database of the D:A:D collaboration of 11 cohorts of HIV-infected individuals, including 212 clinics in Europe, the United States and Australia was used. Multivariate Poisson regression was used to assess the effect of HCV or HBV infection on the development of myocardial infarction after adjustment for potential confounders, including cardiovascular risk factors, diabetes mellitus and exposure to antiretroviral therapy. RESULTS: Of 33,347 individuals, 517 developed a myocardial infarction over 157,912 person-years, with an event rate of 3.3 events/1,000 person-years (95% confidence interval [CI] 3.0-3.6). Event rates (95% CIs) per 1,000 person-years in those who were HCV-seronegative and HCV-seropositive were 3.3 (3.0-3.7) and 2.7 (2.2-3.3), respectively, and for those who were HBV-seronegative, had inactive infection or had active infection were 3.2 (2.8-3.5), 4.2 (3.1-5.2) and 2.8 (1.8-3.9), respectively. After adjustment, there was no association between HCV seropositivity (rate ratio 0.86 [95% CI 0.62-1.19]), inactive HBV infection (rate ratio 1.07 [95% CI 0.79-1.43]) or active HBV infection (rate ratio 0.78 [95% CI 0.52-1.15]) and the development of myocardial infarction. CONCLUSIONS: We found no association between HBV or HCV coinfection and the development of myocardial infarction among HIV-infected individuals.

Seed viability constants for Eucalyptus grandis

This work aimed to analyse Eucalyptus grandis W.Hill ex Maiden seed behaviour, under controlled deterioration, and to estimate viability equation constants for the species. Seeds were harvested in the growing season of 1999, and the moisture contents were adjusted from 11.3% to a range between 1.2 and 18.1% at 25ºC. The subsamples were sealed into laminate aluminium-foil packets, for storage in incubators at 40, 50 and 65±0.5ºC. The seeds presented orthodox performance, in which the constants for predicting seed longevity of E. grandis were K E = 9.661, C W = 6.467, C H = 0.03498 and C Q = 0.0002330. The usual and inverse relationship between water content and seed longevity was also observed. The lowest moisture content limit for application of the viability equation at 65ºC was 4.9%, estimated under hygroscopic equilibrium with 23% of relative humidity in the storage environment.

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.

Pronostic à long terme des patients ayant bénéficié d'une thrombolyse au stade aigu de l'infarctus du myocarde [Long-term prognosis for patients undergoing thrombolysis during the acute phase of myocardial infarction]

OBJECTIVE: The objective of this study was to analyse the long-term mortality and morbidity of a group of patients undergoing thrombolysis during the acute phase of myocardial infarction and to determine the factors influencing the prognosis. One hundred and seventy five patients (149 mean and 26 women, mean age: 54 years) were included in a randomized study, comparing the efficacy of 2 thrombolytic substances administered during the acute phase of myocardial infarction. A standard questionnaire was sent to the various attending physicians to follow-up of these 175 patients. RESULTS: The hospital mortality was 5% (9 patients) and 14 patients (9%) died after a mean follow-up of 4.3 +/- 2.1 years. The 5-year actuarial survival was 81%. Fourteen patients (8%) were lost to follow-up and 49 patients (32%) underwent surgical or percutaneous revascularization during follow-up. Revascularized patients had a significantly better survival than non-revascularized patients. The mean left ventricular ejection fraction of patients who died was lower (48% versus 71%) than that of survivors. Patients with an ejection fraction < 40% also had a significantly lower survival (p = 0.01). Patency of the vessel after thrombolysis was associated with a slightly better survival; this difference was not significant. The ejection fraction at 6 month was also significantly higher (60 +/- 10% versus 49 +/- 11%) for patients with a patent artery. Three risk factors for death or reinfarction were identified: age > 65 years at the time of infarction, disease in more than one coronary vessel and absence of angina pectoris before infarction. The probability of a coronary accident varied from 2 to 88% according to the number of risk factors present. At the time of follow-up, 60% of patients presented hypercholesterolaemia versus only 7% before infarction 73% of patients received anticoagulant or antiaggregant treatment and 81% of patients were asymptomatic. CONCLUSION: The mortality and the acute and long-term morbidity of myocardial infarction remain high, as only 34% of our patients did not develop any events during follow-up, despite serious medical management and follow-up. The ejection fraction has an important prognostic value. Patient management should take the abovementioned risk factors into account.

Rivascolarizzazione miocardica con arteria radiale: tecniche chirurgiche a confronto e risultati a breve termine [Myocardial revascularization and radial artery: different surgical strategies and short-term results]

BACKGROUND: The radial artery is routinely used as a graft for surgical arterial myocardial revascularization. The proximal radial artery anastomosis site remains unknown. In this study, we analyzed the short-term results and the operative risk determinants after having used four different common techniques for radial artery implantation. METHODS: From January 2000 to December 2004, 571 patients underwent coronary artery bypass grafting with radial arteries. Data were analyzed for the entire population and for subgroups following the proximal radial artery anastomosis site: 140 T-graft with the mammary artery (group A), 316 free-grafts with the proximal anastomosis to the ascending aorta (group B), 55 mammary arteries in situ elongated with the radial artery (group C) and 60 radial arteries elongated with a piece of mammary artery and anastomosed to the ascending aorta (group D). RESULTS: The mean age was 53.8 +/- 7.7 years; 55.5% of patients had a previous myocardial infarction and 73% presented with a satisfactory left ventricular function. A complete arterial myocardial revascularization was achieved in 532 cases (93.2%) and 90.2% of the procedures were performed under cardiopulmonary bypass and cardioplegic arrest. The operative mortality rate was 0.9%, a postoperative myocardial infarction was diagnosed in 19 patients (3.3%), an intra-aortic balloon pump was used in 10 patients (1.7%) and a mechanical circulatory device was implanted in 2 patients. The radial artery harvesting site remained always free from complications. The proximal radial artery anastomosis site was not a determinant of early hospital mortality. Group C showed a higher risk of postoperative myocardial infarction (p = 0.09), together with female gender (p = 0.003), hypertension (p = 0.059) and a longer cardiopulmonary bypass time. CONCLUSIONS: The radial artery and the mammary artery can guarantee multiple arterial revascularization also for patients with contraindications to double mammary artery use. The four most common techniques for proximal radial artery anastomosis are not related to a higher operative risk and they can be used alternatively to reach the best surgical results

New universal definition of myocardial infarction applicable after complex percutaneous coronary interventions?

OBJECTIVES: This study aimed to characterize myocardial infarction after percutaneous coronary intervention (PCI) based on cardiac marker elevation as recommended by the new universal definition and on the detection of late gadolinium enhancement (LGE) by cardiovascular magnetic resonance (CMR). It is also assessed whether baseline inflammatory biomarkers are higher in patients developing myocardial injury. BACKGROUND: Cardiovascular magnetic resonance accurately assesses infarct size. Baseline C-reactive protein (CRP) and neopterin predict prognosis after stent implantation. METHODS: Consecutive patients with baseline troponin (Tn) I within normal limits and no LGE in the target vessel underwent baseline and post-PCI CMR. The Tn-I was measured until 24 h after PCI. Serum high-sensitivity CRP and neopterin were assessed before coronary angiography. RESULTS: Of 45 patients, 64 (53 to 72) years of age, 33% developed LGE with infarct size of 0.83 g (interquartile range: 0.32 to 1.30 g). A Tn-I elevation >99% upper reference limit (i.e., myocardial necrosis) (median Tn-I: 0.51 μg/l, interquartile range: 0.16 to 1.23) and Tn-I > 3× upper reference limit (i.e., type 4a myocardial infarction [MI]) occurred in 58% and 47% patients, respectively. LGE was undetectable in 42% and 43% of patients with periprocedural myocardial necrosis and type 4a MI, respectively. Agreement between LGE and type 4a MI was moderate (kappa = 0.45). The levels of CRP or neopterin did not significantly differ between patients with or without myocardial injury, detected by CMR or according to the new definition (p = NS). CONCLUSIONS: This study reports the lack of substantial agreement between the new universal definition and CMR for the diagnosis of small-size periprocedural myocardial damage after complex PCI. Baseline levels of CRP or neopterin were not predictive for the development of periprocedural myocardial damage.

Navigator-gated and real-time motion corrected free-breathing MR Imaging of myocardial late enhancement.

PURPOSE: A new magnetic resonance imaging approach for detection of myocardial late enhancement during free-breathing was developed. METHODS AND RESULTS: For suppression of respiratory motion artifacts, a prospective navigator technology including real-time motion correction and a local navigator restore was implemented. Subject specific inversion times were defined from images with incrementally increased inversion times acquired during a single dynamic scout navigator-gated and real-time motion corrected free-breathing scan. Subsequently, MR-imaging of myocardial late enhancement was performed with navigator-gated and real-time motion corrected adjacent short axis and long axis (two, three and four chamber) views. This alternative approach was investigated in 7 patients with history of myocardial infarction 12 min after i. v. administration of 0.2 mmol/kg body weight gadolinium-DTPA. CONCLUSION: With the presented navigator-gated and real-time motion corrected sequence for MR-imaging of myocardial late enhancement data can be completely acquired during free-breathing. Time constraints of a breath-hold technique are abolished and optimized patient specific inversion time is ensured.