Factors associated with presence of ascending aortic atherosclerosis in CABG patients

Background

The indication for epiaortic scanning during coronary artery operation is still a matter of debate. Whether this test should be carried out selectively or on a routine basis is unclear. The aim of this study was to determine factors that predict the presence of atherosclerotic ascending aortic wall thickening in patients undergoing coronary artery bypass grafting (CABG).

Methods

A total of 500 CABG patients underwent epiaortic scanning using a high-frequency linear ultrasonic probe. Maximum ascending aortic wall thickness was measured and correlated with patient-related variables.

Results

Maximum ascending aortic wall thickness significantly correlated with age (p < 0.001), preoperative creatinine level (p = 0.004), European system for cardiac operative risk evaluation (EuroSCORE, p < 0.001), and maximum descending aortic wall thickness (p < 0.001). Body mass index and left ventricular ejection fraction showed no correlation with maximum ascending aortic wall thickness. Of the categorical variables, hypertension (p = 0.02), unstable angina (p = 0.04), chronic obstructive pulmonary disease (p = 0.02), cerebrovascular disease (p < 0.001), and peripheral vascular disease (p < 0.001) were associated with increased ascending aortic wall thickness whereas sex, diabetes, acute cases, and previous cardiac operation were not. Multivariate analysis revealed maximum descending aortic wall thickness (p < 0.001), cerebrovascular disease (p = 0.03), and peripheral vascular disease (p = 0.04) as independent variables significantly associated with maximum ascending aortic wall thickness.

Conclusions

If epiaortic scanning is not carried out routinely for detection of ascending aortic arteriosclerosis it should at least be performed in patients with old age, hypertension, unstable angina, chronic obstructive pulmonary disease, cerebrovascular disease, peripheral vascular disease, elevated creatinine levels, higher EuroSCOREs, and increased wall thickness of the descending aorta.     

Tenascin-R mediates activity-dependent recruitment of neuroblasts in the adult mouse forebrain

Neuroblasts arising in the adult forebrain that travel to the olfactory bulb use two modes of migration: tangentially, along the rostral migratory stream, and radially, in the core of the olfactory bulb where they start to ascend to the outer layers. Although the mechanisms of tangential migration have been extensively studied, the factors controlling radial migration remain unexplored. Here we report that the extracellular matrix glycoprotein tenascin-R, expressed in the adult mouse olfactory bulb, initiates both the detachment of neuroblasts from chains and their radial migration. Expression of tenascin-R is activity dependent, as it is markedly reduced by odor deprivation. Furthermore, grafting of tenascin-R-transfected cells into non-neurogenic regions reroutes migrating neuroblasts toward these regions. The identification of an extracellular microenvironment capable of directing migrating neuroblasts provides insights into the mechanisms regulating radial migration in the adult olfactory bulb and offers promising therapeutic venues for brain repair.     

Glanzmann thrombasthenia Frankfurt I is associated with a point mutation Thr176Ile in the N-terminal region of alpha IIb subunit integrin

In this study, we report on the characterization of a patient with Glanzmann thrombasthenia (GT). Immunochemical analysis on platelets from the patient showed that the expression of alpha IIb beta 3 was only 25% of that in normal healthy controls, suggesting a case of GT. Functional analysis revealed a total lack of fibrinogen binding capacity. Molecular genetic analysis of the full-length cDNA sequences of alpha IIb and beta 3 subunits showed a novel point mutation C621T in alpha IIb cDNA, leading to a missense substitution of threonine for isoleucine at position 176. Coexpression of normal beta 3 and mutant alpha IIb(1176) isoform in mammalian cells showed a marked reduction in the expression of alpha IIb beta 3 heterodimer when compared to the wild-type and a decreased intracellular level of alpha IIb. The T176 I mutation is located in the N-terminal region in the W3:1-2 connecting strand of the beta-propeller. These data suggest that the N-terminal alpha IIb domain plays an important structural role in the formation of heterodimer and that it is also involved in fibrinogen binding.     

Regional energy metabolism following short-term neural stem cell transplantation into the injured spinal cord

Stem cells have been shown to partly restore central nervous system (CNS) function after transplantation into the injured CNS. However, little is known about their influence on acute energy metabolism after spinal cord injury. The present study was designed to analyze regional changes in energy metabolites. Young adult mice were subjected to laminectomy with subsequent hemisection at the L2/3 vertebral level. Immediately thereafter a stable clone of murine neural stem cells (NSCs) was injected into the lesion site. After 4 and 24 h, spinal cords were removed and ATP, glucose, and lactate were analyzed by a bioluminescence approach in serial sections and compared to a laminectomized (intact control), hemisected-only or hemisected vehicle-injected control group. At both time points, ATP content of the hemisected group in the tissue segments adjacent to the lesion was increased when compared to the laminectomized control. At the lesion site ATP content decreased significantly at 24 h in the cell-transplanted group when compared to the laminectomized control group. Glucose content decreased at the lesion site and in segments adjacent to the lesion at both time points and in all experimental groups when compared to the laminectomized control group. Lactate content decreased significantly at 4 h in the caudal segments of the vehicle-injected group and in both adjacent segments of the transplanted group when compared to the laminectomized control. At the lesion site, lactate content decreased significantly at 4 and 24 h in the cell-transplanted group, when compared to the laminectomized control. The area of ATP decline at the lesion site 24 h postinjury was significantly lower in the vehicle control group as compared to the hemisected or transplanted group. The decrease in glucose combined with an increase in ATP in the lesion-adjacent segments may indicate that the tissue responds with an increased use of glucose to support itself with sufficient ATP. The significant decrease in glucose, lactate, and ATP in the cell-transplanted group at 24 h may indicate a high metabolic need of the stem cells. The lower area of ATP decline 24 h after vehicle administration suggests that the vehicle solution washes out toxic mediators, thus ameliorating hemisection-dependent secondary tissue damage.     

Axon behaviour at Schwann cell - astrocyte boundaries: manipulation of axon signalling pathways and the neural adhesion molecule L1 can enable axons to cross

Axon regeneration in vivo is blocked at boundaries between Schwann cells and astrocytes, such as occur at the dorsal root entry zone and around peripheral nerve or Schwann cell grafts. We have created a tissue culture model of these boundaries in Schwann cell - astrocyte monolayer co-cultures. Axon behaviour resembles that in vivo, with axons showing a strong preference for Schwann cells over astrocytes. At boundaries between the two cell types, axons growing on astrocytes cross readily onto Schwann cells, but only 15% of axons growing on Schwann cells are able to cross onto astrocytes. Treatment with chondroitinase or chlorate to reduce inhibition by proteoglycans did not change this behaviour. The neural adhesion molecule L1 is present on Schwann cells and not astrocytes, and manipulation of L1 by application of an antibody, L1-Fc in solution, or adenoviral transduction of L1 into astrocytes increased the proportion of axons able to cross onto astrocytes to 40-50%. Elevating cAMP levels increased crossing from Schwann cells onto astrocytes in live and fixed cultures, and had a co-operative effect with NT-3 but not with NGF. Inactivation of Rho with a cell-permeant form of C3 exoenzyme also increased crossing from Schwann cells to astrocytes. Our experiments indicate that the preference of axons for Schwann cells is largely mediated by the presence of L1 on Schwann cells but not astrocytes, and that manipulation of growth cone signalling pathways can allow axons to disregard boundaries between the two cell types.     

Oxytocin neuron activation in NCAM-deficient mice: anatomical and functional consequences

During stimulated neurosecretion in the rat, oxytocin neurons display a reduced glial coverage and receive an increased number of synapses, changes that are reversed on arrest of stimulation. We identified polysialic acid on the neural cell adhesion molecule (NCAM) as an important mediator of such plasticity. To investigate further the role of this cell surface glycoprotein, we examined the oxytocin system in mice genetically deficient in NCAM. First, ultrastructural analyses revealed that in wild-type mice, the supraoptic nucleus (SON) underwent the same remodelling as in the rat because oxytocin neurons had a diminished astrocytic coverage and increased synaptic input during lactation or chronic salt loading. Surprisingly, the SON displayed this morphology in NCAM-deficient mice as well, whether they were nongestating and hydrated, lactating or dehydrated. The oxytocin system in NCAM-deficient mice was abnormally hyperactive, as illustrated by enhanced plasma and intranuclear concentrations of oxytocin and reduced anxiety-related behaviour. Plasma oxytocin concentrations were also high in lactating NCAM-deficient dams but certain parameters of lactation and maternal behaviour were impaired. NCAM-deficient mice survived ingestion of 2% saline for 7 days and had increased plasma oxytocin but they did not cope with more severe osmotic challenges. Our observations highlight further the remarkable capacity of the adult oxytocin system to undergo neuronal and glial remodelling whenever it is activated. That lack of NCAM did not prevent remodelling indicates that NCAM can be substituted by other molecular mechanisms. Finally, while NCAM deficiency greatly enhanced oxytocin release, it led to impaired oxytocin-dependent physiological and behavioural responses.     

Tenascin-R as a repellent guidance molecule for newly growing and regenerating optic axons in adult zebrafish

In adult fish, in contrast to mammals, new optic axons are continuously added to the optic projection, and optic axons regrow after injury. Thus, pathfinding of optic axons during development, adult growth, and adult regeneration may rely on the same guidance cues. We have shown that tenascin-R, a component of the extracellular matrix, borders the optic pathway in developing zebrafish and acts as a repellent guidance molecule for optic axons. Here we analyze tenascin-R expression patterns along the unlesioned and lesioned optic pathway of adult zebrafish and test the influence of tenascin-R on growing optic axons of adult fish in vitro. Within intraretinal fascicles of optic axons and in the optic nerve, newly added optic axons grow in a tenascin-R immunonegative pathway, which is bordered by tenascin-R immunoreactivity. In the brain, tenascin-R expression domains in the ventral diencephalon, in non-retinorecipient pretectal nuclei and in some tectal layers closely border the optic pathway in unlesioned animals and during axon regrowth. We mimicked these boundary situations with a sharp substrate border of tenascin-R in vitro. Optic axons emanating from adult retinal explants were repelled by tenascin-R substrate borders. This is consistent with a function of tenascin-R as a repellent guidance molecule in boundaries for adult optic axons. Thus, tenascin-R may guide newly added and regenerating optic axons by a contact-repellent mechanism in the optic pathway of adult fish.     

Comparison of myelin, axon, lipid, and immunopathology in the central nervous system of differentially myelin-compromised mutant mice: a morphological and biochemical study

The present study was carried out to compare different myelin-compromised mouse mutants with regard to myelin morphology in relation to axon-, lipid-, and immunopathology as a function of age. Mouse mutants deficient in the myelin-associated glycoprotein (MAG) and myelin basic protein (MBP) display subtle and severe myelin pathologies in the central nervous system (CNS), respectively. Animals doubly deficient in MAG and the neural cell adhesion molecule (NCAM) show defects similar to those present in MAG single mutants while mice deficient in MAG and the nonreceptor type tyrosine kinase Fyn are severely hypomyelinated, in addition to the MAG-specific myelin abnormalities. These mutant mice showed distinct myelin pathologies in different regions of the central nervous system and generally displayed a decrease in axonal integrity with age. Myelin pathology did not correlate locally with axon transection and with an involvement of the immune system as seen by numbers of CD3-positive lymphocytes and MAC-3-positive macrophages. Interestingly, the degree of these cellular abnormalities also did not correlate with abnormalities in levels of phospholipids, arachidonic acid, cholesterol, and apolipoprotein E (apoE). Moreover, these changes in lipid metabolism, including immune system-related arachidonic acid, preceded cellular pathology. The combined observations point to differences, but also similarities in the relation of myelin, axon, and immunopathology with genotype, and to a common aggravation of the phenotype with age.     

Late onset neurological phenotype of the X-ALD gene inactivation in mice: a mouse model for adrenomyeloneuropathy

Adrenomyeloneuropathy (AMN) and cerebral childhood adrenoleukodystrophy (CCALD) are the main phenotypic variants of an X-linked inherited metabolic disorder causing demyelination, X-linked adrenoleukodystrophy (X-ALD). It is caused by mutations in the ABCD1 (ALD) gene encoding a peroxisomal ABC transporter. Inactivation of the murine ALD gene does not lead to a detectable clinical phenotype in mice up to 6 months, and no cerebral pathology resembling the childhood form (CCALD) was observed. In this work, we show that older ALD-deficient mice exhibit an abnormal neurological and behavioral phenotype, starting at around 15 months. This is correlated with slower nerve conduction, and with myelin and axonal anomalies detectable in the spinal cord and sciatic nerve, but not in brain. The phenotype of ALD-deficient mice mimics features of human AMN, thus providing a model for investigating the pathogenesis of this disease.