The cell biology of atherosclerosis - new developments

In the development of atherosclerotic lesions, three basic processes occur: 1) invasion of the artery wall by leucocytes, particularly monocytes and T-lymphocytes; 2) smooth muscle phenotypic modulation, proliferation, and synthesis of extracellular matrix; and 3) intracellular (macrophage and smooth muscle) lipoprotein uptake and lipid accumulation. Invasion of the vessel wall by leucocytes is mediated through the expression of adhesion molecules on both leucocytes and the endothelium making them 'sticky'. The adhesion molecules are induced by high serum cholesterol levels or complement fragments. Leucocytes which have adhered to the endothelium are chemo-attracted into the vessel wall by cytokines produced by early arriving leucocytes or by low density lipoprotein which has passively passed into the wall, in the process being trapped and oxidised. The oxidised low density lipoprotein is taken up by scavenger receptors (which are not subject to down-regulation) on both macrophages and smooth muscle cells. The overaccumulation of lipid is toxic to the cells and they die contributing to the central necrotic core. The macrophages and T-lymphocytes produce substances which induce smooth muscle cells of the artery wall to change from a 'contractile' (high volume fraction of myofilaments [V(v)myo]) to a 'synthetic' (low V(v)myo) phenotype. In this altered state they respond to growth factors released from macrophages, platelets, regenerating endothelial cells and smooth muscle cells; produce large amounts of matrix; express lipoprotein scavenger receptors; express adhesion molecules for leucocytes; and express HLA-DR following exposure to the T-lymphocyte product, IFN-delta, suggesting that they can become involved in a generalised immune reaction.

Down-regulation of the amyloid protein precursor of Alzheimer's disease by antisense oligonucleotides reduces neuronal adhesion to specific substrata

The hallmark of Alzheimer's disease is the cerebral deposition of amyloid which is derived from the amyloid precursor protein (APP). The function of APP is unknown but there is increasing evidence for the role of APP in cell-cell and/or cell-matrix interactions. Primary cultures of murine neurons were treated with antisense oligonucleotides to down-regulate APP. This paper presents evidence that APP mediates a substrate-specific interaction between neurons and extracellular matrix components collagen type I, laminin and heparan sulphate proteoglycan but not fibronectin or poly-L-lysine. It remains to be determined whether this effect is the direct result of APP-matrix interactions, or whether an intermediary pathway is involved. (C) 1997 Elsevier Science B.V.

Inactivation of a c-Myb/estrogen receptor fusion protein in transformed primary cells leads to granulocyte/macrophage differentiation and down regulation of c-kit but not c-myc or cdc2

Primary murine fetal hemopoietic cells were transformed with a fusion protein consisting of the ligand-binding domain of the estrogen receptor and a carboxyl-terminally truncated c-Myb protein (ERMYB), The ERMYB-transformed hemopoietic cells exhibit an immature myeloid phenotype when grown in the presence of beta-estradiol. Upon removal of beta-estradiol, the ERMYB cells display increased adherence, decreased clonogenicity and differentiate to cells exhibiting granulocyte or macrophage morphology, The expression of the c-myc, c-kit, cdc2 and bcl-2 genes, which are putatively regulated by Myb, was investigated in ERMYB cells grown in the presence or absence of beta-estradiol. Neither c-myc nor cdc2 expression was down-regulated after removal of beta-estradiol demonstrating that differentiation is not a consequence of decreased transactivation of these genes by ERMYB. While bcl-2 expression was reduced by 50% in ERMYB cells grown in the absence of beta-estradiol, there was no increase in DNA laddering, suggesting that Myb was not protecting ERMYB cells from apoptosis, In contrast, a substantial (200-fold) decrease in c-kit mRNA level was observed following differentiation of ERMYB cells, and c-kit mRNA could be partially re-induced by the re-addition of beta-estradiol. Furthermore, a reporter construct containing the c-kit promoter was activated when cotransfected with a Myb expression vector, providing further evidence of a role for Myb in the regulation of c-kit.

Treadmill running protects spinal cord contusion from secondary degeneration

It is known that physical activity triggers changes in the central nervous system Adult rats, trained on treadmills for 4 weeks, and a group of sedentary rats was submitted to contuse moderate spinal cord injury A group of sedentary rats was submitted to a sham operation The trained group continued running on treadmill after lesion for 4 weeks Motor behavior evaluated by BBB score was smaller in the sedentary group compared to the trained rats by 7 days after lesion Computerized activity monitor showed clear-cut differences in spontaneous motor parameters in trained rats only before lesion After surgery, sedentary rats showed changes in motor parameters but not in later periods of analysis Animals were euthanized by 28 days after surgery, and their spinal cords were processed for Nissl staining and immunohistochemistry The number of the remaining neurons and the lesion areal and lesion volume fractions were obtained by stereological method The number of the remaining neurons did not change after training Lesion volume and lesion areal fraction per section were smaller in the trained group Lesion index was more pronounced in the sedentary group Microdensitometric image analysis demonstrated a microglial reaction, astroglial activation, and glial FGF-2 production more pronounced in the spinal cord of sedentary animals GAP-43 was higher in caudal levels of contusion in the sedentary group In conclusion, treadmill running may favor a better functional recovery in the acute period after spinal cord lesion and wound repair processes leading to neuroprotection (C) 2010 Elsevier B V All rights reserved

Effects of bilateral adrenalectomy on systemic kainate-induced activation of the nucleus of the solitary tract. Regulation of blood pressure and local neurotransmitters

Glutamatergic transmission through metabotropic and ionotropic receptors, including kainate receptors, plays an important role in the nucleus of the solitary tract (NTS) functions. Glutamate system may interact with several other neurotransmitter systems which might also be influenced by steroid hormones. In the present study we analyzed the ability of systemic kainate to stimulate rat NTS neurons, which was evaluated by c-Fos as a marker of neuronal activation, and also to change the levels of NTS neurotransmitters such as GABA, NPY, CGRP, GAL, NT and NO by means of quantitative immunohistichemistry combined with image analysis. The analysis was also performed in adrenalectomized and kainate stimulated rats in order to evaluate a possible role of adrenal hormones on NTS neurotransmission. Male Wistar rats (3 month-old) were used in the present study. A group of 15 rats was submitted either to bilateral adrenalectomy or sham operation. Forty-eight hours after the surgeries, adrenalectomized rats received a single intraperitoneal injection of kainate (12 mg/kg) and the sham-operated rats were injected either with saline or kainate and sacrificed 8 hours later. The same experimental design was applied in a group of rats in order to register the arterial blood pressure. Systemic kainate decreased the basal values of mean arterial blood pressure (35%) and heart rate (22%) of sham-operated rats, reduction that were maintained in adrenalectomized rats. Kainate triggered a marked elevation of c-Fos positive neurons in the NTS which was 54% counteracted by adrenalectomy. The kainate activated NTS showed changes in the immunoreactive levels of GABA (143% of elevation) and NPY (36% of decrease), which were not modified by previous ablation of adrenal glands. Modulation in the levels of CGRP, GAL and NT immunoreactivities were only observed after kainate in the adrenalectomized rats. Treatments did not alter NOS labeling. It is possible that modulatory function among neurotransmitter systems in the NTS might be influenced by steroid hormones and the implications for central regulation of blood pressure or other visceral regulatory mechanisms control should be further investigated.

Three-dimensional sonographic measurement of contralateral lung volume in fetuses with isolated congenital diaphragmatic hernia

Purpose. To use 3-dimensional sonography (3DUS) to measure contralateral lung volume and evaluate the potential of this measurement to predict neonatal outcome in isolated congenital diaphragmatic hernia (CDH). Methods. Between January 2002 and December 2004, the contralateral lung volumes of 39 fetuses with isolated CDH were measured via 3DUS using rotational multiplanar imaging. The observed/expected contralateral fetal lung volume ratios (o/eContFLVR) were compared with the lung/head ratio (LHR), observed/expected total fetal lung volume ratio (o/e-TotFLVR), and postnatal outcome. Results. Contralateral lung volumes are less reduced than total lung volumes in CDH. The bias and precision of 3DUS in estimating contralateral lung volumes were 0.99 cm(3) and 1.11 cm(3), respectively, with absolute limits of agreement ranging from -1.19 cm(3) to + 3.17 cm(3). The o/e-ContFLVR was significantly lower in neonatal death cases (median, 0.49 cm(3); range, 0.22-0.99 cm(3)) than in survival cases (median, 0.58 cm(3); range, 0.42-0.92 cm(3) [p < 0.011). Overall accuracy of the o/e-ContFLVR, o/e-TotFLVR, and LHR in predicting neonatal death were 67.7% (21/31), 80.7% (25/31), and 77.4% (24/31), respectively. Conclusion. Although o/e-ContFLVR can be precisely measured with 3DUS and can be used to predict neonatal death in CDH, it is less accurate than LHR and o/e-TotFLVR for that purpose. (C) 2007 Wiley Periodicals, Inc.

Association between symptom severity and internal capsule volume in obsessive-compulsive disorder

Neurobiological models support an involvement of white matter tracts in the pathophysiology of obsessive-compulsive disorder (OCD), but there has been little systematic evaluation of white matter volumes in OCD using magnetic resonance imaging (MRI). We investigated potential differences in the volume of the cingulum bundle (CB) and anterior limb of internal capsule (ALIC) in OCD patients (n = 19) relative to asymptomatic control subjects (n = 15). White matter volumes were assessed using a 1.5T MRI scanner. Between-group comparisons were carried out after spatial normalization and image segmentation using optimized voxel-based morphometry. Correlations between regional white matter volumes in OCD subjects and symptom severity ratings were also investigated. We found significant global white matter reductions in OCD patients compared to control subjects. The voxel-based search for regional abnormalities (with covariance for total white matter volumes) showed no specific white matter volume deficits in brain portions predicted a priori to be affected in OCD (CB and ALIC). However, large clusters of significant positive correlation with OCD severity scores were found bilaterally on the ALIC. These findings provide evidence of OCD-related ALIC abnormalities and suggest a connectivity dysfunction within frontal-striatal-thalamic-cortical circuits. Further studies are warranted to better define the role of such white matter alterations in the pathophysiology of OCD, and may provide clues for a more effectively targeting of neurosurgical treatments for OCD. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

In utero exposure to air pollution lowers erythrocyte antioxidant defense and decreases weight in adult mice

In this study, we tested the influence of ambient air pollution on different phases of development of adult mice. With respect to adult weight, the animals that had spent their in utero period exposed to pollution showed less weight gain over their lifetime, as well as lower activity levels of the antioxidant enzymes catalase, superoxide dismutase (SOD) and glutathione peroxidase (GPx). Our study suggests that contact with atmospheric pollutants during the foetal period produces important changes on enzymatic erythrocyte antioxidant defense and weight in adult mice. (C) 2011 Elsevier B.V. All rights reserved.

Effect of temporal lobe structure volume on memory in elderly depressed patients

Objective: To compare the volume of the hippocampus and parahippocampal gyrus in elderly individuals with and without depressive disorders, and to determine whether the volumes of these regions correlate with scores on memory tests. Method: Clinical and demographic differences, as well as differences in regional gray matter volumes, were assessed in 48 elderly patients with depressive disorders and 31 control subjects. Brain (structural MRI) scans were processed using statistical parametric mapping and voxel-based morphometry. Cognitive tests were administered to subjects in both groups. Results: There were no between-group gray matter volume differences in the hippocampus or parahippocampal gyrus. In the elderly depressed group only, the volume of the left parahippocampal gyrus correlated with scores on the delayed naming portion of the visual verbal learning test. There were also significant direct correlations in depressed subjects between the volumes of the left hippocampus, right and left parahippocampal gyrus and immediate recall scores on verbal episodic memory tests and visual learning tests. In the control group, there were direct correlations only between overall cognitive performance (as assessed with the MMSE) and the volume of right hippocampus, and between the total score on the visual verbal learning test and the volume of the right and left parahippocampal gyrus. Conclusions: These findings highlight different patterns of relationship between cognitive performance and volumes of medial temporal structures in depressed individuals and healthy elderly subjects. The direct correlation between delayed visual verbal memory recall scores with left parahippocampal volumes specifically in elderly depressed individuals provides support to the view that depression in elderly populations may be a risk factor for dementia. (C) 2009 Elsevier Inc. All rights reserved.

Bronchoscopic lung-volume reduction with Exhale airway stents for emphysema (EASE trial): randomised, sham-controlled, multicentre trial

Background Airway bypass is a bronchoscopic lung-volume reduction procedure for emphysema whereby transbronchial passages into the lung are created to release trapped air, supported with paclitaxel-coated stents to ease the mechanics of breathing. The aim of the EASE (Exhale airway stents for emphysema) trial was to evaluate safety and efficacy of airway bypass in people with severe homogeneous emphysema. Methods We undertook a randomised, double-blind, sham-controlled study in 38 specialist respiratory centres worldwide. We recruited 315 patients who had severe hyperinflation (ratio of residual volume [RV] to total lung capacity of >= 0.65). By computer using a random number generator, we randomly allocated participants (in a 2:1 ratio) to either airway bypass (n=208) or sham control (107). We divided investigators into team A (masked), who completed pre-procedure and post-procedure assessments, and team B (unmasked), who only did bronchoscopies without further interaction with patients. Participants were followed up for 12 months. The 6-month co-primary efficacy endpoint required 12% or greater improvement in forced vital capacity (FVC) and 1 point or greater decrease in the modified Medical Research Council dyspnoea score from baseline. The composite primary safety endpoint incorporated five severe adverse events. We did Bayesian analysis to show the posterior probability that airway bypass was superior to sham control (success threshold, 0.965). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00391612. Findings All recruited patients were included in the analysis. At 6 months, no difference between treatment arms was noted with respect to the co-primary efficacy endpoint (30 of 208 for airway bypass vs 12 of 107 for sham control; posterior probability 0.749, below the Bayesian success threshold of 0.965). The 6-month composite primary safety endpoint was 14.4% (30 of 208) for airway bypass versus 11.2% (12 of 107) for sham control (judged non-inferior, with a posterior probability of 1.00 [Bayesian success threshold >0.95]). Interpretation Although our findings showed safety and transient improvements, no sustainable benefit was recorded with airway bypass in patients with severe homogeneous emphysema.

Age-Related Metabolic Profiles in Cognitively Healthy Elders: Results from a Voxel-Based [(18)F]Fluorodeoxyglucose-Positron-Emission Tomography Study with Partial Volume Effects Correction

BACKGROUND AND PURPOSE: Functional brain variability has been scarcely investigated in cognitively healthy elderly subjects, and it is currently debated whether previous findings of regional metabolic variability are artifacts associated with brain atrophy. The primary purpose of this study was to test whether there is regional cerebral age-related hypometabolism specifically in later stages of life. MATERIALS AND METHODS: MR imaging and FDG-PET data were acquired from 55 cognitively healthy elderly subjects, and voxel-based linear correlations between age and GM volume or regional cerebral metabolism were conducted by using SPM5 in images with and without correction for PVE. To investigate sex-specific differences in the pattern of brain aging, we repeated the above voxelwise calculations after dividing our sample by sex. RESULTS: Our analysis revealed 2 large clusters of age-related metabolic decrease in the overall sample, 1 in the left orbitofrontal cortex and the other in the right temporolimbic region, encompassing the hippocampus, the parahippocampal gyrus, and the amygdala. The division of our sample by sex revealed significant sex-specific age-related metabolic decrease in the left temporolimbic region of men and in the left dorsolateral frontal cortex of women. When we applied atrophy correction to our PET data, none of the above-mentioned correlations remained significant. CONCLUSIONS: Our findings suggest that age-related functional brain variability in cognitively healthy elderly individuals is largely secondary to the degree of regional brain atrophy, and the findings provide support to the notion that appropriate PVE correction is a key tool in neuroimaging investigations.

Claudin-7 down-regulation is an important feature in oral squamous cell carcinoma

Aims: Claudins, a large family of essential tight junction (TJ) proteins, are abnormally regulated in human carcinomas, especially claudin-7. The aim of this study was to investigate claudin-7 expression and alterations in oral squamous cell carcinoma (OSCC). Methods and results: Expression of claudin-7 was analysed in 132 cases of OSCC organized in a tissue microarray. Claudin-7 mRNA transcript was evaluated using real-time polymerase chain reaction and the methylation status of the promoter was also assessed. Claudin-7 was negative in 58.3% of the cases. Loss of claudin-7 protein expression was associated with recurrence (P = 0.019), tumour size (P = 0.014), clinical stage of OSCC (P = 0.055) and disease-free survival (P = 0.015). Down-regulation of the claudin-7 mRNA transcripts was observed in 78% of the cases, in accordance with immunoexpression. Analysis of the methylation status of the promoter region of claudin-7 revealed that treatment of O28 cells (that did not express claudin-7 mRNA transcripts) with 5-Aza-2`-Deoxycytidine (5-Aza-dC) led to the re-expression of claudin-7 mRNA transcript. Conclusion: Loss of claudin-7 expression is associated with important subcellular processes in OSCC with impact on clinical parameters.

Morphology of the subgenual prefrontal cortex in pediatric bipolar disorder

Objectives The subgenual prefrontal cortex (SGPFC) is an important brain region involved in emotional regulation and reward mechanisms Volumetric abnormalities in this region have been identified in adults with bipolar disorder but thus far not in pediatric cases We examined the volume of this brain region in subjects with pediatric bipolar disorder (PBD) and compared them to healthy controls Methods Fifty one children and adolescents (mean age +/- SD 13 2 +/- 2 9 y) with DSM-IV PBD and 41 (mean age +/- SD 13 7 +/- 2 7 y) healthy comparison subjects (HC) underwent 1 5 T structural magnetic resonance imaging (MRI) brain scans We traced the SGPFC manually and compared SGPFC gray matter volumes using analysis of covariance with age gender and intracranial volume as covariates We also examined the relationship of family history of affective disorders and medication status to SGPFC volumes Results SGPFC volumes were not significantly different in PBD and HC subjects However exploratory analysis showed PBD subjects who had one or more first degree relatives with mood disorders (n = 33) had significantly smaller left hemisphere SGPFC compared to HC (p = 003 Sidak corrected) Current usage of a mood stabilizer was significantly associated with larger right SGPFC volume in PBD (F = 4 82 df = 1/41 p = 0 03) Conclusion Subjects with PBD and a close family history of mood disorders may have smaller left SGPFC volumes than HC Mood stabilizing medication may also impact SGPFC size and could have masked more subtle abnormalities overall (C) 2010 Elsevier Ltd All rights reserved