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PubMed1998

The cell adhesion molecule E-cadherin is widely expressed in human atherosclerotic lesions.

OBJECTIVE: Various cell adhesion molecules are expressed in atherogenesis and the significance of their involvement in atherosclerotic lesion formation is well appreciated. In the present work, we examined whether the Ca(2+)-dependent cell adhesion molecule E-cadherin is also involved in atherogenesis. METHODS: Specimens of carotid artery and aorta were obtained at operation. Expression of E-cadherin was studied by an immunohistochemical method. The nature of E-cadherin-expressing cells was examined by comparative analysis of consecutive sections and by a double immunostaining procedure. An immunohistochemical approach was also applied to examine how the accumulation of oxidised low density lipoproteins (LDL) by intimal cells is associated with E-cadherin expression. RESULTS: No E-cadherin+ cells were found in normal non-atherosclerotic intima but E-cadherin+ cells were present in 96% of the atherosclerotic lesions. In atherosclerotic intima, E-cadherin was expressed by intimal cells showing varying degrees of transformation into foam cells. These E-cadherin+ cells also contained oxidised LDL in their cytoplasm. Differing numbers of CD68+ foam cells (15% to 60%) expressed E-cadherin but all the CD68+ macrophages without signs of transformation into foam cells were negative for E-cadherin. Neither smooth muscle cells nor foam cells of smooth muscle cell origin (smooth muscle alpha-actin+) were found to be positive for E-cadherin. T-cells (CD3+) and endothelial cells (von Willebrand factor+) were also negative for E-cadherin. Only a few vascular dendritic cells (S-100+) expressed E-cadherin and their expression was weak. We also found that a large proportion (40% to 85%) of E-cadherin+ cells did not stain with any cell-type specific markers. CONCLUSIONS: The finding that E-cadherin is expressed in atherosclerotic lesions expands our knowledge of cell adhesion molecules involved in atherogenesis. That E-cadherin is expressed in intimal cells transforming into foam cells suggests that lipid accumulation might be associated with the alteration and reorganisation of cell-to-cell interactions in atherogenesis. The present observations might assist in understanding the mechanisms associated with intracellular lipid accumulation.

Adult↗
PubMed1975

Hyperglycemia, polyol metabolism, and complications of diabetes mellitus.

This brief review of the sorbitol pathway has attempted to present our current knowledge of this accessory pathway of glucose metabolism in the development of some diabetic complications. Clearly hyperglycemia in the diabetic patient is an important factor controlling the activity of the sorbitol pathway. Hyperglycemia in both diabetic patients and experimental animals results in significant accumulations of the products of this pathway in some tissues, and these diabetic manifestations. The development of inhibitors of the aldose reductase enzyme affords new means for preventing and treating some of these complications. Nevertheless, we are still hampered by the lack of knowledge of the normal role of this pathway in tissue metabolism. Many technical problems still exist concerning sensitive and specific assays for the products of the sorbitol pathway in tissue studies, as well as with valid techniques for the measuremtn of the activity of this pathway in clinical situations. It is hoped that clinical studies with aldose reductase inhibitors in the future will further clarify the importance of this accesory pathway of glucose metabolism in diabetes.

Animals↗
PubMed2004

Environmental routes for platinum group elements to biological materials--a review.

The increased use of platinum group elements (PGE) in automobile catalysts has led to concern over potential environmental and biological accumulation. Platinum (Pt), palladium (Pd) and rhodium (Rh) concentrations have increased in the environment since the introduction of automobile catalysts. This review summarises current knowledge concerning the environmental mobility, speciation and bioavailability of Pt, Pd and Rh. The greater proportion of PGE emissions is from automobile catalysts, in the form of nanometer-sized catalyst particles, which deposit on roadside surfaces, as evidenced in samples of road dust, grass and soil. In soil, PGE can be transformed into more mobile species through complexation with organic matter and can be solubilised in low pH rainwater. There are indications that environmentally formed Pd species are more soluble and hence more mobile in the environment than Rh and Pt. PGE can reach waterbodies through stormwater transport and deposition in sediments. Besides external contamination of grass close to roads, internal PGE uptake has been observed for plants growing on soil contaminated with automobile catalyst PGE. Fine particles of PGE were also detected on the surface of feathers sampled from passerines and raptors in their natural habitat, and internal organs of these birds also contained PGE. Uptake has been observed in sediment-dwelling invertebrates, and laboratory studies have shown an uptake of PGE in eel and fish exposed to water containing road dust. The available evidence indicates that the PGE, especially Pd, are transported to biological materials through deposition in roots by binding to sulphur-rich low molecular weight species in plants. PGE uptake to exposed animals have uptake rates in the following order: Pd>Pt>Rh. The liver and kidney accumulate the highest levels of PGE, especially Pd. Urinary Pd and Rh, but not Pt, levels are correlated with traffic intensity. Dental alloys may lead to elevated urinary Pt levels. Platinum is a well-known allergen and Pd also shows a strong sensitisation potential.

Animals↗
PubMed2006

Scavenger receptors in atherosclerosis: beyond lipid uptake.

Atherosclerotic vascular disease arises as a consequence of the deposition and retention of serum lipoproteins in the artery wall. Macrophages in lesions have been shown to express > or = 6 structurally different scavenger receptors for uptake of modified forms of low-density lipoproteins (LDLs) that promote the cellular accumulation of cholesterol. Because cholesterol-laden macrophage foam cells are the primary component of the fatty streak, the earliest atherosclerotic lesion, lipid uptake by these pathways has long been considered a requisite and initiating event in the pathogenesis of atherosclerosis. Although the removal of proinflammatory modified LDLs from the artery wall via scavenger receptors would seem beneficial, the pathways distal to scavenger receptor uptake that metabolize the modified lipoproteins appear to become overwhelmed, leading to the accumulation of cholesterol-laden macrophages and establishment of a chronic inflammatory setting. These observations have led to the current dogma concerning scavenger receptors, which is that they are proatherogenic molecules. However, recent studies suggest that the effects of scavenger receptors on atherogenesis may be more complex. In addition to modified lipoprotein uptake, these proteins are now known to regulate apoptotic cell clearance, initiate signal transduction, and serve as pattern recognition receptors for pathogens, activities that may contribute both to proinflammatory and anti-inflammatory forces regulating atherogenesis. In this review, we focus on recent advances in our knowledge of scavenger receptor regulation and signal transduction, their roles in sterile inflammation and infection, and the potential impact of these pathways in regulating the balance of lipid accumulation and inflammation in the artery wall.

Animals↗
PubMed2007

Autophagy and CD4+ T lymphocyte destruction by HIV-1.

The first step of HIV-1 infection is mediated by the binding of envelope glycoproteins (Env) to CD4 and two major coreceptors, CCR5 or CXCR4. The HIV-1 strains that use CCR5 are involved in primo-infection whereas those HIV-1 strains that use CXCR4 play a major role in the demise of CD4+ T lymphocytes and a rapid progression toward AIDS. Notably, binding of X4 Env expressed on cells to CXCR4 triggers apoptosis of uninfected CD4+ T cells. We now have just demonstrated that, independently of HIV-1 replication, transfected or HIV-1-infected cells that express X4 Env induce autophagy and accumulation of Beclin 1 in uninfected CD4+ T lymphocytes via CXCR4. Moreover, autophagy is a prerequisite to Env-induced apoptosis in uninfected bystander T cells, and CD4+ T cells still undergo an Env-mediated cell death with autophagic features when apoptosis is inhibited. To the best of our knowledge, these findings represent the first example of autophagy triggered through binding of virus envelope proteins to a cellular receptor, without viral replication, leading to apoptosis. Here, we proposed hypotheses about the significance of Env-induced Beclin 1 accumulation in CD4+ T cell death and about the role of autophagy in HIV-1 infected cells depending on the coreceptor involved.

Apoptosis Regulatory Proteins↗
PubMed2006

Novel aspects of prions, their receptor molecules, and innovative approaches for TSE therapy.

1. Prion diseases are a group of rare, fatal neurodegenerative diseases, also known as transmissible spongiform encephalopathies (TSEs), that affect both animals and humans and include bovine spongiform encephalopathy (BSE) in cattle, scrapie in sheep, chronic wasting disease (CWD) in deer and elk, and Creutzfeldt-Jakob disease (CJD) in humans. TSEs are usually rapidly progressive and clinical symptoms comprise dementia and loss of movement coordination due to the accumulation of an abnormal isoform (PrP(Sc)) of the host-encoded prion protein (PrP(c)). 2. This article reviews the current knowledge on PrP(c) and PrP(Sc), prion replication mechanisms, interaction partners of prions, and their cell surface receptors. Several strategies, summarized in this article, have been investigated for an effective antiprion treatment including development of a vaccination therapy and screening for potent chemical compounds. Currently, no effective treatment for prion diseases is available. 3. The identification of the 37 kDa/67 kDa laminin receptor (LRP/LR) and heparan sulfate as cell surface receptors for prions, however, opens new avenues for the development of alternative TSE therapies.

Animals↗
PubMed1988

The insulin-like growth factors and their binding proteins.

1. This review provides a brief overview of the structure of the insulin-like growth factors (IGFs or somatomedins), their mRNA and genes; the regulation and sites of production of these peptides; their binding and actions in target tissues; and the structure and biological role of their binding proteins. 2. Molecular cloning techniques have allowed the prediction of precursor forms of IGF-I and IGF-II, have provided tools to study the regulation of the synthesis and translation of IGF mRNAs, and have recently yielded the primary sequence of the IGF-I receptor, supplementing other rapidly-accumulating structural data. 3. Several of the IGF binding proteins have also been purified, and initial structural studies performed. 4. The increased knowledge of the structures of the IGFs, their receptors and binding proteins should now permit rapid progress in understanding the physiology and functions of these proteins.

Animals↗
PubMed2005

Link between obesity and type 2 diabetes.

The relationship between obesity and diabetes is of such interdependence that the term 'diabesity' has been coined. The passage from obesity to diabetes is made by a progressive defect in insulin secretion coupled with a progressive rise in insulin resistance. Both insulin resistance and defective insulin secretion appear very prematurely in obese patients, and both worsen similarly towards diabetes. Thus, the classic 'hyperbolic relationship' between insulin resistance and insulin secretion and the 'glucose allostasis concept' remain prevailing concepts in this particular field of knowledge. An increase in overall fatness, preferentially of visceral as well as ectopic fat depots, is specifically associated with insulin resistance. The accumulation of intramyocellular lipids may be due to reduced lipid oxidation capacity. The ability to lose weight is related to the capacity to oxidize fat. Thus, a relative defect in fat oxidation capacity is responsible for energy economy and hampered weight loss.

Diabetes Mellitus, Type 2↗
PubMed2004

Towards a novel class of predictive microbial growth models.

Food safety and quality are influenced by the presence (and possible proliferation) of pathogenic and spoilage microorganisms during the life cycle of the product (i.e., from the raw ingredients at the start of the production process until the moment of consumption). In order to simulate and predict microbial evolution in foods, mathematical models are developed in the field of predictive microbiology. In general, microbial growth is a self-limiting process, principally due to either (i) the exhaustion of one of the essential nutrients, and/or (ii) the accumulation of toxic products that inhibit growth. Nowadays, most mathematical models used in predictive microbiology do not explicitly incorporate this basic microbial knowledge. In this paper, a novel class of microbial growth models is proposed. In contrast with the currently used logistic type models, e.g., the model of Baranyi and Roberts [Baranyi, J., Roberts, T.A., 1994. A dynamic approach to predicting bacterial growth in food. International Journal of Food Microbiology 23, 277-294], the novel model class explicitly incorporates nutrient exhaustion and/or metabolic waste product effects. As such, this novel model prototype constitutes an elementary building block to be extended in a natural way towards, e.g., microbial interactions in co-cultures (mediated by metabolic products) and microbial growth in structured foods (influenced by, e.g., local substrate concentrations). While under certain conditions the mathematical equivalence with classical logistic type models is clear and results in equal fitting capacities and parameter estimation quality (see Poschet et al. [Poschet, F., Vereecken, K.M., Geeraerd, A.H., Nicolai, B.M., Van Impe, J.F., 2004. Analysis of a novel class of predictive microbial growth models and application to co-culture growth. International Journal of Food Microbiology, this issue] for a more elaborated analysis in this respect), the biological interpretability and extendability represent the main added value.

Bacteria↗
PubMed2003

Sensitization of adenylate cyclase: a general mechanism of neuroadaptation to persistent activation of Galpha(i/o)-coupled receptors?

Acute activation of Galphas-coupled receptors stimulates cyclic AMP accumulation leading to the activation of downstream signaling cascades. These Galphas-mediated events can be countered by acute activation of inhibitory G proteins (Galpha(i/o)), which inhibit the activity of adenylate cyclase, thereby attenuating cyclic AMP accumulation. Furthermore, an additional, less direct mechanism for Galpha(i/o) proteins modulation of cyclic AMP signaling also has been described. Persistent activation of several Galpha(i/o)-coupled receptors has been shown to result in a subsequent paradoxical enhancement of adenylate cyclase activity in response to drug-stimulated cyclic AMP accumulation. This sensitization of adenylate cyclase likely represents a cellular adaptive response following prolonged activation of inhibitory receptors. Recent advances in our knowledge of G protein signaling, adenylate cyclase regulation, and other cellular signaling mechanisms have extensively increased our insight into this phenomenon. It is now thought that sensitization occurs as part of a compensatory mechanism by which the cell adapts to chronic inhibitory input. Such a mechanism may be involved in modulating Galphas-coupled receptor signaling following neurotransmitter elevations that occur in psychiatric disease states or following the administration of many drugs of abuse. This review will focus on recent advances in the understanding of molecular signaling pathways that are involved in sensitization and describe the potential role of sensitization in neuronal cell function.

Adaptation, Physiological↗
PubMed1999

Development of a dural arteriovenous fistula around the jugular valve after transvenous embolization of cavernous dural arteriovenous fistula.

BACKGROUND: Endovascular therapy for dural arteriovenous fistulas (DAVFs) is not without any risks, although it has been generally accepted to be a safe procedure. In this paper, we report a very rare complication: metachronous DAVF around a jugular valve 4 months after transvenous embolization. CASE DESCRIPTION: A 43-year-old woman presented with left proptosis, chemosis, and double vision. Cerebral angiography demonstrated a left cavernous DAVF. The patient's symptoms resolved almost completely after embolization with platinum coils via the superior ophthalmic vein. Four months later, angiography revealed a metachronous DAVF around a jugular valve. CONCLUSION: To our knowledge, only four such cases have been reported in the literature. Careful follow-up of patients treated with transvenous embolization and accumulation of such cases are needed to understand the pathogenesis of multiple DAVFs.

Adult↗
PubMed2001

Health and endogenous growth.

The focus of endogenous growth theory on human capital formation and the physical embodiment of knowledge in people, suggests the integration of the growth supporting character of health production and the growth generating services of human capital accumulation in an endogenous growth framework. We show that a slow down in growth may be explained by a preference for health that is positively influenced by a growing income per head, or by an ageing population. Growth may virtually disappear for countries with high rates of decay of health, low productivity of the health-sector, or high rates of discount.

Efficiency↗
PubMed1998

5-Aminolaevulinic acid-induced protoporphyrin IX accumulation in tissues: pharmacokinetics after oral or intravenous administration.

UNLABELLED: In this study, the biodistribution of 5-aminolaevulinic acid (ALA) and accumulation of protoporphyrin IX (PpIX) in rats have been examined. Two groups of 21 WAG/Rij rats are given 200 mg/kg ALA orally or intravenously. Six rats serve as controls. At 1, 2, 3, 4, 6, 12 and 24 h after ALA administration, ALA and porphyrin concentrations are measured in 18 tissues and fluids. Liver enzymes and renal-function tests are measured to determine ALA toxicity. In both groups ALA concentration is highest in kidney, bladder and urine. After oral administration, high concentrations are also found in duodenal aspirate and jejunum. Mild, short-lasting elevation of creatinine is seen in both treatment groups. Porphyrins, especially PpIX, accumulate mainly in duodenal aspirate, jejunum, liver and kidney (> 10 nmol/g tissue), less in oesophagus, stomach, colon, spleen, bladder, heart, lung and nerve (2-10 nmol/g tissue), and only slightly in plasma, muscle, fat, skin and brain (< 2 nmol/g tissue). In situ synthesis of porphyrins rather than enterohepatic circulation contributes to the PpIX accumulation. Confocal laser scanning microscopy shows selective porphyrin fluorescence in epithelial layers. Peak levels and total production of porphyrins are equal after oral and intravenous ALA administration. IN CONCLUSION: administration of 200 mg/kg ALA results in accumulation of photosensitive concentrations of PpIX, 1 to 6 h after ALA administration, in all tissues except muscle, fat, skin and brain. Knowledge of the time-concentration relationship should be helpful in selecting dosages, routes of administration and timing of ALA photodynamic therapy.

Administration, Oral↗
PubMed2000

A multi-modal reasoning methodology for managing IDDM patients.

We present a knowledge management and decision support methodology for insulin dependent diabetes mellitus (IDDM) patients care. Such methodology exploits the integration of case based reasoning (CBR) and rule based reasoning (RBR), with the aim of helping physicians during therapy planning, by overcoming the intrinsic limitations shown by the independent application of the two reasoning paradigms. RBR provides suggestions on the basis of a situation detection mechanism that relies on formalized prior knowledge; CBR is used to specialize and dynamically adapt the rules on the basis of the patient's characteristics and of the accumulated experience. When the case library is not representative of the overall population, only RBR is applied to define a therapy for the input situation, which can then be retained, enriching the case library competence. The paper reports the first evaluation results, obtained both on simulated examples and on real patients. This work was developed within the EU funded telematic management of insulin dependent diabetes mellitus (T-IDDM) project, and is fully integrated in its web-based architecture.

Bayes Theorem↗
PubMed2004

Modeling lead input and output in soils using lead isotopic geochemistry.

The aim of this study is to model downward migration of lead from the plow layer of an experimental site located in Versailles (about 15 km southwest of Paris, France). Since 1928, samples have been collected annually from the topsoil of three control plots maintained in bare fallow. Thirty samples from 10 different years were analyzed for their lead and scandium contents and lead isotopic compositions. The fluxes are simple because of the well-controlled experimental conditions in Versailles: only one output flux, described as a first-order differential function of the anthropogenic lead pool, was taken into account; the inputs were exclusively ascribed to atmospheric deposition. The combination of concentration and isotopic data allows the rate of migration from the plowed topsoil to the underlying horizon and, to a lesser extent, the atmospheric fluxes to be assessed. Both results are in good agreement with the sparse data available. Indeed, the post-depositional migration of lead appears negligible at the human time scale: less than 0.1% of the potentially mobile lead pool migrates downward, out of the first 25 cm of the soil, each year. Assuming future lead inputs equal to 0, at least 700 yr would be required to halve the amount of accumulated lead pollution. Such a low migration rate is compatible with the persistence of a major anthropogenic lead pool deposited before 1928. Knowledge of pollution history seems therefore to be of primary importance.

Agriculture↗
PubMed2000

Endoreduplication in higher plants.

Cell polyploidisation can be achieved by endoreduplication, which consists of one or several rounds of DNA synthesis in the absence of mitosis. As a consequence, chromosomes with 2n chromatids are produced without change in the chromosome number. Endoreduplication is the most common mode of polyploidisation in plants and can be found in many cell types, especially in those undergoing differentiation and expansion. Although accumulating data reveal that this process is developmentally regulated, it is still poorly understood in plants. At the molecular level, the increasing knowledge on plant cell cycle regulators allows the acquisition of new tools and clues to understand the basis of endoreduplication control and, in particular, the switch between cell proliferation and cell differentiation.

Cell Differentiation↗
PubMed2002

Malaria vaccine: candidate antigens, mechanisms, constraints and prospects.

More than 30 years after the first report of successful vaccination against malaria using radiation-attenuated sporozoites, an effective malaria vaccine is not yet available. However, field and experimental data indicate that it can be developed. An astonishing amount of data has accumulated concerning parasite biology, host-parasite interactions, immunity and escape mechanisms, targets and modulators of immune responses. Nevertheless, so far this knowledge has not been enough to make us understand how to properly manipulate the whole system to build an effective vaccine. In this article, we describe candidate antigens, mechanisms, targets and trials performed with potential malaria vaccines and discuss the approaches, in vivo and in vitro models, constraints and how technologies such as DNA vaccination, genomics/proteomics and reverse immunogenetics are providing exciting results and opening new doors to make malaria vaccine a reality.

Adult↗
PubMed2000

Bedside perspectives on the use of opioids: transferring results of clinical research into practice.

1. Transference of research findings to clinical practice has been a challenge for those managing chronic pain. Generally, pain is not well controlled in hospitals and steps need to be taken to make pain control more effective. 2. Clinical trials of opioids have shown that pain can be controlled in the great majority of patients. Apart from the use of the World Health Organization Analgesic Ladder, a 'pain diagnosis' should be made and a comprehensive view of pain needs to be considered by the clinician. This would include pain and other physical symptoms, psychological issues and social and spiritual stresses. 3. Respiratory depression and tolerance for opioids are often seen as negative aspects of opioids and, therefore, may lead to inadequate control of pain. The evidence cited suggests that, in the long-term treatment of cancer pain, respiratory depression almost never occurs. The only situation that warrants caution is when an anaesthetic block or similar procedure relieves pain treated by opioids, when that patient has been receiving large doses of opioids. Long-term studies with opioids show that tolerance may occur, but is not a clinical problem and should not impair their use in adequate doses to relieve the patient's pain. 4. The active morphine metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) do need to be considered when administering morphine. There seems to be considerable interindividual variation in the production and elimination of metabolites. In cases of renal failure or in the elderly, the ratios of M3G and M6G to morphine accumulate exponentially, making opioid toxicity more likely. Even different routes of administration seem to be associated with different ratios of metabolites. A knowledge of these sources of pharmacokinetic variability may lead to more effective use of the opioids in clinical practice.

Analgesics, Opioid↗