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At least 145 records · Page 8Linked to original sources
PubMed1997

Complement factors and their receptors.

In summary, recent advances in molecular cloning of anaphylatoxins and the anaphylatoxin receptors add new dimensions to our investigations and understanding of the molecular mechanisms involved in anaphylatoxin action. Combining knowledge accumulated from peptide modeling of the ligands with mutagenesis studies of these ligands and their receptors makes it possible to more accurately model interactive sites and understand the sequence of molecular interactions required for cellular activation. In addition, these new developments provide valuable tools for investigating, yet unknown, activities and cellular targets of the anaphylatoxin molecules.

Amino Acid Sequence↗
PubMed1995

Glucocorticoids and immune function: physiological relevance and pathogenic potential of hormonal dysfunction.

The more knowledge accumulates on the molecular action of glucocorticoids, the less appears to be known about the physiological relevance of these data. Mechanisms that determine bioactivity of glucocorticoids are largely neglected in studies on their molecular actions in immunoregulation. However, alterations of these mechanisms may contribute to the pathogenesis of acute of chronic inflammation, ranging from septic shock to autoimmune disease, or even acquired immuno deficiency syndrome. In this article, Thomas Wilckens attempts to challenge the long-standing dogma of glucocorticoids being only immunosuppressive in their action, and suggests a physiological role in which they are a prerequisite for a coordinated immune response.

Animals↗
PubMed2001

Memory consolidation of Pavlovian fear conditioning: a cellular and molecular perspective.

Pavlovian fear conditioning has emerged as a leading behavioral paradigm for studying the neurobiological basis of learning and memory. Although considerable progress has been made in understanding the neural substrates of fear conditioning at the systems level, until recently little has been learned about the underlying cellular and molecular mechanisms. The success of systems-level work aimed at defining the neuroanatomical pathways underlying fear conditioning, combined with the knowledge accumulated by studies of long-term potentiation (LTP), has recently given way to new insights into the cellular and molecular mechanisms that underlie acquisition and consolidation of fear memories. Collectively, these findings suggest that fear memory consolidation in the amygdala shares essential biochemical features with LTP, and hold promise for understanding the relationship between memory consolidation and synaptic plasticity in the mammalian brain.

Animals↗
PubMed2000

Depth electrodes in clinical neurophysiology: neuronal activity and human cognitive function.

Depth intracranial electrodes are used in medicine for the diagnosis and treatment of certain medically intractable disorders including epilepsy and parkinsonism. Electrophysiological studies including the recording of neuronal activity via depth electrodes during cognitive tasks allow the mapping of the functional significance of various brain regions for certain cognitive functions. Knowledge accumulated throughout the last several decades allows us to draw some theoretical inferences about neuronal mechanisms of human cognition. The present paper provides a selective review of studies of neuronal activity of the human brain in relation to language, verbal memory and error detection.

Brain↗
PubMed1998

Standardized structure and modular design of a pharmacokinetic database.

BACKGROUND: The accumulated knowledge on drugs can be used for an individual drug dosage adjustment if it is placed at our disposal in an informatically structured form. THEORY AND METHODS: We have started building up a pharmacokinetic database aimed at adjusting drug dosages, in exemplary form, to patients with renal impairment. Parameters needed for the three dosage adjustment rules (Dettli, Kunin, Holford) and the most general concept of pharmacokinetics constituted the theoretical basis. TWO PROCESSES PERTAIN TO ALL DRUGS: Distribution and elimination. Total drug clearance and at least two parameters representing distribution and elimination processes are closely interdependent in mathematical terms (clearance = volume of distribution*rate of elimination). This relation yields the unifying concept that serves as a prerequisite for a structured recording of 30 assigned pharmacokinetic and pharmacodynamic parameters within an informatic database. SOLUTIONS AND RESULTS: The information is retrieved and referenced from 2383 original publications by means of a standardized input module. The complete database at present contains 15,397 records for 1573 drugs. A programmed meta-analytic algorithm is used to calculate the statistical measures for the central value and variance--as available--from the pooled values of primary records. The statistically standardized parameters are extracted for 6601 pharmacokinetic parameters, and placed at the users disposal with the output module. PRACTICAL UTILITY: Following meta-analysis, published pharmacokinetics can be used as statistical estimates of population parameters. The statistical estimates with variances permit an individual drug dosage adjustment by applying the Bayesian approach or neural networks.

Algorithms↗
PubMed2000

The HLA crossroad in tumor immunology.

It is generally accepted that human and experimental tumor cells can lose major histocompatibility complex (MHC) class I molecules. These human leukocyte antigen (HLA) losses are detected when the primary tumor breaks the basal membrane, invades the surrounding tissues, and starts to metastasize. These altered HLA class I phenotypes probably constitute the major tumor escape mechanism facing anti-tumor T-cell mediated responses. Thus, it is important to characterize these phenotypes in clinical tumor samples, analyze the mechanism(s) responsible for them, and counsel patients before and during peptide anti-cancer immunotherapy. The present paper summarizes the most relevant altered HLA class I phenotypes found in human tumor samples, indicates their frequency, and outlines the mechanisms implicated. This review also points out that the natural killer (NK) escape mechanism of HLA class I deficient cancer cells is yet to be defined. Knowledge accumulated to date reveals that HLA class I molecules are an important crossroad in tumor immunology.

Histocompatibility Antigens Class I↗
PubMed2001

Practical improvement of the radiological quality of milk produced by peasant farmers in the territories of Belarus contaminated by the Chernobyl accident. The ETHOS project.

The Chernobyl post-accident situation has highlighted how the sudden emergence of persistent radioactive contamination in the environment is severely affecting the quality of life of the inhabitants in the concerned territories. The management of this situation is complex, mainly conditioned by the ability of the inhabitants themselves to be directly involved in the process of improving their living conditions. In this process, quality of life cannot be restricted solely to the dimension of radiological risk, but needs to encompass the diverse aspects of daily living, including the social, psychological, economic, political and ethical aspects. This paper presents the experience of the involvement of a group of peasant farmers from a village in the Republic of Belarus, in the process of improving the radiological quality of privately produced milk. This experience took place in the context of the ETHOS project, funded by the radiation protection research programme of the European Commission. The principal objective was to implement a complementary approach to the rehabilitation strategies adopted so far in the contaminated territories of the Republic of Belarus. This paper retraces the process of involvement of the inhabitants in a working group. It describes the characterisation of the situation by local actors, the opening of new possible actions to improve the radiological quality of milk at the individual level and the positive consequences at the scale of the village. The ETHOS project also illustrates how the scientific knowledge accumulated over many years since the Chernobyl accident in the field of radiation protection and radioecology can enter into local practices in the form of practical tools, which can be used by the population to produce significant improvements in the radiological situation.

Agriculture↗
PubMed1997

The brain as a symbol-processing machine.

The knowledge accumulated about the biochemistry of the synapsis in the last decades completely changes the notion of brain processing founded exclusively over an electrical mechanism, toward that supported by a complex chemical message exchange occurring both locally, at the synaptic site, as well as at other localities, depending on the solubility of the involved chemical substances in the extracellular compartment. These biochemical transactions support a rich symbolic processing of the information both encoded by the genes and provided by actual data collected from the surrounding environment, by means of either special molecular or cellular receptor systems. In this processing, molecules play the role of symbols and chemical affinity shared by them specifies the syntax for symbol manipulation in order to process and to produce chemical messages. In this context, neurons are conceived as message-exchanging agents. Chemical strings are produced and stored at defined places, and ionic currents are used to speed up message delivery. Synaptic transactions can no longer be assumed to correspond to a simple process of propagating numbers powered by a factor measuring the presynaptic capacity to influence the postsynaptic electrical activity, but they must be modeled by more powerful formal tools supporting both numerical and symbolic calculations. It is proposed here that formal language theory is the adequate mathematical tool to handle such symbolic processing. The purpose of the present review is therefore: (a) to discuss the relevant and recent literature about trophic factors, signal transduction mechanisms, neuromodulators and neurotransmitters in order (b) to point out the common features of these correlated processes; and (c) to show how they may be organized into a formal model supported by the theory of fuzzy formal languages (d) to model the brain as a distributed intelligent problem solver.

Animals↗
PubMedDate not supplied

Selection of levels of prevention.

This article outlines the advantages and disadvantages of universal and targeted intervention programs. Two advantages of universal programs are the absence of labeling and stigmatization, and the inclusion of the middle class which makes it more likely that the program will be well run. Two disadvantages are that they are unappealing to the public and politicians, and they may have their greatest effect on those at lowest risk. Targeted programs have the potential of addressing problems early on, and are potentially efficient if targeting can be done accurately. Disadvantages include difficulties around screening and the possibility of labeling and stigmatization. The argument is put forth that what is needed to reduce the immense burden of suffering from child and adolescent psychiatric disorders is the optimal mix of universal, targeted, and clinical programs carried out in the context of a civic community. There will always be trade-offs among these strategies, and the elements of the combination will change as knowledge accumulates.

Adolescent↗
PubMed2003

Gender and cardiac surgery.

The increased operative mortality and morbidity of women compared with men undergoing CABG surgery results from multiple differences in presentation, preoperative risk profile, and surgical factors. Investigators have found consistently that women present with a different preoperative risk profile than do men. Women more commonly have factors associated with increased short- and long-term mortality, such as less frequent use of IMA grafts. Differences in study design and patient population may contribute to variability in short- and long-term mortality among the various studies. The lack of representation of women in older clinical trials has hindered our understanding of the management of CAD in women; this situation must be remedied in future studies, [95]. Known physiologic and anatomic differences must be evaluated for their effects on outcomes. Further studies are needed to evaluate gender-related differences in autonomic responses to acute coronary occlusion, complications related to cardiopulmonary bypass, susceptibility to abnormalities in coagulation, and other factors that might account for discrepant outcomes in men versus women undergoing CABG [96]. Beyond these factors, specific pharmacologic and therapeutic considerations, such as the role of estrogen replacement therapy, need to be clarified. As further knowledge accumulates, it is hoped that gender-specific risk factors can be mitigated and protective factors exploited, thereby improving the outcomes for all cardiac surgery patients.

Cardiac Surgical Procedures↗
PubMed2000

Modelling during drug development.

With the advancement of both biological and computer sciences, new drug development faces the challenge to integrate a huge amount of knowledge accumulated from the very early quantitative structure-activity relationship investigations of the candidate molecule to the large scale clinical trials in patients. Whereas pharmacokinetics and pharmacodynamics are fields in which modelling has long demonstrated its value, its potential in many other areas of drug development has recently been the object of intensive scientific activity. The present review places emphasis on these newer applications; it includes the opinion of many experts in often highly specialised areas such as in vitro to in vivo extrapolation, toxicokinetics, non-continuous response models, population approaches and computer assisted simulation of clinical trials. It is most probable that in the near future many of these areas of research will be the objects of intensive and interesting developments. This will undoubtedly lead to improve developmental strategies for new drugs as well as more individualised pharmacological strategies for patients.

Animals↗
PubMed2002

Platelet antigens. The role of human platelet alloantigens (HPA) in blood transfusion and transplantation.

In this review, we describe the platelet surface molecules with special focus on the polymorphic glycoproteins giving rise to the human platelet alloantigen (HPA) system. We list the platelet glycoprotein complexes GPIa/IIa, GPIIb/IIIa, GPIb/V/IX and some other molecules, the corresponding genes that encode them and we describe their polymorphisms as well as their physiological function. Based on data obtained by serological and molecular methods, we explain how ancestral HPA alloepitopes have developed into the modern variants. We also describe the tissue distribution of these proteins, which seems to be wider than thought initially, and discuss the significance of the HPA encoding genes distribution in various populations. Methods for their determination are then described briefly Since HPA alloepitopes can induce antibodies with resulting clinical conditions such as: post-transfusion refractoriness to platelets (PTR); post-transfusion thrombocytopenic purpura (PTTP); and fetomaternal alloimmune thrombocytopenia (FMAIT), the mechanism of this alloimmunization and its prevention is described. Although the humoral arm is more important from the clinical viewpoint, the activation of the cytotoxic arm by HPA alloepitopes is also possible. These polymorphisms also seem to have a role in certain other clinical circumstances, therefore their impact on cardiovascular diseases and haemostatic disorders as well as their role in the transplantation of solid organs and bone marrow is addressed. We conclude that during the last decades, the research of the platelet membrane molecules contributed considerably to the diagnostics, prevention and therapy of the blood coagulation and haemostatic disorders, to the management of the neonatal thrombocytopenias, transfusion-related thrombocytopenias, refractoriness to platelet transfusions and autoimmune disorders. It also changed our view on the role of HPA alloepitopes in bone marrow and solid organ transplantation. In the future, this accumulated knowledge will be useful for the development of the cell-based therapies and immune modulation of both acquired and hereditary diseases.

Adult↗
PubMed2003

Gemcitabine, paclitaxel, pemetrexed and other newer agents in urothelial and kidney cancers.

Significant progress has been made in understanding the biology of urothelial and kidney cancers. Approaches to advanced urothelial cancer include dose intensification, reducing toxicity in unfit or elderly patients, doublet and triplet combination chemotherapy and sequential regimens. Promising new chemotherapeutic agents such as the epothilones, pemetrexed (Alimta), topoisomerase inhibitors and vinflunine act at different phases of the cell cycle and on folate metabolism. New agents that are combined with chemotherapy in urothelial cancer include the farnesyl transferase inhibitors and growth factors receptor inhibitors. Renal cell carcinoma (RCC) is particularly resistant to cytotoxic agents, although a gemcitabine/fluorinated pyrimidine combination may have modest but real clinical benefit. In metastatic RCC, new biologic and targeted therapies include anti-angiogenesis agents such as anti-vascular endothelial growth factor (VEGF) antibody and thalidomide, as well as toremifene, CCI-779 and allogeneic stem cell transplantation. Metastatic urothelial and renal cell cancers continue to be the clinical trial focus of many novel agents. The molecular biology of these diseases is being unravelled and as knowledge accumulates, our ability to target these cancers will continue to increase.

Angiogenesis Inhibitors↗
PubMed2001

The natural history of hepatitis C virus infection.

The natural history of HCV infection remains ill-defined. The knowledge accumulated on the progression of HCV to date is important, however. It is now abundantly clear that the progression of disease is generally slow, and the development of cirrhosis and its complications is a possibility, not a probability as hitherto thought. Predicting the outcome remains a quandary for clinicians. Ultimately it will be possible to define the natural history of hepatitis C infection through a combination of research in the fields of virology, immunology, and molecular biology and by monitoring the biochemical and histologic progress of the disease. Only then will it be possible to intervene appropriately and develop new therapies to prevent the progression to cirrhosis and hepatocellular carcinoma.

Hepacivirus↗
PubMed1999

Endothelium-derived agents in pericyte function/dysfunction.

The major components of blood vessels are the vascular endothelium and its supporting smooth muscle. Significant strides have been made in the understanding of the cellular and molecular biology of these two cell types and in particular their interactions have been the subject of much interest and debate over the past two decades. The vascular endothelium is now known to profoundly influence the synthetic and motor functions of the underlying smooth muscle and participate in the pathogenesis of all the major vascular disorders. Similarly, the vascular smooth muscle has important effects on the overlying endothelium, and any disruption in the cellular physiology of either cell type can result in dysfunction with important effects on blood flow and vascular permeability The majority of this accumulated knowledge relates to the vascular cells of the macrocirculation. Pericytes are the supporting cells of the microvasculature and a body of evidence is now available to show that similar regulatory mechanisms and vessel-wall cross-talk exists between these cells and the microvascular endothelium. Nowhere are these interactions more important than in the retinal microcirculation where autoregulation is vital for the maintenance of smooth and uninterrrupted blood flow. This review focuses on the interactions between retinal microvascular endothelial cells and their associated pericytes and examines the role of the endothelial cell and the pericyte in the pathogenesis of disease.

Animals↗
PubMed2003

Plant genome modification by homologous recombination.

The mechanisms and frequencies of various types of homologous recombination (HR) have been studied in plants for several years. However, the application of techniques involving HR for precise genome modification is still not routine. The low frequency of HR remains the major obstacle but recent progress in gene targeting in Arabidopsis and rice, as well as accumulating knowledge on the regulation of recombination levels, is an encouraging sign of the further development of HR-based approaches for genome engineering in plants.

Arabidopsis↗
PubMed2002

Scientists and clinicians test their metal-back to the future with platinum compounds.

After more than two decades of extensive use, drugs based on platinum continue to have a major role in cancer treatment. Although systematic approaches to the development of new analogues have produced agents with less toxicity and novel mechanisms of action, to date such approaches have not achieved more cures than can be achieved with the parent compound, cisplatin. Greater gains might be expected from accumulating knowledge about what makes cancer cells sensitive or resistant to platinum-based chemotherapy. Recent information on drug-efflux pathways, including expression of multidrug-resistance protein 2, and on how tumour cells behave when their DNA is distorted by a platinum adduct, suggests new avenues for translational research. The prospects include modulation of cellular handling of platinum compounds and individualised therapy based on expression of molecules that determine platinum sensitivity.

Cell Survival↗
PubMed2003

Diagnostic and pathogenetic role of antineutrophil cytoplasmic autoantibodies.

Anti-neutrophil cytoplasmic antibodies (ANCA) are mostly known as a useful diagnostic tool in patients with small-vessel vasculitides. With the accumulating knowledge of these autoantibodies, however, it becomes clear that the role of ANCA may not be only limited to a diagnosis of such disorders. The current review addresses, in addition to classical diagnostic associations, other diseases connected with ANCA positivity, both in adults and in children. The etiology of ANCA remains unknown, but still, the importance of both genetic and environmental factors is undoubted. The role of infection and chemicals in the etiology of ANCA-associated diseases is stressed in particular. A pathogenetic role of ANCA is suggested because of clinical observations based on the correlation of the vasculitis activity and the titer of ANCA. Many experiments show the effects of ANCA in various steps of an inflammatory process, particularly on leukocyte microbicidal activity and oxidative burst. Recent findings are analyzed in the experimental field and they are correlated with clinical significance.

Adult↗