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PubMed2006

A flexible integration and visualisation system for biomarker discovery.

Biological data have accumulated at an unprecedented pace as a result of improvements in molecular technologies. However, the translation of data into information, and subsequently into knowledge, requires the intricate interplay of data access, visualisation and interpretation. Biological data are complex and are organised either hierarchically or non-hierarchically. For non-hierarchically organised data, it is difficult to view relationships among biological facts. In addition, it is difficult to make changes in underlying data storage without affecting the visualisation interface. Here, we demonstrate a platform where non-hierarchically organised data can be visualised through the application of a customised hierarchy incorporating medical subject headings (MeSH) classifications. This platform gives users flexibility in updating and manipulation. It can also facilitate fresh scientific insight by highlighting biological impacts across different hierarchical branches. An example of the integration of biomarker information from the curated Proteome database using MeSH and the StarTree visualisation tool is presented.

Algorithms↗
PubMed2001

18F-fluorodeoxyglucose accumulation in the heart, brain and skeletal muscle of rats; the influence of time after injection, depressed lipid metabolism and glucose-insulin.

BACKGROUND: To study the effect of lipid depressing drugs on (18)FDG myocardial concentration. The changes of (18)FDG uptake in myocardium, brain and skeletal muscle of rats were compared as influenced by acipimox, tyloxapol and glucose with insulin. MATERIAL AND METHODS: 5.55 MBq of (18)FDG were administered to Wistar rats. Control rats were killed 15, 30, 45 and 60 minutes following intravenous injection and the radioactivity concentration (cpm/g of tissue) in relation to injected cpm was determined in a well crystal adjusted to 511 KeV in order to check the time of maximal (18)FDG tissue uptake. The radioactivity in myocardium, skeletal muscle and brain in intact animals was compared with that of rats treated with tyloxapol (tritton WR 1339, 125 mg intravenously immediately before (18)FDG injection), acipimox (nicotinic acid derivative, 25 mg by stomach cannula 15 minutes before (18)FDG), or glucose with insulin (intravenous injection of 0.04 g and 0.04 UI immediately before (18)FDG). The animals were killed 45 minutes following (18)FDG injection. RESULTS: Tyloxapol and acipimox significantly elevated myocardial (18)FDG concentration (tyloxapol +37% and acipimox +48%), but the increase in (18)FDG concentration after glucose and insulin was slight and insignificant. The changes in skeletal muscle after lipid depressing agents were quite contrasting; the decrease in (18)FDG concentration was -74% after tyloxapol and -44% following acipimox administration. The accumulation of (18)FDG in brain was not influenced markedly by the drugs used or by glucose with insulin. CONCLUSION: The highest (18)FDG uptake in myocardium could be achieved by depressing the lipid metabolism and not by administration of glucose with insulin only. A marked increase in glucose accumulation in myocardium is not possible without previous shift from the utilisation of fatty acids. This finding is fully in agreement with present knowledge about energetic metabolism of myocardium.

Journal Article↗
PubMed2006

[Trials of casual treatment of silicosis].

Silica-induced lung injury and the development of silicosis is one of the major occupational diseases. Accumulation and deposition of respirable dust containing silica mineral particles in the lung produces chronic lung disease characterized by granulomatous and fibrotic lesions. Knowledge of precise mechanisms, which induce this process is still limited, hence problems faced in the treatment of silicosis, especially the casual one. This article describes various trials of casual silicosis treatment with tetrandrine (Tet), isolated from the root of Stephania tetrandra, tumor necrosis factor (TNF) antagonists, polyvinyl-pyridine-N-oxide (PVNO), aluminum compounds, corticosteroids or bronchoalveolar lavage (BAL). The existing methods are not sufficient, which warrants further investigations. At present, prevention of the disease and treatment of its complications are most important.

Adrenal Cortex Hormones↗
PubMed1995

[Genetics and cancer: advances and perspectives].

Cancer genes can be ranged in three families: oncogenes, stimulating cell divisions; antioncogenes, blocking cell division; anti-apoptotic genes, blocking programmed cell death. Tumor progression usually results from cooperation between modifications of genes belonging to these different families. The familial predispositions to cancer are most frequently due to mutations of antioncogenes or of repair genes; in this later case, the original mutation results in abnormal DNA repair, then in accumulation of somatic mutations which could involve cancer genes. Recently, genes predisposing to familial forms of breast and colon cancers have been identified. Knowledge of such genes leads to possible presymptomatic prediction of the disease, but the preventive possibilities seem to be limited, today, to a preventive surgical exeresis. In the future, it would be desirable that elucidation of the mechanisms of cancer predisposition leads to less aggressive preventive or curative treatments.

Breast Neoplasms↗
PubMed1979

[Infection as indicator of finding complex environmental noxious agents within a short time (author's transl)].

We do not know whether complexes of chemical agents produce an accumulation of their respective noxious effects or whether these effects weaken each other and we have no exact methods to quantify these effects. Knowledge of such methods would be important for investigation of environmental health. In the course of researches how to influence infectious diseases by altering natural resistance we have found that it might be possible to use an indicator method: Animals exposed to such a light environmental toxic influence that they seem to be in a good health have a reduced period of survival time and an altered steroid metabolism after infection. The time of survival (after infection) and the steroid metabolism are the indicators of some hidden trouble caused by environmental influence. Here are three examples: 1) The covered intoxication with exhaust fumes, 2) the covered intoxication with lead salt and 3) the covered intoxication with DDT demonstrate the applicability of this method, results being available within a period of 2--3 weeks.

17-Ketosteroids↗
PubMed1997

99mTc-labelled immunoglobulin scintigraphy in arthritis: an analysis of synovial fluid activity.

The distribution of 99mTc-labelled human polyclonal non-specific immunoglobulin G (HIG) in the synovial fluid was studied in 14 patients with rheumatoid and non-rheumatoid arthritides. Analysis included the determination of the total activity per ml synovial fluid 6 h post-injection (p.i.) of the tracer as well as of the protein- and cell-bound fractions. At 6 h p.i., > 60% of the injected dose remained in plasma as protein-bound radioactivity. Values in the synovial fluid ranged between 0.001 and 0.009% of the injected dose per ml. Importantly, the synovial fluid to plasma ratio was consistently < 1 (range: 0.09-0.43), which is in the range of ratios observed for endogenous proteins in vivo. Similar values were obtained in samples of synovial tissue obtained at surgery in two patients. These data are consistent with the hypothesis that labelled HIG accumulates in the extracellular fluid (both within the synovial tissue and fluid) by non-specific mechanisms (such as increased blood pool and capillary permeability) and does not equilibrate with circulating plasma proteins in accordance with basic knowledge of synovial physiology. In addition, it was found that most of the activity remained bound to the proteins in the fluid and that cell-binding occurred to a very low degree that cannot be considered an important mechanism of uptake of this radiolabelled agent in vivo. These results provide the first evidence in an in vivo human setting that radiolabelled HIG accumulates mainly by non-specific mechanisms in inflamed joints.

Arthritis, Rheumatoid↗
PubMed1995

Psychotherapy for bipolar disorder.

BACKGROUND: Psychosocial factors may contribute 25-30% to the outcome variance in bipolar disorders. Sufferers have identified benefits from psychotherapy, but biological models and treatments dominate the research agenda. The author reviews research on psychosocial issues and interventions in this disorder. METHOD: Research on adjustment to the disorder, interpersonal stressors and obstacles to treatment compliance were located by computerised searches and the author's knowledge of the literature. All published outcome studies of psychosocial interventions in bipolar disorder are reviewed. RESULTS: There is an inadequate database on psychosocial factors associated with onset and maintenance of bipolar disorder. While the outcome studies available are methodologically inadequate, the accumulated evidence suggests that psychosocial interventions may have significant benefits for bipolar sufferers and their families. CONCLUSIONS: Given the significant associated morbidity and mortality, there is a clear need for more systematic clinical management that addresses psychosocial as well as biological aspects of bipolar disorder. The author identifies appropriate research strategies to improve knowledge of effective psychosocial interventions.

Adaptation, Psychological↗
PubMed2005

Liver fibrosis.

Liver fibrosis is the excessive accumulation of extracellular matrix proteins including collagen that occurs in most types of chronic liver diseases. Advanced liver fibrosis results in cirrhosis, liver failure, and portal hypertension and often requires liver transplantation. Our knowledge of the cellular and molecular mechanisms of liver fibrosis has greatly advanced. Activated hepatic stellate cells, portal fibroblasts, and myofibroblasts of bone marrow origin have been identified as major collagen-producing cells in the injured liver. These cells are activated by fibrogenic cytokines such as TGF-beta1, angiotensin II, and leptin. Reversibility of advanced liver fibrosis in patients has been recently documented, which has stimulated researchers to develop antifibrotic drugs. Emerging antifibrotic therapies are aimed at inhibiting the accumulation of fibrogenic cells and/or preventing the deposition of extracellular matrix proteins. Although many therapeutic interventions are effective in experimental models of liver fibrosis, their efficacy and safety in humans is unknown. This review summarizes recent progress in the study of the pathogenesis and diagnosis of liver fibrosis and discusses current antifibrotic strategies.

Angiotensin II↗
PubMedDate not supplied

Identification of systems failures in successful paediatric cardiac surgery.

Patient safety will benefit from an approach to human error that examines systemic causes, rather than blames individuals. This study describes a direct observation methodology, based on a threat and error model, prospectively to identify types and sources of systems failures in paediatric cardiac surgery. Of substantive interest were the range, frequency and types of failures that could be identified and whether minor failures could accumulate to form more serious events, as has been the case in other industries. Check lists, notes and video recordings were employed to observe 24 successful operations. A total of 366 failures were recorded. Coordination and communication problems, equipment problems, a relaxed safety culture, patient-related problems and perfusion-related problems were most frequent, with a smaller number of skill, knowledge and decision-making failures. Longer and more risky operations were likely to generate a greater number of minor failures than shorter and lower risk operations, and in seven higher-risk cases frequently occurring minor failures accumulated to threaten the safety of the patient. Non-technical errors were more prevalent than technical errors and task threats were the most prevalent systemic source of error. Adverse events in surgery are likely to be associated with a number of recurring and prospectively identifiable errors. These may be co-incident and cumulative human errors predisposed by threats embedded in the system, rather than due to individual incompetence or negligence. Prospectively identifying and reducing these recurrent failures would lead to improved surgical standards and enhanced patient safety.

Adolescent↗
PubMed1992

Dioctanoylglycerol stimulates accumulation of [methyl-14C]choline and its incorporation into acetylcholine and phosphatidylcholine in a human cholinergic neuroblastoma cell line.

Dioctanoylglycerol, a synthetic diacylglycerol, stimulated [14C]choline uptake in cultured human neuroblastoma (LA-N-2) cells. As this effect has not, to our knowledge, been reported before, it was of interest to characterize it in more detail. In the presence of 500 microM dioctanoylglycerol the levels of [14C]choline attained during a 2 hour labeling period were elevated by 78 +/- 12%, while [14C]acetylcholine and long fatty acyl chain [14C]phosphatidylcholine levels increased by 26 +/- 2% and 19 +/- 5%, respectively (mean +/- S.E.M.). Total (long chain plus dioctanoyl-) [14C]phosphatidylcholine was increased by 198 +/- 33%. Kinetic analysis showed that dioctanoylglycerol reduced the apparent Km for choline uptake to 56 +/- 9% of control (n = 4). The Vmax was not significantly altered. The stimulation of [14C]choline accumulation by dioctanoylglycerol was not dependent on protein kinase C activation; the effect was not mimicked by phorbol ester or by 1-oleoyl-2-acetylglycerol, and was not inhibited by the protein kinase C inhibitors H-7 or staurosporine, or by prolonged pretreatment with phorbol 12-myristate 13-acetate. The effect of dioctanoylglycerol was slightly (but not significantly) reduced by EGTA and strongly inhibited by the cell-permeant calcium chelator bis(o-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid, tetra(acetoxymethyl)ester. Although these results implicate elevated intracellular calcium in the response, dioctanoylglycerol did not increase phosphatidylinositol hydrolysis in LA-N-2 cells, and its effect was not inhibited by the diacylglycerol kinase inhibitor R 59 022 (which blocks the conversion of diacylglycerol to phosphatidic acid, a known stimulator of phosphatidylinositol hydrolysis).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1996

Pharmacological activities of heparin chains: should our past knowledge be revised?

Unfractionated heparin is a heterogeneous mixture of sulphated polysaccharides. The anticoagulant activity of unfractionated heparin is mainly accounted for by its fractions with a sequence with binding affinity for antithrombin III. The interaction of heparin with antithrombin III markedly enhances the ability of the latter to inhibit factor Xa and thrombin. Only about one third of the unfractionated heparin molecules contain the high-affinity material and its distribution along the heparin molecules appears to be random-hence the development of low-molecular-weight heparins. Most of the saccharide chains of low-molecular-weight heparins are composed of less than 18 saccharides and have reduced ability to inhibit thrombin relative to their ability to inhibit factor Xa. The potential dissociation of anti-factor IIa activity and the anti-Xa activity provided the pharmacological background for the clinical development of low-molecular-weight heparins. During the last few years, evidence has accumulated on the importance of anti-factor IIa for the expression of the antithrombotic activity of low-molecular-weight heparins. This paper reviews the evidence and revises our knowledge about the pharmacological activity of the heparin chains.

Adult↗
PubMed2003

Current progress in the understanding of IgE-FcepsilonRI interaction.

The last decade has seen a wealth of studies aimed at the characterization of the binding between IgE and its high-affinity receptor, FcepsilonRI. IgE-FcepsilonRI complex formation is a major molecular event in atopic allergy. IgE-FcepsilonRI binding connects allergen recognition to cellular triggering, ultimately leading to disease manifestations. Consequently, pharmacological intervention at this site is of universal relevance for atopic allergy. Until recent years, the complexity of IgE-FcepsilonRI binding, together with the difficulty in obtaining fully functional recombinant IgE and FcepsilonRI derivatives, often led to confusion and difficulty in data interpretation. Major advances in the understanding of this intricate protein-protein interaction have now been accomplished. Most of the current knowledge on the IgE-FcepsilonRI recognition mode derives from long-lasting efforts in the field of structural biology. Protein engineering, high-throughput screening, immunological and biochemical studies also made relevant contributions in this domain. The data accumulated to date predict that IgE and FcepsilonRI use their modular architecture to approach each other in an asymmetric stepwise manner determining a 1:1 stoichiometry. This recognition appears to be enhanced by conformational changes occurring upon binding, leading to the well-known high-affinity. In conclusion, the vast amount of high-quality data available broadened our knowledge on the IgE-FcepsilonRI system; however, the fine structural details of the recognition process are still largely hypothetical. More studies are necessary to provide the experimental comprehensive picture required to carefully design efficient drugs acting at the IgE-FcepsilonRI interface.

Binding Sites↗
PubMed2006

Efficacy of psychoeducational approaches on bipolar disorders: a review of the literature.

BACKGROUND: To evaluate the efficacy of psychoeducation in the treatment of bipolar disorder according to specific therapeutic targets such as treatment compliance, patients' and families' knowledge of the illness and its treatments, relapse prevention, symptomatic (depressive or (hypo)manic) phases of the illness or social and occupational functioning. METHODS: A systematic review of the literature published on psychoeducation up to July 2006 was carried out using the main electronic data bases (Medline, PubMed). The key words employed included bipolar disorder, psychoeducation, depression, mania, relapse prevention and treatment compliance. RESULTS: Although the methodological shortcomings of the early studies must be taken into account, most data accumulated to date suggest that psychoeducation, used alone or as a component of more complex interventions, makes it possible to improve the course of the illness, notably by increasing the patients' and their families' knowledge of the disorder and of treatment options, by decreasing the risk of (hypo)manic or depressive relapse and of hospitalization and by improving treatment compliance. LIMITATIONS: More studies based solely on psychoeducation, rather than psychoeducation as part of a multicomponent approach, are needed to confirm the efficacy of PE reported to date. CONCLUSIONS: Given the results published to date, psychoeducation should be part of the integrated treatment of bipolar disorder. As a complement to pharmacotherapy, psychoeducation delivered individually or in a group setting constitutes a first-line psychological intervention. Applicable to a majority of patients and their families, it can be delivered by a wide range of health professionals trained in this approach.

Bipolar Disorder↗
PubMedDate not supplied

In vitro testing of antibiotics.

To enhance knowledge in the area of in vitro testing of antibiotics and to understand the limitations of available methods for susceptibility testing, we conducted a MEDLINE literature search in the English language to accumulate relevant articles. Headings searched included microbial sensitivity tests; Kirby-Bauer; laboratory tests; antiinfective agents; antibiotics, combined; microbiological techniques; blood bactericidal assay; and pharmacology, clinical. The management of patients with serious life-threatening infections can be complicated by recent changes in organism nomenclature, newly marketed antibiotics, and new isolation and sensitivity testing methods. With the addition of formulary constraints, many problems and controversies arise regarding interpretation of antibiotic sensitivity results. Comprehensive care for infected patients requires assessment of current antibiotic therapy and options for alternative therapy. By applying pharmacodynamic and pharmacokinetic knowledge to known limits of in vitro testing results, the clinician is able to select the most efficient antibiotic or antibiotic combination.

Anti-Bacterial Agents↗
PubMed2000

Targeted deletion of matrix metalloproteinase-9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infarction.

Matrix metalloproteinase-9 (MMP-9) is prominently overexpressed after myocardial infarction (MI). We tested the hypothesis that mice with targeted deletion of MMP9 have less left ventricular (LV) dilation after experimental MI than do sibling wild-type (WT) mice. Animals that survived ligation of the left coronary artery underwent echocardiographic studies after MI; all analyses were performed without knowledge of mouse genotype. By day 8, MMP9 knockout (KO) mice had significantly smaller increases in end-diastolic and end-systolic ventricular dimensions at both midpapillary and apical levels, compared with infarcted WT mice; these differences persisted at 15 days after MI. MMP-9 KO mice had less collagen accumulation in the infarcted area than did WT mice, and they showed enhanced expression of MMP-2, MMP-13, and TIMP-1 and a reduced number of macrophages. We conclude that targeted deletion of the MMP9 gene attenuates LV dilation after experimental MI in mice. The decrease in collagen accumulation and the enhanced expression of other MMPs suggest that MMP-9 plays a prominent role in extracellular matrix remodeling after MI.

Animals↗
PubMed1994

Toxicology and seafood toxins: domoic acid.

Marine and terrestrial food sources are susceptible to contamination by various industrial chemicals and microbial pathogens. Both types of hazard are amenable to regulatory assessment using a single toxicology data base, along with some knowledge of contaminant levels and consumption figures for food. On the other hand, regulatory problems persist with acutely toxic naturally occurring phycotoxins, which may accumulate unpredictably to toxic levels in seafood. However, a scarce supply of pure toxin often precludes the availability of acceptable toxicology studies describing their biological effects. An exception to this situation is domoic acid, a neurotoxin phycotoxin that produced numerous cases of severe human intoxication which demanded extensive toxicological study. This paper describes a series of ongoing studies initiated in the wake of the outbreak of domoic acid toxicity that occurred in 1987 in Eastern Canada.

Animals↗
PubMed2003

Remodelling of the host cell RNA splicing machinery during an adenovirus infection.

Adenovirus makes extensive use of RNA splicing to produce a complex set of spliced mRNAs during virus replication. All transcription units, except pIX and IVa2, encode multiple alternatively spliced mRNAs. The accumulation of viral mRNAs is subjected to a temporal regulation, a mechanism that ensures that proteins that are needed at certain stages of the viral life cycle are produced. The complex interaction between host cell RNA splicing factors and viral regulatory elements has been studied intensely during the last decade. Such studies have begun to produce a picture of how adenovirus remodels the host cell RNA splicing machinery to orchestrate the shift from the early to the late profile of viral mRNA accumulation. Recent progress has to a large extent focused on the mechanisms regulating E1A and L1 alternative splicing. Here we will review the current knowledge of cis-acting sequence element, trans-acting factors and mechanisms controlling E1A and L1 alternative splicing.

Adenoviridae Infections↗
PubMed2005

Analysis of activated EGFR signalling pathways and their relation to laminin-5 gamma2 chain expression in oral squamous cell carcinoma (OSCC).

Overexpression of epidermal growth factor receptor (EGFR) was shown for the majority of squamous cell carcinomas. The EGFR expression correlates to tumour size, stage and cytoplasmic accumulation of the laminin-5 gamma2 chain (Ln-5/gamma2), which is known as a marker of invading tumour cells. There is only limited knowledge if and how EGFR signalling pathways are important for invasion-associated processes and for the regulation of Ln-5/gamma2. Therefore the distribution of phosphorylated Erk1/2, p38 MAPK and Akt was immunohistochemically defined in oral squamous cell carcinoma (OSCC) of different histological grade and compared to histological criteria of invasion and cytoplasmic Ln-5/gamma2 deposition. With raising histological grade, there is a slight increase in nuclear pErk1/2-stained tumour cells (P=0.398) and a loss of nuclear (P=0.593) and increased cytoplasmic staining (P=0.144) of pAkt mainly in invading OSCC cells. Nuclear pp38 MAPK could only be sporadically detected in few cases. In case of pErk1/2 and pAkt, only a partial co-localisation could be revealed in cases with abundant kinases and Ln-5/gamma2. Among the investigated kinases, only pAkt shows a relation to histological grade and invasion in OSCC. pErk1/2, pp38 MAPK and pAkt do not represent a direct link between EGFR and Ln-5 synthesis. Therefore, enhanced Ln-5/gamma2 may be a secondary phenomenon of EGFR-induced tumour cell proliferation and dissemination.

Biomarkers, Tumor↗