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At least 865 records · Page 48Linked to original sources
PubMed2004

Prevention pathways: application of the critical path methodology in occupational health services.

Occupational health services face important changes as a result of changes in work environment, changing health and safety concepts, and legislation. To ensure good quality at a good price, it is important to control the processes in occupational health services. The concept of "prevention pathways" is presented for the management of occupational health services. The model is based on the critical pathway concept. The approach is illustrated by means of a case study performed in a Belgian occupational health service. A prevention pathway for the evaluation of chemical risks at the workplace was constructed. The prevention pathway methodology revealed inefficiencies and quality problems in the current practice of chemical risk assessment and biomonitoring. The case shows how prevention pathways can be used to pilot the members of a multidisciplinary team by focusing on a specific occupational risk.

Accidents, Occupational↗
PubMed1999

Loss of a gp130 cardiac muscle cell survival pathway is a critical event in the onset of heart failure during biomechanical stress.

Biomechanical stress is a major stimulus for cardiac hypertrophy and the transition to heart failure. By generating mice that harbor a ventricular restricted knockout of the gp130 cytokine receptor via Cre-IoxP-mediated recombination, we demonstrate a critical role for a gp130-dependent myocyte survival pathway in the transition to heart failure. Such conditional mutant mice have normal cardiac structure and function, but during aortic pressure overload, these mice display rapid onset of dilated cardiomyopathy and massive induction of myocyte apoptosis versus the control mice that exhibit compensatory hypertrophy. Thus, cardiac myocyte apoptosis is a critical point in the transition between compensatory cardiac hypertrophy and heart failure. gp130-dependent cytokines may represent a novel therapeutic strategy for preventing in vivo heart failure.

Animals↗
PubMed1999

Antidromic reciprocating tachycardia in patients with paraseptal accessory pathways: importance of critical delay in the reentry circuit.

Previous studies in patients with antidromic reciprocating tachycardia (ART) have observed a critical anatomic requirement (> 4 cm) between an antegrade bypass tract limb and a retrograde AV nodal limb. We report two patients with ART utilizing a paraseptal accessory pathway. In both cases, a critical degree of slow conduction within the circuit provides unusual electrophysiologic substrate to overcome the expected anatomical constraints.

Adult↗
PubMed2001

The p38 mitogen-activated protein kinase pathway plays a critical role in thrombin-induced endothelial chemokine production and leukocyte recruitment.

Thrombin, the terminal serine protease in the coagulation cascade, is a proinflammatory molecule in vivo and induces endothelial activation in vitro. The cellular signaling mechanisms involved in this function are unknown. The role of the p38 mitogen-activated protein kinase (MAPK) signaling pathway in thrombin-induced chemokine production was studied. Phosphorylation of both p38 MAPK and its substrate, ATF-2, was observed in human umbilical vein endothelial cells (HUVECs) stimulated with thrombin, with a maximum after 5 minutes of stimulation. Using the selective p38 MAPK inhibitor SB203580, there was a significant decrease in thrombin-induced interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1) protein production and messenger RNA steady-state levels. In addition, SB203580 decreased IL-8 and MCP-1 production induced by the thrombin receptor-1 agonist peptide (TRAP), suggesting functional links between the thrombin G protein-coupled receptor and the p38 MAPK pathway. Furthermore, endothelial activation in the presence of SB203580 decreased the chemotactic activity of thrombin-stimulated HUVEC supernatant on neutrophils and monocytic cells. In contrast, the p42/p44 MAPK pathway did not appear to be involved in thrombin- or TRAP-induced endothelial chemokine production, because there was no reduction in the presence of the p42/p44-specific inhibitor PD98059. These results demonstrate that the p38 rather than p42/44 MAPK signaling pathway plays an important role in thrombin-induced endothelial proinflammatory activation and suggest that inhibition of p38 MAPK may be an interesting target for anti-inflammatory strategies in vascular diseases combining thrombosis and inflammation. (Blood. 2001;98:667-673)

Cells, Cultured↗
PubMed2005

Phosphatidylinositol 3-kinase-Akt pathway plays a critical role in early cardiomyogenesis by regulating canonical Wnt signaling.

We have recently reported that activation of phosphatidylinositol 3-kinase (PI3K) plays a critical role in the early stage of cardiomyocyte differentiation of P19CL6 cells. We here examined molecular mechanisms of how PI3K is involved in cardiomyocyte differentiation. DNA chip analysis revealed that expression levels of Wnt-3a were markedly increased and that the Wnt/beta-catenin pathway was activated temporally during the early stage of cardiomyocyte differentiation of P19CL6 cells. Activation of the Wnt/beta-catenin pathway during this period was required and sufficient for cardiomyocyte differentiation of P19CL6 cells. Inhibition of the PI3K/Akt pathway suppressed the Wnt/beta-catenin pathway by activation of glycogen synthase kinase-3beta (GSK-3beta) and degradation of beta-catenin. Suppression of cardiomyocyte differentiation by inhibiting the PI3K/Akt pathway was rescued by forced expression of a nonphosphorylated, constitutively active form of beta-catenin. These results suggest that the PI3K pathway regulates cardiomyocyte differentiation through suppressing the GSK-3beta activity and maintaining the Wnt/beta-catenin activity.

Animals↗
PubMed2000

The phosphoinositide 3-OH kinase/AKT2 pathway as a critical target for farnesyltransferase inhibitor-induced apoptosis.

Farnesyltransferase inhibitors (FTIs) represent a novel class of anticancer drugs that exhibit a remarkable ability to inhibit malignant transformation without toxicity to normal cells. However, the mechanism by which FTIs inhibit tumor growth is not well understood. Here, we demonstrate that FTI-277 inhibits phosphatidylinositol 3-OH kinase (PI 3-kinase)/AKT2-mediated growth factor- and adhesion-dependent survival pathways and induces apoptosis in human cancer cells that overexpress AKT2. Furthermore, overexpression of AKT2, but not oncogenic H-Ras, sensitizes NIH 3T3 cells to FTI-277, and a high serum level prevents FTI-277-induced apoptosis in H-Ras- but not AKT2-transformed NIH 3T3 cells. A constitutively active form of AKT2 rescues human cancer cells from FTI-277-induced apoptosis. FTI-277 inhibits insulin-like growth factor 1-induced PI 3-kinase and AKT2 activation and subsequent phosphorylation of the proapoptotic protein BAD. Integrin-dependent activation of AKT2 is also blocked by FTI-277. Thus, a mechanism for FTI inhibition of human tumor growth is by inducing apoptosis through inhibition of PI 3-kinase/AKT2-mediated cell survival and adhesion pathway.

Alkyl and Aryl Transferases↗
PubMed2000

Regular articles: conditional disruption of hedgehog signaling pathway defines its critical role in hair development and regeneration.

Members of the vertebrate hedgehog family (Sonic, Indian, and Desert) have been shown to be essential for the development of various organ systems, including neural, somite, limb, skeletal, and for male gonad morphogenesis. Sonic hedgehog and its cognate receptor Patched are expressed in the epithelial and/or mesenchymal cell components of the hair follicle. Recent studies have demonstrated an essential role for this pathway in hair development in the skin of Sonic hedgehog null embryos. We have further explored the role of the hedgehog pathway using anti-hedgehog blocking monoclonal antibodies to treat pregnant mice at different stages of gestation and have generated viable offspring that lack body coat hair. Histologic analysis revealed the presence of ectodermal placode and primodium of dermal papilla in these mice, yet the subsequent hair shaft formation was inhibited. In contrast, the vibrissae (whisker) development appears to be unaffected upon anti-hedgehog blocking monoclonal antibody treatment. Strikingly, inhibition of body coat hair morphogenesis also was observed in mice treated postnatally with anti-hedgehog monoclonal antibody during the growing (anagen) phase of the hair cycle. The hairless phenotype was reversible upon suspension of monoclonal antibody treatment. Taken together, our results underscore a direct role of the Sonic hedgehog signaling pathway in embryonic hair follicle development as well as in subsequent hair cycles in young and adult mice. Our system of generating an inducible and reversible hairless phenotype by anti-hedgehog monoclonal antibody treatment will be valuable for studying the regulation and mechanism of hair regeneration.

Animals↗
PubMed2006

Upregulated transcription of plasmid and chromosomal ribulose monophosphate pathway genes is critical for methanol assimilation rate and methanol tolerance in the methylotrophic bacterium Bacillus methanolicus.

The natural plasmid pBM19 carries the key mdh gene needed for the oxidation of methanol into formaldehyde by Bacillus methanolicus. Five more genes, glpX, fba, tkt, pfk, and rpe, with deduced roles in the cell primary metabolism, are also located on this plasmid. By using real-time PCR, we show that they are transcriptionally upregulated (6- to 40-fold) in cells utilizing methanol; a similar induction was shown for two chromosomal genes, hps and phi. These seven genes are involved in the fructose bisphosphate aldolase/sedoheptulose bisphosphatase variant of the ribulose monophosphate (RuMP) pathway for formaldehyde assimilation. Curing of pBM19 causes higher methanol tolerance and reduced formaldehyde tolerance, and the methanol tolerance is reversed to wild-type levels by reintroducing mdh. Thus, the RuMP pathway is needed to detoxify the formaldehyde produced by the methanol dehydrogenase-mediated conversion of methanol, and the in vivo transcription levels of mdh and the RuMP pathway genes reflect the methanol tolerance level of the cells. The transcriptional inducer of hps and phi genes is formaldehyde, and not methanol, and introduction of multiple copies of these two genes into B. methanolicus made the cells more tolerant of growth on high methanol concentrations. The recombinant strain also had a significantly higher specific growth rate on methanol than the wild type. While pBM19 is critical for growth on methanol and important for formaldehyde detoxification, the maintenance of this plasmid represents a burden for B. methanolicus when growing on mannitol. Our data contribute to a new and fundamental understanding of the regulation of B. methanolicus methylotrophy.

Alcohol Oxidoreductases↗
PubMed2001

Lipid metabolism in the heart--contribution of BMIPP to the diseased heart.

Lipid contributes greatly in cardiac metabolism to produce high energy ATPs, and is suggested to be related to the progression and deterioration of heart disease. It is fortunate that the I-123-betamethyliodophenylpentadecanoic acid (BMIPP) imaging technique is now available in determining heart condition, but we must be cautious about the interpretation of images obtained with this new tracer. From the uptake of BMIPP into the cell to breakdown and catabolism of it, there exist so many critical enzymatical pathways relating to the modification of BMIPP imaging. In clinical evaluation, the image will be translated as the integral effects of these pathways. In other words, we must be aware of these critical pathways regulating lipid metabolism and modifying factors in order to correctly understand BMIPP imaging. Lipid transport is affected by the albumin/FFA ratio in the blood, and extraction with membrane transporter proteins. Fatty acid binding protein (FABP) in the cytosole will play an important role in regulating lipid flux and following metabolism. Lipid will be utilized either for oxidation, triglyceride or phospholipid formation. For oxidation, carnitine palmitoil transferase is the key enzyme for the entrance of lipid into mitochondria, and oxidative enzymes such as acyl CoA dehydrogenase (MCAD, LCAD, HAD) will determine lipid use for the TCA cycle. ATPs produced in the mitochondria again limit the TG store. It is well known that BMIPP imaging completely changes in the ischemic condition, and is also shown that lipid metabolical regulation completely differs from normal in the very early phase of cardiac hypertrophy. In the process of deteriorating heart failure, metabolical switching of lipid with glucose will take place. In such a different heart disease conditions, it is clear that lipid metabolical regulation, including many lipid enzymes, works differently from in the healthy condition. These lipid enzymes are regulated by nuclear factor peroxisome proliferator-activated receptors (PPAR) just like a conductor of an orchestra. Most of the regulating mechanisms of the PPAR are still unknown, but reduction of this nuclear factor is shown in the process of decompensated heart failure. This review is based by mostly on our fundamental and Japanese clinical data. BMIPP has been used clinically in abundant cases in Japan. In such situations, further correct information on lipid metabolism, including BMIPP, will contribute to the understanding of deteriorating heart disease and its prognosis.

Animals↗
PubMed2002

Fas pathway is a critical mediator of cardiac myocyte death and MI during ischemia-reperfusion in vivo.

Fas is a widely expressed cell surface receptor that can initiate apoptosis when activated by its ligand (FasL). Whereas Fas abundance on cardiac myocytes increases in response to multiple pathological stimuli, direct evidence supporting its role in the pathogenesis of heart disease is lacking. Moreover, controversy exists even as to whether Fas activation induces apoptosis in cardiac myocytes. In this study, we show that adenoviral overexpression of FasL, but not beta-galactosidase, results in marked apoptosis both in cultures of primary neonatal cardiac myocytes and in the myocardium of intact adult rats. Myocyte killing by FasL is a specific event, because it does not occur in lpr (lymphoproliferative) mice that lack functional Fas. To assess the contribution of the Fas pathway to myocardial infarction (MI) in vivo, lpr mice were subjected to 30 min of ischemia followed by 24 h of reperfusion. Compared with wild-type mice, lpr mice exhibited infarcts that were 62.3% smaller with 63.8% less myocyte apoptosis. These data provide direct evidence that activation of Fas can induce apoptosis in cardiac myocytes and that Fas is a critical mediator of MI due to ischemia-reperfusion in vivo.

Animals↗
PubMed2000

The phosphatidylinositol 3-kinase/AKT signal transduction pathway plays a critical role in the expression of p21WAF1/CIP1/SDI1 induced by cisplatin and paclitaxel.

The cyclin-dependent kinase inhibitor p21WAF1/CIP1/SD11 (p21) plays a crucial role in DNA repair, cell differentiation, and apoptosis through regulation of the cell cycle. A2780 human ovarian carcinoma cells, which are sensitive to cisplatin and paclitaxel, express wild-type p53 and exhibit a p53-mediated increase in p21 in response to the chemotherapeutic agents. Here, we demonstrate that phosphatidylinositol 3-kinase (PI3K) and its downstream targets serine/threonine kinases AKT1 and AKT2 (AKT), are required for the full induction of p21 in A2780 cells treated with cisplatin or paclitaxel. Inactivation of the PI3K/AKT signal transduction pathway either by its specific inhibitor LY294002 or by expression of dominant negative AKT inhibited p21 expression but had no inhibitory effect on the expression of the proapoptotic protein BAX by cisplatin and paclitaxel treatment. In addition, overexpression of wild-type or constitutively active AKT in A2780 cells sustained the regulation of p21 induction or increased the level of p21 expression, respectively. Experiments with additional ovarian carcinoma cell lines revealed that PI3K is involved in the expression of p21 induced by cisplatin or paclitaxel in OVCAR-10 cells, which have wild-type p53, but not in OVCAR-5 cells, which lack functional p53. These data indicate that the PI3K/AKT signal transduction pathway mediates p21 expression and suggest that this pathway contributes to cell cycle regulation promoted by p53 in response to drug-induced stress. However, inactivation of PI3K/AKT signaling did not result in significant alteration of the drug sensitivity of A2780 cells, suggesting that the cell death induced by cisplatin or paclitaxel proceeds independently of cell protective effects of PI3K and AKT.

Antineoplastic Agents↗
PubMed2006

The sequence-dependent unfolding pathway plays a critical role in the amyloidogenicity of transthyretin.

Human transthyretin (TTR) is an amyloidogenic protein whose aggregation is associated with several types of amyloid diseases. The following mechanism of TTR amyloid formation has been proposed. TTR tetramer at first dissociates into native monomers, which is the rate-limiting step in fibril formation. The monomeric species then partially unfold to form amyloidogenic intermediates that subsequently undergo a downhill self-assembly process. The amyloid deposit can be facilitated by disease-associated point mutations. However, only subtle structural differences were observed between the crystal structures of the wild type and the disease-associated variants. To investigate how single-point mutations influence the effective energy landscapes of TTR monomers, molecular dynamics (MD) simulations were performed on wild-type TTR and two pathogenic variants. Principal coordinate analysis on MD-generated ensembles has revealed multiple unfolding pathways for each protein. Amyloidogenic intermediates with the dislocated C strand-loop-D strand motif were observed only on the unfolding pathways of V30M and L55P variants and not for wild-type TTR. Our study suggests that the sequence-dependent unfolding pathway plays a crucial role in the amyloidogenicity of TTR. Analyses of side chain concerted motions indicate that pathogenic mutations on "edge strands" disrupt the delicate side chain correlated motions, which in turn may alter the sequence of unfolding events.

Amyloid↗
PubMed1994

An IFN-gamma-dependent pathway plays a critical role in the pathogenesis of murine immunodeficiency syndrome induced by LP-BM5 murine leukemia virus.

The murine acquired immunodeficiency syndrome (MAIDS) caused by a defective murine leukemia virus produces severe immunodeficiency with abnormal lymphoproliferation and hypergammaglobulinemia. The presence of both CD4+ T cells and B cells is critical for the development of this disease. Remarkably elevated mRNA expression for IFN-gamma and IL-10 was observed in spleen cells of C57BL/6 mice starting from the early phase of viral infection. IFN-gamma production was induced by spleen cells from virus-infected mice upon stimulation with concanavalin A or lipopolysaccharide in both the early and late phases of MAIDS progression. When mice that had been passively administered anti-IFN-gamma mAb were infected with the virus, the development and progression of lymphadenopathy, immunodeficiency and elevated levels of serum IgG2a associated with MAIDS were delayed. Treatment with anti-IL-4 or anti-IL-10 mAb in place of anti-IFN-gamma mAb did not induce the delayed progression of MAIDS. These data support the concept that IFN-gamma-dependent pathway may be involved in the development of MAIDS.

Animals↗
PubMed1993

ICAM-1-dependent pathway is not critically involved in the inflammatory process of autoimmune encephalomyelitis or in cytokine-induced inflammation of the central nervous system.

To determine whether the rat homolog of intercellular adhesion molecule 1 (ICAM-1) plays an important role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) we examined the effect of anti-ICAM-1 mAb, 1A29, on both active and passive EAE. We also examined its effect on a model of cytokine-induced inflammation in the central nervous system. Treatment of recipients of EAE effector cells with anti-ICAM-1 had no inhibitory activity, and in fact at high doses, treatment enhanced disease as evidenced by an earlier onset of symptoms. Treatment of active EAE with anti-ICAM-1 beginning on the day of sensitization did protect a proportion of animals from development of disease as well as reduce the severity of clinical signs in those which developed symptoms. Lymphocytes from both the draining lymph nodes and spleens of myelin basic protein (MBP)-immunized rats treated with anti-ICAM-1 failed to proliferate in response to MBP in vitro, suggesting that the antibody had prevented the animals from becoming sensitized to the antigen. Microinjection of tumor necrosis factor (TNF)-alpha into the spinal cords of rats led to the expression of ICAM-1 on vascular endothelium, and to the accumulation of leukocytes at sites of injection. The peak expression of ICAM-1 by endothelium and the peak accumulation of leukocytes following TNF alpha injection were not positively correlated. Furthermore, treatment of TNF alpha injected rats with anti-ICAM-1 did not inhibit the accumulation of leukocytes at the site of cytokine injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1982

Monitoring the critical radiation exposure pathways at a BWR nuclear power station.

Iodine-131 in milk and gamma radiation from radionuclides in air in the environment of a 3-unit nuclear power station were measured at the levels predicted for airborne effluent. These measurements were part of a modified environmental radiological monitoring program to confirm the population doses computed from radionuclide release rates and environmental transfer models. The limits of detection were lowered relative to conventional monitoring programs by analyzing 21 L samples of milk for 131I and by determining external gamma radiation with a system that combined use of thermoluminescent dosimeters, pressurized ionization chambers, and NaI(T1) survey meters. For monitoring periods slightly longer than 6 months, during a time when fallout from atmospheric nuclear tests contributed very little, the average measured 131I concentration in milk was 0.1 pCi/L for cows on a nearby pasture and 0.02 pCi/L for cows at a more distant control location, compared to predicted values of 0.07 and 0.02 pCi/L, respectively; the average radiation exposure from airborne radionuclides measured at 16 nearby dosimeter locations was 7 mR, compared to the average of predicted values of 4 mR.

Animals↗