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At least 361 records · Page 20Linked to original sources
PubMed2002

Post-transcriptional down-regulation of ROCKI/Rho-kinase through an MEK-dependent pathway leads to cytoskeleton disruption in Ras-transformed fibroblasts.

Transformation by oncogenic Ras profoundly alters actin cytoskeleton organization. We investigated Ras-dependent signaling pathways involved in cytoskeleton disruption by transfecting normal rat kidney (NRK) cells with different Ras mutants. RasV12S35, a mutant known to activate specifically the Raf/MAPK pathway, led to stress fiber and focal contact disruption, whereas the adherens junctions remained intact. Next, we found that pharmacological inhibition of MEK was sufficient to restore the cytoskeletal defects of ras-transformed NRK cells, including assembly of stress fibers and focal contacts, but it did not induce reorganization of the cell-cell junctions. Investigating the mechanism underlying this phenotypic reversion, we found that the sustained MAPK signaling resulting from Ras-transformation down-regulated the expression of ROCKI and Rho-kinase, two-Rho effectors required for stress fiber formation, at the post-transcriptional level. On MEK inhibition, ROCKI/Rho-kinase expression and cofilin phosphorylation were increased, demonstrating that the Rho-kinase/LIM-kinase/cofilin pathway was functionally restored. Finally, using dominant negative or constitutively active mutants, we demonstrated that expression of ROCKI/Rho-kinase was both necessary and sufficient to promote cytoskeleton reorganization in NRK/ras cells. These findings further establish the Ras/MAPK pathway as the critical pathway involved in cytoskeleton disruption during Ras-transformation, and they suggest a new mechanism, involving alteration in ROCKI/Rho-kinase expression, by which oncogenic Ras can specifically target the actin-based cytoskeleton and achieve morphological transformation of the cells.

Actin Cytoskeleton↗
PubMedDate not supplied

Case management of chronic ventilator patients. Reduce average length of stay and cost by half.

The implementation of the case management model and the use of critical pathways has become a major strategy to improve quality of care and cope with measuring and managing costs. Grant Medical Center, a 640-bed Level I Trauma Center, began case managing its chronic ventilator patients in July, 1993. A 30-day critical pathway was developed using a multidisciplinary team approach. In case managing these patients, many problematic issues were identified, such as lack of adequate involvement by staff experienced in specific disciplines and multiple physician decision makers for each case. By increasing multidisciplinary collaboration, care of these patients was systematically changed and streamlined. Over a 2-year period, the average length of stay for chronic ventilator patients decreased from 74.5 days to 41.9 days, and the average cost per case decreased from $189,080 to $107,019.

Case Management↗
PubMed1996

Wound care nurses' judgements on healing time in chronic wounds.

With the current push to develop critical pathways for chronic wound patients, information on "normal" versus problematic wound healing is important. This descriptive study begins to define chronic wound healing time markers by examining clinicians' own healing expectations with pressure ulcers. A 30-item questionnaire concerning partial and full thickness pressure ulcers on the sacrum, trochanter and heel was sent to 272 wound/ET nurses. Total response rate was 32.3% with 74 analyzable questionnaires returned. Data was analyzed using descriptive statistics and correlations where appropriate. Results were: (1) The longer respondents thought it would take for wounds to heal, the more variable their responses. (2) Respondents viewed heel wounds as taking the longest to heal and were more certain about time to healing in sacral wounds. (3) Responses indicated longer healing times than those shown in recent studies looking at change in wound surface area. (4) Results on time of 3.2 weeks to autolytic debridement of wounds with black eschar does not differ greatly from published time for enzymatic debridement, in spite of guidelines stating that autolysis may take longer than other methods. This study demonstrates that there remains variability in wound nurses' perceptions of time to healing and, therefore, recent attempts at defining critical pathways may be premature.

Critical Pathways↗
PubMed1996

Same day surgery for radical retropubic prostatectomy: is it an attainable goal?

OBJECTIVES: Economic forces are stimulating a re-evaluation of various management strategies. Recent critical pathways for radical prostatectomy have resulted in reduced length of stay to as low as 2.9 days. METHODS: The time in the operating room and recovery room, average blood loss, length of hospitalization, patient charges, and estimated hospital costs were compared for 20 patients undergoing radical prostatectomy up to 1 year before and for 27 men after initiation of a critical pathway. Under the protocol, patients receive an education booklet and preoperative teaching in preparation for early discharge and an epidural for anesthesia. An anonymous questionnaire was mailed to all patients treated by the pathway after catheter removal. RESULTS: The new pathway resulted in a significant reduction in average time in the operating room (3.7 +/- 0.4 hours versus 4.9 +/- 1.2 hours), estimated blood loss (1204 +/- 527 cc versus 1948 +/- 740 cc), and length of hospitalization (1.7 +/- 0.6 days versus 4.6 +/- 1.5 days). In addition, patient charges and hospital costs were reduced by 32% and 35%, respectively. Thirty-seven percent of the study group was discharged after 1 night compared with 0% in the group treated before the pathway was initiated. Forty-one percent of the study group was not transfused and did not donate blood. Outcome surveys completed by 25 of 27 study patients revealed an overall satisfaction of 96% with 0 of 10 patients who were discharged after one night indicating they would have preferred to be hospitalized longer. CONCLUSIONS: Conventional management of men undergoing radical prostatectomy can be safely modified while preserving patient satisfaction without increasing morbidity. Avoiding peripheral narcotics and emphasizing preoperative teaching has enabled us to reduce length of stay greatly, with same day discharge now an attainable goal.

Adult↗
PubMed1996

Safety and cost-efficiency of 24-hour hospitalization for carotid endarterectomy.

The safety and cost savings of carotid endarterectomy (CEA) were determined with guidelines developed after vascular "critical pathways" were implemented. Using these guidelines, our goal was to admit patients the day of surgery and to discharge them the next morning. Morbidity, mortality, readmission rates, same-day admissions, duration of stay, and hospital costs were compared between patients undergoing CEA who were electively admitted between September 1, 1992 and August 31, 1993 (group 1) and January 1, 1994 and March 31, 1995 (group 2). Between these two time periods, vascular critical pathways were instituted and all preoperative examinations were performed on an outpatient basis. The majority of CEAs were performed with the patient under general anesthesia. We found no significant differences between group 2 (n = 68) vs. group 1 (n = 40) in terms of mortality (1.5% [1 of 68] vs. 2.5% [1 of 40]), cardiac events (2.9% [2 of 68] vs. 2.5% [1 of 40]), neurologic events (2.9% [2 of 68] vs. 2.5% [1 of 40]), or readmission rate (1.5% [1 of 68] vs. 0% [0 of 40]). Same-day admissions were significantly higher (94% [64 of 68] vs. 5% [2 of 40]; p < 0.0001), and average duration of stay was significantly lower (1.3 vs. 5.1 days; p < 0.0001) in group 2 vs. group 1, respectively. Hospital charges were decreased by $5510 per patient in group 2. We conclude that hospital costs can be significantly reduced for most patients undergoing CEA when they are admitted on the day of surgery and discharged the following morning, with no negative impact on morbidity and mortality.

Aged↗
PubMed1981

Problems in evaluating radiation dose via terrestrial and aquatic pathways.

This review is concerned with exposure risk and the environmental pathways models used for predictive assessment of radiation dose. Exposure factors, the adequacy of available data, and the model subcomponents are critically reviewed from the standpoint of absolute error propagation. Although the models are inherently capable of better absolute accuracy, a calculated dose is usually overestimated by from two to six orders of magnitude, in practice. The principal reason for so large an error lies in using "generic" concentration ratios in situations where site specific data are needed. Major opinion of the model makers suggests a number midway between these extremes, with only a small likelihood of ever underestimating the radiation dose. Detailed evaluations are made of source considerations influencing dose (i.e., physical and chemical status of released material); dispersal mechanisms (atmospheric, hydrologic and biotic vector transport); mobilization and uptake mechanisms (i.e., chemical and other factors affecting the biological availability of radioelements); and critical pathways. Examples are shown of confounding in food-chain pathways, due to uncritical application of concentration ratios. Current thoughts of replacing the critical pathways approach to calculating dose with comprehensive model calculations are also shown to be ill-advised, given present limitations in the comprehensive data base. The pathways models may also require improved parametrization, as they are not at present structured adequately to lend themselves to validation. The extremely wide errors associated with predicting exposure stand in striking contrast to the error range associated with the extrapolation of animal effects data to the human being.

Animals↗
PubMed2003

Obstacles for shortening hospitalization after video-assisted pulmonary resection for lung cancer.

BACKGROUND: Video-assisted thoracic surgery for lung cancer facilitates early postoperative recovery when patients are treated by critical pathway management. Thus, we developed an original programmed regimen for postoperative management, evaluated the validity of this regimen, and analyzed clinical factors influencing postoperative recovery. METHODS: Forty consecutive patients with suspicious lung cancer undergoing anatomic pulmonary resection with video-assisted thoracic surgery were enrolled in this prospective study. After surgery, all patients who underwent anatomic resection were managed using our programmed regimen; a patient was considered recovered when the regimen had been completed. RESULTS: On final pathologic examination, 37 cases were determined to have lung cancer and underwent anatomic resection. The mean number of resected segments was 3.6. There were no complications caused by postoperative management. The mean day of postoperative recovery was 3.7 days and median, 3 days. Significant preoperative factors related to recovery were age, breathlessness, performance status, radiologic emphysema, partial pressure of arterial oxygen, and predictive postoperative forced expiratory volume in 1 second. The overall number of these risk factors was specifically related to postoperative recovery (p < 0.01): the rate of recovery on postoperative day 3 was 100% in patients with no risk, 68% in those with one to three risks, and 22% in those with four to six risks. CONCLUSIONS: Our original regimen is useful as a critical pathway for the management of lung cancer patients undergoing video-assisted thoracic surgery. Furthermore, we created specific criteria to identify risk factors related to postoperative recovery that may be useful in planning hospitalization for patients undergoing video-assisted thoracic surgery.

Aged↗
PubMed2005

The phosphoinositol-3-kinase-protein kinase B/Akt pathway is critical for Pseudomonas aeruginosa strain PAK internalization.

Several Pseudomonas aeruginosa strains are internalized by epithelial cells in vitro and in vivo, but the host pathways usurped by the bacteria to enter nonphagocytic cells are not clearly understood. Here, we report that internalization of strain PAK into epithelial cells triggers and requires activation of phosphatidylinositol 3-kinase (PI3K) and protein kinase B/Akt (Akt). Incubation of Madin-Darby canine kidney (MDCK) or HeLa cells with the PI3K inhibitors LY294002 (LY) or wortmannin abrogated PAK uptake. Addition of the PI3K product phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3] to polarized MDCK cells was sufficient to increase PAK internalization. PtdIns(3,4,5)P3 accumulated at the site of bacterial binding in an LY-dependent manner. Akt phosphorylation correlated with PAK invasion. The specific Akt phosphorylation inhibitor SH-5 inhibited PAK uptake; internalization also was inhibited by small interfering RNA-mediated depletion of Akt phosphorylation. Expression of constitutively active Akt was sufficient to restore invasion when PI3K signaling was inhibited. Together, these results demonstrate that the PI3K signaling pathway is necessary and sufficient for the P. aeruginosa entry and provide the first example of a bacterium that requires Akt for uptake into epithelial cells.

Animals↗
PubMed2000

The Rb-CDK4/6 signaling pathway is critical in neural precursor cell cycle regulation.

The tumor suppressor, retinoblastoma (Rb), is involved in both terminal mitosis and neuronal differentiation. We hypothesized that activation of the Rb pathway would induce cell cycle arrest in primary neural precursor cells, independent of the proposed function of cyclin-dependent kinases 4/6 (CDK4/6) to sequester the CIP/KIP CDK inhibitors (CKIs) p21 and p27 from CDK2. We expressed dominant negative adenovirus mutants of CDKs 2, 4, and 6 (dnCDK2, dnCDK4, and dnCDK6) in neural progenitor cells derived from E12.5 wild type and Rb-deficient mouse embryos. In contrast to previous studies, our results demonstrate that in addition to dnCDK2, the dnCDK4/6 mutants can induce growth arrest. Moreover, the dnCDK4/6-mediated inhibition is Rb-dependent. The dnCDK2 partially inhibited cell growth in Rb-deficient cells, suggesting that CDK2 may have additional targets. A previously proposed function of CDK4/6 is CKI sequestration, thereby preventing the resulting inhibition of CDK2, believed to be the key regulator of cell cycle. However, our immunoprecipitations revealed that the dominant negative CDK mutants could arrest cell growth despite their interaction with p21 and p27. Taken together, our results demonstrate that both CDK2 and CDK4/6 are crucial for cell cycle regulation. Furthermore, our data underscore the importance of the Rb regulatory pathway in neuronal development and cell cycle regulation, independent of CKI sequestration.

Animals↗
PubMed1984

Enkephalinergic-dopaminergic "reward" pathways: a critical substrate for the stimulatory, euphoric and memory-enhancing actions of alcohol--a hypothesis.

Recent evidence indicates that alcohol (ethanol) exerts specific effects on dopaminergic-enkephalinergic neuronal pathways which are involved with natural drive-induction and have also been implicated in reward and memory consolidation. It is proposed herein that the euphorigenic and "paradoxical" memory-enhancing effects of low doses of alcohol are related to its direct actions on this specific brain substrate.

Animals↗
PubMed1995

Putting pressure ulcers on the map.

Critical pathways are effective tools to coordinate care, decrease length of stay, and increase communication among health caregivers. This article presents a critical pathway for pressure ulcer management. The pathway is designed for use in a variety of settings, including acute care, home care, and extended care, to monitor and describe wound status and treatment regimens.

Humans↗
PubMed1995

The ablative techniques from surgery to catheter ablation in the treatment of cardiac arrhythmias : a 20 year experience.

The first European surgical intervention of a Wolff-Parkinson-White syndrome guided by epicardial mapping was performed by C. Cabrol and G. Guiraudon in May 1971 in Paris, in a patient with a type AB syndrome. Experiments had been performed in animal models for six months before its application to the humans, in order to develop the equipment (amplifiers, electrodes and protocols). In December 1971, the same methodology was used to manage one case of post-myocardial infarction ventricular tachycardia. An incision in the diaphragmatic wall of the left ventricle (where the "site of origin" was determined) proved successful. In one patient with VT studied in December 1972, the first detailed sinus rhythm epicardial mapping was performed in 85 test points to describe completely the epicardial activation. This case presented with a left bundle branch block and superimposed trouble of parietal conduction because of an important anteroseptal aneurysm. In May 1973, in a patient with idiopathic dilated cardiomyopathy two transmural incisions at the "site of origin" of ventricular tachycardias proved effective in preventing recurrence of ventricular arrhythmias of two different morphologies. Epicardial delayed potentials were clearly documented. In October 1973 in the 1st case of Arrhythmogenic Right Ventricular Dysplasia, a simple incision made at the site of origin of ventricular tachycardia proved successful to prevent recurrence of the arrhythmia and contributed to the identification of this disease. The endocavitary catheter ablation (fulguration) was discovered in our laboratory in 1979. It was used intentionally for the first time in 1986 in a patient with Wolff-Parkinson-White syndrome with multiple mechanisms of reciprocating tachycardia. His bundle ablation proved clinically effective confirming that it was the elective critical pathway for tachycardia perpetuation. Localization of the site of slow conduction in ventricular tachycardia was important to delineate precisely the VT critical pathway in order to guide radiofrequency and fulguration techniques.

Animals↗
PubMed2006

Complement activation via alternative pathway is critical in the development of laser-induced choroidal neovascularization: role of factor B and factor H.

The objective of this study was to explore the role of classical, lectin, and alternative pathways of complement activation in laser-induced choroidal neovascularization (CNV). The classical and alternative pathways were blocked in C57BL/6 mice by small interfering RNAs (siRNA) directed against C1q and factor B, respectively. C4(-/-) mice developed CNV similar to their wild-type controls and inhibition of C1q by siRNA had no effect on the development of CNV. In contrast, CNV was significantly inhibited (p < 0.001) in C5(-/-) mice and C57BL/6 mice treated with factor B siRNA. Inhibition of the alternative pathway by factor B siRNA resulted in decreased levels of membrane attack complex and angiogenic factors-vascular endothelial growth factor and TGF-beta2. Furthermore, factor B was up-regulated in complement sufficient C57BL/6 mice at day 1 postlaser and remained elevated at day 7. Significantly reduced levels of factor H were observed at day 3 in these animals. In conclusion, our results demonstrate that activation of the factor B-dependent alternative pathway, but not the classical or lectin pathways, was essential for the development of CNV in mouse model of laser-induced CNV. Thus, specific blockade of the alternative pathway may represent a therapeutically relevant strategy for the inhibition of CNV.

Animals↗
PubMed2002

PI3K-FRAP/mTOR pathway is critical for hepatocyte proliferation whereas MEK/ERK supports both proliferation and survival.

Growth factors are known to favor both proliferation and survival of hepatocytes. In this work, we investigated the role of 2 main signaling pathways, phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK), in these processes. First, evidence was provided that the PI3K cascade as well as the MEK/ERK cascade is a key transduction pathway controlling hepatocyte proliferation, as ascertained by arrest of DNA synthesis in the presence of LY294002, a specific PI3K inhibitor. Inhibition of FRAP/mTOR by rapamycin also abrogated DNA replication and protein synthesis induced by growth factor. We showed that expression of cyclin D1 at messenger RNA (mRNA) and protein levels was regulated by this pathway. We highlighted that 4E-BP1 phosphorylation was not activated by epidermal growth factor (EGF) but was under an insulin-regulation mechanism through a PI3K-FRAP/mTOR activation that could account for the permissive role of insulin on hepatocyte proliferation. No interference between the MEK/ERK pathway and 4E-BP1 phosphorylation was detected, whereas p70S6K phosphorylation induced by EGF was under a U0126-sensitive regulation. Last, we established that the antiapoptotic function of EGF was dependent on MEK, whereas LY294002 and rapamycin had no direct effect on cell survival. Taken together, these data highlight the regulation and the role of 2 pathways that mediate growth-related response by acting onto distinct steps. In conclusion, hepatocyte progression in late G1 phase induced by EGF generates survival signals depending on MEK activation, whereas PI3K and MEK/ERK cascades are both necessary for hepatocyte replication.

Animals↗
PubMed1995

Case management. A means to improve quality and control the costs of cure in children with acute myelogenous leukemia.

UNLABELLED: Acute myelogenous leukemia (AML) is a costly disease to treat, as patients experience many hospital stays secondary to chemotherapy, the side effects of treatment, and bone marrow transplantation. The trend for some medical centers has been to reduce costs and increase quality through case management. The case manager uses critical pathways and one-on-one interaction to facilitate the patients' progress through the hospital system and to decrease delays and duplication. CONCLUSION: Case management and critical pathways could become an indispensable tool for the management of pediatric patients with cancer.

Adolescent↗
PubMed1981

Evidence from lesion studies for epileptogenic and non-epileptogenic neurotoxic interactions between kainic acid and excitatory innervation.

The toxicity of kainic acid toward rat hippocampal neurons depends on the presence of specific excitatory afferents. Acute destruction of the critical pathway essentially abolishes the neurotoxicity of intraventricular kainic acid, but some or all hippocampal neurons continue to be destroyed by locally-injected kainic acid until the critical pathway(s) degenerates. These results support the view that kainic acid destroys hippocampal neurons in two ways: (1) by initiating a lethal status epilepticus; and (2) by interacting with certain pathways independently of on-going electrical activity within those pathways.

Afferent Pathways↗
PubMed1993

Presentation of a general algorithm to include secondary poisoning in effect assessment.

A general algorithm for effect assessment on secondary poisoning for birds and mammals is presented. This algorithm (Maximum Permissible Concentration = NOECbird/mammal/BCF) was drawn up by analysing an aquatic food chain (water--fish--bird or mammal) and a terrestrial food chain (soil--worm--bird or mammal). NOECs and bioconcentration factors (BCFs) were collected for a set of selected compounds: lindane, dieldrin, cadmium and mercury in both water and soil, PCB153 only in water and DDT and PCP only in soil. BCFs for the terrestrial pathway are frequently < 1 and rarely above 10, though for the aquatic pathway BCFs up to 10(4) were found for the same compounds. By calculating MPCs for fish-eaters and comparing these to MPCs calculated for aquatic organisms, secondary poisoning could be a critical pathway for methyl-mercury and PCB153. For lindane the conclusion depends on whether a separate or combined data set is chosen for birds and mammals. By calculating MPCs for a standard soil situation and comparing these to MPCs for terrestrial organisms, secondary poisoning could be a critical pathway for cadmium and methyl-mercury.

Algorithms↗