A critical new pathway for toxin secretion?
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Animals↗
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Prospective evaluation of a critical care pathway for clearance of the cervical spine using the bolster and active range-of-motion flexion/extension techniques.
BACKGROUND: Clearance of the cervical spine after blunt trauma remains controversial in patients with normal radiologic evaluation. METHODS: Blunt trauma patients with midline boney cervical tenderness and plain films that disclose no abnormalities and computed tomography (CT) scans were entered into a care pathway for spinal clearance using the Bolster or active range-of-motion (AROM) flexion/extension techniques. The quality of films between the two techniques was then compared. RESULTS: In all, 159 patients entered the pathway with 14 patients (9%) unable to complete the examination secondary to pain. The Bolster was used in 129 patients (89%) and AROM was used in 16 (11%). The total range of motion was significantly better with AROM at 51.4 +/- 19.4 degrees of motion compared with 32.0 +/- 13.0 degrees with the Bolster (p < or = 0.05). The most distal level visualized was not different between groups with 6.6 +/- 0.8 cervical vertebrae visualized on average in the Bolster group and 6.8 +/- 0.7 in the AROM group. Positive findings occurred in five patients (3.4%) in the Bolster group. CONCLUSION: The incidence of occult cervical injury in patients with boney cervical pain despite normal plain films and CT scans in this study was 3.4%. The AROM technique has better total range of motion than the Bolster, although results of the Bolster technique remain within acceptable standards. The present care pathway appears to be an effective screening tool for evaluation of this population of patients. Additional evaluation of the obtunded patient is necessary before broad implementation of this technique.
Adult↗
Science review: key inflammatory and stress pathways in critical illness - the central role of the Toll-like receptors.
A pure reductionist approach can sometimes be used to solve an exceptionally complicated biologic problem, and sepsis is nothing if not complicated. A serious infection promptly leads to changes in many aspects of host physiology, including alterations in circulation, metabolism, renal, hepatic, and neuroendocrine function; all of these changes happen at once, and each influences one another. It is difficult to tease apart a problem of this sort, if only because the systems affected are so profoundly interactive. The key to understanding sepsis, insofar as we do understand it at present, was found in the use of genetic tools to study the very earliest events that take place at the interface of the pathogen and the host. The continued application of both forward and reverse genetic methods, in both mammals and insects, is steadily revealing the central biochemical events that occur during infection.
Animals↗
Translational control via the mammalian target of rapamycin pathway is critical for the formation and stability of long-term fear memory in amygdala neurons.
The mammalian target of rapamycin kinase (mTOR) regulates protein synthesis in neurons at the translational level through phosphorylation of several intracellular targets. Recent work in invertebrates indicates that mTOR-dependent translational control may be critical for the induction and maintenance of activity-dependent synaptic plasticity underlying memory formation. Here, we report that training rats in a simple fear conditioning procedure evokes a time-dependent increase in the phosphorylation of p70s6 kinase, a major direct downstream target of mTOR. When the activation of mTOR was prevented by posttraining injection of rapamycin into the amygdala, formation of the memory and the increase in p70s6 kinase phosphorylation was attenuated. Furthermore, when rapamycin was applied to the amygdala after the recall of a previously stored fear memory, subsequent retention was disrupted, indicating that local translational control at active synapses is required for the stability as well as the formation of long-term memory in this system.
Acoustic Stimulation↗
Linking outcomes analysis to critical clinical pathways.
Expert decision-support soft-ware systems, when integrated with outcomes analyses, provide the opportunity to develop behavioral healthcare delivery systems in which providers are equipped to act decisively in a socially responsible manner. Key benefits of such systems include: enhancing the consistency and quality of clinical decision making across providers with varying professional backgrounds; providing a mechanism to ensure the rapid dissemination and implementation of new clinical research findings; performing severity-adjusted profiling of providers and programs based on the outcomes their services produce; and linking the prospective focus of clinical pathways with the retrospective rigor of outcomes analysis to accelerate advances in behavioral health. Integrating expert systems with outcomes analyses has the potential to rectify the historical failure by the behavioral healthcare professions to systematically link patient assessment data and their analysis to actual clinical decision making. Such systems will help make behavioral healthcare practice more accountable, thereby strengthening the argument for psychiatric patients to gain parity in healthcare benefits.
Expert Systems↗
The early growth response gene EGR-1 behaves as a suppressor gene that is down-regulated independent of ARF/Mdm2 but not p53 alterations in fresh human gliomas.
PURPOSE: EGR-1 is an immediate early gene with diverse functions that include the suppression of growth. EGR-1 is down-regulated many cancer cell types, suggesting a tumor suppressor role, and may critically involve the p53 pathway. The aim of this work was to measure the expression of EGR-1 and the p16/INK4a/ARF-Mdm2-p53 pathway status in fresh human gliomas. EXPERIMENTAL DESIGN: Thirty-one human gliomas with different grades of malignancy were investigated for Egr-1 mRNA and the protein expression, frequency, and spectrum of p53 gene mutations, mdm2 gene amplification, and p16/INK4a/ARF allele loss. RESULTS: The amplification of Mdm2 and the deletion of the p16/INK4a gene was found in 3 and 5 cases, respectively, whereas mutations of p53, including two novel mutations, were observed in 10 other cases. The three types of changes occurred strictly mutually exclusively, emphasizing that these genes operate in a common pathway critical to glioma progression. EGR-1 mRNA was significantly down-regulated in astrocytomas (14.7 +/- 5.1%) and in glioblastomas (33.6 +/- 10.0%) versus normal brain. Overall, EGR-1 mRNA was strongly suppressed (average, 15.2 +/- 13.9%) in 27 of 31 cases (87%), independent of changes in p16/INK4a/ARF and Mdm2; whereas 4 of 31 cases with residual EGR-1 expression as well as the highest EGR-1 variance segregated with p53 mutations. Immunohistochemical analyses confirmed the suppression of EGR-1 protein. CONCLUSIONS: These results indicate that EGR-1 is commonly suppressed in gliomas independent of p16/INK4a/ARF and Mdm2 and that suppression is less crucial in tumors bearing p53 mutations, and these results implicate an EGR-1 growth regulatory mechanism as a target of inactivation during tumor progression.
Blotting, Northern↗
PI3K/PTEN/AKT pathway. A critical mediator of oncogenic signaling.
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Animals↗
Does public health nurse home visitation make a difference in the health outcomes of pregnant clients and their offspring?
Public health nurses (PHNs) at Lincoln-Lancaster County Health Department have used the Care Pathway tool to track client progress. Conceptually similar to critical pathways used in hospital settings, the Care Pathway is used by the PHN to document milestones of progress by trimester of pregnancy. Data for this research was gathered from chart review of 55 prenatal clients. Study results demonstrate that subjects who had from five to nine home visits by a PHN during pregnancy showed a higher average hemoglobin for the mothers and a higher average birthweight for the babies than those visited four or fewer times. None of the low birthweight babies was born to mothers in the "more visits" category. Furthermore, more breastfeeding was recorded for those who had received more PHN visits. This documentation enabled us to describe better the referent population and to begin to estimate the effect of PHN home visitation on the health outcomes of clients. In essence, we addressed the questions: (1) "Does PHN home visitation make a difference in health outcomes of clients and their families?" and (2) "If so, how can effects be measured?"
Adolescent↗
Structure of 2C-methyl-D-erythritol 2,4- cyclodiphosphate synthase: an essential enzyme for isoprenoid biosynthesis and target for antimicrobial drug development.
The crystal structure of the zinc enzyme Escherichia coli 2C-methyl-d-erythritol 2,4-cyclodiphosphate synthase in complex with cytidine 5'-diphosphate and Mn(2+) has been determined to 1.8-A resolution. This enzyme is essential in E. coli and participates in the nonmevalonate pathway of isoprenoid biosynthesis, a critical pathway present in some bacterial and apicomplexans but distinct from that used by mammals. Our analysis reveals a homotrimer, built around a beta prism, carrying three active sites, each of which is formed in a cleft between pairs of subunits. Residues from two subunits recognize and bind the nucleotide in an active site that contains a Zn(2+) with tetrahedral coordination. A Mn(2+), with octahedral geometry, is positioned between the alpha and beta phosphates acting in concert with the Zn(2+) to align and polarize the substrate for catalysis. A high degree of sequence conservation for the enzymes from E. coli, Plasmodium falciparum, and Mycobacterium tuberculosis suggests similarities in secondary structure, subunit fold, quaternary structure, and active sites. Our model will therefore serve as a template to facilitate the structure-based design of potential antimicrobial agents targeting two of the most serious human diseases, tuberculosis and malaria.
Amino Acid Sequence↗
Integrated genomic and proteomic analyses of a systematically perturbed metabolic network.
We demonstrate an integrated approach to build, test, and refine a model of a cellular pathway, in which perturbations to critical pathway components are analyzed using DNA microarrays, quantitative proteomics, and databases of known physical interactions. Using this approach, we identify 997 messenger RNAs responding to 20 systematic perturbations of the yeast galactose-utilization pathway, provide evidence that approximately 15 of 289 detected proteins are regulated posttranscriptionally, and identify explicit physical interactions governing the cellular response to each perturbation. We refine the model through further iterations of perturbation and global measurements, suggesting hypotheses about the regulation of galactose utilization and physical interactions between this and a variety of other metabolic pathways.
Computational Biology↗
Recent advances in melanoma research.
At the end of the last decade, sporadic melanomas were still considered a genetic black box. Fortunately, in the last few years the box has been opened bringing to light melanoma-relevant oncogenes, aberrant signal transduction pathways, critical alterations in the melanoma cell cycle that go beyond p16INK4a, and melanoma- microenvironment interactions that are essential for tumor progression. This review will discuss some of the latest findings in melanoma research including the critical role of the MAPK pathway in the genesis of melanoma and senescence of nevi, the paradoxical tumor suppressor and oncogenic activities of the transcription factor MITF, and the unexpected oncogenic activities of the low molecular weight forms of cyclin E.
Cell Cycle↗
Tissue inhibitor of metalloproteinase-1 inhibits apoptosis of human breast epithelial cells.
The signaling pathways critical for cell survival are mediated in part by the composition and integrity of the extracellular matrix and the action of its components on specific cell adhesion receptors. Withdrawal of anchorage-dependent epithelial cells from their association with ECM results in apoptotic cell death. Consistently, the matrix metalloproteinases (MMPs) or their inhibitors (TIMPs) have been suggested to regulate apoptosis. In this report, we investigated whether bcl-2 inhibition of apoptosis involves regulation of TIMP expression. We have found that bcl-2 overexpression induces TIMP-1 expression in breast epithelial cell lines (MCF10A, MCF10AneoT.TG3B, and MCF-7), whereas it has no effect on TIMP-2 expression. We demonstrated that TIMP-1 inhibits cell death induced by hydrogen peroxide, Adriamycin, or X-ray irradiation. In addition, TIMP-1 overexpression inhibits apoptosis after the loss of cell adhesion (anoikis) in MCF10A cells, suggesting that the antiapoptotic activity of TIMP-1 does not depend on its ability to stabilize cell-matrix interactions. We also showed that TIMP-1 overexpression is associated with constitutive activation of focal adhesion kinase, a signaling molecule known to be critical for the cell survival pathway.
Apoptosis↗
Aryl hydrocarbon receptor, cell cycle regulation, toxicity, and tumorigenesis.
Most effects of exposure to halogenated and polycyclic aromatic hydrocarbons are mediated by the aryl hydrocarbon receptor (AHR). It has long been recognized that the AHR is a ligand-activated transcription factor that plays a central role in the induction of drug-metabolizing enzymes and hence in xenobiotic detoxification. Of late, it has become evident that outside this well-characterized role, the AHR also functions as a modulator of cellular signaling pathways. In this Prospect, we discuss the involvement of the AHR in pathways critical to cell cycle regulation, mitogen-activated protein kinase cascades, immediate-early gene induction, and the functions of the RB protein. Ultimately, the toxicity of AHR xenobiotic ligands may be intrinsically connected with the perturbation of these pathways and depend on the many critical signaling pathways and effectors with which the AHR itself interacts.
Animals↗
Innovative approaches in the treatment of emesis.
Over the last 15 years, appreciation of the role of dopaminergic (D2) receptors and serotonergic (5-HT3) receptors has led to the development of a series of highly effective antiemetic agents. However, in spite of the suggestion of additional significant receptors (such as the NK-1 receptor and the opiate mu receptor), recent innovations in antiemetic treatment have concentrated on refinement of schedule, route, and dose. Single-dose regimens and oral formulations improve the convenience of antiemetic administration, while identification of the minimum effective dose has important economic implications. Involvement of experienced supportive care investigators in objective determination of utility scores for various supportive care modalities will be vital for rational inclusion of supportive care in pharmacoeconomic analysis, critical pathways, and clinical guidelines.
Administration, Oral↗
Partnership and managed care: a way forward.
As the programme of health reform in New Zealand gains momentum the number of new concepts and terms used to describe them is increasing to an extent where it would be easy for nurses, on whom the changes have major impact, to become overwhelmed. Most prominent and influential among the current ideas are managed care, evidence based practice, critical pathways and cultural safety. All these are permeated by the change process. In this paper critical issues surrounding aforementioned terms are discussed from both a professional and a consumer viewpoint, with reference to both the literature and media sources. The purpose is clarification, with the aim of assisting nurses to be more engaged in the debate.
Critical Pathways↗
Psychiatric hospital updates its discharge planning path.
Good Samaritan Hospital in Downers Grove, IL, has developed diagnosis-driven critical pathways for inpatient and outpatient psychiatric services.
Critical Pathways↗
Impact of a clinical pathway for radical retropubic prostatectomy.
OBJECTIVES: Cost containment has become an important issue in medical practice. With the implementation of collaborative care programs and critical pathways, substantial reduction in overall costs can be achieved while maintaining the quality of care and patient satisfaction. METHODS: Our series consists of 856 consecutive patients treated with radical retropubic prostatectomy by 24 surgeons in a single hospital between January 1, 1994, and January 31, 1997. A clinical pathway for radical retropubic prostatectomy was implemented July 1, 1994. The patients were subdivided into three groups: (1) baseline: patients who underwent surgery in the 6 months immediately before the pathway onset (n = 113); (2) nonpathway: 75 patients treated off the clinical pathway; and (3) pathway: 668 men placed on the clinical pathway. We compare average length of stay and average hospital charges among the three groups. We also compare average length of stay among physician volume groups: high volume physicians performed at least 12 operations per year; low volume physicians performed less than 12 operations per year. Charges were further broken down by department. Patient satisfaction was recorded by an outside source after discharge. Postoperative complications were assessed in the clinical pathway and nonpathway groups. RESULTS: Average hospital charges and average length of stay were $12,926 and 5.8 days for baseline patients, $11,795 and 5.0 days for nonpathway patients, and $10,042 and 4.0 days for pathway patients, respectively. Implementation of the clinical pathway was associated with lower charges and length of stay in the pathway group as well as the nonpathway group, with larger reductions in pathway patients. With continuous reassessment and modification of the clinical pathway, both average hospital charges and average length of stay have progressively decreased from $10,540 and 4.9 days in 1994 to $8766 and 2.7 days in January 1997. Charges were uniformly reduced in radiology, laboratory, pharmacy, operating room, anesthesia, and nursing or routine care. Patient satisfaction was similar in the pathway group and the nonpathway group. Incidence of postoperative complications did not differ significantly between the pathway and nonpathway groups. Length of stay and hospital charges were significantly lower for high than low volume surgeons, irrespective of the declines observed over time (P = 0.0001 and 0.0001, respectively). CONCLUSIONS: Average hospital charges and average length of stay for all surgeons were lowered significantly with the implementation of a clinical pathway and continue to decrease with continuous reassessment. The pathway was not associated with any increase in postoperative complications or patient dissatisfaction. Surgeons who operate frequently have lower average lengths of stay and hospital charges than those who operate infrequently.
Adult↗
Diabetic ketoacidosis: implications for the medical-surgical nurse.
Diabetic ketoacidosis (DKA) is an acute complication associated with type 1 diabetes mellitus. DKA accounts for a significant portion of annual health care expenditures and is considered a medical emergency. Previously treated in the ICU, DKA is now treated on general medical-surgical nursing units. To manage this crisis successfully, medical-surgical nurses must have a comprehensive knowledge and understanding of the pathophysiologic mechanisms, clinical manifestations, and treatment protocols. A critical pathway is presented to guide clinical care.
Critical Pathways↗