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PubMed2005

Pediatric traumatic brain injury: beyond the guidelines.

In 2003, a multidisciplinary group of physicians formulated the first guidelines for the management of severe traumatic brain injury in infants and children. Initial treatment of these patients is focused on stabilization to prevent the occurrence of secondary insults such as hypotension and hypoxemia. However, this article focuses on the established and emerging therapies used in the intensive care unit management of intracranial hypertension--which represents the key target for contemporary therapy of this condition. A critical pathway for the treatment of this condition was established within the guidelines, and this pathway is appropriately focused on limiting intracranial hypertension and optimizing cerebral perfusion during the intensive care unit phase. This includes first- and second-tier therapies. This article contains a brief synopsis of this critical pathway and discusses important new developments for the management of this condition. Key new developments include a better understanding of the optimal cerebral perfusion pressure target for intracranial pressure-directed therapy, with emerging evidence supporting the use of two therapeutic modalities, mild-moderate hypothermia and decompressive craniectomy.

Journal Article↗
PubMed2002

Bid-mediated mitochondrial pathway is critical to ischemic neuronal apoptosis and focal cerebral ischemia.

We have investigated the role of the BH3-only pro-death Bcl-2 family protein, Bid, in ischemic neuronal death in a murine focal cerebral ischemia model. Wild-type and bid-deficient mice of inbred C57BL/6 background were subjected to 90-min ischemia induced by left middle cerebral artery occlusion followed by 72-h reperfusion. The volume of ischemic infarct was significantly smaller in the bid-deficient brains than in the wild-type brains, suggesting that Bid participated in the ischemic neuronal death. Indeed, following the ischemic treatment there was a significant reduction of apoptosis in the ischemic areas, particularly in the inner infarct border zone (the penumbra), of the bid-deficient brains. In addition, activation of Bid in the wild-type brains could be readily detected at approximately 3 h after ischemia, as evidenced by its proteolytic cleavage and translocation to the mitochondria as determined using Western blot analysis and immunofluorescence staining. Correspondingly, mitochondrial release of cytochrome c could be detected around the same time Bid was cleaved in the wild-type brains. However, no significant cytochrome c release was detected in the bid-deficient brains until 24 h later. This suggests that, although the mitochondrial apoptosis pathway might be activated by multiple mechanisms during focal cerebral ischemia, Bid is critical to its early activation. This notion was further supported by the finding that caspase-3 activation was severely impaired in the bid-deficient brains, whereas activation of caspase-8 was much less affected. Taken together, these data suggest that Bid is activated early in neuronal ischemia in a caspase-8-dependent fashion and that Bid is perhaps one of the earliest and most potent activators of the mitochondrial apoptosis pathway. Thus, the role of Bid in the induction of ischemic neuronal death may render this molecule an attractive target for future therapeutic intervention.

Animals↗
PubMedDate not supplied

Collaborative care: pathways to quality outcomes.

In 1990, The Memorial Hospital at Easton, Maryland, Inc., a not-for-profit 183-bed rural community hospital, recognized a need to explore alternative patient care methods or approaches to improve the continuity of care, focus on healthier patient outcomes, and contain costs. The concept of collaborative care became the focus for patient care delivery. Multidisciplinary teams were established to coordinate patient care activities for patient populations process. Plans of care, referred to as critical pathways, identify intermediate goals and interventions, providing guidance for the patient, family, and healthcare providers as they work to achieve quality outcomes. As the patient progresses along the critical pathway, variances from the established goals are monitored and become the focus of quality reviews.

Clinical Protocols↗
PubMed1994

Presentation of a general algorithm to include effect assessment on secondary poisoning in the derivation of environmental quality criteria. 2. Terrestrial food chains.

In a previous study a simple algorithm was presented for effect assessment on secondary poisoning of birds and mammals. This algorithm (MPC = NOECfish-eater/BCFfish) was drawn up by analyzing a two-step aquatic food chain (water-fish-bird/mammal). The algorithm was used to test whether quality criteria set for surface water, based on effect assessment for aquatic organisms, constitute a "safe" level for secondary poisoning. The present study analyzes whether this algorithm can equally well be used for effect assessment in a terrestrial food chain. The pathway soil-earthworm-bird/mammal was used as an example for a terrestrial food chain. Literature data of six selected compounds (lindane, dieldrin, DDT, PCP, cadmium, and mercury) on both bioconcentration factors for earthworms and toxicity data for birds and mammals were studied. Important differences were found between BCFs for this terrestrial pathway and BCFs for the aquatic pathway analyzed in the previous study. It was found that BCFs for earthworms were more dependent on soil-related properties than on compound-specific properties. Hence, it was concluded that the algorithm MPC = NOECworm-eater/BCFworm can be used only for effect assessment on terrestrial food chain in defined situations. By calculating maximum permissible concentrations for secondary poisoning (MPCsp) for a standard soil situation and comparing these to MPCs for soil organisms, it was concluded that secondary poisoning could be a critical pathway for cadmium and methyl mercury. For methyl mercury secondary poisoning in an aquatic food chain was also a critical pathway. Secondary poisoning of fish-eating birds and mammals is not likely to occur for cadmium at concentrations in water below the MPC calculated for aquatic organisms.

Algorithms↗
PubMed2005

Central amygdala ERK signaling pathway is critical to incubation of cocaine craving.

Using a rat model of craving and relapse, we have previously found time-dependent increases in cue-induced cocaine seeking over the first months of withdrawal from cocaine, suggesting that drug craving incubates over time. Here, we explored the role of the amygdala extracellular signal-regulated kinase (ERK) signaling pathway in this incubation. Cocaine seeking induced by exposure to cocaine cues was substantially higher after 30 withdrawal days than after 1 withdrawal day. Exposure to these cues increased ERK phosphorylation in the central, but not the basolateral, amygdala after 30 d, but not 1 d, of withdrawal. After 30 d of withdrawal from cocaine, inhibition of central, but not basolateral, amygdala ERK phosphorylation decreased cocaine seeking. After 1 d of withdrawal, stimulation of central amygdala ERK phosphorylation increased cocaine seeking. Results suggest that the incubation of cocaine craving is mediated by time-dependent increases in the responsiveness of the central amygdala ERK pathway to cocaine cues.

Amygdala↗
PubMed2004

Phosphatidylinositol-3-OH kinase/AKT and survivin pathways as critical targets for geranylgeranyltransferase I inhibitor-induced apoptosis.

Geranylgeranyltransferase I inhibitors (GGTIs) represent a new class of anticancer drugs. However, the mechanism by which GGTIs inhibit tumor cell growth is still unclear. Here, we demonstrate that GGTI-298 and GGTI-2166 induce apoptosis in both cisplatin-sensitive and -resistant human ovarian epithelial cancer cells by inhibition of PI3K/AKT and survivin pathways. Following GGTI-298 or GGTI-2166 treatment, kinase levels of PI3K and AKT were decreased and survivin expression was significantly reduced. Ectopic expression of constitutively active AKT2 and/or survivin significantly rescue human cancer cells from GGTI-298-induced apoptosis. Previous studies have shown that Akt mediates growth factor-induced survivin, whereas p53 inhibits survivin expression. However, constitutively active AKT2 failed to rescue the GGTIs downregulation of survivin. Further, GGTIs suppress survivin expression and induce programmed cell death in both wild-type p53 and p53-deficient ovarian cancer cell lines. These data indicate that GGTI-298 and GGTI-2166 induce apoptosis by targeting PI3K/AKT and survivin parallel pathways independent of p53. Owing to the fact that upregulation of Akt and survivin as well as inactivation of p53 are frequently associated with chemoresistance, GGTIs could be valuable agents to overcome antitumor drug resistance.

Alkyl and Aryl Transferases↗
PubMed1997

Clinical pathways can help you prevent, win malpractice lawsuits.

By adopting critical pathways and closely adhering to nationally accepted guidelines, you can substantially reduce your risk of facing a malpractice lawsuit and increase your chances of winning if you are sued, experts say. Pathways introduced as evidence in your defense can serve as "expert testimony," establishing that you worked in accordance with an appropriate standard of care. To avoid any appearance that you breached the standard of care, make sure you document and justify any deviations from the clinical paths in place at your institution.

Critical Pathways↗
PubMed2003

Protein kinase A-induced negative regulation of the corticotropin-releasing hormone R1alpha receptor-extracellularly regulated kinase signal transduction pathway: the critical role of Ser301 for signaling switch and selectivity.

Activation of CRH receptors type 1 (CRH-R1) by CRH or urocortin (UCN) leads to stimulation of multiple G proteins with consequent effects on diverse signaling cascades in a tissue-specific manner. In human myometrium and human embryonic kidney (HEK)293 cells, binding of UCN to CRH-R1alpha receptors activates both the Gs and Gq, leading to activation of the adenylyl cyclase/protein kinase A (PKA) and the phospholipase C/protein kinase C and ERK1/2 signaling pathways, respectively. The overall result of these signals is often unpredictable, as these two signaling pathways can interact in many cellular systems, with either potentiation or inhibition of ERK1/2 activity. In the present studies we investigated potential signaling interactions after stimulation of CRH-R1alpha receptors in human cultured pregnant myometrial cells or HEK293 cells overexpressing recombinant CRH-R1alpha receptors. We found that the adenylyl cyclase/PKA pathway has the capacity to markedly decrease UCN-induced ERK1/2 activation, and that these effects were due in part to the ability of PKA to phosphorylate the CRH-R1alpha at position Ser(301) in the third intracellular loop. Mutant CRH-R1alpha receptors with substitutions at position Ser(301), which is the only potential PKA phosphorylation site, were resistant to PKA-dependent phosphorylation and showed altered signaling characteristics, which were dependent upon the amino acid substitution at this position. We conclude that Ser(301), which is located in the third intracellular loop of CRH-R1alpha, is critical for efficient coupling of the receptor to G proteins and to second messenger generation. Phosphorylation by PKA prevents maximal coupling of the CRH-R1alpha to Gq-protein, and thereby reduces activation of ERK 1/2.

Cells, Cultured↗
PubMed2003

Diffusion pathways to critical cysteines in the vesicular acetylcholine transporter of Torpedo.

Previous work had demonstrated that organomercurial-mediated modification of two cysteine residues in the vesicular acetylcholine transporter (VAChT) from Torpedo californica inhibits binding of vesamicol. The cysteines are protected by acetylcholine and vesamicol (Keller et al. 2000. J. Neurochem. 74:1739-1748). Modified "cysteine 1" is accessible to glutathione from the cytoplasmic surface, whereas modified "cysteine 2" is not. Different organomercurials and aqueous environments were used here to characterize diffusion pathway(s) leading to the cysteines. para-Chloromercuriphenylsulfonate modifies VAChT much more slowly than do more hydrophobic p-chloromercuribenzoate and phenylmercury chloride. Permeabilization of vesicles with cholate detergent increases the rate of modification by p-chloromercuriphenylsulfonate. Permeabilization does not affect the ability of glutathione to reverse modification by p-chloromercuriphenylsulfonate. Higher ionic strength causes about four-fold increase in the rate of modification. The results suggest that hydrophobic and electrostatic barriers inhibit modification of Torpedo VAChT by negatively charged organomercurials and glutathione cannot reach cysteine 2 from either side of the membrane.

4-Chloromercuribenzenesulfonate↗
PubMed2000

Activation of insulin-like growth factor I receptor signaling pathway is critical for mouse plasma cell tumor growth.

Plasma cell neoplasia in humans generally occurs as multiple myeloma, an incurable form of cancer. Tumors with marked similarity can be induced in mice by a variety of agents, including chemicals, silicone, and oncogene-containing retroviruses, suggesting the use of murine tumors as an informative model to study plasma cell disease. Herein, we have focused on the role of insulin-like growth factor I receptor (IGF-IR) signaling in the development of plasma cell disease. The insulin receptor substrate 2/phosphatidylinositol 3'-kinase/p70S6K pathway was found to be either constitutively or IGF-I-dependently activated in all plasma cell tumors. Biological relevance was demonstrated in that plasma cell lines with up-regulated IGF-IR expression levels exhibited mitogenic responses to IGF-I. More importantly, expression of a dominant-negative mutant of IGF-IR in these lines strongly suppressed tumorigenesis in vivo. Taken together, these results demonstrate that up-regulation and activation of IGF-IR and the downstream signaling pathway involving insulin receptor substrate 2, phosphatidylinositol 3'-kinase, and p70S6K may play an important role in the development of a broad spectrum of plasma cell tumors.

Animals↗
PubMed1999

Characteristics of asthma care provided by hospitals in a large metropolitan area: results from the Chicago Asthma Surveillance Initiative.

INTRODUCTION: Little is known of the approaches of United States hospitals to the management of persons with asthma. The purpose of this study is to characterize the extent to which hospitals within a large community have implemented various types of asthma-specific health-care delivery processes. METHODS: A cross-sectional, self-administered survey was mailed to a "key informant" in asthma care at each of the hospitals in the Chicago area. The survey instrument covered the following content areas: asthma-related inpatient services, asthma-related outpatient services, selected asthma-related quality improvement activities, and asthma-related community outreach. The survey was administered between August 1996 and January 1997. RESULTS: Data were collected from respondents at 59 of the 89 eligible hospitals, yielding a response rate of 66.3%. Of the responding hospitals, 42.4% indicated they had clinical practice guidelines for inpatient asthma management, and 37.3% reported using critical pathways. Four selected aspects of bedside care were also explored. All of the responding hospitals reported routine provision of nebulization therapy at the bedside, and nearly all routinely obtained peak flow measurements (96.6%). In the area of patient instruction, 93.2% provided bedside evaluation of proper inhaler technique, and 86.4% routinely provided instruction on the use of peak flowmeters. Only 54.0% of the hospitals reported routinely administering some type of asthma education program prior to discharge. The hospitals with clinical practice guidelines in place were also more likely to have critical pathways (p < 0.01); to have asthma-specific ICU policies/guidelines/critical pathways (p < 0.01); to provide bedside instruction on the use of peak flowmeters (p < 0.01); to provide an asthma education (p < 0.01) prior to discharge; and to conduct utilization review. Very few hospitals indicated that they had community outreach programs for asthma care. CONCLUSION: The results of this survey suggest that among Chicago-area hospitals appropriate bedside care for persons with asthma is provided, but there are large variations in other types of asthma services and programs. The hospitals that have adopted asthma clinical practice guidelines are more likely to have other asthma-specific quality improvement activities than hospitals without guidelines. This relationship between use of guidelines and quality of services needs further exploration, as it may prove to be an important marker for hospitals with staff that are interested in improving asthma care.

Adolescent↗
PubMed2004

A sustained activation of PI3K/NF-kappaB pathway is critical for the survival of chronic lymphocytic leukemia B cells.

The progressive rise of mature CD5+ B lymphocytes, despite the low proportion of proliferating cells, has led to the notion that B cell chronic lymphocytic leukemia (B-CLL) is primarily related to defective apoptosis. The microenvironment likely plays a prominent role because the malignant cells progressively accumulate in vivo, whereas they rapidly undergo spontaneous apoptosis when cultured in vitro. To assess microenvironment-mediated survival signals, B-CLL cells were cultured with a murine fibroblast cell line, Ltk-, with and without an agonistic antibody to CD40. Spontaneous apoptosis was associated with the loss of Akt and NF-kappaB activities. Interactions with fibroblasts sustained a basal level of Akt and NF-kappaB activities, which was dependent on phosphatidylinositol-3 kinase (PI3K). Constitutive activity of the PI3K pathway in B-CLL cells when cultured with fibroblasts prevented the downregulation of the prosurvival Bcl-2 family protein Bcl-xL and the caspase inhibitor proteins FLIPL and XIAP, and consequently caspase-3 activation and apoptosis. CD40 crosslinking in B-CLL cells did not further prevent murine fibroblasts-mediated apoptosis but induced cell proliferation, which was associated with an increase of Akt and NF-kappaB activation compared with cells cultured with fibroblasts alone. The PI3K pathway seems to play a pivotal role in B-CLL cell survival and growth.

Adult↗
PubMed2007

Syncope evaluation in the emergency department.

PURPOSE OF REVIEW: In the absence of an established critical pathway to evaluate patients with syncope presenting to the emergency department, this review is timely because of new clinical evidences supporting a specialized syncope management unit in the emergency department, and it is relevant because of the potential impact on a very large and heterogeneous population. RECENT FINDINGS: Three observational syncope studies from Italy showed a high degree of variability in practice patterns, diagnostic yields, and lengths of hospital stay. An appropriate and efficacious syncope management pathway in the emergency department remains far from established. In a randomized trial from a tertiary care hospital in the US, the SEEDS study demonstrated that a designated 'syncope unit' in the emergency department, with a multidisciplinary effort and appropriate resources, significantly improved diagnostic yield, reduced hospital admission and total length of hospital stay in intermediate-risk patients. Long-term follow-up showed that reduced hospital stay did not negatively affect survival and recurrent syncope. SUMMARY: Limited randomized trial data suggest a designated syncope unit in the emergency department holds promise to provide specialized and efficient care for patients with syncope. Additional data are needed to assess the general applicability of this critical pathway in community-based hospitals.

Emergency Service, Hospital↗
PubMed1996

Cost and efficacy of surgical ligation versus transcatheter coil occlusion of patent ductus arteriosus.

OBJECTIVE: The purpose of this study was to compare cost and efficacy of surgical closure of patent ductus arteriosus using new critical pathway methods with outpatient transcatheter coil occlusion of patent ductus arteriosus. METHODS: Surgical techniques included a transaxillary, muscle-sparing thoracotomy, triple ligation of the patent ductus arteriosus, no chest tube, and discharge from the hospital within 24 hours. Transcatheter coil occlusion of patent ductus arteriosus was done as an outpatient procedure. Costs were compared with inclusion of all hospital and professional charges. RESULTS: From July 1994 until March 1996, 20 patients underwent coil occlusion of patent ductus arteriosus and 20 patients underwent surgical closure of patent ductus arteriosus. Duration of hospitalization was significantly less for the patients receiving coil occlusion (11 +/- 6 hours) as compared with that for the patients having surgical ligation (28 +/- 7 hours, p < 0.05). Total charges were similar for surgical ligation ($7101 +/- $408) as compared with those for coil occlusion ($7104 +/- $886, p > 0.05). Morbidity in coil occlusion included inability to occlude the patent ductus arteriosus in two patients (2/20, 10%) and residual patency in two patients (2/18, 11%). Morbidity in the surgical group included nausea and vomiting necessitating hospitalization for more than 36 hours in one patient (1/20, 5%), transient left recurrent laryngeal nerve palsy in one (1/20, 5%), and pneumothorax in two patients (2/20, 10%). There were no instances of residual patency in the surgical group. CONCLUSIONS: Transaxillary thoracotomy without tube thoracostomy and with critical pathway methods allows safe and effective ligation of a patent ductus arteriosus with early hospital discharge. This surgical method has similar cost, higher efficacy rate, and applicability in all patients as compared with newer transcatheter coil occlusion techniques for closure of a patent ductus arteriosus.

Adolescent↗
PubMed1999

Protein kinase c-dependent pathway is critical for the production of pro-inflammatory cytokines (TNF-alpha, IL-1beta, IL-6).

The authors hypothesized that certain PKC isoforms play an important role in the induction of pro-inflammatory cytokine (TNF-alpha, IL-1beta, IL-6) synthesis. To test this hypothesis, the cytosol-to-membrane translocation of select PKC isoforms with tested cytokine production in human monocytes cultured in vitro was correlated. It is reported that in monocytes treated with phorbol ester (PMA), translocation of PKC isoforms alpha, betaII, delta and epsilon precede cytokine synthesis. Moreover, specific inhibition of PKC translocation that occurs in the presence of Calphostin C is reflected in downstream events: lack of MAP kinases phosphorylation, loss of DNA binding ability by AP-1 transcription factor, and the reduction of pro-inflammatory cytokine synthesis. Thus, the cytosol-to-membrane translocation of PKC isoforms alpha, betaII, delta and epsilon with the subsequent activation of: (1) MAP kinases; and (2) AP-1 transcription factor, may represent critical steps in the induction of signalling cascade leading to TNF-alpha, IL-1beta, IL-6 synthesis in human monocytes.

Cells, Cultured↗
PubMed2004

Exposure of Tg.AC transgenic mice to benzene suppresses hematopoietic progenitor cells and alters gene expression in critical signaling pathways.

The effects of acute benzene (BZ) exposure on hematopoietic progenitor cells (HPCs) derived from bone marrow cells were studied using homozygous male v-Ha-ras Tg.AC mice at 8-10 weeks of age. The mice were given 0.02% BZ in their drinking water for 28 days with the dose rate estimated to be 34 mg benzene/kg BW/day. Analysis of cultured HPCs indicated that BZ suppressed the proliferation of the multilineage colony forming unit-granulocyte, erythrocyte, macrophage, megakaryocyte (CFU-GEMM); colony forming unit-granulocyte, macrophage (CFU-GM); and blast forming unit erythrocyte/colony forming unit erythrocyte (BFUE/CFUE). A gene expression profile was generated using nylon arrays spotted with 23 cDNAs involved in selected signal pathways involved in cell distress, inflammation, DNA damage, cell cycle arrest, and apoptosis. Of the 23 marker genes, 6 (bax, c-fos, E124, hsf1, ikBa, and p57) were significantly (Mann-Whitney U tests, P < 0.05) overexpressed in BZ-exposed mice. Two genes (c-myc and IL-2) approached significance (at P = 0.053). The pattern of gene expression was consistent with BZ toxicity and the suppression of HPCs.

Animals↗
PubMed1990

Children with urinary tract infection; a critical diagnostic pathway.

A protocol for the radiological investigation of children with urinary tract infection was introduced in a district general hospital in 1985. Every boy, and every girl under 5 years was investigated after one documented infection, and every girl over 5 years after two infections. Each child had an abdominal radiograph and a sonar scan of the urinary tract. Four years later the results were assessed by reviewing the radiology file or contacting the general practitioner of each of the first 200 children examined. Ten of 15 children diagnosed as not normal on screening and investigated further had an abnormality confirmed. Four of 25 children thought normal on screening had minor abnormalities shown on further examination. The results are assessed in the light of a review of recent literature and indicate that this screening protocol is efficient and effective.

Child↗
PubMed2006

Retroviral DNA integration: reaction pathway and critical intermediates.

The key DNA cutting and joining steps of retroviral DNA integration are carried out by the viral integrase protein. Structures of the individual domains of integrase have been determined, but their organization in the active complex with viral DNA is unknown. We show that HIV-1 integrase forms stable synaptic complexes in which a tetramer of integrase is stably associated with a pair of viral DNA ends. The viral DNA is processed within these complexes, which go on to capture the target DNA and integrate the viral DNA ends. The joining of the two viral DNA ends to target DNA occurs sequentially, with a stable intermediate complex in which only one DNA end is joined. The integration product also remains stably associated with integrase and likely requires disassembly before completion of the integration process by cellular enzymes. The results define the series of stable nucleoprotein complexes that mediate retroviral DNA integration.

Blotting, Western↗