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PubMedDate not supplied

Multidisciplinary outcome indicators.

Health care has been given a mandate by an educated public, managed care reimbursement sources, and the need to constantly improve patient care: to measure the quality of the outcomes of care. Multidisciplinary outcome indicators are basic to that measurement. A tool to assist with that measurement is a multidisciplinary clinical pathway.

Critical Pathways↗
PubMed2000

Multiple pathways of recombination define cellular responses to cisplatin.

BACKGROUND: Cisplatin is a DNA-damaging drug used for treatment of testicular tumors. The toxicity of cisplatin probably results from its ability to form DNA adducts that inhibit polymerases. Blocked replication represents a particular challenge for tumor cells, which are committed to unremitting division. Recombination provides a mechanism by which replication can proceed despite the presence of lesions and therefore could be significant for managing cisplatin toxicity. RESULTS: Recombination-deficient Escherichia coli mutants were strikingly sensitive to cisplatin when compared with the parental strain. Our data identified both daughter-strand gap and double-strand break recombination pathways as critical for survival following treatment with cisplatin. Although it is established that nucleotide excision repair (NER) significantly protects against cisplatin toxicity, most recombination-deficient strains were as sensitive to the drug as the NER-deficient uvrA mutant. Recombination/NER deficient double mutants were more sensitive to cisplatin than the corresponding single mutants, suggesting that recombination and NER pathways play independent roles in countering cisplatin toxicity. Cisplatin was a potent recombinogen in comparison with the trans isomer and canonical alkylating agents. Mitomycin C, which like cisplatin, forms DNA cross-links, was also recombinogenic at minimally toxic doses. CONCLUSIONS: We have demonstrated that all of the major recombination pathways are critical for E. coli survival following treatment with cisplatin. Moreover, recombination pathways act independently of NER and are of equal importance to NER as genoprotective systems against cisplatin toxicity. Taken together, these results shed new light on how cells survive and succumb to this widely used anticancer drug.

Antineoplastic Agents↗
PubMed2006

Critical role of the c-JunNH2-terminal kinase and p38 mitogen-activated protein kinase pathways on sodium butyrate-induced apoptosis in DU145 human prostate cancer cells.

Sodium butyrate (NaBu) is known to exhibit anti-cancer effects via the differentiation and apoptosis of various carcinoma cells. However, the mechanism by which NaBu induces apoptosis and the involvement of protein kinases during apoptosis is not completely understood. To investigate the underlying pathways, we performed cell culture experiments in androgen-independent human prostate cancer (DU145 cells) focusing on various protein kinases. NaBu causes concentration-dependent cell detachment and growth inhibition. Exposure of DU145 cells to NaBu for 24 h caused a strong apoptotic effect with 26% nuclear fragmentation and condensation. In addition, NaBu induced caspase-3 and poly-ADP ribose polymerase cleavage and up-regulation of bax, suggesting that mitochondrial damage is involved in NaBu-induced caspase-dependent apoptosis. Interestingly, NaBu stimulated p38 mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal kinase (JNK) activation, but not extracellular signal-regulated kinase 1/2 activation during apoptosis. Furthermore, NaBu up-regulated total protein levels and phospho forms of MAPK kinase 3 (MKK3) and MAPK kinase 4 (MKK4) as the upstream kinases of p38 MAPK and JNK independently of oxidative stress. Taken together, it is suggested that NaBu can be a promising chemopreventive agent for prostate cancer and the p38 MAPK and JNK pathways have critical roles in NaBu-induced apoptosis in DU145 cells.

Apoptosis↗
PubMed2005

Psychosocial assessment by phone for high-scoring patients taking the Edinburgh Postnatal Depression Scale: communication pathways and strategies.

The well-documented risks associated with perinatal depression provide a strong argument for universal screening. However, uncertainty about what to do with findings is a significant barrier to implementing screenings where obstetric care is provided. Based on experience with a comprehensive screening program, we describe a protocol for those critical communication pathways that encourage a dynamic phone exchange between a mental health caller and the patient who has scored in the high range on the Edinburgh Postnatal Depression Scale. In addition, we present guidelines for developing an action plan for addressing intervention needs and closing the feedback loop to the original administrators of the scale.

Adult↗
PubMed1971

Effects of synergists on the metabolism and toxicity of anticholinesterases.

Insecticide synergists enhance insecticidal action through their ability to block the enzymatic detoxification of insecticides with which they are combined. The structure of the synergist is therefore determined by the nature of the insecticide and the critical biochemical pathway responsible for its degradation.Synergists can be broadly classified as either analogue synergists, whose structure closely resembles that of the insecticide they synergize, or inhibitors of microsomal oxidation. Metabolism of the phenyl methylcarbamates is effected largely by the microsomal enzymes. Consequently microsomal enzyme inhibitors, such as the methylenedioxyphenyl compounds, the aryloxyalkylamines, the thiocyanates, the propynyl aryl ethers, and the 1,2,3-benzothiadiazoles, are all effective carbamate synergists. The detoxification pathways of the organophosphates, however, are more complex and include hydrolysis, dealkylation, and carboxylesterase pathways as well as oxidation. Because phosphorothioates are activated by oxidation, their toxicity is often antagonized by oxidase inhibitors. The effectiveness of different synergists towards resistant strains of insects is likely to vary in a manner that reflects the critical metabolic pathway on which resistance depends.

Amines↗
PubMed2004

HIF-VEGF-VEGFR-2, TNF-alpha and IGF pathways are upregulated in critical human skeletal muscle ischemia as studied with DNA array.

Critical lower limb ischemia is a common cause for amputation. To develop new therapeutic strategies, more information is needed about molecular mechanisms of tissue responses to ischemic stress and factors inducing angiogenesis. Using a DNA array of 8400 genes, gene expression patterns in human skeletal muscle samples collected from lower limbs amputated due to acute-on-chronic or chronic critical lower limb ischemia, were compared with the control samples collected from the same limb. The results were confirmed by RT-PCR and immunohistochemistry. In acute-on-chronic ischemia, 291 genes were significantly upregulated and 174 genes were downregulated (change in 5.5% of all genes) as compared to control samples. Significant induction of the hypoxia-inducible angiogenic pathway involving hypoxia-inducible factor-1alpha (HIF-1alpha), HIF-2alpha, vascular endothelial growth factor (VEGF) and its angiogenic receptor VEGFR-2, as well as tumor necrosis factor-alpha (TNF-alpha) with its downstream signaling machinery promoting inflammation and cell death, were found in acute-on-chronic ischemia. In chronic critical ischemia, gene expression changes were much less striking than in acute-on-chronic ischemia, with 74 genes significantly upregulated and 34 genes downregulated (change in 1.3% of all genes). In the chronic situation, the anabolic and survival factors, insulin-like growth factor-1 (IGF-1) and IGF-2, were upregulated in atrophic and regenerating myocytes together with attenuated HIF, VEGF, and VEGFR-2 expression in the same cells. In conclusion, acute-on-chronic and chronic human skeletal muscle ischemia result in distinct gene expression patterns. These findings may be of importance in the design of novel therapies, such as therapeutic vascular growth, for patients suffering from lower limb ischemia.

Acute Disease↗
PubMed1997

Aspartate residue 7 in amyloid beta-protein is critical for classical complement pathway activation: implications for Alzheimer's disease pathogenesis.

Fibrillar amyloid beta-protein has been implicated in the pathogenesis of Alzheimer's disease because of its neurotoxicity and its ability to activate complement. Reactive microglia, astrocytes and complement (C') components (reviewed in ref. 6) are associated with senile plaques, the fibrillar, beta-sheet assemblies of amyloid beta-peptide found predominantly in brain from individuals with AD (ref. 7). These indications of inflammatory events are not prevalent in the nonfibrillar "diffuse" plaques often seen in age-matched control cases without dementia. Clinical studies over the past several years have correlated the use of anti-inflammatory drugs with a decrease in the incidence and progression of AD dementia and/or dysfunction, supporting a role for gliosis and inflammation in AD pathogenesis (reviewed in ref. 6). C5a, a product of C' activation, is chemotactic for microglia. Thus, complement activation provides a specific mechanism for recruiting reactive glial cells to the site of the fibrillar amyloid beta-protein plaque, which could lead to inflammatory events, neuronal dysfunction and degeneration. With the use of truncated amyloid beta-peptides, the region of amyloid beta-protein limited by residues 4 and 11 has been identified as critical in the interaction between amyloid beta-protein and C1q, the recognition component of the classical complement pathway (CCP), which results in the activation of C'. Furthermore, substitution of an isoaspartic acid for aspartic acid at amyloid beta-protein residue 7 resulted in the complete elimination of CCP-activating activity. A molecular model of this interaction has been generated that should be useful in the design of candidate therapeutic inhibitors of CCP activation by amyloid beta-protein.

Alzheimer Disease↗
PubMedDate not supplied

Implementing case management and developing clinical pathways.

Efforts to implement case management and, subsequently, to develop critical paths at Birmingham Baptist Medical Center Montclair in Birmingham, AL, began in the late 1980s. Under the case management system, registered nurses using the CareMap system manage the care of 60-80% of the medical center's patients. Those patients whose care does not follow a map are managed by nurse case managers. The patients who do not meet the identified goals for care require a collaborative effort from all the healthcare professionals associated with their care. Since the inception of the case management program, Montclair has made significant strides in decreasing the cost per discharge, decreasing the variable cost per case, and, most importantly, improving quality outcomes for designated case types.

Alabama↗
PubMed2006

Nonendothelial mesenchymal cell-derived MCP-1 is required for FGF-2-mediated therapeutic neovascularization: critical role of the inflammatory/arteriogenic pathway.

OBJECTIVE: Monocyte chemoattractant protein-1 (MCP-1) is a C-C chemokine that is known as an inflammatory/arteriogenic factor. Angiogenesis contributes to the inflammatory process; however, the molecular and cellular mechanisms of the links among the inflammatory pathway, arteriogenesis, and angiogenesis have not been well elucidated. METHODS AND RESULTS: Using murine models of fibroblast growth factor-2 (FGF-2)-mediated therapeutic neovascularization, we here show that FGF-2 targets nonendothelial mesenchymal cells (NEMCs) enhancing both angiogenic (vascular endothelial growth factor [VEGF]) and arteriogenic (MCP-1) signals via independent signal transduction pathways. Severe hindlimb ischemia stimulated MCP-1 expression that was strongly enhanced by FGF-2 gene transfer, and a blockade of MCP-1 activity via a dominant negative mutant as well as a deficiency of its functional receptor CCR2 resulted in the diminished recovery of blood flow attributable to adaptive and therapeutic neovascularization. Tumor necrosis factor (TNF)-alpha stimulated MCP-1 expression in all cell types tested, whereas FGF-2-mediated upregulation of MCP-1 was found only in NEMCs but not in others, a finding that was not affected by VEGF in vitro and in vivo. CONCLUSIONS: These results indicate that FGF-2 targets NEMCs independently, enhancing both angiogenic (VEGF) as well as inflammatory/arteriogenic (MCP-1) pathways. Therefore, MCP-1/CCR2 plays a critical role in adaptive and FGF-2-mediated therapeutic neovascularization.

Adaptation, Physiological↗
PubMed1993

Generation and transit pathway of H+ is critical for inhibition of palmar sweating by iontophoresis in water.

Passing galvanic current across the skin (known as "tap water iontophoresis" or TWI) inhibits sweating; however, its mechanism of action is unclear. Using improved methods, we confirmed that anodal current has more of an inhibitory effect than cathodal current, water is superior to saline, and the inhibitory effect is a function of the amperage used. To address the importance of current flowing through the pores, a layer of silicone grease was placed on the skin to reduce the shunt pathway across the epidermis. With silicone, total skin conductance decreased 60% without the sweat pores being occluded, swelling of the stratum corneum and collapse of the poral lumen was prevented, and current-induced inhibition of sweating was enhanced, most likely because of an increase in current density in the pores. The pH of anodal water, but not of saline, dropped to 3, whereas that of cathodal water increased to 10 during passage of current through the skin. Acidified anodal water was superior to alkaline water. Sweat glands isolated from TWI-induced anhidrotic palmar skin responded to methacholine in vitro, but the sweat rate and pharmacological sensitivity were slightly lowered. Thus the strong acidity generated by hydrolysis of water in the anodal bath and the further accumulation of H+ in the sweat duct by anodal current may be responsible for TWI-induced inhibition of sweating due to an unknown lesion(s) in the duct or sweat pore. The secretory coil function may also be altered because of exposure to intense acidity during TWI. The importance of H+ movement into the sweat pore for inhibition of sweating could be further exploited to develop new strategies for the control of sweating.

Adolescent↗
PubMed2006

Improving the management of patients after myocardial infarction, from admission to discharge.

BACKGROUND: Recent developments in pharmacologic and device therapy, as well as initiatives to increase the use of standard orders and promote in-hospital communication, have improved the care of patients with myocardial infarction (MI). The increased presence of hospitalists, physicians who provide in-hospital care as a specialty, promises to provide further improvements. OBJECTIVE: This article reviews current information on evidence-based care of the hospitalized MI patient, with a particular emphasis on identifying left ventricular dysfunction (LVD) and appropriate treatments. METHODS: MEDLINE was searched for all large-scale clinical trials providing information on the care of post-MI patients with or without LVD and/or heart failure (HF), with no limit on time period. The search terms were post-myocardial infarction, large-scale, randomized, clinical trial, left ventricular dysfunction, and/or heart failure. All trials investigating therapies currently recommended in the American College of Cardiology/American Heart Association ST-elevation MI (ACC/AHA STEMI) guidelines and including post-MI patients with or without LVD and/or HF, as indicated by signs and symptoms of HF or Killip class, were included. RESULTS: In the acute setting, the ACC/AHA STEMI guidelines recommend the use of aspirin, clopidogrel, beta-blockers, angiotensin-converting enzyme inhibitors, heparin (low molecular weight or unfractionated), and glycoprotein IIb/IIIa inhibitors (if the patient is undergoing a percutaneous coronary intervention). The guidelines recommend use of aldosterone antagonists and statins at discharge, in addition to continuation of all acute therapies. The ACC/AHA guidelines apply to all patients after MI and do not specify whether the recommended therapies are effective in post-MI patients with LVD or HE Reviewing the trials that included post-MI patients with LVD and/or HF, it appears that in some cases, only certain agents within a class have been evaluated (eg, post-MI beta-blocker trials often excluded patients with LVD, and the efficacy of atenolol has not been evaluated in post-MI patients with LVD or HF), and some agents have not shown as much efficacy as others in this high-risk patient population (eg, metoprolol appeared to be associated with poorer outcomes in this population than carvedilol). Rather than recommending an entire class, hospital care maps and critical-care pathway tools should incorporate the use of evidence-based agents. CONCLUSIONS: The use of evidence-based care in the hospital has the potential to substantially reduce morbidity and mortality in post-MI patients with LVD and/or HE The hospitalist can facilitate the best practices and best care of the post-MI patient through the use of in-hospital critical-care pathway tools.

Continuity of Patient Care↗