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PubMed2004

Microarray screening of lymphocyte gene expression differences in a multiplex schizophrenia pedigree.

In order to help prioritize the selection of candidate genes and to study possible trait and not state related changes in gene expression, we compared lymphocytic gene expression patterns of five individual family members with schizophrenia and nine unaffected individuals from a large multiplex high density pedigree. We screened gene expression by microarray consisting of 1128 brain focused genes. Three criteria for selection of microarray gene differences between schizophrenia and unaffected family members were employed: a significant t-test, expression in a majority of subjects, and fold change magnitude. Gene expression levels were significantly different for nine genes between individuals with schizophrenia compared to unaffected controls, and two genes were validated by real-time PCR. The expression of the neuropeptide Y receptor Y1 gene (NPY1R localized at 4q31.3-q32) and the human guanine nucleotide-binding regulatory protein Go-alpha (GNAO1 localized at 16q13) was significantly decreased in individuals with schizophrenia compared to unaffected family controls by microarray and real-time PCR. The cytosolic malate dehydrogenase gene (MDH1 localized at 2p13.3) was also significantly increased by microarray analysis and showed a trend for increase by real-time PCR. The significant genes are discussed in terms of proximity to linkage regions, prior association studies of schizophrenia, and other reports of microarray screening of schizophrenia tissue. Evidence from these studies taken together with the present study suggests critical pathways in schizophrenia may be studied in peripheral tissue as part of the strategy in functional genomic convergence. This preliminary study needs to be repeated by screening a larger set of genes in additional families with schizophrenia. The present study offers support for examination of gene expression patterns using lymphocytic RNA for complex neuropsychiatric disorders from large cohorts of patients.

Adult↗
PubMed1997

MEKKs, GCKs, MLKs, PAKs, TAKs, and tpls: upstream regulators of the c-Jun amino-terminal kinases?

Regulation of the mitogen-activated protein kinase (MAPK) family members - which include the extracellular response kinases (ERKs), p38/HOG1, and the c-Jun amino-terminal kinases (JNKs) - plays a central role in mediating the effects of diverse stimuli encompassing cytokines, hormones, growth factors and stresses such as osmotic imbalance, heat shock, inhibition of protein synthesis and irradiation. A rapidly increasing number of kinases that activate the JNK pathways has been described recently, including the MAPK/ERK kinase kinases, p21-activated kinases, germinal center kinase, mixed lineage kinases, tumor progression locus 2, and TGF-beta-activated kinase. Thus, regulation of the JNK pathway provides an interesting example of how many different stimuli can converge into regulating pathways critical for the determination of cell fate.

Animals↗
PubMed1998

Linking extracellular survival signals and the apoptotic machinery.

The survival of cells in multicellular organisms requires continuous stimulation from the extracellular environment. The phosphatidylinositol-3' kinase/Akt signaling cascade has been identified as a critical pathway for the transduction of extracellular survival signals. The finding that the pro-apoptotic protein BAD is a substrate of Akt/PKB has provided the first link between extracellular survival signals and the apoptotic machinery.

Animals↗
PubMed2003

Exposing oncogenic dependencies for cancer drug target discovery and validation using RNAi.

Oncogenesis occurs through the acquisition and selection of multiple somatic mutations--each contributing to the growth, survival and spread of the cancer. Key attributes of the malignant phenotype, such as unchecked proliferation and cell survival, can often be "reversed" by the selective diminution of dominant oncogenes by chemical or genetic means (e.g. beta-catenin in colorectal carcinomas; bcr-abl in chronic myelogenous leukemias (CMLs)). These observations suggest that the products of oncogenes, or of secondary genes that mediate and maintain tumor phenotypes, might be revealed through the systematic disruption of each and every gene in tumor-derived cells. Some of these genes may encode proteins amenable to therapeutic intervention, thus fueling the cancer drug discovery process. However, a functional assessment of each known or predicted gene in mammalian cells is a daunting task and represents the rate-limiting step in drug target identification and validation. In this regard, RNA interference (RNAi) by small interfering RNAs (siRNA) holds great promise as the "tool of choice" to mediate the selective attenuation of mammalian gene expression and protein function. Here, we review strategies by which RNAi might be used to determine the genetic alterations that contribute to malignant transformation via large-scale cell-based screens, and propose how this information can be used in conjunction with small molecule screens to identify pathways critical to cancer cell survival.

Animals↗
PubMed2000

Atrial form and function: lessons from human molecular genetics.

Molecular genetic analyses of human hereditary disorders that affect cardiac atrial structure and function have recently identified several genes that regulate atrial morphogenesis. Mutations of the TBX5, NKX2.5, EVC, and PRKAR1 alpha genes all result in abnormalities of human atrial growth and development, and mutations in at least one gene results in familial atrial fibrillation and is as yet unidentified. Ongoing studies to find interactions between these transcription factors and intracellular signaling molecules and other as yet unknown genes are establishing critical pathways in human cardiogenesis. Human investigation and experimental animal models of heart development synergize to elucidate etiologies of common congenital heart disease.

Abnormalities, Multiple↗
PubMed2002

Prostate cancer gene therapy.

Numerous gene therapy trials in the United States and throughout the world using various strategies are in progress for the treatment of locally advanced and metastatic prostate cancer. Although vector technology advances at a rapid pace, progress in elucidating the molecular pathways critical for the development and progression of prostate cancer has been slower and more deliberate. Thus far, prostate gene therapy appears to be safe and well tolerated. Through these early clinical trials, the safety and efficacy of gene therapy alone or in combination with more conventional therapy as a basis for the treatment of prostate cancer will ultimately be determined.

Adenoviridae↗
PubMed1996

Using qualitative and quantitative patient satisfaction data to improve the quality of cardiac care.

BACKGROUND: In early 1993 leaders within the Hitchcock Clinic and cardiac services section at Dartmouth-Hitchcock Medical Center (Lebanon, NH) formed the Cardiac Services Improvement Group (CSIG) as a pilot program for patient-centered quality improvement (QI) at the sectional level. CSIG PROGRAM: For open heart surgery (OHS) and percutaneous transluminal coronary angioplasty (PTCA), a flowchart was constructed of sequential patient experiences. Content analysis of focus group discussions resulted in six key patient-defined quality characteristics: comfort, caring, certainty, convenience, communication, and cost. Linking of patient comments to points on the patient experience flowchart made it possible to determine where particular quality characteristics were most relevant. A patient satisfaction survey with questions that were specific to a patient experience and to a quality characteristic was mailed to 100 consecutively discharged OHS and PTCA patients; 35 of the 50 patients in each group responded. EVALUATING SUCCESS: Analysis of the survey results led to the formation of two QI teams. One team began work on development of a critical pathway for discharge preparation and identified marker questions to track and monitor pathway success in subsequent surveys. Another team began the development of protocols for more effective pain management during and after the PTCA procedure. A repeat patient satisfaction survey that took place from November 1994 to March 1995 suggested a global improvement in patient satisfaction for all patient experiences and all key quality characteristics. CONCLUSION: The CSIG pilot program of patients-based quality measurement and management at the sectional level has been successful in fostering QI team formation and has been associated with a positive deflection in patient-based quality measures. Additional sections of the medical center have initiated similar projects, beginning with process definition and focus groups.

Angioplasty, Balloon, Coronary↗
PubMed1996

Improving health care, Part 3: Clinical benchmarking for best patient care.

BACKGROUND: Benchmarking, which shows that a much better way of doing something may be possible, stimulates local interest in changing and in making changes previously thought not possible. A PLANNING WORKSHEET: The Worksheet has five basic steps: Identify measures, determine resources needed to find the "best of the best," design a data collection method and gather data, measure the best against own performance to determine gap, and identify the best practices producing best-in-class results. CASE EXAMPLE--BOWEL SURGERY: The Accelerating Clinical Improvement Bowel Surgery Team at Dartmouth-Hitchcock Medical Center (Lebanon, NH) was formed in November 1994 to improve the care of patients with diagnosis-related group (DRG) 148 or 149. Consulting two large, administrative databases and the medical literature, the team found that a substantial gap existed between the bowel surgery delivery process and the best results, as far as they were known, among comparable organizations. After flowcharting the delivery process, the team identified the high-leverage steps: same-day services, general surgery clinic, and routine care. The team then planned three successive PDCA (plan-do-check-act) cycles: utilization of same-day services for all elective surgery patients, establishment of a standardized preoperative bowel preparation, and utilization of pre- and postoperative routine care orders. These improvement cycles resulted in a reduction in length of stay from 9.66 to 8.29 days. Implementation of a critical pathway resulted in a further reduction to 5.04 days. CONCLUSION: Benchmarking can play an integral role in clinical improvement work and can stimulate wise clinical changes and promote measured improvements in quality and value.

Academic Medical Centers↗
PubMedDate not supplied

A comprehensive strategy for the evaluation and triage of the chest pain patient: a cost comparison study.

BACKGROUND: Our objective was to determine the cost-effectiveness of a comprehensive, risk-based triage system, composed of multiple critical pathways, with the use of early myocardial perfusion imaging (MPI) in low-risk patients. We found previously that a chest pain evaluation system that uses MPI in low-risk patients was safe and effective, but the cost-effectiveness of this approach was not studied. METHODS AND RESULTS: We compared two groups. The Acute Cardiac Team (ACT) group (n = 874) was assigned prospectively to 1 of 4 risk levels by emergency department (ED) physicians. Level 1, 2, and 3 patients were admitted; level 4 patients were evaluated in the ED. Level 3 and 4 patients underwent ED MPI. The control group (n = 713) represented consecutive patients evaluated in the prior year according to standard care and assigned retrospectively to an ACT level based on the presenting electrocardiographic and clinical data. Record and hospital administrative data were assessed for clinical variables, outcomes, lengths of stay, and all expenses incurred within 30 days of the index visit. The baseline characteristics of the two groups were similar, including age, sex, myocardial infarction prevalence, and 30-day revascularization rates within each level or between the two groups. Mean costs per encounter were reduced for the ACT patients for each level, which was significant when all patients were compared ($5,030 +/- $7,081 vs $6,044 +/- $10,432, P =.02). Use of MPI in the low-risk patients was associated with reduced costs (level 3, $4,958 +/- $4,948 vs $5,051 +/- $7,036; level 4, $1,529 +/- $2,664 vs $1,794 +/- $6,854) and was associated with a significantly lower angiography rate and shorter length of stay. CONCLUSIONS: Implementation of a comprehensive strategy for chest pain evaluation and triage reduced overall costs for patients with chest pain on presentation. Acute MPI in the ED setting did not increase net cost.

Adult↗
PubMedDate not supplied

Using information systems to measure and improve quality.

Information systems (IS) are increasingly important for measuring and improving quality. In this paper, we describe our integrated delivery system's plan for and experiences with measuring and improving quality using IS. Our belief is that for quality measurement to be practical, it must be integrated with the routine provision of care and whenever possible should be done using IS. Thus, at one hospital, we now perform almost all quality measurement using IS. We are also building a clinical data warehouse, which will serve as a repository for quality information across the network. However, IS are not only useful for measuring care, but also represent powerful tools for improving care using decision support. Specific areas in which we have already seen significant benefit include reducing the unnecessary use of laboratory testing, reporting important abnormalities to key providers rapidly, prevention and detection of adverse drug events, initiatives to change prescribing patterns to reduce drug costs and making critical pathways available to providers. Our next major effort will be introduce computerized guidelines on a more widespread basis, which will be challenging. However, the advent of managed care in the US has produced strong incentives to provide high quality care at low cost and our perspective is that only with better IS than exist today will this be possible without compromising quality. Such systems make feasible implementation of quality measurement, care improvement and cost reduction initiatives on a scale which could not previously be considered.

Computer Communication Networks↗
PubMed2003

IRE1: a role in UPREgulation of ER degradation.

The unfolded protein response entered the mechanistic realm with the discovery of IRE1 as the key signal transducer in yeast. Although also found in mammals, it appeared to function in assisting the work of other players. The featured studies indicate a separate role for IRE1, and highlight the flexibility that bigger eukaryotes possess in this critical pathway.

Animals↗
PubMed2003

NO-NSAIDs and cancer: promising novel agents.

Three potential applications of NO-donating NSAIDs in human cancer include their use: as chemopreventive agents; against already developed cancers (chemotherapy); and for the control of cancer symptoms, notably cancer pain. The evidence to date of greater safety and enhanced efficacy of NO-donating NSAIDs underscores their potential to prevent colon cancer and overcome the limitations of traditional NSAIDs. NO-donating NSAIDs affect several pathways critical to colon carcinogenesis and this may explain in part their greater efficacy in colon cancer prevention as assessed in preclinical models.

Animal Experimentation↗
PubMed2005

Extended glucuronidation is another major path of cyanidin 3-O-beta-D-glucopyranoside metabolism in rats.

We previously determined that five rather hydrophobic metabolites appeared in blood plasma after oral administration of cyanidin 3-O-beta-D-glucopyranoside, but a group of hydrophilic metabolites still remained unidentified. In the present study, 12 hydrophilic metabolites found were collected from urine and plasma samples by high-performance liquid chromatography (HPLC) and then analyzed by tandem MS spectrometry. From the MS spectra, four metabolites out of 12 were assigned as glucuronides of cyanidin 3-O-beta-D-glucopyranoside and six out of 12 were glucuronides of the primary metabolites of cyanidin 3-O-beta-D-glucopyranoside (O-methyl cyanidin 3-O-beta-D-glucopyranoside). Extended glucuronides of cyanidin 3-O-beta-D-glucopyranoside and O-methyl cyanidin 3-O-beta-D-glucopyranoside showed their maximum plasma concentrations at 15 and 60 min (or 30 min) after oral administration, respectively. Their maximum plasma concentrations ranged from 15 to 70 nM. From the profile of urinary-excreted anthocyanins after intravenous administration, it was deduced that extended glucuronides of cyanidin 3-O-beta-D-glucopyranoside and O-methyl cyanidin 3-O-beta-D-glucopyranoside were mainly produced in the liver rather than by intestinal flora. The area under the plasma concentration curve was 0.25 micromol min/L for extended glucuronides of cyanidin 3-O-beta-D-glucopyranoside and 0.14 micromol min/L for O-methyl cyanidin 3-O-beta-D-glucopyranoside, respectively, when evaluated as cyanidin 3-O-beta-D-glucopyranoside equivalent, indicating that extended glucuronidation is a critical pathway in cyanidin 3-O-beta-D-glucopyranoside metabolism in rats.

Animals↗
PubMed2003

The pyridyloxobutyl DNA adduct, O6-[4-oxo-4-(3-pyridyl)butyl]guanine, is detected in tissues from 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-treated A/J mice.

The tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), is a potent pulmonary carcinogen. This unsymmetric nitrosamine can be metabolically activated to lung DNA methylating and pyridyloxobutylating intermediates. The methyl DNA adducts are well characterized. The pyridyloxobutyl adducts are unstable under DNA hydrolysis conditions and decompose to release 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB). One of the HPB-releasing adducts,O6-[4-oxo-4-(3-pyridyl)butyl]guanine (O6-pobG), has been detected in DNA reacted in vitro with the model pyridyloxobutylating agent, 4-(acetoxymethylnitrosamino)-1-(3-pyridyl)-1-butanone (NNKOAc). To determine whether this adduct was formed in vivo, A/J mice were treated with 10 mumol of [5-3H]NNK and sacrificed 24 h postinjection. The mutagenic O6-pobG was detected in liver but not lung DNA from these animals. Since 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) is a major metabolite of NNK, it is also possible that these animals are activating NNAL to a pyridylhydroxybutylating agent. Therefore, we also measured the levels of O6-[4-hydroxy-4-(3-pyridyl)butyl]guanine (O6-phbG) in these DNA samples. While radioactivity did coelute with synthetic standard for this potential NNAL adduct in one lung DNA sample, significant levels of O6-phbG were not detected in any other lung or liver DNA samples. The pyridyloxobutyl adduct, O6-pobG, was also observed in lung and liver DNA from mice treated with 4.2 mumol of [5-3H]NNKOAc in the presence but not absence of 2.5 mumol of O6-benzylguanine, a known depletor of the repair protein O6-alkylguanine-DNA alkyltransferase (AGT). These data indicate that this adduct is formed in vivo but is repaired in part by AGT. Cell-free extracts from A/J mouse lung and liver were used to determine the relative rate of O6-alkylguanine repair. O6-mG and O6-pobG were removed from DNA to the same extent in a competitive assay, suggesting that low levels of O6-pobG in lungs of NNK-treated mice did not result from preferential repair of O6-pobG by AGT. It is more likely that initial levels of O6-pobG are much lower than initial levels of O6-mG in lung DNA from NNK-treated A/J mice. These data are consistent with previous studies, which indicate that DNA methylation is the critical pathway for NNK-induced lung carcinogenesis in A/J mice.

Animals↗
PubMed2003

Iron-induced oxidative stress modify tau phosphorylation patterns in hippocampal cell cultures.

Oxidative stress phenomena have been related with the onset of neurodegenerative diseases. Particularly in Alzheimer Disease (AD), oxygen reactive species (ROS) and its derivatives can be found in brain samples of postmortem AD patients. However, the mechanisms by which oxygen reactive species can alter neuronal function are still not elucidated. There is a growing amount of evidence pointing to a role for mitochondrial damage as the source of free radicals involved in oxidative stress. Among the species that participate in the production of oxygen reactive radicals, transition metals are one of the most important. Several reports have implicated the involvement of redox-active metals with the onset of different neurodegenerative diseases such as Alzheimer's Disease (AD), Progressive Supranuclear Palsy (PSP), Amyotrophic Lateral Sclerosis (ALS) and Parkinson's Disease (PD). On the other hand, our previous studies have indicated that A beta-induced deregulation of the protein kinase Cdk5 associated with tau protein hyperphosphorylation constitute a critical pathway toward neurodegeneration. In the current paper we have shown that iron induces an imbalance in the function of Cdk5/p25 system of hippocampal neurons, resulting in a marked decrease in tau phosphorylation at the typical Alzheimer's epitopes. The loss of phosphorylated tau epitopes correlated with an increase in 4-hydroxy-nonenal (HNE) adducts revealing damage by oxidative stress. This effects on tau phosphorylation patterns seems to be a consequence of a decrease in the Cdk5/p25 complex activity that appears to result from a depletion of the activator p25, a mechanism in which calcium transients could be implicated.

Animals↗
PubMed2002

Chemoprevention of prostate cancer: current status and future directions.

Prostate cancer chemoprevention can be described as the administration of natural products and pharmaceutical agents that inhibit one or more steps in the natural history of prostatic carcinogenesis. The principle components of the chemoprevention strategy are closely connected to this natural history and include: (a) agents and their molecular targets; (b) strategic intermediate endpoint biomarkers (IEBs) and their critical pathways; (c) cohorts identified by genetic and acquired risk factors and (d) efficient designs that combine these elements into a cohesive clinical trial. The primary goal is to find effective noncytotoxic agents that modulate the promotion and progression from normal epithelium to dysplasia to high-grade prostatic intraepithelial neoplasia (HGPIN) to locally invasive cancer and metastatic disease. Another important target for chemoprevention is to modulate progression to clinically aggressive disease and to maintain an androgen-sensitive clinical state and delay the emergence of androgen resistance. There is a rationale for use of antiandrogens as the lead class, e.g., 5 alpha receptor inhibitors (5ARI), for chemoprevention of prostate cancer. Nevertheless, the desire to improve the therapeutic index, achieve synergy (5ARI may have only modest anticancer effects) and prevent the emergence of drug (androgen) resistance provide incentives for developing other effective agents and combinations. The availability of more than a dozen classes of noncytotoxic pharmaceutical and natural products already in clinical development create many opportunities for rational combination therapy. Several agent classes have a pharmacodynamic basis for combination with antiandrogens including antiproliferatives, selective estrogen receptor modulators (SERMs), proapoptotic antioxidant micronutrients and selective cyclo-oxygenase (COX)-2 inhibitors. Many other rational pharmacodynamic combinations without antiandrogens are feasible. It is anticipated that in the future, a selective COX-2 inhibitor may be combined with other agent classes such as proapoptotic antioxidant micronutrients, receptor tyrosine kinase modulators, antiangiogenic modulators, antiproliferative/differentiating agents, NFkappaB modulators, IGF-1 modulators and other novel proapototic nonsteroidal drugs. A novel target for rational combinations is the hypermethylation of GST-PI leading to functional silencing of this key anticarcinogen defense enzyme in precursors (HGPIN) and prostate cancer. Factorial designs are well suited for evaluating the individual and combined effects of each agent in a single trial design. There are a number of moderate to high-risk cohorts and clinical models of primary and secondary prevention that can be employed in both short-term developmental (translational) trials for proof of biologic activity and in intermediate sized longer-term chemoprevention trials for proof of efficacy against prostate cancer. Strategic IEBs are needed to more efficiently monitor short-term biologic activity and validate efficacy. The emergence of new powerful tools such as gene chip cDNA microarrays for multiplex gene expression profiling and proteomic analysis of tissue based and secreted proteins will accelerate the identification of new molecular targets, strategic endpoints, cohorts at risk and the design of rational combination trials.

Anticarcinogenic Agents↗
PubMed2003

Amiodarone prevents symptomatic atrial fibrillation and reduces the risk of cerebrovascular accidents and ventricular tachycardia after open heart surgery: results of the Atrial Fibrillation Suppression Trial (AFIST).

BACKGROUND: Atrial fibrillation (AF) is a common complication after cardiothoracic surgery (CTS). The role of amiodarone added to beta blocker as a preventive strategy in elderly patients undergoing CTS is not known. The Atrial Fibrillation Suppression Trial (AFIST) was a double blind, placebo-controlled trial that evaluated the efficacy of oral amiodarone in patients 60 years or older undergoing CTS. Beta blockers were administered as part of a critical pathway. METHODS: Elderly patients (n = 220, mean age 72 +/- 6.7 years) received amiodarone (n = 120) or placebo (n = 100). Patients enrolled less than 5 days before CTS received 6 g of drug over 6 days beginning on the day prior to OHS. Patients enrolled 5 days before CTS received 7 g of study drug over 9-10 days, starting on preoperative day 4 or 5. RESULTS: Amiodarone treated patients had a lower incidence of AF (22.5% vs. 38%, p = 0.01), symptomatic AF (4.2% vs. 18%, p = 0.001), cerebral vascular accident (1.7 vs. 7.0%, p = 0.04), and ventricular tachycardia (1.7% vs. 7.0%, p = 0.04) vs. placebo. Beta blocker use (87.5% vs. 91.0% ), nausea (26.7% vs. 16%, p = 0.056), symptomatic bradycardia (7.5% vs. 7%, p = 0.89), hypotension (14.2% vs. 10.0%) and 30 day mortality (3.3 vs. 4.0%, p = 0.79) were similar. Amiodarone treated patients receiving the 4/5 day preoperative regimen had a reduced incidence of AF (19.6% vs. 38%, p = 0.013), while those receiving the 1-day preoperative regimen showed a trend (25% vs. 38%, p = 0.06) vs. placebo. CONCLUSIONS: In an elderly population undergoing CTS, Amiodarone prophylaxis reduces AF, the incidence of symptomatic AF, cerebrovascular accident and ventricular tachycardia.

Administration, Oral↗
PubMed2004

Utilization of guidelines and computer-based technology to achieve optimal care in atherothrombotic vascular disease.

Recently there have been numerous advances in the treatment of UA/NSTEMI based on large randomized trials. However, there are also data from several registries that have shown underutilization of these therapies. National guidelines, such as the ACC/AHA Guidelines are designed to provide clinicians recommendations for optimal care. There are some initial data from the TIMI 3 and GUARANTEE registries that publication of such guidelines does appear to help improve compliance with evidence-based optimal care, however, it appears that critical pathways and specific tools such as standardized orders or checklists are needed to more fully implement the recommendations. One newer type of tool are Palm Pilot programs such as the 3 presented here, where it is hoped that their use at the bedside with provide clinicians rapid access to evidence-based medicine ina format that can be useful in a busy practice setting.

Arteriosclerosis↗