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The nuclear peroxisome proliferator-activated receptor δ (PPARδ) is an important regulator of lipid metabolism. In contrast to its known effects on energy homeostasis, its biological role on inflammation is not well understood. We investigated the role of PPARδ in the modulation of the nuclear factor-κB (NF-κB)-driven inflammatory response to polymicrobial sepsis in vivoand in macrophages in vitro. We demonstrated that administration of GW0742, a specific PPARδ ligand, provided beneficial effects to rats subjected to cecal ligation and puncture, as shown by reduced systemic release of pro-inflammatory cytokines and neutrophil infiltration in lung, liver, and cecum, when compared with vehicle treatment. Molecular analysis revealed that treatment with GW0742 reduced NF-κB binding to DNA in lung and liver. In parallel experiments, heterozygous PPARδ-deficient mice suffered exaggerated lethality when subjected to cecal ligation and puncture and exhibited severe lung injury and higher levels of circulating tumor necrosis factor-α (TNFα) and keratinocyte-derived chemokine than wild-type mice. Furthermore, in lipopolysaccharide-stimulated J774.A1 macrophages, GW0742 reduced TNFα production by inhibiting NF-κB activation. RNA silencing of PPARδ abrogated the inhibitory effects of GW0742 on TNFα production. Chromatin immunoprecipitation assays revealed that PPARδ displaced the NF-κB p65 subunit from the κB elements of the TNFα promoter, while recruiting the co-repressor BCL6. These data suggest that PPARδ is a crucial anti-inflammatory regulator, providing a basis for novel sepsis therapies.

Hepatic encephalopathy is a syndrome whose pathophysiology is poorly understood, for which we lack high-quality diagnostic tests and markers, and whose treatment has improved only slightly over the last several decades. Serum ammonia levels remain the diagnostic gold standard.

The authors administered surveys to develop an operational definition of oral neglect in institutionalized elderly (ONiIE) in the United States.

Research was conducted for the FTA Office of Program Management to refine contingency estimation and application within the transit project development process. General analytical methodologies were developed for contingencies, and applications were suggested for the estimation of contingency values, including cost and schedule contingencies proposed for the related Project Management Oversight Program guidance. The results present various cost and schedule contingency approaches that have been applied successfully to major transit projects and other public infrastructure projects examined within the research. The results of the research indicate which contingency applications and values may contribute to more successful project management in the future. These strategies, tools, and techniques form the basis to the conclusions for this research. The cost performance of construction projects is a key success criterion for project sponsors, including the grantees and the FTA. Major transit capital projects have, at times, overrun initial and subsequent project budgets. Cost contingency has been proposed by many funding and research organizations to manage cost escalation and maintain project budgets. Schedule contingencies have been proposed more recently similarly to control and manage schedule delays, because of their identified cost impacts. Estimation of cost and schedule contingencies and its ultimate adequacy is of critical importance to projects. The results of the research present various cost and schedule contingency concepts, including definition of terms, estimation of values, and application of contingency approaches within the transit project development process.

To ascertain whether increases in psychological symptoms in children and parents after meningococcal disease are sustained over time, and to examine the psychosocial and illness associations of 12-mo psychological outcome.

A robust screen for compound interaction with P-glycoprotein (P-gp) has some obvious requirements, such as a cell line expressing P-gp and a probe substrate that is transported solely by P-gp and passive permeability. It is actually difficult to prove that a particular probe substrate interacts only with P-gp in the chosen cell line. Using a confluent monolayer of MDCKII-hMDR1 cells, we have determined the elementary rate constants for the P-gp efflux of amprenavir, digoxin, loperamide, and quinidine. For amprenavir and quinidine, transport was fitted with just P-gp and passive permeability. For digoxin and loperamide, fitting required a basolateral transporter (p < 0.01), which was inhibited by the P-gp inhibitor N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918). This means that when digoxin is used as a probe substrate and a compound is shown to inhibit digoxin flux, it could be that the inhibition occurs at the basolateral transporter rather than at P-gp. Digoxin basolateral>apical efflux also required an apical importer (p < 0.05). We propose that amprenavir and quinidine are robust probe substrates for assessing P-gp interactions using the MDCKII-hMDR1 confluent cell monolayer. Usage of another cell line, e.g., LLC-hMDR1 or Caco-2, would require the same kinetic validation to ensure that the probe substrate interacts only with P-gp. Attempts to identify the additional digoxin and loperamide transporters using a wide range of substrates/inhibitors of known epithelial transporters (organic cation transporters, organic anion transporters, organic ion-transporting polypeptide, uric acid transporter, or multidrug resistance-associated protein) failed to inhibit the digoxin or loperamide transport through their basolateral transporter.

Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated nuclear receptor with effects on inflammation, atherosclerosis, and apoptosis. The endogenous PPARγ ligand, 15-deoxy-Δ12,14-PGJ2(15d-PGJ2), and the synthetic ligand, ciglitazone, have anti-inflammatory properties in endothelial cells. In addition to PPARγ-dependent effects on the anti-inflammatory process, it has been proposed that PPARγ ligands may also inhibit the nuclear transcription factor κB (NFκB) pathway in a PPARγ-independent manner. The purpose of this study was to compare the effects of 15d-PGJ2and ciglitazone on the cytokine-induced activation of the NFκB pathway. Human umbilical vein endothelial cells (HUVECs) were transiently transfected with NFκB-luciferase or PPARγ elements-luciferase reporter constructs for 48 h. The HUVECs were pretreated with 15d-PGJ2or ciglitazone (30 μM) for 1 h, followed by a 4-h stimulation with tumor necrosis factor α (100 U/mL). Luciferase assay was performed to determine reporter activity. Additionally, HUVECs were transiently transfected with a dominant-negative mutant, which retains ligand and DNA binding but exhibits markedly reduced transactivation. Stimulation of HUVEC with tumor necrosis factor α increased NFκB activation while decreasing PPARγ activity. Overexpression of a dominant-negative PPARγ mutant prevented the inhibitory effect of ciglitazone on cytokine-induced NFκB activation in transfected human endothelial cells. Conversely, 15d-PGJ2inhibited the cytokine-induced NFκB activation even in the absence of PPARγ. Our data suggest that 15d-PGJ2exerts direct inhibitory effects on the NFκB pathway through a PPARγ-independent mechanism. On the contrary, the inhibitory effect of ciglitazone on the NFκB pathway seems to require PPARγ activation.

Peroxisome proliferator-activated receptor-γ (PPAR-γ) is a nuclear receptor that regulates diverse biological functions including inflammation. The PPARγ ligands have been reported to exert cardioprotective effects and attenuate myocardial reperfusion injury. Here, we examined the molecular mechanisms of their anti-inflammatory effects. Male Wistar rats were subjected to myocardial ischemia and reperfusion and were treated with the PPAR-γ ligands, 15-deoxy-Δ12,14-prostaglandin J2(15d-PGJ2) or ciglitazone, or with vehicle only, in the absence or presence of the selective PPAR-γ antagonist GW-9662. In vehicle-treated rats, myocardial injury was associated with elevated tissue activity of myeloperoxidase, indicating infiltration of neutrophils, and elevated plasma levels of creatine kinase and tumor necrosis factor-α. These events were preceded by activation of the nuclear factor-κB pathway. The PPAR-γ DNA binding was also increased in the heart after reperfusion. Treatment with ciglitazone or 15d-PGJ2reduced myocardial damage and neutrophil infiltration and blunted creatine kinase levels and cytokine production. The beneficial effects of both ligands were associated with enhancement of PPAR-γ DNA binding and reduction of nuclear factor-κB activation. Treatment with 15d-PGJ2, but not ciglitazone, enhanced DNA binding of heat shock factor 1 and upregulated the expression of the cardioprotective heat shock protein 70. Treatment with 15d-PGJ2, but not ciglitazone, also induced a significant increase in nuclear phosphorylation of the prosurvival kinase Akt. The cardioprotection afforded by ciglitazone was attenuated by the PPAR-γ antagonist GW-9662. In contrast, GW-9662 did not affect the beneficial effects afforded by 15d-PGJ2. Thus, our data suggest that treatment with these chemically unrelated PPAR-γ ligands results in diverse anti-inflammatory mechanisms.

The article reports on building social capital in the U.S. According to the author, social capital increases when students get involved in their communities via school activities. The author states that creating relationships between schools and communities benefit both parties. The author mentions the use of service-learning to build social capital.

Peroxisome proliferator-activated receptor- (PPAR) and liver X receptor- (LXR) are nuclear ligand-activated transcription factors, which regulate lipid metabolism and inflammation. Murine J774.2 macrophages were stimulated with Escherichia colilipopolysaccharide (concentration, 10 g/mL) with or without the PPAR ligand, 15-deoxy-12,14prostaglandin J2(15d-PGJ2), or the LXR ligands, 22(R)-hydroxycholesterol and T0901317 (concentration range, 0.01-10 mol/L), alone or in combination. Nitric oxide (NO) metabolites and tumor necrosis factor production, inducible NO synthase expression, and mitochondrial respiration were measured. When added to the cells as single agents, 15d-PGJ2, 22(R)-hydroxycholesterol, or T0901317 reduced the lipopolysaccharide-induced NO and tumor necrosis factor production and the inducible NO synthase expression, and partially maintained mitochondrial respiration in a concentration-dependent manner. When added to the cells in combination at suboptimal concentrations, 15d-PGJ2with 22(R)-hydroxycholesterol, or 15d-PGJ2with T0901317, exerted anti-inflammatory effects similar to much higher concentrations (10,000-fold to 100,000-fold) of each ligand alone. The anti-inflammatory effects of these ligands, alone or in combination, were associated with reduction of nuclear factor-B activation and with enhancement of PPAR DNA binding. LXR expression was upregulated in response to 15d-PGJ2and to the LXR ligands when added alone or in combination. Immunoprecipitation experiments revealed that PPAR interacted with LXR. Our data demonstrate that the PPAR ligand, 15d-PGJ2, and the LXR ligands, 22(R)-hydroxycholesterol and T0901317, although binding to different nuclear receptors (i.e., PPAR and LXR, respectively), affect mediator production through common cell signaling events and exert a synergistic potentiation in a combined treatment at suboptimal concentrations. Thus, our data suggest that PPAR and LXR may interact in controlling the inflammatory response in macrophages.

Healthcare systems, especially hospital operating room suites, have properties that make them ideal for the study of the cognitive work using the naturalistic decision-making (NDM) approach. This variable, complex, high-tempo setting provides a unique opportunity to examine the ways that clinicians plan, monitor, and cope with the irreducible uncertainty that underlies this work domain. As frontline managers, anesthesia coordinators plan and manage anesthesia assignments for surgical procedures. As frontline managers, coordinators develop and use cognitive artifacts to distribute cognition across time and among members of the acute care staff. Examination of these cognitive artifacts and their use reveals the hidden subtleties of the coordinators’ work. The use of NDM methods including cognitive artifact analysis to understand cognitive work generates insights that extend beyond the operator level to the study of team-level cognition. Results can be used to create computer-based artifacts that aid individual and team cognition.

Pancreatic cancer is the fourth leading cause of cancer death in the United States. It is highly aggressive with no uniformly effective chemotherapy available for metastatic disease. The sodium–iodide symporter (NIS) is a transmembrane protein responsible for uptake of iodide into cells. The presence of NIS in thyroid cells permits diagnostic imaging and therapy of thyroid tumors, using radioiodide. Previous studies from this laboratory reported mucin-1 (MUC1)-driven expression of NIS in cancer cells. MUC1 overexpression has also been reported in 90% of pancreatic tumors. In this study Ad5/MUC1/NIS was used to infect pancreatic cancer cells both in vitro and in vivo, to investigate the potential for radioiodide imaging and ablation of this disease. In vitro studies revealed a 43-fold increase in iodide uptake in NIS-transduced cells compared with controls. In vivo imaging revealed effective iodide uptake and retention at the site of NIS-transduced tumors, with optimal uptake (13% of injected dose) observed 5 hr after iodide administration. Intravenous delivery was performed to investigate potential hepatotoxicity of the construct in the event of virus leakage. Intravenous injection of Ad5/CMV/NIS resulted in robust iodide uptake throughout mouse liver, whereas no uptake was detected in the liver of animals given Ad5/MUC1/NIS intravenously. Administration of therapeutic doses of 131I resulted in significant regression of NIS-transduced tumors, with a mean 50% reduction in volume within 10 weeks of therapy (p < 0.0001). The ability to target NIS expression to pancreatic cancer, which has such limited treatment options, may be highly beneficial and warrants further investigation.

Periodic pulses of the insect steroid molting hormone 20‐hydroxyecdysone (20E), acting via its nuclear receptor complex (EcR/USP), control gene expression at many stages throughout Drosophila development. However, during the last larval instar of some lepidopteran insects, subtle changes in titers of ecdysteroids have been documented, including the so‐called “commitment peak.” This small elevation of 20E reprograms the larva for metamorphosis to the pupa. Similar periods of ecdysteroid immunoreactivity have been observed during the last larval instar of Drosophila. However, due to low amplitude and short duration, along with small body size and staging difficulties, their timing and ecdysteroid composition have remained uncertain. Employing a rigorous regimen of Drosophila culture and a salivary gland reporter gene, Sgs3‐GFP, we used RP‐HPLC and differential ecdysteroid RIA analysis to determine whole body titers of 20E during the last larval instar. Three small peaks of 20E were observed at 8, 20, and 28 hr following ecdysis, prior to the well‐characterized large peak around the time of pupariation. The possible regulation of 20E levels by biosynthetic P450 enzymes and the roles of these early peaks in coordinating gene expression and late larval development are discussed. Developmental Dynamics 235:315–326, 2006. © 2005 Wiley‐Liss, Inc.

Accurate detection of West Nile virus (WNV) in corvids is essential for monitoring the spread of virus during the mosquito season. Viremia in corvids is very high, with titers approaching 108viral particles/ml. In the presence of such marked viremia, the sensitivity of real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis is unnecessary, and more cost-effective methods should be assessed. To this end, antigen-capture ELISA (ACE) and immunohistochemical (IHC) assays were evaluated. Skin, cloacal swab specimens, and feathers from corvids were tested by use of ACE, and results were compared with results obtained from use of real-time RT-PCR analysis. Of the 3 sample types, skin gave the best sensitivity (98%) and specificity (100%). Skin, brain, kidney, and spleen from corvids were analyzed by IHC, and results were compared with real-time RT-PCR results. Kidney and spleen were more often positive by use of IHC than were brain and skin tissue; however, IHC did not perform as well as ACE in the identification of virus-positive birds. Results of this study support the use of a skin sample in an ACE format as an effective surveillance method for corvids.

The article highlights the 21st Annual Historic Brass Society's Early Brass Festival at Bennington College in Bennington, Vermont. Two ensembles presented concerts of brass band music that covered the second half of the nineteenth-century. The event also featured lectures and performances on cornet, ophicleide, keyed bugle, and post horn.

Reports on the innovation of base and stations of the U.S. Marine Corps' air-ground task force. Implementation of countertactics in the fight against the terrorist enemies; Transformation of bases and stations to a regional management model; Creation of the Installation Advocacy Board and Regional News Boards.

Peroxisome proliferator-activated receptor-γ (PPARγ) is a nuclear receptor that requires ligand activation for transcription. Experimental studies have shown that 15-deoxy-Δ12,14-PGJ2(15d-PGJ2) is a natural PPARγ ligand which has potent anti-inflammatory properties. This study was designed to examine the effect and the molecular mechanisms of 15d-PGJ2on tissue neutrophil infiltration and survival in endotoxic shock. Male Swiss albino mice were subjected to intraperitoneal injection of Escherichia colilipopolysaccharide (LPS, 25 mg/kg). Three hours after LPS mice received vehicle or 15d-PGJ2(1 mg/kg) and continued treatment every 12 hours. Survival was monitored for 72 hours. In a separate experiment, mice were sacrificed 6 hours after LPS and tissue examined. In vehicle-treated mice, LPS injection resulted in a survival rate of 9%. Marked lung injury was characterized by hemorrhage, infiltration of inflammatory cells and reduction of alveolar space. Elevated levels of myeloperoxidase activity in lung and small intestine were indicative of infiltration of neutrophils. Increased expression of intercellular adhesion molecule-1, vascular cellular adhesion molecule-1 and E-selectin were observed in the lung and small intestine. These inflammatory events were associated with reduced expression of PPARγ and with activation of nuclear factor-κB (NF-κB) in the lung. Treatment with 15d-PGJ2improved survival rate to 55%, downregulated expression of adhesion molecules and reduced neutrophil infiltration in tissues. These beneficial effects were associated with reduced activation of NF-κB DNA binding, whereas expression and DNA binding of PPARγ and expression of the cytoprotective heat shock protein (HSP) 70 were increased in the lung. Our data demonstrate that 15d-PGJ2ameliorates endotoxic shock most likely through repressing the proinflammatory pathway of NF-κB and enhancement of the cytoprotective heat shock response.

Previous studies have shown that a single dose of methylnaltrexone, a unique peripheral opioid antagonist, reverses opioid‐induced gut hypomotility in humans. Because repeated drug doses are likely to be needed to treat patients with opioid‐induced or postsurgical bowel dysfunction, the authors have now examined the safety, pharmacological activity, and pharmacokinetics of a multiple‐dose regimen of methylnaltrexone, administered as 12 consecutive intravenous doses (0.3 mg/kg every 6 hours) in 12 healthy subjects. Steady state was achieved rapidly, and after repeated dosing for 3 days, methylnaltrexone decreased oral‐cecal transit time from a pretreatment baseline value of 101.3 ± 29.4 min (mean ± SD) to 82.5 ± 20.7 min. Maximum observed plasma concentrations, measured 5 minutes postdose, were 538 ± 237 and 675 ± 180 ng/mL after doses 1 and 2, respectively. Based on 6‐hour sampling periods, the plasma half‐life, 2.5 ± 0.5 and 2.9 ± 0.9 hours following the 1st and 12th doses, respectively, was unchanged at steady state. There was essentially no accumulation of methylnaltrexone, based on the ratio of AUC values after doses 12 and 1. This study showed that repeated administration of intravenous methylnaltrexone is well tolerated in humans, with no significant adverse events or changes in opioid subjective ratings and no clinically noteworthy alterations in pharmacokinetics. The observation of a significant reduction in the gut transit time after repeated administration of methylnaltrexone to these opioid‐naive volunteers suggests that endogenous opioids modulate human gut motility.

To compare the performance characteristics of three compact gamma camera systems for scintimammography.

During myocardial reperfusion injury, oxidative stress induces DNA damage and activation of the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1), resulting in cardiovascular dysfunction. In this study, we investigated the biological effects and the molecular mechanisms of two structurally unrelated selective inhibitors of PARP-1, 3-aminobenzamide (3-AB) and 1,5-dihydroxyisoquinoline (1,5-DIQ), in an in vivomodel of myocardial ischemia and reperfusion. Male Wistar rats were subjected to 30 min of occlusion followed by reperfusion (up to 24 h) of the left anterior descending coronary artery. In vehicle-treated rats, ischemia and reperfusion induced extensive myocardial damage and marked neutrophil infiltration (as indicated by myeloperoxidase activity). Caspase 3 was maximally activated within 15 to 30 min after reperfusion, suggesting the occurrence of apoptosis. These inflammatory events were associated with activation of the transcription factor activator protein-1 (AP-1) in the reperfused hearts. Treatment of the rats with the PARP-1 inhibitors, 3-AB or 1,5-DIQ, reduced myocardial damage, neutrophil infiltration, and caspase activation. This cardioprotection was associated with reduction of AP-1 activation. Furthermore, in in vitrocytokine-stimulated human endothelial cells, expression of intercellular adhesion molecule 1, vascular cellular adhesion molecule 1, and P- and E-selectin was significantly reduced by treatment with 3-AB or 1,5-DIQ. On the contrary, in vivoor in vitrotreatment with nicotinic acid, a chemical analogue of PARP inhibitors, which lacks the ability to inhibit the catalytic activity of PARP-1, was unable to afford any protective effect and to prevent activation of AP-1. Our data demonstrate that inhibition of catalytic activity of PARP-1 may provide cardioprotection by regulating stress-induced signal transduction pathways.

In myocardial perfusion imaging, the type of orbit that provides the best image quality is still the subject of debate. This study correlates the effects of angular rotation (180° vs. 360°), type of orbit (circular vs. body contouring) and location of the heart within the orbit, with changes in spatial resolution and consequential changes in the uniformity of short axis slices of a normal myocardial phantom.

Scenario planning was used to identify issues and drivers of change that are relevant to community efforts to improve regional prospects in the Western Australian Wheatbelt. The region, some 20 million hectares in area, is under pressure to respond to a variety of environmental (salinity, erosion, acidification, biodiversity decline), economic (declining agricultural terms of trade), and social forces (rural decline, isolation). Regional strategic plans have been increasingly seen as the means of achieving sustainability in the face of these challenges, but until recently typically had single-activity outlook and timeframes of up to a decade into the future. Systematic futures-based research has been used in various regions to avoid reliance on business-as-usual as the default strategy, and to identify opportunities and challenges not presently apparent. The Avon River Basin, the central region of the Wheatbelt, was selected as the geographic focus of the project, and the time horizon was set at 2050. The project was developed by a group of 50 stakeholders from the basin, with expertise and strategic interests across a wide range of economic, social, and environmental themes. Through a series of workshops the stakeholders identified critical issues and their attendant drivers, then documented relevant past trends. Four regional scenarios, Saline Growth, Grain and Drain, Landcare Bounty, and Harmony with Prosperity, were developed based on positive and negative combinations of 2 clusters of uncertain and important drivers: environmental change and access to new markets. Common opportunities, threats, and critical success factors for the Avon River Basin region out to 2050 were also identified. We also found that the stakeholders have a tendency to strive for positive outcomes despite negative initial conditions. This resulted in 4 scenarios that were superficially similar due to the regional scale of analysis and the continuation of agricultural industries as significant shapers of economy, society, and environment. However, each scenario represents profoundly different outcomes for the residents and communities of the Avon River Basin in 2050. The triple-bottom line outcomes for the Avon River Basin in 2050 were estimated to be in the range 4.9?9.7 Mt of wheat (currently 4.0), 46 000?66 000 people (currently 43 000), and 10?30% of farmland salinised (currently 6). The application of these results to other regions in Australia is discussed.

Sera from 1,448 adult ewes in 91 flocks, representing all 26 counties in the Republic of Ireland, were examined for pestivirus antibodies using a commercially available ELISA which detected IgG1antibody to border disease virus. Eighty-one sheep (5.6%) in 42 flocks (46.0%) were antibody-positive. Within infected flocks, the mean seroprevalence level was 11.4% with a range of 6.3% to 30.0%. The highest antibody prevalence was detected in sheep from central lowland counties of Ireland. Comparative neutralisation testing of 42 ELISA-positive sera detected geometric mean antibody titres of 136 to the NADL strain of bovine viral diarrhoea virus (BVDV), 92 to the Moredun strain of border disease virus and 21 to the 137/4 strain of border disease virus. These results suggest that BVDV may be the major ruminant pestivirus infecting sheep in Ireland. Although there are high numbers of infected flocks, many sheep within such flocks remain antibody-negative and are at risk of giving birth to lambs with congenital border disease.

The Edmonston vaccine strain of measles virus (MV-Edm) propagates efficiently in a broad range of human tumor cells, killing them selectively. However, the oncolytic potency of MV-Edm in different human tumor xenograft therapy models is highly variable and there is no convenient way to map the distribution of virus-infected tissues in vivo. To enhance the oncolytic potency of MV-Edm against radiosensitive malignancies and to facilitate noninvasive imaging of infected tissues, we generated a recombinant MV-Edm encoding the human thyroidal iodide symporter (NIS). MV-NIS replicated almost as efficiently as unmodified MV-Edm, and human tumor cells efficiently concentrated radioiodine when infected with MV-NIS. Intratumoral spread of MV-NIS was noninvasively demonstrated by serial gamma-camera imaging of iodine-123 (123I) uptake both in MV-sensitive KAS-6/1 myeloma xenografts, which regressed completely after a single intravenous dose of MV-NIS, and in MM1 myeloma xenografts, which were unresponsive to MVNIS therapy. However, MV-resistant MM1 tumors regressed completely when 131I was administered 9 days after a single intravenous injection of MV-NIS (radiovirotherapy). 131I alone had no effect on MM1 tumor growth. While the potential hematopoietic toxicity of this new therapy requires further evaluation, image-guided radiovirotherapy is a promising new approach to the treatment of multiple myeloma, an incurable but highly radiosensitive plasma cell malignancy. Testing in other radiosensitive cancers is warranted.

Multiple myeloma is a disseminated neoplasm of terminally differentiated plasma cells that is incurable with currently available therapies. Although the disease is radiosensitive, external beam radiation leads to significant toxicity due to sensitive end-organ damage. Thus, genetic approaches for therapy are required. We hypothesized that the incorporation of immunoglobulin promoter and enhancer elements in a self-inactivating (SIN) lentiviral vector should lead to specific and high-level transgene expression in myeloma cells. A SIN lentivector with enhanced green fluorescent protein (EGFP) expression under the control of a minimal immunoglobulin promoter as well as the Kappa light chain intronic and 3′ enhancers transduced myeloma cell lines with high efficiency (30%-90%). EGFP was expressed at a high level in myeloma cells but silent in all nonmyeloma cell lines tested compared with the cytomegalovirus (CMV) promoter/enhancer. Transduction of myeloma cells with the targeted vector coding for the human sodiumiodide symporter (hNIS) led to hNIS expression by these cells allowing them to concentrate radioiodine up to 18-fold compared with controls. Tumor xenografts in severe combined immunodeficiency mice expressing hNIS could be imaged using iodine-123 (123I) and shown to retain iodide for up to 48 hours. These tumor xenografts were completely eradicated by a single dose of the therapeutic isotope iodine-131 (131I) without evidence of recurrence up to 5 months after therapy. We conclude that lentivectors can be transcriptionally targeted for myeloma cells and the use of hNIS as a therapeutic gene for myeloma in combination with 131I needs further exploration.

Poly(ADP-ribose) polymerase-1 (PARP-1) is activated in response to DNA injury in eukaryotic cells and has been implicated in cell dysfunction in reperfusion injury. In this study we investigated the role of PARP-1 on apoptosis in early myocardial reperfusion injury. Mice genetically deficient of PARP-1 (PARP-1−/−) and wild-type littermates were subjected to myocardial ischemia and reperfusion. Myocardial injury was assessed by measuring the serum levels of creatine phosphokinase and oligonucleosomal DNA fragments in the infarcted area. Expression of the anti-apoptotic protein, Bcl-2, and the pro-apoptotic protein, Bax, was analyzed by Western blot. Activation of caspases, important executioners of apoptosis, and activation of the nuclear factor κB (NF-κB) pathway were evaluated. Gene expression profiles for apoptotic regulators between PARP-1−/−and wild-type mice also were compared. Myocardial damage in PARP-1−/−mice was reduced significantly, as indicated by lower serum creatine phosphokinase levels and reduction of apoptosis, as compared with wild-type mice. Western blot analyses showed increased expression of Bcl-2, which was associated with reduction of caspase-1 and caspase-3 activation. This cardioprotection was associated with significant reduction of the activation of IκB kinase complex and NF-κB DNA binding. Microarray analysis demonstrated that the expression of 29 known genes of apoptotic regulators was significantly altered in PARP-1−/−mice compared with wild-type mice, whereas 6 known genes were similarly expressed in both genotypes. The data indicate that during reperfusion absence of PARP-1 leads to reduction of myocardial apoptosis, which is associated with reduced NF-κB activation and altered gene expression profiles.

Maori stories and symbols offer Westerns counselors a rich heritageof wisdom. This article provides a summary of key Maori mythologyand worldview highlighting the profound significance of sacredgeography—manifested in the marae(meeting ground) andthe wharenui(meeting house)—and family (whenau) imbedded in genealogy (whakapa). The authors then considerrelated significance for contemporary Maori, offer questions andapplications for western counsellors, and acknowledge essentialconsultation from a Maori staff advisor (te kaiurungi).

The role of nitric oxide (NO) generated by the inducible NO synthase (iNOS) during myocardial ischemia and reperfusion is not understood. We investigated the role of iNOS during early reperfusion damage induced in genetically deficient iNOS (iNOS‐/‐) mice and wild‐type littermates. In wild‐type mice, ischemia (60 min) and reperfusion (60 min) induced an elevation in serum levels of creatine phosphokinase and myocardial injury characterized by the presence of scattered apoptotic myocytes and mild neutrophil infiltration. Northern blot analysis showed increased expression of iNOS, whose activity was markedly elevated after reperfusion. Immunohistochemistry showed staining for nitrotyrosine; Western blot analysis showed elevated expression of heat shock protein 70 (HSP70), a putative cardioprotective mediator. Plasma levels of nitrite and nitrate, tumor necrosis factor α (TNF‐α), interleukin 6 (IL‐6), and IL‐10 were also increased. These events were preceded by degradation of inhibitor κBα (IκBα), activation of IκB kinase complex (IKK) and c‐Jun‐NH2‐terminal kinase (JNK), and subsequently activation of nuclear factor‐κB (NF‐κB) and activator protein 1 (AP‐1) as early as 15 min after reperfusion. In contrast, iNOS‐/‐mice experienced 35% mortality after reperfusion. The extensive myocardial injury was associated with marked apoptosis and infiltration of neutrophils whereas expression of HSP70 was less pronounced. Nitrotyrosine formation and plasma levels of nitrite and nitrate were undetectable. TNF‐α and IL‐6 were increased and IL‐10 was reduced in earlier stages of reperfusion. Activation of IKK and JNK and binding activity of NF‐κB and AP‐1 were significantly reduced. Thus, we conclude that iNOS plays a beneficial role in modulating the early defensive inflammatory response against reperfusion injury through regulation of signal transduction.—Zingarelli, B., Hake, P. W., Yang, Z., O’Connor, M., Denenberg, A., Wong, H. R. Absence of inducible nitric oxide synthase modulates early reperfusion‐induced NF‐κB and AP‐1 activation and enhances myocardial damage. FASEB J.16, 327–342 (2002)

ABSTRACTObjectives:1) To describe injuries experienced by the male prisoner population in the Kingston, Ontario area, and to compare them with those observed in the general population; and 2) to compare the incidence and patterns of prisoner injuries seen in emergency departments (EDs) before and after the introduction of a prison injury triage system.Design:A chart review.Setting:The catchment area surrounding 2 hospital-based EDs in Kingston, Ontario, which includes 8 federal and provincial prisons for adult males.Observations:Injuries to male prisoners (ages 18–75 years) who were treated in the ED during 1996–98 were compared with injuries to the general male population of the same age range. An on-site emergency care triage system was introduced to area prisons in 1993. Prisoner injuries seen in the ED during 1996–98 were compared with those seen during a similar period prior to the introduction of the triage system (1981–84). Available comparators included patient demographics, disposition, intent and nature of injury, the need for surgery, and lengths of hospital stay.Results:148 prisoner injuries were identified for 1996–98. Prisoner injuries seen in the ED were relatively severe when compared with the general male population, as indicated by the higher frequency of fractures (31.8% prisoner vs. 13.4% general, p< 0.001), blunt head injuries (10.1% vs. 2.2%, p< 0.001), hospital admissions (42.6% vs. 4.1%, p< 0.001) and deaths (2.7% vs. 0.6%, p< 0.001). Since the introduction of the triage system there has been a reduction in the rate of prisoner injuries seen in local hospital EDs (6.1/100/yr [before] vs. 1.6/100/yr [after], p< 0.001). There has been an increase in the relative severity of prisoner injuries seen in the EDs as indicated by the increased hospital admission rate (42.6% vs. 22.7%, p< 0.001), increased rate of surgical intervention (27.7% vs. 12.1%, p< 0.001), and increased length of hospital stay (4.0 days vs. 2.1 days, p< 0.05). The mortality rate has remained low and unchanged (0.7% vs. 1.1%, p= 0.99).Conclusions:The introduction of the new triage system appeared to be associated with a decrease in the total number of ED visits by prisoners. The relative acuity of prisoner injuries seen in the EDs appeared to increase following introduction of the triage system.

Many patients believe that the education they receive about their health and their illnesses is inadequate or lacking. Nurse executives are in a key position to influence their patients’ abilities to become more informed and to take greater responsibility for their healthcare decisions. In the article, the authors discuss Massachusetts General Hospital’s state-of-the-art consumer health information library, including how the project was planned, organized, and implemented.

This article summarises the regulatory regime underlying the Irish petroleum industry. This includes an overview of the incentives offered for petroleum activities offshore Ireland. It also examines the key provisions of a typical petroleum lease between an applicant and the Minister for the Marine and Natural Resources.

This paper presents our findings on the knowledge and use of the 1997 Earned Income Tax Credit (EITC) based on a sample of Chicago area households, with children, that filed tax returns in the winter and spring of 1998. Respondents reported in detail about using their federal tax refunds (including the EITC) to pay bills, purchase new items, or save. Data were also gathered on respondents' prior knowledge of the EITC and their ability to make particular expenditures without the help of the EITC. Uses of the EITC are divided into those that improve economic and social mobility (e. g., purchase a car, pay tuition, change residence) and those that primarily help to make ends meet (e. g., pay routine bills, purchase food). This is among the first papers to address these issues, despite the fact that the EITC is our largest refundable tax credit program targeted at low-income families.

The science and technology of transfusion have improved dramatically over the past decade. Improvements in screen ing for viral pathogens have reduced the risk of transfusion transmitted viral infections to historic lows. Newly recog nized entities, including the transfusion transmitted virus and Parvo viruses are being investigated as pathogens. There is increasing appreciation that bacterial infection and parasites may be transmitted via transfusion, and a variety of approaches are being developed to deal with them. Clin ical studies continue to conflict about what the ideal hemo globin for patients with cardiovascular disease should be, but several studies suggest that higher hematocrits may be beneficial. Factor deficiency may play a more important role in massive transfusion than previously believed. The impor tance of autologous predeposit of red cells and hemodilu tion may diminish as the blood supply becomes ever safer, but intraoperative salvage is likely to remain an important technique. Finally, although blood substitutes have been under development for more than 10 years, they have not yet become widely used in medicine. The few remaining products under development are presently in advanced clin ical trials but face a variety of clinical and economic obsta cles before they can rise to their potential.

The objective of this study was to determine whether reverse transcriptase inhibitors (RTIs) could decrease viral replication in microglia. Human microglia obtained from individuals undergoing temporal lobectomy were cultured and infected with HIV-1 isolates from the central nervous system (CNS) as previously described (Strizki JM, et al. J Virol 1996;70:7654-7662). These microglial cultures were treated with one of three nucleoside RTIs (NRTIs) or with efavirenz, a nonnucleoside RTI (NNRTI), at various time points before and during HIV-1 infection. The drug levels sufficient to provide > 90% inhibition of microglial HIV replication (IC90) were determined by comparison of p24gag release in the cultures among treated and untreated microglia. Infectious virus released from the infected cultures was also measured with U373-MAGI-CCR5 cells. Efavirenz, an NNRTI, blocked HIV-1DS-br infection of microglia with an IC90 of 0.7-7 nM. This value is similar to the efavirenz IC90 values for inhibition of laboratory and clinical isolates in lymphocytes, is 2-3 logs lower than the IC90 values of AZT and d4T, and is 1-2 logs lower than that of ddC in microglia. Efavirenz also inhibited infection with other neurotropic isolates, and with viruses isolated from other compartments that also replicated well in microglia. Thus, efavirenz is a potent inhibitor of HIV-1 infection in microglia. Furthermore, efavirenz IC90 drug levels are present in the cerebrospinal fluid (CSF) of patients taking this once daily NNRTI.