Secondary Surgical Cytoreduction for Recurrent Ovarian Cancer.

BACKGROUND: Secondary surgical cytoreduction in women with platinum-sensitive, recurrent epithelial ovarian, primary peritoneal, or fallopian-tube ("ovarian") cancer is widely practiced but has not been evaluated in phase 3 investigation. METHODS: We randomly assigned patients with recurrent ovarian cancer who had received one previous therapy, had an interval during which no platinum-based chemotherapy was used (platinum-free interval) of 6 months or more, and had investigator-determined resectable disease (to no macroscopic residual disease) to undergo secondary surgical cytoreduction and then receive platinum-based chemotherapy or to receive platinum-based chemotherapy alone. Adjuvant chemotherapy (paclitaxel-carboplatin or gemcitabine-carboplatin) and use of bevacizumab were at the discretion of the investigator. The primary end point was overall survival. RESULTS: A total of 485 patients underwent randomization, 240 to secondary cytoreduction before chemotherapy and 245 to chemotherapy alone. The median follow-up was 48.1 months. Complete gross resection was achieved in 67% of the patients assigned to surgery who underwent the procedure. Platinum-based chemotherapy with bevacizumab followed by bevacizumab maintenance was administered to 84% of the patients overall and was equally distributed between the two groups. The hazard ratio for death (surgery vs. no surgery) was 1.29 (95% confidence interval [CI], 0.97 to 1.72; P = 0.08), which corresponded to a median overall survival of 50.6 months and 64.7 months, respectively. Adjustment for platinum-free interval and chemotherapy choice did not alter the effect. The hazard ratio for disease progression or death (surgery vs. no surgery) was 0.82 (95% CI, 0.66 to 1.01; median progression-free survival, 18.9 months and 16.2 months, respectively). Surgical morbidity at 30 days was 9%; 1 patient (0.4%) died from postoperative complications. Patient-reported quality of life decreased significantly after surgery but did not differ significantly between the two groups after recovery. CONCLUSIONS: In this trial involving patients with platinum-sensitive, recurrent ovarian cancer, secondary surgical cytoreduction followed by chemotherapy did not result in longer overall survival than chemotherapy alone. (Funded by the National Cancer Institute and others; GOG-0213 ClinicalTrials.gov number, NCT00565851.).

Initial testing of the use of the Safer Nursing Care Tool in a Canadian acute care context.

AIM: Initial testing of England's Safer Nursing Care Tool for adult in-patient acute care wards in a university-affiliated Canadian hospital. BACKGROUND: Safe-nursing staffing decisions have significant impacts on patients' safety and quality of care. The Safer Nursing Care Tool was developed in England to provide managers with a validated formula for making appropriate nursing staffing decisions. The tool has been widely used and studied in the UK but has yet to be tested in a Canadian context. METHOD: Ten high service quality acute care wards from a university-affiliated Canadian hospital tested the use of the Safer Nursing Care Tool. Service quality, patients' dependency/acuity and staff activity data were benchmarked against information collected in 726 comparable UK wards. RESULTS: Higher bed occupancy and patient dependency/acuity mix were found in the 10 Canadian wards compared to their UK counterparts. Overall staff activity was comparable between UK and Canadian wards. CONCLUSION: The Safer Nursing Care Tool can be applied in this Canadian hospital, and further testing in other hospitals and specialties is required. IMPLICATION FOR NURSING MANAGEMENT: The Safer Nursing Care Tool is a valid staffing tool to use that, when combined with professional judgement, can help managers to properly establish nursing staff in acute care wards.

Placental Chorionic Cyst Fluid Has Prothrombotic Properties and Differs From Amniotic Fluid.

INTRODUCTION: Chorionic cysts of the chorion laeve, fetal chorionic plate, septum, and free membranes have been associated with placental hypoxia, but they have no clear clinical significance. Although immunohistochemistry has identified fibronectin and collagen IV in cyst fluid, the contents have yet to be fully characterized. METHODS: Placental chorionic cysts (N = 10) were sampled by fluid extraction and hemotoxylin and eosin-stained sections. Amniotic fluid samples (N = 8) were obtained from pregnant women who had cytogenetic evaluation. The content of the cysts was tested for thrombogenicity using thromboelastography. The cyst content was tested by Luminex multiplex and ELISA assays and for known prothrombotic and proinflammatory factors. RESULTS: We identified cysts, especially those in the chorionic plate, adjacent to intervillous thrombi with apparent cyst rupture. Thromboelastography revealed a significantly shorter R time compared to whole blood control samples. Concentration of creatinine, α-fetoprotein, and surfactant D in the cyst fluid differed significantly from amniotic fluid. Cyst fluids had a significantly higher expression of all prothrombotic and some proinflammatory factors. DISCUSSION: Our data provide the first evidence that chorionic cyst fluid is prothrombotic and different from amniotic fluid. The association of ruptured cysts with adjacent thrombi and the prothrombotic properties of cyst fluid suggest a causal relationship; however, further studies are needed.

A tool to calculate safe nurse staffing levels.

A guideline from the National Institute for Health and Care Excellence and a NICE-endorsed tool on safer nursing care allow decisions on safe staffing levels to be made at a local level. Decisions must be based on sound evidence and factoring in patients' individual needs as well as numbers of patients. The Safer Nursing Care Tool helps nurses decide on safe nurse staffing for acute wards based on patients' level of sickness and dependency. It also includes quality indicators linked to nursing care to help ensure staffing levels achieve best patient care. The tool is easy to use by frontline nursing staff, but must be applied correctly and consistently for data to be valid, and to allow benchmarking against agreed standards. It should be combined with nurses' professional judgement and account for local factors.

Isoprostane and isofuran lipid mediators accumulate in stored red blood cells and influence platelet function in vitro.

BACKGROUND: Stored red blood cells (RBCs) release hemoglobin (Hb) that leads to oxidative damage, which may contribute to thrombosis in susceptible transfusion recipients. Oxidative stress stimulates the generation of a new class of lipid mediators called F2 -isoprostanes (F2 -IsoPs) and isofurans (IsoFs) that influence cellular behavior. This study investigated RBC-derived F2 -IsoPs and IsoFs during storage and their influence on human platelets (PLTs). STUDY DESIGN AND METHODS: F2 -IsoP and IsoF levels in RBC supernatants were measured by mass spectrometry during storage and after washing. The effects of stored supernatants, cell-free Hb, or a key F2 -IsoP, 8-iso-prostaglandin F2α (PGF2α ), on PLT function were examined in vitro. RESULTS: F2 -IsoPs, IsoFs, and Hb accumulated in stored RBC supernatants. Prestorage leukoreduction reduced supernatant F2 -IsoPs and IsoFs levels, which increased again over storage time. Stored RBC supernatants and 8-iso-PGF2α induced PLT activation marker CD62P (P-selectin) expression and prothrombotic thromboxane A2 release. Cell-free Hb did not alter PLT mediator release, but did inhibit PLT spreading. Poststorage RBC washing reduced F2 -IsoP and IsoF levels up to 24 hours. CONCLUSIONS: F2 -IsoPs and IsoFs are produced by stored RBCs and induce adverse effects on PLT function in vitro, supporting a potential novel role for bioactive lipids in adverse transfusion outcomes. F2 -IsoP and IsoF levels could be useful biomarkers for determining the suitability of blood components for transfusion. A novel finding is that cell-free Hb inhibits PLT spreading and could adversely influence wound healing. Poststorage RBC washing minimizes harmful lipid mediators, and its use could potentially reduce transfusion complications.

Alterations of platelet function and clot formation kinetics after in vitro exposure to anti-A and -B.

BACKGROUND: ABO-mismatched platelets (PLTs) are commonly transfused despite reported complications. We hypothesized that because PLTs possess A and B antigens on their surface, ABO-mismatched transfused or recipient PLTs could become activated and/or dysfunctional after exposure to anti-A or -B in the transfused or recipient plasma. We present here in vitro modeling data on the functional effects of exposure of PLTs to ABO antibodies. STUDY DESIGN AND METHODS: PLT functions of normal PLTs of all ABO types were assessed before and after incubation with normal saline, ABO-identical plasma samples, or O plasma samples with varying titers of anti-A and anti-B (anti-A/B). Assays used for this assessment include PLT aggregation, clot kinetics, thrombin generation, PLT cytoskeletal function, and mediator release. RESULTS: Exposure of antigen-bearing PLTs to O plasma with moderate to high titers of anti-A/B significantly inhibits aggregation, prolongs PFA-100 epinephrine closure time, disrupts clot formation kinetics, accelerates thrombin generation, reduces total thrombin production, alters PLT cytoskeletal function, and influences proinflammatory and prothrombotic mediator release. CONCLUSIONS: Our findings demonstrate a wide range of effects that anti-A/B have on PLT function, clot formation, thrombin generation, PLT cytoskeletal function, and mediator release. These data provide potential explanations for clinical observations of increased red blood cell utilization in trauma and surgical patients receiving ABO-nonidentical blood products. Impaired hemostasis caused by anti-A/B interacting with A and B antigens on PLTs, soluble proteins, and perhaps even endothelial cells is a potential contributing factor to hemorrhage in patients receiving larger volumes of ABO-nonidentical transfusions.

The aryl hydrocarbon receptor ligand ITE inhibits TGFß1-induced human myofibroblast differentiation.

Fibrosis can occur in any human tissue when the normal wound healing response is amplified. Such amplification results in fibroblast proliferation, myofibroblast differentiation, and excessive extracellular matrix deposition. Occurrence of these sequelae in organs such as the eye or lung can result in severe consequences to health. Unfortunately, medical treatment of fibrosis is limited by a lack of safe and effective therapies. These therapies may be developed by identifying agents that inhibit critical steps in fibrotic progression; one such step is myofibroblast differentiation triggered by transforming growth factor-ß1 (TGFß1). In this study, we demonstrate that TGFß1-induced myofibroblast differentiation is blocked in human fibroblasts by a candidate endogenous aryl hydrocarbon receptor (AhR) ligand 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE). Our data show that ITE disrupts TGFß1 signaling by inhibiting the nuclear translocation of Smad2/3/4. Although ITE functions as an AhR agonist, and biologically persistent AhR agonists, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin, cause severe toxic effects, ITE exhibits no toxicity. Interestingly, ITE effectively inhibits TGFß1-driven myofibroblast differentiation in AhR(-/-) fibroblasts: Its ability to inhibit TGFß1 signaling is AhR independent. As supported by the results of this study, the small molecule ITE inhibits myofibroblast differentiation and may be useful clinically as an antiscarring agent.

PCBs in indoor air and human blood in Pittsfield, Massachusetts.

Concentrations of polychlorinated biphenyls (PCBs) and three chlorinated pesticides were determined in serum from 21 residents of Pittsfield, MA and in the basement, living room and outdoor air of the 10 homes in which they lived. Median serum PCB levels were 4.2 ng/g, which are at least four times the average level in the US population, and consisted primarily of more highly chlorinated, persistent congeners. This reflects contamination with PCBs coming from the local General Electric facility. Median basement air concentration was 20.3 ng/m3, while the median living room air was 11.4 ng/m3 and median outdoor air concentration was 3.0 ng/m3. The PCB congeners detected in air were primarily low chlorinated (four and fewer) congeners, reflecting the greater volatility of PCBs with fewer chlorines. The congener pattern between basement and living room air showed a 95% correlation, while correlation with outdoor air was much less. While the congener pattern in air is very different from that of the PCB products used in Pittsfield (Aroclors 1254 and 1260), low chlorinated PCBs are detected in the vapor phase after air is blown across the commercial mixtures. The human serum samples did not show detectible levels of many of the congeners seen in the basement air samples, reflecting rapid metabolism of lower chlorinated PCBs by the human body. However, with continuous inhalation of indoor air, especially in the living room, the exposure to these non-persistent congeners may still have adverse health effects. Cellular studies of some of these non-persistent, low chlorinated congeners indicate that they are neurotoxic, mutagenic and cytotoxic. These results demonstrate the importance of consideration of inhalation of PCBs as a route of exposure, especially in indoor sites, and suggest that monitoring serum PCB concentration may not always provide a good measurement of exposure, especially to congeners that are relatively rapidly metabolized but have significant toxicity.

Platelets and megakaryocytes contain functional nuclear factor-kappaB.

OBJECTIVE: To investigate the presence and role of NF-kappaB proteins in megakaryocytes and platelets. The nuclear factor-kappaB (NF-kappaB) transcription factor family is well known for its role in eliciting inflammation and promoting cell survival. We discovered that human megakaryocytes and platelets express the majority of NF-kappaB family members, including the regulatory inhibitor-kappaB (I-kappaB) and I-kappa kinase (IKK) molecules. METHODS AND RESULTS: Anucleate platelets exposed to NF-kappaB inhibitors demonstrated impaired fundamental functions involved in repairing vascular injury and thrombus formation. Specifically, NF-kappaB inhibition diminished lamellapodia formation, decreased clot retraction times, and reduced thrombus stability. Moreover, inhibition of I-kappaB-alpha phosphorylation (BAY-11-7082) reverted fully spread platelets back to a spheroid morphology. Addition of recombinant IKK-beta or I-kappaB-alpha protein to BAY inhibitor-treated platelets partially restored platelet spreading in I-kappaB-alpha inhibited platelets, and addition of active IKK-beta increased endogenous I-kappaB-alpha phosphorylation levels. CONCLUSIONS: These novel findings support a crucial and nonclassical role for the NF-kappaB family in modulating platelet function and reveal that platelets are sensitive to NF-kappaB inhibitors. As NF-kappaB inhibitors are being developed as antiinflammatory and anticancer agents, they may have unintended effects on platelets. On the basis of these data, NF-kappaB is also identified as a new target to dampen unwanted platelet activation.

Occurrence of PCBs in raw and finished drinking water at seven public water systems along the Hudson River.

Polychlorinated biphenyls (PCBs) were measured in raw and finished drinking water at seven Public Water Systems (PWSs) along the Hudson River as part of a baseline monitoring program prior to the extensive sediment dredging of the Upper Hudson River. Water samples were either analyzed using an Aroclor method (based on USEPA Method 508) or a congener method (Modified Green Bay Mass Balance Method). Using the congener-based method, raw water concentrations ranged from <9.3 to 164.3 ng/L and finished water concentrations ranged from <9.3 to 186.6 ng/L. Using the Aroclor method, finished water concentrations ranged from <5.0 to 200.9 ng/L. Most finished water samples above 73.0 ng/L were from a PWS with wells drilled near the river. Excluding the well data, total PCB concentrations in raw water at systems in the Upper River were similar to concentrations at systems in the Lower River, though the congener patterns differed. Paired comparison of total PCB concentrations using the two analytical methods showed good agreement, although raw water showed a different relationship than finished water.

Comparing existing national and international classification systems of surgical procedures with the CEN/ISO 1828 ontology framework standard.

Among different standardization strategies for biomedical terminologies the European Standard Body CEN TC 251 followed by ISO TC 215 have stated that it was not possible to convince the different European or international member states using different national languages to agree on a reference clinical terminology or to standardize a detailed language independent biomedical ontology. Since 1990 they have developed since an approach named the Categorial Structure that standardises only the terminologies' model structure. The methodology for the Categorial Structure development and a comparison of the different existing classification systems based on this ontology framework is presented as a step towards increased interoperability between biomedical terminologies through conformity to a minimum set of ontological requirements.

Developing, testing and applying instruments for measuring rising dependency-acuity's impact on ward staffing and quality.

PURPOSE: This paper aims to explains how relatively simple nurse staffing formulas from "best practice" ward dependency-acuity data can be used for nursing workforce planning and development. DESIGN/METHODOLOGY/APPROACH: The paper combines literature, detailed ward surveys, workshop and expert group/stakeholder information to generate and test care levels/nurse multipliers for setting ward establishments. FINDINGS: The paper finds that professional-judgement based ward staffing can be abandoned, while complex acuity-quality, timed-task and regression-based nurse staffing algorithms for setting ward establishments may be unnecessary since the new multipliers, underpinned by robust validity and reliability testing, seem to be remarkably accurate nurse-staffing determiners at a fraction of the cost. RESEARCH LIMITATIONS/IMPLICATIONS: As care levels and multipliers stand they are suitable only for UK National Health Service acute wards. Primary care, mental health, learning disability and other specialist group care levels and multipliers need developing. PRACTICAL IMPLICATIONS: Users, at a minimum, can adopt care level data and multiplier staffing recommendations for benchmarking purposes. Ultimately, the algorithms can be used to: adjust ward establishments according to workload; or set staffing for new, inpatient services. ORIGINALITY/VALUE: The paper offers a simple system for assessing patients' nursing needs and setting ward staffing accordingly.

Infectivity of herpes simplex virus type-1 (HSV-1) amplicon vectors in dendritic cells is determined by the helper virus strain used for packaging.

Herpes simplex virus type-1 (HSV-1) amplicon vectors are being explored for a wide range of potential applications, including vaccine delivery and immunotherapy of cancer. While extensive effort has been directed towards the improvement of the amplicon "payload" in these vectors, relatively little attention has been paid to the effect of the packaging HSV-1 strains on the biological properties of co-packaged amplicon vectors. We therefore compared the biological properties of amplicon stocks prepared using a panel of primary HSV-1 isolates, a molecularly cloned strain used to package helper-free amplicons (designated here as F5), and two laboratory isolates (KOS and strain 17, which is the parent of the F5 clone). This analysis revealed considerable inter-strain variability in the ability of amplicon stocks packaged by different primary HSV-1 isolates to efficiently transduce established cell lines and primary human dendritic cells (DC). Amplicons packaged by both the F5 molecularly cloned virus and its laboratory-adapted parent (strain 17) were very inefficient at transducing DC, when compared to amplicons packaged by KOS or by several of the primary virus isolates. These finding have important implications for the future development of improved amplicon-based vaccine delivery systems and suggest that DC tropism may be an instrinsic property of some HSV-1 strains, independent of passage history or molecular cloning.

HSV amplicon-mediated Abeta vaccination in Tg2576 mice: differential antigen-specific immune responses.

Given the participation of amyloid beta (Abeta) in Alzheimer's disease (AD) pathogenesis the derivation of experimental therapeutics to prevent Abeta fibrillogenesis and/or enhance removal of parenchymal amyloid deposits represent viable disease-modifying approaches. Active Abeta-based immunotherapies have shown promise in mouse AD models, but application in human trials was accompanied by moderate brain inflammation in a subset of patients. Immune-shaping vaccine platforms may mitigate adverse effects. Herein, we describe the use of herpes simplex virus (HSV)-derived amplicons to elicit distinctive immune responses against Abeta. Two vaccine vectors were constructed: one expressing Abeta1-42 alone (HSVAbeta), and a second expressing Abeta1-42 fused with the molecular adjuvant tetanus toxin Fragment C (HSVAbeta/TtxFC). Peripheral administration of these vaccines augmented humoral responses to Abeta and reduced CNS Abeta deposition in Tg2576 AD mice. Interestingly and unexpectedly, HSVAbeta vaccination was uniquely toxic and incited the expression of pro-inflammatory molecule transcripts within the hippocampi of Tg2576 mice, suggesting that this paradigm may serve as a relevant model to study Abeta vaccine-elicited CNS inflammatory syndromes.

From dogs to frogs: how pets, laboratory animals, and wildlife aided in elucidating harmful effects arising from a hazardous dumpsite.

The medical literature contains many examples of cases in which serendipitous observations have led to important findings. In the example described in this article, laboratory and field observations conducted at the Mohawk Nation Community of Akwesasne led to the important and unexpected finding that frogs once plentiful in the area were no longer observed. Laboratory tests comparing river sediments from Akwesasne to pristine sediment from Ithaca, NewYork, indicated multiple adverse health effects on developing frogs. Some of the behavioral changes observed in the laboratory were similar to those described by residents of Akwesasne before the onset of amphibian decline. The magnitude of changes paralleled frog body burden of polychlorinated biphenyls acquired from the Akwesasne sediment. The impact of these findings on the identification of a hazardous waste site and global amphibian decline are discussed.

Platelet proteome changes associated with diabetes and during platelet storage for transfusion.

Human platelets play a key role in hemostasis and thrombosis and have recently emerged as key regulators of inflammation. Platelets stored for transfusion produce pro-thrombotic and pro-inflammatory mediators implicated in adverse transfusion reactions. Correspondingly, these mediators are central players in pathological conditions including cardiovascular disease, the major cause of death in diabetics. In view of this, a mass spectrometry based proteomics study was performed on platelets collected from healthy and type-2 diabetics stored for transfusion. Strikingly, our innovative and sensitive proteomic approach identified 122 proteins that were either up- or down-regulated in type-2 diabetics relative to nondiabetic controls and 117 proteins whose abundances changed during a 5-day storage period. Notably, our studies are the first to characterize the proteome of platelets from diabetics before and after storage for transfusion. These identified differences allow us to formulate new hypotheses and experimentation to improve clinical outcomes by targeting "high risk platelets" that render platelet transfusion less effective or even unsafe.