Impaired mitochondrial function is abrogated by dexrazoxane in doxorubicin-treated childhood acute lymphoblastic leukemia survivors.

BACKGROUND: Impaired cardiac function in doxorubicin-treated childhood cancer survivors is partly mediated by the disruption of mitochondrial energy production. Doxorubicin intercalates into mitochondrial DNA (mtDNA) and disrupts genes encoding for polypeptides that make adenosine triphosphate. METHODS: This cross-sectional study examined mtDNA copy numbers per cell and oxidative phosphorylation (OXPHOS) in peripheral blood mononuclear cells (PBMCs) in 64 childhood survivors of high-risk acute lymphoblastic leukemia (ALL) who had been treated on Dana-Farber Cancer Institute childhood ALL protocols and had received doxorubicin alone (42%) or doxorubicin with the cardioprotectant dexrazoxane (58%). The number of mtDNA copies per cell and the OXPHOS enzyme activity of nicotinamide adenine dinucleotide dehydrogenase (complex I [CI]) and cytochrome c oxidase (complex IV [CIV]) were measured with quantitative real-time polymerase chain reaction immunoassays and thin-layer chromatography, respectively. RESULTS: At a median follow-up of 7.8 years after treatment, the median number of mtDNA copies per cell for patients treated with doxorubicin alone (1106.3) was significantly higher than the median number for those who had also received dexrazoxane (310.5; P = .001). No significant differences were detected between the groups for CI or CIV activity. CONCLUSIONS: Doxorubicin-treated survivors had an increased number of PBMC mtDNA copies per cell, and concomitant use of dexrazoxane was associated with a lower number of mtDNA copies per cell. Because of a possible compensatory increase in mtDNA copies per cell to maintain mitochondrial function in the setting of mitochondrial dysfunction, overall OXPHOS activity was not different between the groups. The long-term sustainability of this compensatory response in these survivors at risk for cardiac dysfunction over their lifespan is concerning.

Role of membrane oxidation in controlling the activity of human group IIa secretory phospholipase A(2) toward apoptotic lymphoma cells.

The membranes of healthy lymphocytes normally resist hydrolysis by secretory phospholipase A(2). However, they become susceptible during the process of apoptosis. Previous experiments have demonstrated the importance of certain physical changes to the membrane during cell death such as a reduction in membrane lipid order and exposure of phosphatidylserine on the membrane surface. Nevertheless, those investigations also showed that at least one additional factor was required for rapid hydrolysis by the human group IIa phospholipase isozyme. This study was designed to test the possibility that oxidation of membrane lipids is the additional factor. Flow cytometry and confocal microscopy with a fluorescent probe of oxidative potential suggested that oxidation of the plasma membrane occurs during apoptosis stimulated by thapsigargin. When oxidative potential was high, the activity of human group IIa secretory phospholipase A(2) was enhanced 30- to 100-fold compared to that observed with conditions sufficient for maximal hydrolysis by other secretory phospholipase A(2) isoforms. Direct oxidation of cell membranes with either of two oxidizing agents also stimulated hydrolysis by secretory phospholipase A(2). Both oxidizers caused externalization of phosphatidylserine, but a change in lipid order did not always occur. These results demonstrated that membrane oxidation strongly stimulates human group IIa secretory phospholipase A(2) activity toward apoptotic cells. Interestingly, the change in membrane order, previously thought to be imperative for high rates of hydrolysis, was not required when membrane lipids were oxidized. Whether phosphatidylserine exposure is still necessary with oxidation remains unresolved since the two events could not be deconvoluted.

Pressure injury prevention success in a regional hospital.

BACKGROUND: This paper describes quality improvement strategies implemented following the identification of a significantly high prevalence rate and severity of pressure injuries in a regional health care facility in a large health district in Queensland, Australia. AIM: The aim of this paper is to inform health professionals of processes employed to reduce the incidence and financial burden of pressure injuries following the detection of rates that were significantly above the State average. METHOD: An audit of pressure injury prevalence data was conducted on a single day throughout a regional hospital. Prevalence data was compared to State averages and hospital strategies used to prevent injuries were examined. FINDINGS: Audit reports for this acute setting revealed that despite best practice guidelines, prevalence was a major concern. Lack of accountability, poor documentation, limited education and knowledge of risk assessment and prevention were central to the need to implement quality improvement processes. CONCLUSION: This paper outlines the results associated with implementing quality measures to reduce the prevalence of pressure injuries. Following an audit of pressure injury prevalence data, strategies were implemented to reduce noteworthy rates. Employing specific techniques can result in significantly decreasing hospital acquired pressure injuries in health care settings throughout the world.

Investigation into the role of phosphatidylserine in modifying the susceptibility of human lymphocytes to secretory phospholipase A(2) using cells deficient in the expression of scramblase.

Normal human lymphocytes resisted the hydrolytic action of secretory phospholipase A(2) but became susceptible to the enzyme following treatment with a calcium ionophore, ionomycin. To test the hypothesis that this susceptibility requires exposure of the anionic lipid phosphatidylserine on the external face of the cell membrane, experiments were repeated with a human Burkitt's lymphoma cell line (Raji cells). In contrast to normal lymphocytes or S49 mouse lymphoma cells, most of the Raji cells (83%) did not translocate phosphatidylserine to the cell surface upon treatment with ionomycin. Those few that did display exposed phosphatidylserine were hydrolyzed immediately upon addition of phospholipase A(2). Interestingly, the remaining cells were also completely susceptible to the enzyme but were hydrolyzed at a slower rate and after a latency of about 100s. In contradistinction to the defect in phosphatidylserine translocation, Raji cells did display other physical membrane changes upon ionomycin treatment that may be relevant to hydrolysis by phospholipase A(2). These changes were detected by merocyanine 540 and trimethylammonium diphenylhexatriene fluorescence and were common among normal lymphocytes, S49 cells, and Raji cells. The levels of these latter effects corresponded well with the relative rates of hydrolysis among the three cell lines. These results suggested that while phosphatidylserine enhances the rate of cell membrane hydrolysis by secretory phospholipase A(2), it is not an absolute requirement. Other physical properties such as membrane order contribute to the level of membrane susceptibility to the enzyme independent of phosphatidylserine.

Recyclable thermosets based on modified epoxy-amine network polymers.

The development of high performance, recyclable thermoset materials for applications in plastics, composites, coatings and adhesives requires a synthetic approach where recyclability is designed into the molecular structure of the material. This paper describes a single stage process for the creation of materials from simple, low-cost molecular building blocks, where the polymerisation of liquid epoxy resins and aliphatic amines in the presence of an n-butyl diboronic ester, delivers epoxy-amine-dioxazaborocane materials with tunable physical properties including glass transition temperature (Tg). Mechanical (thermal) recycling and reprocessing of the epoxy-amine-dioxazaborocane thermoset is demonstrated, with retention of Young's modulus and ultimate tensile strength. Most notably, an efficient and low-cost process for the chemical recycling, disassembly and dissolution of the thermoset is demonstrated via two complementary processes using either pinacol (diol) or mono-functional phenylboronic ester.

Phase contrast imaging in neonates.

Magnetic resonance phase images can yield superior gray and white matter contrast compared to conventional magnitude images. However, the underlying contrast mechanisms are not yet fully understood. Previous studies have been limited to high field acquisitions in adult volunteers and patients. In this study, phase imaging in the neonatal brain is demonstrated for the first time. Compared to adults, phase differences between gray and white matter are significantly reduced but not inverted in neonates with little myelination and iron deposits in their brains. The remaining phase difference between the neonatal and adult brains may be due to a different macromolecule concentration in the unmyelinated brain of the neonates and thus a different frequency due to water macromolecule exchange. Additionally, the susceptibility contrast from brain myelination can be separately studied in neonates during brain development. Therefore, magnetic resonance phase imaging is suggested as a novel tool to study neonatal brain development and pathologies in neonates.

Multi-contrast human neonatal brain atlas: application to normal neonate development analysis.

MRI is a sensitive method for detecting subtle anatomic abnormalities in the neonatal brain. To optimize the usefulness for neonatal and pediatric care, systematic research, based on quantitative image analysis and functional correlation, is required. Normalization-based image analysis is one of the most effective methods for image quantification and statistical comparison. However, the application of this methodology to neonatal brain MRI scans is rare. Some of the difficulties are the rapid changes in T1 and T2 contrasts and the lack of contrast between brain structures, which prohibits accurate cross-subject image registration. Diffusion tensor imaging (DTI), which provides rich and quantitative anatomical contrast in neonate brains, is an ideal technology for normalization-based neonatal brain analysis. In this paper, we report the development of neonatal brain atlases with detailed anatomic information derived from DTI and co-registered anatomical MRI. Combined with a diffeomorphic transformation, we were able to normalize neonatal brain images to the atlas space and three-dimensionally parcellate images into 122 regions. The accuracy of the normalization was comparable to the reliability of human raters. This method was then applied to babies of 37-53 post-conceptional weeks to characterize developmental changes of the white matter, which indicated a posterior-to-anterior and a central-to-peripheral direction of maturation. We expect that future applications of this atlas will include investigations of the effect of prenatal events and the effects of preterm birth or low birth weights, as well as clinical applications, such as determining imaging biomarkers for various neurological disorders.

Phylogeographic history of white spruce during the last glacial maximum: uncovering cryptic refugia.

Although a recent study of white spruce using chloroplast DNA uncovered the presence of a glacial refuge in Alaska, chloroplast failed to provide information on the number or specific localities of refugia. Recent studies have demonstrated the utility of nuclear microsatellites to refine insights into postglacial histories. The greater relative rate of mutation may allow finer scale resolution of historic dynamics, including the number, location, and sizes of refugia. Genetic data were acquired from screening 6 microsatellite loci on approximately 14 trees from each of 22 populations located across the central and western boreal forests of Canada and Alaska. Our studies combining microsatellites with Bayesian analyses of population structure in white spruce support the phylogeographic patterns uncovered using chloroplast, separating Alaskan from non-Alaskan regions. Results also support the idea that north-central Alaska served as a glacial refugium during the last glacial maximum. Additionally, the relationship between the degree of genetic differentiation and geographic distance indicated that gene flow played a more important role in structuring non-Alaskan populations, whereas drift played a more important role in structuring Alaskan populations (R(ST)'s for non-Alaskan populations 0.029 ± 0.007 and 0.083 ± 0.012 for Alaskan populations). Microsatellites also substantiate the bidirectional patterns of gene flow previously uncovered using chloroplast DNA but indicate much greater movement and mixing. Results from our Bayesian analyses also suggest the existence of additional cryptic refugia. However, the locations have been obscured by high gene flow (R(ST) averaging 0.057 ± 0.004).

States' Performance in Reducing Uninsurance Among Black, Hispanic, and Low-Income Americans Following Implementation of the Affordable Care Act.

Purpose: To assess state-level variation in changes in uninsurance among Black, Hispanic, and low-income Americans after implementation of the Affordable Care Act (ACA). Methods: We analyzed data from the Behavioral Risk Factor Surveillance System from 2012 to 2016, excluding 2014. For Black, Hispanic, and low-income (<$35,000/year) adults 18-64 years of age, we estimated multivariable regression adjusted pre- (2012-2013) to post-ACA (2015-2016) percentage point changes in uninsurance for each U.S. state. We compared absolute and relative changes and the proportion remaining uninsured post-ACA across states. We also examined whether state-level variation in coverage gains was associated with changes in forgoing needed care due to cost. Results: The range in the percentage point reduction in uninsurance varied substantially across states: 19-fold for Black (0.9-17.4), 18-fold for Hispanic (1.2-21.5), and 23-fold for low-income (1.0-27.8) adults. State-level variation in changes in uninsurance relative to baseline uninsurance rates also varied substantially. In some states, more than one quarter of Black, one half of Hispanic, and approaching one half of low-income adults remained uninsured after full implementation of the ACA. Compared with states in the lowest quintile of change in coverage, states in the highest quintile experienced greater improvements in ability to see a physician. Conclusions: Performance on reducing uninsurance for Black, Hispanic, and low-income Americans under the ACA varied substantially among U.S. states with some making substantial progress and others making little. Post-ACA uninsurance rates remained high for these populations in many states.

The relationship between structural empowerment and psychological empowerment for nurses: a systematic review.

AIM: To describe the findings of a systematic review examining the relationship between structural empowerment and psychological empowerment for registered nurses (RNs). BACKGROUND: Workplace empowerment research reveals a link between empowerment and positive work behaviours and attitudes. Research demonstrating the essential relationship between structural empowerment and psychological empowerment will provide direction for future interventions aimed at the development of a strong and effective health care sector. METHODS: Published research articles examining structural empowerment and psychological empowerment for nurses were selected from computerized databases and selected websites. Data extraction and methodological quality assessment were completed for the included research articles. RESULTS: Ten papers representing six studies reveal significant associations between structural empowerment and psychological empowerment for RNs. IMPLICATIONS FOR NURSING MANAGEMENT: Creation of an environment that provides structural empowerment is an important organizational strategy that contributes to RNs' psychological empowerment and ultimately leads to positive work behaviours and attitudes. Critical structural components of an empowered workplace can contribute to a healthy, productive and innovative RN workforce with increased job satisfaction and retention.

Biobehavioral measures in a critical-care healing environment.

Critical-care settings have an opportunity to create healing environments (HEs). For the last decade, achieving this goal has been the task of the American Association of Critical Care Nurses. Today, several models used in these settings embrace synergistic care, healing therapies for patients, and the development of organizational models to improve the HEs for nurses themselves. Creating the HE is not impossible; however, researching the patient's experience within it is complex. This complexity requires researchers to consider biological, behavioral, and social variables on the unit. This article will describe biological and behavioral measures that may be used to examine the critically ill patient's response to an HE. Limitations of these measures are considerable. Future researchers will need to consider a multiplistic approach to the study of this construct.

Additivity of nebivolol/valsartan single-pill combinations versus other single-pill combinations for hypertension.

The single-pill combination (SPC) comprising nebivolol (5 mg), a vasodilatory ß1 -selective antagonist/ß3 -agonist, and valsartan (80 mg), a renin-angiotensin-aldosterone system inhibitor, is the only Food and Drug Administration-approved ß-blocker/renin-angiotensin-aldosterone system inhibitor SPC for hypertension. Additive effects of four nebivolol/valsartan SPC doses (5 mg/80 mg, 5/160 mg, 10/160 mg, 10/320 mg nebivolol/valsartan) were compared with five Food and Drug Administration-approved non-ß-blocker/renin-angiotensin-aldosterone system inhibitor SPCs (aliskiren/hydrochlorothiazide, aliskiren/amlodipine, valsartan/amlodipine, aliskiren/valsartan, and telmisartan/amlodipine). Additivity is the ratio of placebo-adjusted SPC blood pressure (BP) reduction to the placebo-adjusted monotherapy component BP reduction sums. A weighted average of comparator scores was calculated and compared vs nebivolol/valsartan. Additivity ratio scores for nebivolol/valsartan SPCs (diastolic BP range: 0.735-0.866; systolic BP range: 0.717-0.822) were similar to the comparator weighted average (diastolic BP: 0.837; systolic BP: 0.825). Among the nebivolol/valsartan SPCs, 5/80 mg had the greatest additivity (diastolic BP: 0.866; systolic BP: 0.822). BP reduction contributions with monotherapy were similar for nebivolol/valsartan 5/80 mg SPC. Additivity scores for nebivolol/valsartan and select non-ß-blocker/renin-angiotensin-aldosterone system inhibitor SPCs were comparable.

Institutional and IACUC responsibilities for animal care and use education and training programs.

Training and instruction of personnel are important components of animal care and use programs because they help to ensure the health and welfare of the animals and the integrity of the research or testing results. Training also helps to promote the consideration of alternatives, recognition of animal pain and distress, appropriate use of pain-relieving agents, aseptic technique, pre- and post-procedural care, and personnel health and safety. While individuals who provide the care for or conduct research or testing in laboratory animals should take personal responsibility for ensuring that they have the skills to perform their duties, the institution is ultimately responsible for ensuring their competency. The institution is also responsible for providing the training or instruction that is required by federal legislation, regulations, and policies. The institutional animal care and use committee (IACUC) is responsible for ensuring, as part of their review of research activities, that the personnel are capable of performing the procedures described. The IACUC must also assess the institution's training program as part of their semiannual animal care and use program review and make recommendations regarding training to the institutional official. This article provides a comprehensive overview of the US regulatory mandates for training and personnel qualification.

Fundamental training for individuals involved in the care and use of laboratory animals: a review and update of the 1991 NRC Core Training Module.

Public trust demands that individuals who do research, testing, or teaching with animals use humane, ethical, and scientifically sound methods. Furthermore, the Animal Welfare Act and the Public Health Service Policy require research institutions to provide basic training and to ensure that anyone who cares for and/or works with laboratory animals has the appropriate training or experience relevant to their job responsibilities. Institutions accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International must also provide training programs and ensure the qualifications of personnel. The primary goal of this training is to provide individuals with basic knowledge and to reinforce attitudes and behaviors that help to ensure humane animal care and use. This article provides an overview of the core training module outline and content from the 1991 report of the Institute for Laboratory Animal Research, Education and Training in the Care and Use of Laboratory Animals: A Guide for Developing Institutional Programs, as well as pertinent updates for introducing personnel to information regarding the care and use of laboratory animals. Both mandatory and suggested training topics are reviewed, including relevant regulations and standards, ethical considerations, humane methods of animal experimentation and maintenance, and other pertinent topics. Although the fundamental training course content and delivery will vary depending on the nature and complexity of an institution's animal care and use program, this basic training provides the foundation for more in-depth training programs and supports humane and ethical animal care and use.

A workforce in crisis: a case study to expand allied ophthalmic personnel.

OBJECTIVE: To examine how the development of allied ophthalmic personnel training programs affects human resource capacity. DESIGN: Using a qualitative case study method conducted at a single Ontario institution, this article describes 6 years of establishing a 2-tiered allied ophthalmic personnel training program. PARTICIPANTS: The Kingston Ophthalmic Training Centre participated in the study with 8 leadership and program graduate interviews. METHODS: To assess regional eye health workforce needs, a case study and iterative process used triangulations of the literature, case study, and qualitative interviews with stakeholders. This research was used to develop a model for establishing allied ophthalmic personnel training programs that would result in expanding human resource capacity. RESULTS: Current human resource capacity development and deployment is inadequate to provide the needed eye care services in Canada. A competency-based curriculum and accreditation model as the platform to develop formal academic training programs is essential. Access to quality eye care and patient services can be met by task-shifting from ophthalmologists to appropriately trained allied ophthalmic personnel. CONCLUSION: Establishing formal training programs is one important strategy to supplying a well-skilled, trained, and qualified ophthalmic workforce. This initiative meets the criteria required for quality, relevance, equity, and cost-effectiveness to meet the future demands for ophthalmic patient care.

The transcription factor Nurr1 in human NT2 cells and hNT neurons.

Human, neuronally committed hNT or NT2-N cells, originally derived from the Ntera2/D1 (NT2) clone after exposure to retinoic acid (RA), represent a potentially important source of cells to treat neurodegenerative diseases. Our previous in vitro experiments showed that hNT cells possess immunocytochemically detectable markers typical of dopaminergic (DA) ventral mesencephalic (VM) neurons, including tyrosine hydroxylase (TH), dopamine transporter (DAT), dopamine receptor (D2), and aldehyde dehydrogenase (AHD-2). In the current study, we sought to examine whether Nurr1, an orphan receptor of the nuclear receptor superfamily shown to be essential for the development, differentiation and survival of midbrain DA neurons, would be expressed in 3, 4, or 5 week RA-induced hNT neurons and their NT2 precursors. Our immunocytochemical analyses indicate that NT2 cells as well as hNT neurons independent of the length of RA-driven differentiation were Nurr1-immunoreactive. RT-PCR analysis confirmed the expression of Nurr1-specific mRNA in both NT2 precursors and the hNT neurons. Furthermore, immunocytochemical co-expression of Nurr1 and TH was detected in hNT neurons. The findings of this study suggest that Nurr1 may be important during the development of hNT neurons and involved in their differentiation into the dopaminergic phenotype.

Reliability and validity of the Tobacco Craving Questionnaire and validation of a craving-induction procedure using multiple measures of craving and mood.

AIMS: To determine the reliability and validity of the Tobacco Craving Questionnaire (TCQ) and the validity of imagery scripts to elicit self-reported tobacco craving. DESIGN: Active imagery of three auditory scripts that described no-, low- and high-intensity of smoking urge. PARTICIPANTS: Current cigarette smokers (24 men, 24 women) not attempting to quit or reduce smoking. MEASUREMENTS: After each imagery condition, participants completed the 47-item TCQ, a Mood Form and Visual Analog Scale (VAS) questions. FINDINGS: Reliability of measures was demonstrated by internal consistency and unidimensionality of the four TCQ factors across imagery conditions. Criterion-related validity was demonstrated by an orderly increase in scores on the TCQ and VAS craving measures as a function of craving intensity of the imagery scripts. Increases in effect size parameters and parallel decreases in the stability of test-retest reliability for all craving measures indicated the validity of the imagery procedure. Convergent and discriminant validity were established by the craving scripts increasing self-reported craving, the no-craving (positive-affect) script increasing positive mood, the no-craving script not affecting craving and the craving scripts not affecting positive mood. CONCLUSIONS: Findings further demonstrated the reliability and validity of the TCQ as a multi-factorial instrument to assess the construct of tobacco craving and suggested that the lability of craving, rather than inconsistency and instability in its measurement, was responsible for observed effects.