Release of Proinflammatory Cytokines During Pediatric Cardiopulmonary Bypass: Heparin-Bonded Versus Nonbonded Oxygenators

Background. Heparin bonding of the cardiopulmonary bypass (CPB) circuit may be associated with a reduced inflammatory response and improved clinical outcome. The relative contribution of a heparin-bonded oxygenator (ie, >80% of circuit surface area) to these effects was assessed in a group of pediatric patients.

Methods. Twenty-one pediatric patients undergoing CPB operations were assigned randomly to receive either a heparin-bonded oxygenator (group H, n = 11) or a nonbonded oxygenator (group C, n = 10) in otherwise nonbonded circuits. The two groups were similar in pathology, age, weight, CPB time, and cross-clamp time. Plasma levels of the cytokines tumor necrosis factor-, interleukin-6, and interleukin-8, as well as terminal complement complex, neutrophils, and elastase, were analyzed before, during, and after CPB.

Results. Significant levels of tumor necrosis factor- were not detected in either group. Plasma levels of all other markers increased during and after CPB compared with baseline. Plasma levels of interleukin-6 peaked in both groups 2 hours after the administration of protamine but remained significantly higher in group C 24 hours after operation. Plasma concentrations of interleukin-8 peaked at similar levels in both groups 30 minutes after protamine administration and returned to baseline thereafter. Levels of terminal complement complex and elastase peaked in both groups 30 minutes after protamine administration. Plasma levels of terminal complement complex were significantly higher at the end of CPB and after protamine administration in group C. Elastase levels were significantly higher 2 and 24 hours after CPB in group C. The ventilation time of patients in group H was significantly lower than that of patients in group C: 10 (range, 3 to 24) versus 22 (range, 7 to 24) hours, respectively (p < 0.01).

Conclusions. The present study confirms the proinflammatory nature of pediatric operations and demonstrates a lessened systemic inflammatory response with the use of heparin-bonded oxygenators. This is achieved without bonding of the entire circuit, which could have significant cost-benefit implications by negating the need for custom-built heparin-bonded circuitry.     

Novel Mutations in the DYNC1H1 Tail Domain Refine the Genetic and Clinical Spectrum of Dyneinopathies

The heavy chain 1 of cytoplasmic dynein (DYNC1H1) is responsible for movement of the motor complex along microtubules and recruitment of dynein components. Mutations in DYNC1H1 are associated with spinal muscular atrophy (SMA), hereditary motor and sensory neuropathy (HMSN), cortical malformations, or a combination of these. Combining linkage analysis and whole‐exome sequencing, we identified a novel dominant defect in the DYNC1H1 tail domain (c.1792C>T, p.Arg598Cys) causing axonal HMSN. Mutation analysis of the tail region in 355 patients identified a de novo mutation (c.791G>T, p.Arg264Leu) in an isolated SMA patient. Her phenotype was more severe than previously described, characterized by multiple congenital contractures and delayed motor milestones, without brain malformations. The mutations in DYNC1H1 increase the interaction with its adaptor BICD2. This relates to previous studies on BICD2 mutations causing a highly similar phenotype. Our findings broaden the genetic heterogeneity and refine the clinical spectrum of DYNC1H1, and have implications for molecular diagnostics of motor neuron diseases.     

Persistence of Efficacy of 0.1% Cyclosporin A Cationic Emulsion in Subjects with Severe Keratitis Due to Dry Eye Disease: A Nonrandomized,Open-label Extension of the SANSIKA Study

Purpose

Results from a 6-month double-masked and a 6-month open-label study (SANSIKA) established the efficacy and safety of once-daily 0.1% cyclosporin A cationic emulsion (CsA CE) in severe keratitis due to dry eye disease (DED). This article presents results from the Post-SANSIKA study, a 24-month extension of SANSIKA assessing the sustained efficacy of CsA CE after treatment discontinuation.

Power wheelchair driving challenges in the community: a users’ perspective

Purpose: There is limited information on the difficulties individuals experience in manoeuvring their power wheelchairs during daily activities. The aim of this study was to describe the nature and context of power wheelchair driving challenges from the perspective of the user. Methods: A qualitative design using semi-structured interviews with power wheelchair users. Qualitative content analysis was used to identify themes. Results: Twelve experienced power wheelchair users were interviewed. Findings revealed that power wheelchair driving difficulties were related to the accomplishment of activities of daily living, and the influence of environmental context. Four key themes emerged: (1) difficulties accessing and using public buildings-facilities, (2) outdoor mobility, (3) problems in performing specific wheelchair mobility tasks/manoeuvres and (4) barriers and circumstances that are temporary, unforeseen or specific to a particular context. Conclusion: This qualitative study furthers our understanding of the driving difficulties powered wheelchair (PW) users experience during daily activities. This knowledge will assist clinicians and researchers in two areas: in choosing assessment measures that are ecologically valid for power wheelchair users; and, in identifying and refining the content of training programs specific to the use of power wheelchairs.

• Implications for Rehabilitation

• A better understanding of the everyday challenges individuals experience in driving their power wheelchair will assist clinicians and researchers in:

• Choosing assessment measures and identifying training programs for this population.

• Refining the content of power wheelchair training programs.

     

Lifestyle Risk Factors Associated with Arm Swelling Among Women with Breast Cancer

Background

Breast cancer-related lymphedema (BCRL) is a feared complication for breast cancer patients who have undergone axillary surgery. Although clinical risk factors for BCRL are defined, data are sparse regarding common exposures that might induce incident arm swelling. The goal of this study was to quantify the association between common exposures thought to be potential risk factors and the occurrence of incident arm swelling among breast cancer survivors with or at risk for BCRL.

Methods

This is a prospective subanalysis of the Physical Activity and Lymphedema (PAL) trial, a randomized controlled trial of 295 breast cancer survivors. Participants reported their exposure to 30 different potential risk factors at 3 month intervals for 1 year. Incident arm swelling was defined as a ≥5 % increase in interlimb water volume difference between two consecutive time points.

Results

Twenty-seven participants (9 %) experienced incident arm swelling and 268 patients (91 %) did not. Sauna use was the only exposure that was significantly predictive of incident arm swelling (p = 0.05). Nonwhite and nonblack participants had a significantly increased risk for experiencing incident arm swelling (p = 0.005 for both comparisons).

Conclusions

In our patient cohort, many common exposures that have been reported to be risk factors did not prove to have a significant predictive relationship for incident arm swelling. This study supports the recommendation that breast cancer patients who have had axillary surgery should avoid sauna use. The results do not confirm the need for other restrictions that may interfere with the quality of life in women with breast cancer.     

Genome-wide toxicogenomic study of the lanthanides sheds light on the selective toxicity mechanisms associated with critical materials

Lanthanides are a series of critical elements widely used in multiple industries, such as optoelectronics and healthcare. Although initially considered to be of low toxicity, concerns have emerged during the last few decades over their impact on human health. The toxicological profile of these metals, however, has been incompletely characterized, with most studies to date solely focusing on one or two elements within the group. In the current study, we assessed potential toxicity mechanisms in the lanthanide series using a functional toxicogenomics approach in baker’s yeast, which shares many cellular pathways and functions with humans. We screened the homozygous deletion pool of 4,291 Saccharomyces cerevisiae strains with the lanthanides and identified both common and unique functional effects of these metals. Three very different trends were observed within the lanthanide series, where deletions of certain proteins on membranes and organelles had no effect on the cellular response to early lanthanides while inducing yeast sensitivity and resistance to middle and late lanthanides, respectively. Vesicle-mediated transport (primarily endocytosis) was highlighted by both gene ontology and pathway enrichment analyses as one of the main functions disturbed by the majority of the metals. Protein–protein network analysis indicated that yeast response to lanthanides relied on proteins that participate in regulatory paths used for calcium (and other biologically relevant cations), and lanthanide toxicity included disruption of biosynthetic pathways by enzyme inhibition. Last, multiple genes and proteins identified in the network analysis have human orthologs, suggesting that those may also be targeted by lanthanides in humans.

Since their discovery, lanthanides have presented both difficulty and opportunity for researchers. As a series, these elements behave rather similarly: most of them form +3 ions in aqueous solution (1), prefer highly electronegative anionic ligands (2), and form insoluble hydroxide precipitates at neutral pH if not otherwise complexed (3). Although the chemical similarities between these elements made their initial isolation and characterization a significant challenge, they now have unique applications in industry and medicine. Several lanthanides have become critical materials for many clean and sustainable energy technologies that will drive the future of our societies and are used, for example, in the production of batteries, magnets, motors, and other electronic components (4); low-concentration mixtures of lanthanides are used in Chinese agriculture to increase body weight gain among livestock (5, 6); lanthanum carbonate (sold under the commercial name of Fosrenol) is a noncalcium phosphate binder used to control hyperphosphataemia (7); and gadolinium is employed in diagnostic medicine, as an essential component of MRI contrast agents (8, 9).The growing use of lanthanides has increased the potential for human exposure to large concentrations of these metals, requiring more detailed investigations into their toxicological properties. For instance, administration of gadolinium-based contrast agents has been associated with the development of nephrogenic systemic fibrosis in patients with compromised renal function (10–12). Moreover, accumulation of gadolinium in the brains of patients who received repeated doses of gadolinium-based contrast agents has also been reported (13). Despite the current ubiquity of lanthanides, their toxicological profile has been incompletely characterized because until recently they were considered to be of low toxicological concern (14, 15). Previous toxicity studies primarily focused on lanthanum or cerium (and, to a lesser extent, neodymium and gadolinium), with the notion that these metals were representative of the series (14, 16–18). However, to our knowledge, no comprehensive mechanistic assay has been conducted to evaluate metal toxicity across the series, and little is known about what toxicological mechanisms may be shared by the different lanthanides.Saccharomyces cerevisiae is one of the best-characterized model organisms (19, 20), and there are many tools available for analyzing its genomic data (21–23). For example, yeast functional toxicogenomic screening is a powerful tool for investigating cellular mechanisms of cytotoxicity (24, 25). This method makes use of the yeast deletion libraries generated by the Yeast Deletion Project (26), a consortium of researchers across the United States and Canada, to establish relationships between genes and chemical exposures. Researchers used heterozygous and homozygous deletion pools of barcoded yeast strains to derive mechanistic toxicological information about a wide array of chemicals, pharmaceuticals, metals, and biological compounds (27, 28). As eukaryotes, yeast and humans share many cellular pathways and functions, and many components of cell biology identified in S. cerevisiae have homologs in human biology (29–31). Consequently, functional toxicogenomic screening offers unique opportunities to evaluate the mechanisms of cytotoxicity and general biological activity across the lanthanide series in yeast and explore potentially conserved mechanisms in humans.Here, we identify fundamental cellular functions disrupted by lanthanides using functional toxicogenomics in S. cerevisiae. The metals studied had distinct behaviors: early lanthanides showed limited unique functional effects, while middle and late lanthanides had prominent and distinct ones. Although the functional effects of each lanthanide were different and suggested some very efficient element discrimination by endogenous molecules, we observed a few common trends. In particular, vesicle-mediated transport (primarily endocytosis) was perturbed by the majority of the lanthanides tested. Moreover, protein–protein network analysis suggested that lanthanides mimic calcium ions, interacting with calcium-binding proteins and disrupting processes regulated by this cation. Finally, several of the highly interconnected proteins targeted by multiple lanthanides in the network analysis are conserved in humans, suggesting their roles in the origin of the human health issues associated with lanthanide exposure and opening many directions for the determination of mechanisms associated with toxicity.     

Inter-Organizational Collaboration in the Implementation of Evidence-based Practices Among Public Agencies Serving Abused and Neglected Youth

This study examined the role of inter-organizational collaboration in implementing new evidence-based practices for addressing problem behaviors in at-risk youth. Semi-structured interviews were conducted with 38 systems leaders of probation, mental health, and child welfare departments of 12 California counties participating in a large randomized controlled trial to scale-up the use of Multidimensional Treatment Foster Care. Three sets of collaboration characteristics were identified: (1) characteristics of collaboration process, (2) characteristics of the external environment, and (3) characteristics of participating organizations and individuals. Inter-organizational collaboration enables an exchange of information and advice and a pooling of resources individual agencies may require for successful implementation.