Liprin-α4 Is Required for Nickel Induced Receptor Protein Tyrosine Phosphatase-Leukocyte Antigen Related Receptor F (RPTP-LAR) Activity

Liprin-α4 was strongly induced following nickel (II) chloride exposure in a variety of cell types including BEAS-2B, A549, BEP2D and BL41 cells. Liprin-α4, a member of the Liprin alpha family, has seven isoforms but only three of these variants were detected in BEAS-2B cells (004, 201 and 202). The level of Liprin-α4 variants 201 and 004 were highly increased in BEAS-2B cells in response to nickel. We showed that Liprin-α4 bound directly to the cytoplasmic region of RPTP-LAR (receptor protein tyrosine phosphatase-leukocyte antigen-related receptor F). The cytoplasmic region of RPTP-LAR contains two phosphatase domains but only the first domain shows activity. The second domain interacts with other proteins. The phosphatase activity was increased both following nickel treatment and also in the presence of nickel ions in cell extracts. Liprin-α4 knock-down lines with decreased expression of Liprin-α4 variants 004 and 201 exhibited greater nickel toxicity compared to controls. The RPTP-LAR phosphatase activity was only slightly increased in a Liprin-α4 knock-down line. Liprin-α4 appeared necessary for the nickel induced tyrosine phosphatase activity. The presence of Liprin-α4 and nickel increased tyrosine phosphatase activity that reduced the global levels of tyrosine phosphorylation in the cell

Teleconsultation service to improve healthcare in rural areas: acceptance, organizational impact and appropriateness

Background: Nowadays, new organisational strategies should be indentified to improve primary care and its link with secondary care in terms of efficacy and timeliness of interventions thus preventing unnecessary hospital accesses and costs saving for the health system. The purpose of this study is to assess the effects of the use of teleconsultation by general practitioners in rural areas. Methods: General practitioners were provided with a teleconsultation service from 2006 to 2008 to obtain a second opinion for cardiac, dermatological and diabetic problems. Access, acceptance, organisational impact, effectiveness and economics data were collected. Clinical and access data were systematically entered in a database while acceptance and organisational data were evaluated through ad hoc questionnaires. Results: There were 957 teleconsultation contacts which resulted in access to health care services for 812 symptomatic patients living in 30 rural communities. Through the teleconsultation service, 48 general practitioners improved the appropriateness of primary care and the integration with secondary care. In fact, the level of concordance between intentions and consultations for cardiac problems was equal to 9%, in 86% of the cases the service entailed a saving of resources and in 5% of the cases, it improved the timeliness. 95% of the GPs considered the overall quality positively. For a future routine use of this service, trust in specialists, duration and workload of teleconsultations and reimbursement should be taken into account. Conclusions: Managerial and policy implications emerged mainly related to the support to GPs in the provision of high quality primary care and decision-making processes in promoting similar services

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Abstract 3590: Depleted uranium-induced leukemia: Epigenetic and genetic changes.

Abstract Epigenetic and genetic changes are associated with leukemia development. Depleted uranium is used in military missions and U.S. military personnel have been wounded with DU shrapnel. In vivo studies have demonstrated that DU is leukemogenic. To further understand DU leukemogenic effects in vivo, we used a murine model to characterize and compare the DU-induced epigenetic and genetic changes in a variety of tissues including, spleen, hind limb muscle, thymus, and kidney. DU exposure (high and low dose) was evaluated in five groups of males and females: control group, DU-low dose, and DU-high dose. To determine the status of DNA methylation in female and male mice after DU exposure, the sensitive HpaII-based cytosine extension assay was used. The data from samples from DU-exposed animals demonstrated that low dose DU exposure for 3 months was associated with a 2.2- to 4.5- fold increase in the [3H]dCTP incorporation in female and male spleen, muscle, and thymus indicative of hypomethylation of DNA. Similarly data from high dose DU exposed mice indicated that DU was associated with a 4.6- to 11.5- fold increase in the [3H]dCTP incorporation in murine spleen, muscle, and bone marrow. These observations are important since the spleen and thymus are important components of hematopoietic and lymphatic systems and are significantly affected in lymphomas and leukemias. These data support the hypothesis that DNA hypomethylation is one possible mechanism involved in the development of DU-induced leukemia. To assess gene expression changes associated with DU internalized exposure in vivo kidneys from three DU-exposed and three age-matched control mice were subject to RNA extraction and Affymetrix analysis with the MoGene-1_0-st-v1.na32.mm array. Data were analyzed with GeneSpring software.There was a clear distinction in kidney mRNA expression between DU-exposed and control mice. As compared to the control mice, the DU-exposed mice showed a decrease in expression of genes related to fatty acid metabolism and the Peroxisome proliferator-activated receptor (PPAR) pathway. From a subset of 49 genes involved in the metabolism of fatty acids, 86% of genes were down-regulated. Additionally, 45 different members of the solute carrier family of genes displayed differential expression, with 84% of the changes being down-regulation as compared to the controls. These results indicate that further gene expression studies are warranted to better understand the functional impact of these DU-effects. Both these results support the hypothesis that DU exposure leads to genome destabilization and further studies are necessary to fully understand the epigenetic and genetic effects of DU exposure. Citation Format: Alexandra C. Miller, Hailey Clancy, Thomas Kluz, Stuart Cohen, Rafael Rivas, Karvelisse Miller, Max Costa. Depleted uranium-induced leukemia: Epigenetic and genetic changes. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3590. doi:10.1158/1538-7445.AM2013-3590</jats:p

Data from Gene Expression Profiles in Peripheral Blood Mononuclear Cells of Chinese Nickel Refinery Workers with High Exposures to Nickel and Control Subjects

&lt;div&gt;Abstract&lt;p&gt;&lt;b&gt;Background:&lt;/b&gt; Occupational exposure to nickel (Ni) is associated with an increased risk of lung and nasal cancers. Ni compounds exhibit weak mutagenic activity, alter the cell's epigenetic homeostasis, and activate signaling pathways. However, changes in gene expression associated with Ni exposure have only been investigated &lt;i&gt;in vitro&lt;/i&gt;. This study was conducted in a Chinese population to determine whether occupational exposure to Ni was associated with differential gene expression profiles in the peripheral blood mononuclear cells (PBMC) of Ni-refinery workers when compared with referents.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Methods:&lt;/b&gt; Eight Ni-refinery workers and ten referents were selected. PBMC RNA was extracted and gene expression profiling was conducted using Affymetrix exon arrays. Differentially expressed genes (DEG) between both groups were identified in a global analysis.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; There were a total of 2,756 DEGs in the Ni-refinery workers relative to the referents [false discovery rate (FDR) adjusted &lt;i&gt;P&lt;/i&gt; &lt; 0.05] with 770 upregulated genes and 1,986 downregulated genes. DNA repair and epigenetic genes were significantly overrepresented (&lt;i&gt;P&lt;/i&gt; &lt; 0.0002) among the DEGs. Of 31 DNA repair genes, 29 were repressed in the Ni-refinery workers and 2 were overexpressed. Of the 16 epigenetic genes, 12 were repressed in the Ni-refinery workers and 4 were overexpressed.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Conclusions:&lt;/b&gt; The results of this study indicate that occupational exposure to Ni is associated with alterations in gene expression profiles in PBMCs of subjects.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Impact:&lt;/b&gt; Gene expression may be useful in identifying patterns of deregulation that precede clinical identification of Ni-induced cancers. &lt;i&gt;Cancer Epidemiol Biomarkers Prev; 22(2); 261–9. ©2012 AACR.&lt;/i&gt;&lt;/p&gt;&lt;/div&gt;</jats:p

Supplementary Table 5 from Gene Expression Profiles in Peripheral Blood Mononuclear Cells of Chinese Nickel Refinery Workers with High Exposures to Nickel and Control Subjects

&lt;p&gt;XLSX file - 26K, Genes changed 1.5 fold in acute nickel exposure of PBMCs in vitro. Genes were changed for all doses of 0.25, 0.5, and 1.0 mM NiCl2&lt;/p&gt;</jats:p

Supplementary Table 2 from Gene Expression Profiles in Peripheral Blood Mononuclear Cells of Chinese Nickel Refinery Workers with High Exposures to Nickel and Control Subjects

&lt;p&gt;XLSX file - 192K, Gene list for genes associated with nasopharyngeal carcinoma found in study set. All genes were differentially expressed in referent population (p&lt;0.05)&lt;/p&gt;</jats:p

Supplementary Table 3 from Gene Expression Profiles in Peripheral Blood Mononuclear Cells of Chinese Nickel Refinery Workers with High Exposures to Nickel and Control Subjects

&lt;p&gt;XLSX file - 17K, List of DNA repair genes differentially expressed between subjects with occupational exposure and referents&lt;/p&gt;</jats:p

Supplementary Table 3 from Gene Expression Profiles in Peripheral Blood Mononuclear Cells of Chinese Nickel Refinery Workers with High Exposures to Nickel and Control Subjects

XLSX file - 17K, List of DNA repair genes differentially expressed between subjects with occupational exposure and referents</p