"Superheroes? No, thanks." Accepting vulnerability in healthcare professionals.

In this commentary, we develop a conceptual proposal aimed to explain why a discourse of praise and admiration for healthcare professionals´ limitless dedication can trigger a general indifference to the burnout and suffering they experience. Ultimately, this can lead to the justification of the lack of resources dedicated to preventing these problems. We first start by pointing out the stigmatisation of healthcare professionals suffering from burnout and showing their vulnerability, highlighting the complex interactions that occur in the healthcare context and that increase the risk of perpetuating their suffering. Then, we appeal to the recognition of one's own vulnerability as a key element towards the creation of a culture more focused on the duty of care for those who care for others. We conclude with several proposals for action to cope with burnout-related stigma, trying to change the superhuman image of health personnel and incorporating the vulnerability inherent to human beings.

Identifying the Main Functional Pathways Associated with Cognitive Resilience to Alzheimer's Disease.

Understanding the mechanisms involved in cognitive resilience in Alzheimer's disease (AD) represents a promising strategy to identify novel treatments for dementia in AD. Previous findings from our group revealed that the study of aged-Tg2576 cognitive resilient individuals is a suitable tool for this purpose. In the present study, we performed a transcriptomic analysis using the prefrontal cortex of demented and resilient Tg2576 transgenic AD mice. We have been able to hypothesize that pathways involved in inflammation, amyloid degradation, memory function, and neurotransmission may be playing a role on cognitive resilience in AD. Intriguingly, the results obtained in this study are suggestive of a reduction of the influx of peripheral immune cells into the brain on cognitive resilient subjects. Indeed, CD4 mRNA expression is significantly reduced on Tg2576 mice with cognitive resilience. For further validation of this result, we analyzed CD4 expression in human AD samples, including temporal cortex and peripheral blood mononuclear cells (PBMC). Interestingly, we have found a negative correlation between CD4 mRNA levels in the periphery and the score in the Mini-Mental State Exam of AD patients. These findings highlight the importance of understanding the role of the immune system on the development of neurodegenerative diseases and points out to the infiltration of CD4+ cells in the brain as a key player of cognitive dysfunction in AD.

Non-occupational allergic contact dermatitis caused by long-lasting nail polish kits for home use: 'the tip of the iceberg'.

BACKGROUND: Allergic contact dermatitis (ACD) from (meth)acrylates caused by long lasting nail polish (also known as "permanent", "semi-permanent" or "gel nail polish") has been described both in occupational and non-occupational settings. Inexpensive kits for home use have been available for purchase in many stores or through the Internet. OBJECTIVE: To report on several further cases of consumers sensitised to these nail products. METHODS: Patch test results and evaluation of ingredient labelling of products brought in by the patients. RESULTS: Four new cases are presented. Three of the patients reacted to 2-hydroxypropyl methacrylate, 2-hydroxyethyl methacrylate and ethyleneglycol dimethacrylate (EGDMA), and all 4 to 2-hydroxy ethylacrylate. CONCLUSIONS: Acrylates are present in a wide range of products including medical materials. Sensitization from (meth)acrylates caused by a merely aesthetic procedure might significantly impact health by jeopardizing access to several types of medical interventions. Policies should be implemented restricting the use of long-lasting nail polishes to qualified professionals and banning the indiscriminate sale of kits for home use.

"Nails Only" Phenotype and Partial Dominance of p.Glu170Lys Mutation in a Family with Epidermolysis Bullosa Simplex.

Epidermolysis bullosa (EB) is a heterogeneous group of rare, chronic, inherited skin disorders characterized by marked mechanical fragility of epithelial tissues, with blistering and erosions after minor trauma. We present the first report of a nails-only phenotype in two patients with epidermolysis bullosa simplex (EBS) and a heterozygous pGlu170Lys mutation and the second reported case of EBS associated with a homozygous p.Glu170Lys mutation in the KRT5 gene. Our findings may be relevant for genetic counseling and for understanding the inheritance pattern of EBS.

Methotrexate selectively targets human proinflammatory macrophages through a thymidylate synthase/p53 axis.

OBJECTIVES: Methotrexate (MTX) functions as an antiproliferative agent in cancer and an anti-inflammatory drug in rheumatoid arthritis (RA). Although macrophages critically contribute to RA pathology, their response to MTX remains unknown. As a means to identify MTX response markers, we have explored its transcriptional effect on macrophages polarised by GM-CSF (GM-MØ) or M-CSF (M-MØ), which resemble proinflammatory and anti-inflammatory macrophages found in RA and normal joints, respectively. METHODS: The transcriptomic profile of both human macrophage subtypes exposed to 50 nM of MTX under long-term and short-term schedules were determined using gene expression microarrays, and validated through quantitative real time PCR and ELISA. The molecular pathway involved in macrophage MTX-responsiveness was determined through pharmacological, siRNA-mediated knockdown approaches, metabolomics for polyglutamylated-MTX detection, western blot, and immunofluorescence on RA and normal joints. RESULTS: MTX exclusively modulated gene expression in proinflammatory GM-MØ, where it influenced the expression of 757 genes and induced CCL20 and LIF at the mRNA and protein levels. Pharmacological and siRNA-mediated approaches indicated that macrophage subset-specific MTX responsiveness correlates with thymidylate synthase (TS) expression, as proinflammatory TS+ GM-MØ are susceptible to MTX, whereas anti-inflammatory TSlow/- M-MØ and monocytes are refractory to MTX. Furthermore, p53 activity was found to mediate the TS-dependent MTX-responsiveness of proinflammatory TS+ GM-MØ. Importantly, TS and p53 were found to be expressed by CD163+/TNFα+ GM-CSF-polarised macrophages from RA joints but not from normal synovium. CONCLUSIONS: Macrophage response to MTX is polarisation-dependent and determined by the TS-p53 axis. CCL20 and LIF constitute novel macrophage markers for MTX responsiveness in vitro.

Automated neuromelanin imaging as a diagnostic biomarker for Parkinson's disease.

BACKGROUND: We aimed to analyze the diagnostic accuracy of an automated segmentation and quantification method of the SNc and locus coeruleus (LC) volumes based on neuromelanin (NM)-sensitive MRI (NM-MRI) in patients with idiopathic (iPD) and monogenic (iPD) Parkinson's disease (PD). METHODS: Thirty-six patients (23 idiopathic and 13 monogenic PARKIN or LRRK2 mutations) and 37 age-matched healthy controls underwent 3T-NM-MRI. SNc and LC volumetry were performed using fully automated multi-image atlas segmentation. The diagnostic performance to differentiate PD from controls was measured using the area under the curve (AUC) and likelihood ratios based on receiver operating characteristic (ROC) analyses. RESULTS: We found a significant reduction of SNc and LC volumes in patients, when compared to controls. ROC analysis showed better diagnostic accuracy when using SNc volume than LC volume. Significant differences between ipsilateral and contralateral SNc volumes, in relation to the more clinically affected side, were found in patients with iPD (P = 0.007). Contralateral atrophy in the SNc showed the highest power to discriminate PD subjects from controls (AUC, 0.93-0.94; sensitivity, 91%-92%; specificity, 89%; positive likelihood ratio: 8.4-8.5; negative likelihood ratio: 0.09-0.1 at a single cut-off point). Interval likelihood ratios for contralateral SNc volume improved the diagnostic accuracy of volumetric measurements. CONCLUSION: SNc and LC volumetry based on NM-MRI resulting from the automated segmentation and quantification technique can yield high diagnostic accuracy for differentiating PD from health and might be an unbiased disease biomarker. © 2015 International Parkinson and Movement Disorder Society.

No evidence of association between common European mitochondrial DNA variants in Alzheimer, Parkinson, and migraine in the Spanish population.

Certain mitochondrial DNA (mtDNA) variants and haplogroups have been found to be associated with neurological disorders. Several studies have suggested that mtDNA variation could have an etiologic role in these disorders by affecting the ATP production on high-energy demanding organs, such as the brain. We have analyzed 15 mtDNA SNPs (mtSNPs) in five cohorts of cases presenting Alzheimer disease (AD), Parkinson disease (PD), and migraine, and in controls, to evaluate the role mtDNA variation in disease risk. Association tests were undertaken both for mtSNPs and mitochondrial haplogroups. No significant association was detected for any mtSNP or haplogroup in AD and PD cohorts. Two mtSNPs were associated with one migraine cohort after correcting for multiple tests, namely, T4216C and G13708A and haplogroup J (FDR q-value = 0.02; Santiago's cohort). However, this association was not confirmed in a second replication migraine series. A review of the literature reveals the existence of inconsistent findings and methodological shortcomings affecting a large proportion of mtDNA association studies on AD, PD, and migraine. A detailed inspection of the literature highlights the need for performing more rigorous methodological and statistical standards in mtDNA genetic association studies aimed to avoid false positive results of association between mtDNA variants and neurological diseases.

Online training course on critical appraisal for nurses: adaptation and assessment.

BACKGROUND: Research is an essential activity for improving quality and efficiency in healthcare. The objective of this study was to train nurses from the public Basque Health Service (Osakidetza) in critical appraisal, promoting continuous training and the use of research in clinical practice. METHODS: This was a prospective pre-post test study. The InfoCritique course on critical appraisal was translated and adapted. A sample of 50 nurses and 3 tutors was recruited. Educational strategies and assessment instruments were established for the course. A course website was created that contained contact details of the teaching team and coordinator, as well as a course handbook and videos introducing the course. Assessment comprised the administration of questionnaires before and after the course, in order to explore the main intervention outcomes: knowledge acquired and self-learning readiness. Satisfaction was also measured at the end of the course. RESULTS: Of the 50 health professionals recruited, 3 did not complete the course for personal or work-related reasons. The mean score on the pre-course knowledge questionnaire was 70.5 out of 100, with a standard deviation of 11.96. In general, participants' performance on the knowledge questionnaire improved after the course, as reflected in the notable increase of the mean score, to 86.6, with a standard deviation of 10.00. Further, analyses confirmed statistically significant differences between pre- and post-course results (p < 0.001). With regard to self-learning readiness, after the course, participants reported a greater readiness and ability for self-directed learning. Lastly, in terms of level of satisfaction with the course, the mean score was 7 out of 10. CONCLUSIONS: Participants significantly improved their knowledge score and self-directed learning readiness after the educational intervention, and they were overall satisfied with the course. For the health system and nursing professionals, this type of course has the potential to provide methodological tools for research, promote a research culture, and encourage critical thinking for evidence-based decision making.

The Development and Validation of an Intercultural Nursing Educator Profile Using the Delphi Method.

INTRODUCTION: Educators require focused training to foster the development of intercultural competence in nurses. Training programs for educators need to be based on a comprehensive profile with a focus on intercultural learning. This study aims to define and validate a profile of the Intercultural Nursing Educator (INE). METHOD: The Delphi method was used with an iterative, multi-stage process to transform opinions into group consensus. A total of 46 European, African, and American experts from the nursing and intercultural field participated. Inclusion criteria required English at a level of B2, expertise in the field of intercultural competence, experience in teaching intercultural competence in the nursing context, and publications focused on intercultural topics. RESULTS: The INE profile was developed and all 126 competencies were validated. DISCUSSION AND CONCLUSION: The profile is freely available on the project website and provides the basis for curricula, training programs and assessment of the required competences.

LINGO1 rs9652490 and rs11856808 polymorphisms are not associated with risk for multiple sclerosis.

BACKGROUND: Some recent experimental data suggest a possible role of LINGO-1 in the pathogenesis of multiple sclerosis (MS). In an attempt to identify genetic biomarkers related to MS susceptibility, we genotyped two common SNPs in the LINGO1 gene which have been associated to other neurological conditions, in patients with MS and in healthy subjects. These SNPs are linked to several SNPs within the LINGO1 gene, especially in individuals of Oriental or Caucasian descent. METHODS: We analyzed the allelic and genotype frequency of two LINGO1 variants (rs9652490 and rs11856808) in 293 patients with MS and 318 healthy controls, using KASPar assays. RESULTS: LINGO1 rs9652490 and rs11856808 allelic and genotype frequencies did not differ significantly between MS patients and controls. The minor allele frequencies for rs9652490 were 0.171 (95% CI = 0.140-0.201) and 0.167 (95% CI = 0.138-0.196 for cases and controls respectively (p = 0.853). For rs11856808 the minor allele frequencies were 0.317 (95% CI = 0.280-0.355) and 0.310 (95% CI = 0.274-0.346) for cases and controls, respectively (p = 0.773). Allele and genotype frequencies were unrelated with the age of onset of MS, gender, and clinical course of MS. In addition, haplotype analyses did not reveal any putative risk related to haplotypes. CONCLUSIONS: These results suggest that LINGO1 rs9652490 and rs11856808 polymorphisms are not related with risk for MS. This study adds to other published evidence indicating that, to date, the LINGO1 SNPs studied here could be useful risk biomarkers of developing essential tremor, but not other movement disorders.

LRRK2 haplotype-sharing analysis in Parkinson's disease reveals a novel p.S1761R mutation.

BACKGROUND AND OBJECTIVE: Mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene at chromosome 12q12 are the most common genetic cause of sporadic and familial late-onset Parkinson's disease. Our aim was to identify novel LRRK2 mutations in late-onset Parkinson's disease families. DESIGN: We analyzed chromosome 12p11.2-q13.1 haplotypes in 14 late-onset Parkinson's disease families without known LRRK2 mutations. RESULTS: Haplotype analysis identified 12 families in which the affected subjects shared chromosome 12p11.2-q13.1 haplotypes. LRRK2 sequencing revealed a novel co-segregating missense mutation in exon 36 (c.5281A>C; p.S1761R) located within a highly conserved region of the COR [C-terminal of ROC (Ras of complex proteins)] domain wherein it could deregulate LRRK2 kinase activity by modifying ROC-COR dimer stability. p.S1761R was present in a late-onset Parkinson's disease family and in 2 unrelated Parkinson's disease subjects, but not in 2491 healthy controls. LRRK2 p.S1761R carriers developed levodopa-responsive asymmetrical parkinsonism, with variable age at onset (range: 37-72 years) suggesting age-dependent penetrance. These findings indicate that mutations interfering with LRRK2 ROC-COR domain dimerization lead to typical Parkinson's disease.

Scaling up neodomestication for climate-ready crops.

We can increase the stability of our food systems against environmental variability and climate change by following the footsteps of our ancestors and domesticating edible wild plants. Reinforced by recent advances in comparative genomics and gene editing technologies, neodomestication opens possibilities for a rapid generation of new crops. By starting the candidate selection pipeline with climatic parameters, we orient neodomestication efforts to increase food security against climate change. We highlight the fact that the edible species conservation and characterization will be key in this process. Utilization of genetic resources, entrusted to conservationists and researchers by local communities, has to be conducted with highest ethical standards and benefit-sharing in mind.

Potential Distribution of Cedrela odorata L. in Mexico according to Its Optimal Thermal Range for Seed Germination under Different Climate Change Scenarios.

Cedrela odorata is a native tree of economic importance, as its wood is highly demanded in the international market. In this work, the current and future distributions of C. odorata in Mexico under climate change scenarios were analyzed according to their optimal temperature ranges for seed germination. For the present distribution, 256 localities of the species' presence were obtained from the Global Biodiversity Information Facility (GBIF) database and modelled with MaxEnt. For the potential distribution, the National Center for Atmospheric Research model (CCSM4) was used under conservative and drastic scenarios (RCP2.6 and RCP8.5 Watts/m2, respectively) for the intermediate future (2050) and far future (2070). Potential distribution models were built from occurrence data within the optimum germination temperature range of the species. The potential distribution expanded by 5 and 7.8% in the intermediate and far future, respectively, compared with the current distribution. With the increase in temperature, adequate environmental conditions for the species distribution should be met in the central Mexican state of Guanajuato. The states of Chihuahua, Mexico, Morelos, Guerrero, and Durango presented a negative trend in potential distribution. Additionally, in the far future, the state of Chihuahua it is likely to not have adequate conditions for the presence of the species. For the prediction of the models, the precipitation variable during the driest month presented the greatest contribution. When the humidity is not limiting, the thermal climatic variables are the most important ones. Models based on its thermal niche for seed germination allowed for the identification of areas where temperature will positively affect seed germination, which will help maximize the establishment of plant populations and adaptation to different climate change scenarios.

LINGO1 gene analysis in Parkinson's disease phenotypes.

BACKGROUND: Parkinson's disease (PD) and essential tremor (ET) may share some etiopathogenic factors. A genome-wide association study has shown that LINGO1 gene variants are associated with increased risk of ET. We hypothesized that LINGO1 variants could increase susceptibility to PD. METHODS: A large series of PD subjects and healthy controls were genotyped for rs9652490 and rs11856808 LINGO1 single nucleotide polymorphisms (SNPs). RESULTS: We found an increased frequency of the rs11856808(T/T) genotype in PD compared with controls (odds ratio = 1.46; corrected P value = 0.02). A recessive genetic model was the best fit for rs11856808 influence on PD (recessive gene action test: corrected P value = 0.01). Stratification analysis showed that rs11856808(T/T) genotype frequency was higher in the tremor-dominant PD and the classical PD (C-PD) subgroups (recessive gene action test for the C-PD subgroup: corrected P value = 0.004). DISCUSSION: Our results indicate that LINGO1 variants could increase risk of PD, specifically those presenting the non-rigid-akinetic phenotypes, which suggests that LINGO1 may have a role in the etiology of tremor in PD at least in the Spanish population.

PINK1-linked parkinsonism is associated with Lewy body pathology.

Phosphatase and tensin homolog-induced putative kinase 1 gene mutations have been associated with autosomal recessive early-onset Parkinson's disease. To date, no neuropathological reports have been published from patients with Parkinson's disease with both phosphatase and tensin homolog-induced putative kinase 1 gene copies mutated. We analysed the coding region of phosphatase and tensin homolog-induced putative kinase 1 gene in a large Spanish family with six members with parkinsonism. The phenotype was characterized by an early-onset (mean: 31.6, standard deviation: 9.6 years, range: 14-45 years), slowly progressive levodopa-responsive parkinsonism, initial gait impairment and psychiatric symptoms. We identified two segregating pathogenic phosphatase and tensin homolog-induced putative kinase 1 mutations that were either in homozygous or heterozygous compound state in all affected family members. We found an exon 7 deletion (g.16089_16383del293; c.1252_1488del) and a novel+1U1-dependent 5' splice-site mutation in exon 7 (g.16378G>A; c.1488+1G>A). Leukocyte-derived messenger RNA analysis showed that both mutations caused exon 7 skipping and c.1488+1G>A also lead to an in-frame transcript with a 33 base-pair deletion (p.L485_R497del) resulting from activation of a 5' cryptic exon 7 splice site. Single photon emission computed tomography quantification of striatal dopamine transporter binding (123I-Ioflupane) revealed a posterior-anterior gradient similar to that of idiopathic Parkinson's disease, but there was no correlation between striatal reduced uptake and disease duration. Post-mortem neuropathological examination of an early-onset Parkinson's disease carrier of two heterozygous compound phosphatase and tensin homolog-induced putative kinase 1 mutations showed neuronal loss in the substantia nigra pars compacta, Lewy bodies and aberrant neurites in the reticular nuclei of the brainstem, substantia nigra pars compacta and Meynert nucleus, but the locus ceruleus and the amygdala were spared. This is the first neuropathological report of the brain from an early-onset phosphatase and tensin homolog-induced putative kinase 1-linked parkinsonism showing that mutated phosphatase and tensin homolog-induced putative kinase 1 protein induces Lewy body pathology. Unbalanced preservation of the locus ceruleus may well play a role in the slow evolution of motor symptoms and, probably, in the psychiatric symptoms often encountered in Parkinson's disease associated with phosphatase and tensin homolog-induced putative kinase 1 mutation.

Molecular Survey of Babesia spp. and Anaplasma phagocytophilum in Roe Deer from a Wildlife Rescue Center in Italy.

Babesia ssp. and Anaplasma spp. are tick-borne microorganisms representing a possible health risk for domestic and wild animals, as well as humans. Roe deer serve as a suitable reservoir host for some species ascribed to Babesia spp. and Anaplasma phagocytophilum taxa, also due to its important role in the maintenance of large populations of Ixodes ricinus, the main tick vector of these pathogens in Europe. Roe deer populations have been recently expanding throughout Europe, namely in Italy. However, the collection of samples from free-ranging wild animals for diagnostic investigations often includes several practical issues. This problem can be overcome using samples provided by wildlife rescue centers making them available for investigations following routine analyses. The presence of Babesia spp. and Anaplasma spp. in blood samples of 43 roe deer rescued by a wildlife rescue center in Emilia-Romagna region (Italy) was molecularly investigated. PCR screening revealed the presence of at least one pathogen in 86.05% of the animals, while co-infection occurred in 18.92% of the tested individuals. Zoonotic Babesia venatorum was found in 6.98% of the samples, while Babesia capreoli and Anaplasma phagocytophilum were detected in 74.42% and in 20.93%, respectively. No hematological signs compatible with clinical anaplasmosis or piroplasmosis, as well as absence of intracellular circulating microorganisms in blood smears, were observed, suggesting asymptomatic infection in the tested animals. These results confirm the usefulness of wild rescued animals as convenient source of biological samples for tick-borne pathogens investigation and the role of roe deer as a key factor in the endemic cycle of Babesia species and A. phagocytophilum.