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1.  Effectiveness of a cognitive behavioral intervention in patients with medically unexplained symptoms: cluster randomized trial 
BMC Family Practice  2012;13:35.
Background
Medically unexplained symptoms are an important mental health problem in primary care and generate a high cost in health services.
Cognitive behavioral therapy and psychodynamic therapy have proven effective in these patients. However, there are few studies on the effectiveness of psychosocial interventions by primary health care. The project aims to determine whether a cognitive-behavioral group intervention in patients with medically unexplained symptoms, is more effective than routine clinical practice to improve the quality of life measured by the SF-12 questionary at 12 month.
Methods/design
This study involves a community based cluster randomized trial in primary healthcare centres in Madrid (Spain). The number of patients required is 242 (121 in each arm), all between 18 and 65 of age with medically unexplained symptoms that had seeked medical attention in primary care at least 10 times during the previous year. The main outcome variable is the quality of life measured by the SF-12 questionnaire on Mental Healthcare. Secondary outcome variables include number of consultations, number of drug (prescriptions) and number of days of sick leave together with other prognosis and descriptive variables. Main effectiveness will be analyzed by comparing the percentage of patients that improve at least 4 points on the SF-12 questionnaire between intervention and control groups at 12 months. All statistical tests will be performed with intention to treat. Logistic regression with random effects will be used to adjust for prognostic factors. Confounding factors or factors that might alter the effect recorded will be taken into account in this analysis.
Discussion
This study aims to provide more insight to address medically unexplained symptoms, highly prevalent in primary care, from a quantitative methodology. It involves intervention group conducted by previously trained nursing staff to diminish the progression to the chronicity of the symptoms, improve quality of life, and reduce frequency of medical consultations.
Trial registration
The trial was registered with ClinicalTrials.gov, number NCT01484223 [ http://ClinicalTrials.gov].
doi:10.1186/1471-2296-13-35
PMCID: PMC3515424  PMID: 22551252
2.  EPB41L3, TSP-1 and RASSF2 as new clinically relevant prognostic biomarkers in diffuse gliomas 
Oncotarget  2015;6(1):368-380.
Hypermethylation of tumor suppressor genes is one of the hallmarks in the progression of brain tumors. Our objectives were to analyze the presence of the hypermethylation of EPB41L3, RASSF2 and TSP-1 genes in 132 diffuse gliomas (astrocytic and oligodendroglial tumors) and in 10 cases of normal brain, and to establish their association with the patients’ clinicopathological characteristics. Gene hypermethylation was analyzed by methylation-specific-PCR and confirmed by pyrosequencing (for EPB41L3 and TSP-1) and bisulfite-sequencing (for RASSF2). EPB41L3, RASSF2 and TSP-1 genes were hypermethylated only in tumors (29%, 10.6%, and 50%, respectively), confirming their cancer-specific role. Treatment of cells with the DNA-demethylating-agent 5-aza-2′-deoxycytidine restores their transcription, as confirmed by quantitative-reverse-transcription-PCR and immunofluorescence. Immunohistochemistry for EPB41L3, RASSF2 and TSP-1 was performed to analyze protein expression; p53, ki-67, and CD31 expression and 1p/19q co-deletion were considered to better characterize the tumors. EPB41L3 and TSP-1 hypermethylation was associated with worse (p = 0.047) and better (p = 0.037) prognosis, respectively. This observation was confirmed after adjusting the results for age and tumor grade, the role of TSP-1 being most pronounced in oligodendrogliomas (p = 0.001). We conclude that EPB41L3, RASSF2 and TSP-1 genes are involved in the pathogenesis of diffuse gliomas, and that EPB41L3 and TSP-1 hypermethylation are of prognostic significance.
PMCID: PMC4381601  PMID: 25621889
Brain tumors; EPB41L3; DNA methylation; prognosis; RASSF2; TSP-1
4.  Incomplete Reversibility of Estimated Glomerular Filtration Rate Decline Following Tenofovir Disoproxil Fumarate Exposure 
Jose, Sophie | Hamzah, Lisa | Campbell, Lucy J. | Hill, Teresa | Fisher, Martin | Leen, Clifford | Gilson, Richard | Walsh, John | Nelson, Mark | Hay, Phillip | Johnson, Margaret | Chadwick, David | Nitsch, Dorothea | Jones, Rachael | Sabin, Caroline A. | Post, Frank A. | Ainsworth, Jonathan | Anderson, Jane | Babiker, Abdel | Chadwick, David | Delpech, Valerie | Dunn, David | Fisher, Martin | Gazzard, Brian | Gilson, Richard | Gompels, Mark | Hay, Phillip | Hill, Teresa | Johnson, Margaret | Kegg, Stephen | Leen, Clifford | Nelson, Mark | Orkin, Chloe | Palfreeman, Adrian | Phillips, Andrew | Pillay, Deenan | Post, Frank | Sabin, Caroline | Sachikonye, Memory | Schwenk, Achim | Walsh, John | Hill, Teresa | Huntington, Susie | Josie, Sophie | Phillips, Andrew | Sabin, Caroline | Thornton, Alicia | Dunn, David | Glabay, Adam | Orkin, C. | Garrett, N. | Lynch, J. | Hand, J. | de Souza, C. | Fisher, M. | Perry, N. | Tilbury, S. | Churchill, D. | Gazzard, B. | Nelson, M. | Waxman, M. | Asboe, D. | Mandalia, S. | Delpech, V. | Anderson, J. | Munshi, S. | Korat, H. | Poulton, M. | Taylor, C. | Gleisner, Z. | Campbell, L. | Babiker, Abdel | Dunn, David | Glabay, Adam | Gilson, R. | Brima, N. | Williams, I. | Schwenk, A. | Ainsworth, J. | Wood, C. | Miller, S. | Johnson, M. | Youle, M. | Lampe, F. | Smith, C. | Grabowska, H. | Chaloner, C. | Puradiredja, D. | Walsh, J. | Weber, J. | Ramzan, F. | Mackie, N. | Winston, A. | Leen, C. | Wilson, A. | Gompels, M. | Allan, S. | Palfreeman, A. | Moore, A. | Chadwick, D. | Wakeman, K. | Kegg, Stephen | Main, Paul | Mitchell,  | Hunter,  | Sachikonye, Memory | Hay, Phillip | Dhillon, Mandip
The Journal of Infectious Diseases  2014;210(3):363-373.
Background. Tenofovir disoproxil fumarate (TDF) has been linked to renal impairment, but the extent to which this impairment is reversible is unclear. We aimed to investigate the reversibility of renal decline during TDF therapy.
Methods. Cox proportional hazards models assessed factors associated with discontinuing TDF in those with an exposure duration of >6 months. In those who discontinued TDF therapy, linear piecewise regression models estimated glomerular filtration rate (eGFR) slopes before initiation of, during, and after discontinuation of TDF therapy. Factors associated with not achieving eGFR recovery 6 months after discontinuing TDF were assessed using multivariable logistic regression.
Results. We observed declines in the eGFR during TDF exposure (mean slopes, −15.7 mL/minute/1.73 m2/year [95% confidence interval {CI}, −20.5 to −10.9] during the first 3 months and −3.1 mL/minute/1.73 m2/year [95% CI, −4.6 to −1.7] thereafter) and evidence of eGFR increases following discontinuation of TDF therapy (mean slopes, 12.5 mL/minute/1.73 m2/year [95% CI, 8.9–16.1] during the first 3 months and 0.8 mL/minute/1.73 m2/year [95% CI, .1–1.5] thereafter). Following TDF discontinuation, 38.6% of patients with a decline in the eGFR did not experience recovery. A higher eGFR at baseline, a lower eGFR after discontinuation of TDF therapy, and more-prolonged exposure to TDF were associated with an increased risk of incomplete recovery 6 months after discontinuation of TDF therapy.
Conclusions. This study shows that a decline in the eGFR during TDF therapy was not fully reversible in one third of patients and suggests that prolonged TDF exposure at a low eGFR should be avoided.
doi:10.1093/infdis/jiu107
PMCID: PMC4091582  PMID: 24585896
tenofovir; highly active antiretroviral therapy; eGFR; eGFR slopes; renal function; kidney
5.  A functional ABCA1 gene variant is associated with low HDL-cholesterol levels and shows evidence of positive selection in Native Americans 
Human Molecular Genetics  2010;19(14):2877-2885.
It has been suggested that the higher susceptibility of Hispanics to metabolic disease is related to their Native American heritage. A frequent cholesterol transporter ABCA1 (ATP-binding cassette transporter A1) gene variant (R230C, rs9282541) apparently exclusive to Native American individuals was associated with low high-density lipoprotein cholesterol (HDL-C) levels, obesity and type 2 diabetes in Mexican Mestizos. We performed a more extensive analysis of this variant in 4405 Native Americans and 863 individuals from other ethnic groups to investigate genetic evidence of positive selection, to assess its functional effect in vitro and to explore associations with HDL-C levels and other metabolic traits. The C230 allele was found in 29 of 36 Native American groups, but not in European, Asian or African individuals. C230 was observed on a single haplotype, and C230-bearing chromosomes showed longer relative haplotype extension compared with other haplotypes in the Americas. Additionally, single-nucleotide polymorphism data from the Human Genome Diversity Panel Native American populations were enriched in significant integrated haplotype score values in the region upstream of the ABCA1 gene. Cells expressing the C230 allele showed a 27% cholesterol efflux reduction (P< 0.001), confirming this variant has a functional effect in vitro. Moreover, the C230 allele was associated with lower HDL-C levels (P = 1.77 × 10−11) and with higher body mass index (P = 0.0001) in the combined analysis of Native American populations. This is the first report of a common functional variant exclusive to Native American and descent populations, which is a major determinant of HDL-C levels and may have contributed to the adaptive evolution of Native American populations.
doi:10.1093/hmg/ddq173
PMCID: PMC2893805  PMID: 20418488
6.  Transcriptomic and metabolomic profiling of ionic liquid stimuli unveils enhanced secondary metabolism in Aspergillus nidulans 
BMC Genomics  2016;17:284.
Background
The inherent potential of filamentous fungi, especially of Ascomycota, for producing diverse bioactive metabolites remains largely silent under standard laboratory culture conditions. Innumerable strategies have been described to trigger their production, one of the simplest being manipulation of the growth media composition. Supplementing media with ionic liquids surprisingly enhanced the diversity of extracellular metabolites generated by penicillia. This finding led us to evaluate the impact of ionic liquids’ stimuli on the fungal metabolism in Aspergillus nidulans and how it reflects on the biosynthesis of secondary metabolites (SMs).
Results
Whole transcriptional profiling showed that exposure to 0.7 M cholinium chloride or 1-ethyl-3-methylimidazolium chloride dramatically affected expression of genes encoding both primary and secondary metabolism. Both ionic liquids apparently induced stress responses and detoxification mechanisms but response profiles to each stimulus were unique. Primary metabolism was up-regulated by choline, but down-regulated by 1-ethyl-3-methylimidazolium chloride; both stimulated production of acetyl-CoA (key precursor to numerous SMs) and non proteinogenic amino acids (building blocks of bioactive classes of SMs). In total, twenty one of the sixty six described backbone genes underwent up-regulation. Accordingly, differential analysis of the fungal metabolome showed that supplementing growth media with ionic liquids resulted in ca. 40 differentially accumulated ion masses compared to control conditions. In particular, it stimulated production of monodictyphenone and orsellinic acid, otherwise cryptic. Expression levels of genes encoding corresponding polyketide biosynthetic enzymes (i.e. backbone genes) increased compared to control conditions. The corresponding metabolite extracts showed increased cell polarity modulation potential in an ex vivo whole tissue assay (Thelial Live Targeted Epithelia; theLiTE™).
Conclusions
Ionic liquids, a diverse class of chemicals composed solely of ions, can provide an unexpected means to further resolve the diversity of natural compounds, guiding discovery of fungal metabolites with clinical potential.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-016-2577-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s12864-016-2577-6
PMCID: PMC4830055  PMID: 27072538
Aspergillus nidulans; Monodictyphenone; Orsellinic acid; Secondary metabolism; Ionic liquids; Metabolomics; Transcriptomics
8.  Neural selectivity for communicative auditory signals in Phelan-McDermid syndrome 
Background
Phelan-McDermid syndrome (PMS), a neurodevelopmental disorder caused by deletion or mutation in the SHANK3 gene, is one of the more common single-locus causes of autism spectrum disorder (ASD). PMS is characterized by global developmental delay, hypotonia, delayed or absent speech, increased risk of seizures, and minor dysmorphic features. Impairments in language and communication are one of the most consistent characteristics of PMS. Although there is considerable overlap in the social communicative deficits associated with PMS and ASD, there is a dearth of data on underlying abnormalities at the level of neural systems in PMS. No controlled neuroimaging studies of PMS have been reported to date. The goal of this study was to examine the neural circuitry supporting the perception of auditory communicative signals in children with PMS as compared to idiopathic ASD (iASD).
Methods
Eleven children with PMS and nine comparison children with iASD were scanned using functional magnetic resonance imaging (fMRI) under light sedation. The fMRI paradigm was a previously validated passive auditory task, which presented communicative (e.g., speech, sounds of agreement, disgust) and non-communicative vocalizations (e.g., sneezing, coughing, yawning).
Results
Previous research has shown that the superior temporal gyrus (STG) responds selectively to communicative vocal signals in typically developing children and adults. Here, selective activity for communicative relative to non-communicative vocalizations was detected in the right STG in the PMS group, but not in the iASD group. The PMS group also showed preferential activity for communicative vocalizations in a range of other brain regions associated with social cognition, such as the medial prefrontal cortex (MPFC), insula, and inferior frontal gyrus. Interestingly, better orienting toward social sounds was positively correlated with selective activity in the STG and other “social brain” regions, including the MPFC, in the PMS group. Finally, selective MPFC activity for communicative sounds was associated with receptive language level in the PMS group and expressive language in the iASD group.
Conclusions
Despite shared behavioral features, children with PMS differed from children with iASD in their neural response to communicative vocal sounds and showed relative strengths in this area. Furthermore, the relationship between clinical characteristics and neural selectivity also differed between the two groups, suggesting that shared ASD features may partially reflect different neurofunctional abnormalities due to differing etiologies.
Electronic supplementary material
The online version of this article (doi:10.1186/s11689-016-9138-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s11689-016-9138-9
PMCID: PMC4763436  PMID: 26909118
9.  Mesenchymal Stromal Cells Prevent Renal Fibrosis in a Rat Model of Unilateral Ureteral Obstruction by Suppressing the Renin-Angiotensin System via HuR 
PLoS ONE  2016;11(2):e0148542.
We studied Mesenchymal Stromal Cells (MSC) effects in experimental Unilateral Ureteral Obstruction (UUO), a fibrogenic renal disease. Rats were divided in 5 groups: sham, UUO, MSC treated-UUO, ACEi treated-UUO, MSC+ACEi treated- UUO. Data were collected at 1, 7, 21 days. UUO induced monocyte renal infiltration, tubular cell apoptosis, tubular atrophy, interstitial fibrosis and overexpression of TGFβ, Renin mRNA (RENmRNA), increase of Renin, Angiotensin II (AII) and aldosterone serum levels. Both lisinopril (ACEi) and MSC treatment prevented monocyte infiltration, reduced tubular cell apoptosis, renal fibrosis and TGFβ expression. Combined therapy provided a further suppression of monocyte infiltration and tubular injury. Lisinopril alone caused a rebound activation of Renin-Angiotensin System (RAS), while MSC suppressed RENmRNA and Renin synthesis and induced a decrease of AII and aldosterone serum levels. Furthermore, in in-vitro and in-vivo experiments, MSC inhibit Human antigen R (HuR) trascription, an enhancer of RENmRNA stability by IL10 release. In conclusion, we demonstrate that in UUO MSC prevent fibrosis, by decreasing HuR-dependent RENmRNA stability. Our findings give a clue to understand the molecular mechanism through which MSC may prevent fibrosis in a wide and heterogeneous number of diseases that share RAS activation as common upstream pathogenic mechanism.
doi:10.1371/journal.pone.0148542
PMCID: PMC4750962  PMID: 26866372
10.  Predictive significance of DNA damage and repair biomarkers in triple-negative breast cancer patients treated with neoadjuvant chemotherapy: An exploratory analysis 
Oncotarget  2015;6(40):42773-42780.
Response of cancer cells to chemotherapy-induced DNA damage is regulated by the ATM-Chk2 and ATR-Chk1 pathways. We investigated the association between phosphorylated H2AX (γ-H2AX), a marker of DNA double-strand breaks that trigger the ATM-Chk2 cascade, and phosphorylated Chk1 (pChk1), with pathological complete response (pCR) in triple-negative breast cancer (TNBC) patients treated with neoadjuvant chemotherapy. γ-H2AX and pChk1 were retrospectively assessed by immunohistochemistry in a series of pretreatment biopsies related to 66 patients. In fifty-three tumors hormone receptor status was negative in both the diagnostic biopsies and residual cancers, whereas in 13 cases there was a slight hormone receptor expression that changed after chemotherapy. Internal validation was carried out. In the entire cohort elevated levels of γ-H2AX, but not pChk1, were associated with reduced pCR rate (p = 0.009). The association tested significant in both uni- and multivariate logistic regression models (OR 4.51, 95% CI: 1.39–14.66, p = 0.012, and OR 5.07, 95% CI: 1.28–20.09, p = 0.021, respectively). Internal validation supported the predictive value of the model. The predictive ability of γ-H2AX was further confirmed in the multivariate model after exclusion of tumors that underwent changes in hormone receptor status during chemotherapy (OR 7.07, 95% CI: 1.39–36.02, p = 0.018). Finally, in residual diseases a significant decrease of γ-H2AX levels was observed (p < 0.001). Overall, γ-H2AX showed ability to predict pCR in TNBC and deserves larger, prospective studies.
PMCID: PMC4767469  PMID: 26544894
DNA damage and repair; triple-negative breast cancer; pathological complete response
11.  Hepatic and Splenic Acoustic Radiation Force Impulse Shear Wave Velocity Elastography in Children with Liver Disease Associated with Cystic Fibrosis 
BioMed Research International  2015;2015:517369.
Background. Liver disease associated with cystic fibrosis (CFLD) is the second cause of mortality in these patients. The diagnosis is difficult because none of the available tests are specific enough. Noninvasive elastographic techniques have been proven to be useful to diagnose hepatic fibrosis. Acoustic radiation force impulse (ARFI) imaging is an elastography imaging system. The purpose of the work was to study the utility of liver and spleen ARFI Imaging in the detection of CFLD. Method. 72 patients with cystic fibrosis (CF) were studied and received ARFI imaging in the liver and in the spleen. SWV values were compared with the values of 60 healthy controls. Results. Comparing the SWV values of CFLD with the control healthy group, values in the right lobe were higher in patients with CFLD. We found a SWV RHL cut-off value to detect CFLD of 1.27 m/s with a sensitivity of 56.5% and a specificity of 90.5%. CF patients were found to have higher SWC spleen values than the control group. Conclusions. ARFI shear wave elastography in the right hepatic lobe is a noninvasive technique useful to detect CFLD in our sample of patients. Splenic SWV values are higher in CF patients, without any clinical consequence.
doi:10.1155/2015/517369
PMCID: PMC4644813  PMID: 26609528
12.  Normative data on the n-back task for children and young adolescents 
Frontiers in Psychology  2015;6:1544.
The n-back task is a frequently used measure of working memory (WM) in cognitive neuroscience research contexts, and it has become widely adopted in other areas over the last decade. This study aimed to obtain normative data for the n-back task from a large sample of children and adolescents. To this end, a computerized verbal n-back task with three levels of WM load (1-back, 2-back, and 3-back) was administered to 3722 Spanish school children aged 7–13 years. Results showed an overall age-related increase in performance for the different levels of difficulty. This trend was less pronounced at 1-back than at 2-back when hits were considered. Gender differences were also observed, with girls outperforming boys although taking more time to respond. The theoretical implications of these results are discussed. Normative data stratified by age and gender for the three WM load levels are provided.
doi:10.3389/fpsyg.2015.01544
PMCID: PMC4597481  PMID: 26500594
n-back; working memory updating; working memory development; memory development in children; working memory
13.  Effect of Infliximab Dose Increase in Rheumatoid Arthritis at Different Trough Concentrations: A Cohort Study in Clinical Practice Conditions 
Background
Evidence supporting treatment intensification in rheumatoid arthritis (RA) is limited and controversial. We explored outcomes of infliximab dose increases and accounted for pre-existing trough levels in patients with active RA.
Methods
This study was a retrospective study of 42 RA patients who received increased infliximab following an insufficient response (DAS28 >3.2). Serum concentrations of infliximab and antibodies to infliximab (ATI) and DAS28 and EULAR clinical response parameters were recorded for 1 year. Analyses were performed in three patient groups that were defined by infliximab serum concentration prior to treatment enhancement: no detectable, low (<1.1 μg/mL) or high (≥1.1 μg/mL) drug levels.
Results
No circulating infliximab was detected in 20 patients (47.6%), but 13 (31%) and 9 (21.4%) patients exhibited low and high levels, respectively. ATI was only detected in patients with no detectable drug levels because the drug interferes with ELISA. DAS28 disease activity globally showed a modest improvement after dose escalation, but this improvement did not persist after 6 and 12 months. Infliximab serum levels increased significantly in the high group (p = 0.016), but no increase was achieved in the low and no detectable groups. The three study groups exhibited similar disease activity over time, and no improvement was observed in the non-responder EULAR rates.
Conclusion
These results suggest that the efficacy of an infliximab dose increase is limited, and the response is independent of the infliximab trough serum concentration that is achieved prior to escalation.
doi:10.3389/fmed.2015.00071
PMCID: PMC4597116  PMID: 26501060
rheumatoid arthritis; infliximab; dose increase; clinical efficacy
14.  Plasma betatrophin levels in patients with liver cirrhosis 
World Journal of Gastroenterology : WJG  2015;21(37):10662-10668.
AIM: To investigate the plasma levels of betatrophin in patients with cirrhosis.
METHODS: Forty patients diagnosed at the clinic with liver cirrhosis according to biological, ultrasonographic, or histological criteria were included. The severity of cirrhosis was classified according to Pugh’s modification of Child’s classification and MELD score. Insulin resistance (IR) was assessed by the Homeostasis Model Assessment. A total of 20 patients showed a MELD score higher than 14. The control group consisted in 15 sex-and aged-matched subjects. Fasting blood samples were obtained for subsequent analysis. Serum insulin was determined by Liaison automated immune chemiluminiscence assay (DiaSorin S.p.A.) using a sandwich assay. The sensitivity of the assay was 0.2 μU/mL. The intra and interassay variation coefficients were < 4% and < 10%, respectively. The normal values were between 2 and 17 μU/mL. Human active betatrophin was analyzed by specific quantitative sandwich ELISA (Aviscera Bioscience®). The sensitivity of the assay was 0.4 ng/mL, and the intra and interassay reproducibility were < 6% and < 10%, respectively.
RESULTS: Plasma betatrophin levels were significantly increased in patients with cirrhosis compared with those in healthy subjects (P = 0.0001). Betatrophin levels were also associated with disease severity, being higher in Child-Pugh C patients compared to Child-Pugh B (P < 0.0005) and in patients who displayed a MELD score higher than 14 points compared to patients with lower punctuation (P = 0.01). In addition, we found a positive correlation between plasma betatrophin levels and the severity of cirrhosis according to Child-Pugh classification (r = 0.53; P < 0.01) or MELD score (r = 0.45; P < 0.01). In the overall cohort, a moderate correlation between serum betatrophin and plasmatic bilirrubin (r = 0.39; P < 0.01) has been observed, as well as an inverse correlation between betatrophin and albumin (r = -0.41; P < 0.01) or prothrombin time (r = -0.44; P <0.01). Moreover, insulin resistance was observed in 82.5% of the cirrhotic patients. In this group of patients, betatrophin levels were significantly higher than those in the group of patients without IR (P < 0.05).
CONCLUSION: Plasma betatrophin is increased in patients with cirrhosis. This increase is related to the severity of cirrhosis, as well as with the emergence of insulin resistance.
doi:10.3748/wjg.v21.i37.10662
PMCID: PMC4588088  PMID: 26457026
Liver cirrhosis; Betatrophin; Insulin resistance; Betatrophin liver; Betatrophin insulin
15.  Whole-Genome Analysis of Diversity and SNP-Major Gene Association in Peach Germplasm 
PLoS ONE  2015;10(9):e0136803.
Peach was domesticated in China more than four millennia ago and from there it spread world-wide. Since the middle of the last century, peach breeding programs have been very dynamic generating hundreds of new commercial varieties, however, in most cases such varieties derive from a limited collection of parental lines (founders). This is one reason for the observed low levels of variability of the commercial gene pool, implying that knowledge of the extent and distribution of genetic variability in peach is critical to allow the choice of adequate parents to confer enhanced productivity, adaptation and quality to improved varieties. With this aim we genotyped 1,580 peach accessions (including a few closely related Prunus species) maintained and phenotyped in five germplasm collections (four European and one Chinese) with the International Peach SNP Consortium 9K SNP peach array. The study of population structure revealed the subdivision of the panel in three main populations, one mainly made up of Occidental varieties from breeding programs (POP1OCB), one of Occidental landraces (POP2OCT) and the third of Oriental accessions (POP3OR). Analysis of linkage disequilibrium (LD) identified differential patterns of genome-wide LD blocks in each of the populations. Phenotypic data for seven monogenic traits were integrated in a genome-wide association study (GWAS). The significantly associated SNPs were always in the regions predicted by linkage analysis, forming haplotypes of markers. These diagnostic haplotypes could be used for marker-assisted selection (MAS) in modern breeding programs.
doi:10.1371/journal.pone.0136803
PMCID: PMC4564248  PMID: 26352671
16.  I Want More and Better Cells! – An Outreach Project about Stem Cells and Its Impact on the General Population 
PLoS ONE  2015;10(7):e0133753.
Although science and technology impact every aspect of modern societies, there is still an extensive gap between science and society, which impairs the full exercise of citizenship. In the particular case of biomedical research increased investment should be accompanied by parallel efforts in terms of public information and engagement. We have carried out a project involving the production and evaluation of educational contents focused on stem cells - illustrated newspaper chronicles, radio interviews, a comic book, and animated videos - and monitored their impact on the Portuguese population. The study of the outreach materials in a heterogeneous sample of the population suggests that they are valuable tools to disseminate scientific messages, and that this is especially true for the comic-book format. Furthermore, the data showed that clear and stimulating outreach materials, that are able to teach new concepts and to promote critical thinking, increase engagement in science at different levels, depending on the depth of the concepts involved. Additionally, these materials can influence political, social and personal attitudes toward science. These results, together with the importance attributed to scientific research in stem cells by the population sampled, validates the diffusion of such materials as a significant contribution towards an overall public understanding and engagement in contemporary science, and this strategy should thus be considered in future projects. Regardless, stringent quality control must be implemented in order to efficiently communicate accurate scientific developments, and the public stimulated in terms of finding additional sources of reliable information.
doi:10.1371/journal.pone.0133753
PMCID: PMC4519251  PMID: 26222053
17.  Determining the Drivers of Academic Success in Surgery: An Analysis of 3,850 Faculty 
PLoS ONE  2015;10(7):e0131678.
Objective
Determine drivers of academic productivity within U.S. departments of surgery.
Methods
Eighty academic metrics for 3,850 faculty at the top 50 NIH-funded university- and 5 outstanding hospital-based surgical departments were collected using websites, Scopus, and NIH RePORTER.
Results
Mean faculty size was 76. Overall, there were 35.3% assistant, 27.8% associate, and 36.9% full professors. Women comprised 21.8%; 4.9% were MD-PhDs and 6.1% PhDs. By faculty-rank, median publications/citations were: assistant, 14/175, associate, 39/649 and full-professor, 97/2250. General surgery divisions contributed the most publications and citations. Highest performing sub-specialties per faculty member were: research (58/1683), transplantation (51/1067), oncology (41/777), and cardiothoracic surgery (48/860). Overall, 23.5% of faculty were principal investigators for a current or former NIH grant, 9.5% for a current or former R01/U01/P01. The 10 most cited faculty (MCF) within each department contributed to 42% of all publications and 55% of all citations. MCF were most commonly general (25%), oncology (19%), or transplant surgeons (15%). Fifty-one-percent of MCF had current/former NIH funding, compared with 20% of the rest (p<0.05); funding rates for R01/U01/P01 grants was 25.1% vs. 6.8% (p<0.05). Rate of current-NIH MCF funding correlated with higher total departmental NIH rank (p < 0.05).
Conclusions
Departmental academic productivity as defined by citations and NIH funding is highly driven by sections or divisions of research, general and transplantation surgery. MCF, regardless of subspecialty, contribute disproportionally to major grants and publications. Approaches that attract, develop, and retain funded MCF may be associated with dramatic increases in total departmental citations and NIH-funding.
doi:10.1371/journal.pone.0131678
PMCID: PMC4503730  PMID: 26177096
18.  Significant Differences Characterise the Correlation Coefficients between Biocide and Antibiotic Susceptibility Profiles in Staphylococcus aureus 
Current Pharmaceutical Design  2015;21(16):2054-2057.
There is a growing concern by regulatory authorities for the selection of antibiotic resistance caused by the use of biocidal products. We aimed to complete the detailed information on large surveys by investigating the relationship between biocide and antibiotic susceptibility profiles of a large number of Staphylococcus aureus isolates using four biocides and antibiotics commonly used in clinical practice. The minimal inhibitory concentration (MIC) for most clinically-relevant antibiotics was determined according to the standardized methodology for over 1600 clinical S. aureus isolates and compared to susceptibility profiles of benzalkonium chloride, chlorhexidine, triclosan, and sodium hypochlorite. The relationship between antibiotic and biocide susceptibility profiles was evaluated using non-linear correlations.
The main outcome evidenced was an absence of any strong or moderate statistically significant correlation when susceptibilities of either triclosan or sodium hypochlorite were compared for any of the tested antibiotics. On the other hand, correlation coefficients for MICs of benzalkonium chloride and chlorhexidine were calculated above 0.4 for susceptibility to quinolones, beta-lactams, and also macrolides.
Our data do not support any selective pressure for association between biocides and antibiotics resistance and furthermore do not allow for a defined risk evaluation for some of the compounds. Importantly, our data clearly indicate that there does not involve any risk of selection for antibiotic resistance for the compounds triclosan and sodium hypochlorite. These data hence infer that biocide selection for antibiotic resistance has had so far a less significant impact than feared.
doi:10.2174/1381612821666150310103238
PMCID: PMC4460275  PMID: 25760337
Staphylococcus aureus; antibiotic resistance; biocides; benzalkonium chloride; chlorhexidine; triclosan; sodium hypochlorite
19.  Identification of Tf1 integration events in S. pombe under nonselective conditions 
Gene  2014;542(2):221-231.
Integration of retroviral elements into the host genome is a phenomena observed among many classes of retroviruses. Much information concerning integration of retroviral elements has been documented based on in vitro analysis or expression of selectable markers. To identify possible Tf1 integration events within silent regions of the S. pombe genome, we focused on performing an in vivo genome-wide analysis of Tf1 integration events from the nonselective phase of the retrotransposition assay. We analyzed 1000 individual colonies streaked from four independent Tf1 transposed patches under nonselection conditions. Our analysis detected a population of G418S/neo+ Tf1 integration events that would have been overlooked during the selective phase of the assay. Further RNA analysis from the G418S/neo+ clones revealed 50% of clones expressing the neo selectable marker. Our data reveals Tf1’s ability to insert within silent regions of S. pombe’s genome.
doi:10.1016/j.gene.2014.03.030
PMCID: PMC4041700  PMID: 24680781
20.  Effect of N2 and H2 plasma treatments on band edge emission of ZnO microrods 
Scientific Reports  2015;5:10783.
ZnO microrods were grown by laser assisted flow deposition technique in order to study their luminescence behaviour in the near band edge spectral region. Transmission electron microscopy analysis put in evidence the high crystallinity degree and microrod’s compositional homogeneity. Photoluminescence revealed a dominant 3.31 eV emission. The correlation between this emission and the presence of surface states was investigated by performing plasma treatments with hydrogen and nitrogen. The significant modifications in photoluminescence spectra after the plasma treatments suggest a connexion between the 3.31 eV luminescence and the surface related electronic levels.
doi:10.1038/srep10783
PMCID: PMC4450596  PMID: 26027718
21.  Luminescence studies on green emitting InGaN/GaN MQWs implanted with nitrogen 
Scientific Reports  2015;5:9703.
We studied the optical properties of metalorganic chemical vapour deposited (MOCVD) InGaN/GaN multiple quantum wells (MQW) subjected to nitrogen (N) implantation and post-growth annealing treatments. The optical characterization was carried out by means of temperature and excitation density-dependent steady state photoluminescence (PL) spectroscopy, supplemented by room temperature PL excitation (PLE) and PL lifetime (PLL) measurements. The as-grown and as-implanted samples were found to exhibit a single green emission band attributed to localized excitons in the QW, although the N implantation leads to a strong reduction of the PL intensity. The green band was found to be surprisingly stable on annealing up to 1400°C. A broad blue band dominates the low temperature PL after thermal annealing in both samples. This band is more intense for the implanted sample, suggesting that defects generated by N implantation, likely related to the diffusion/segregation of indium (In), have been optically activated by the thermal treatment.
doi:10.1038/srep09703
PMCID: PMC4389667  PMID: 25853988
22.  Live bacterial vaccine vectors: An overview 
Brazilian Journal of Microbiology  2015;45(4):1117-1129.
Genetically attenuated microorganisms, pathogens, and some commensal bacteria can be engineered to deliver recombinant heterologous antigens to stimulate the host immune system, while still offering good levels of safety. A key feature of these live vectors is their capacity to stimulate mucosal as well as humoral and/or cellular systemic immunity. This enables the use of different forms of vaccination to prevent pathogen colonization of mucosal tissues, the front door for many infectious agents. Furthermore, delivery of DNA vaccines and immune system stimulatory molecules, such as cytokines, can be achieved using these special carriers, whose adjuvant properties and, sometimes, invasive capacities enhance the immune response. More recently, the unique features and versatility of these vectors have also been exploited to develop anti-cancer vaccines, where tumor-associated antigens, cytokines, and DNA or RNA molecules are delivered. Different strategies and genetic tools are constantly being developed, increasing the antigenic potential of agents delivered by these systems, opening fresh perspectives for the deployment of vehicles for new purposes. Here we summarize the main characteristics of the different types of live bacterial vectors and discuss new applications of these delivery systems in the field of vaccinology.
PMCID: PMC4323283  PMID: 25763014
bacterial vector; vaccine delivery system; DNA vaccine; cancer vaccine; antigen presentation
25.  Survival of Mexican Children with Acute Lymphoblastic Leukaemia under Treatment with the Protocol from the Dana-Farber Cancer Institute 00-01 
BioMed Research International  2015;2015:576950.
Our aim in this paper is to describe the results of treatment of acute lymphoblastic leukaemia (ALL) in Mexican children treated from 2006 to 2010 under the protocol from the Dana-Farber Cancer Institute (DFCI) 00-01. The children were younger than 16 years of age and had a diagnosis of ALL de novo. The patients were classified as standard risk if they were 1–9.9 years old and had a leucocyte count <50 × 109/L, precursor B cell immunophenotype, no mediastinal mass, CSF free of blasts, and a good response to prednisone. The rest of the patients were defined as high risk. Of a total of 302 children, 51.7% were at high risk. The global survival rate was 63.9%, and the event-free survival rate was 52.3% after an average follow-up of 3.9 years. The percentages of patients who died were 7% on induction and 14.2% in complete remission; death was associated mainly with infection (21.5%). The relapse rate was 26.2%. The main factor associated with the occurrence of an event was a leucocyte count >100 × 109/L. The poor outcomes were associated with toxic death during induction, complete remission, and relapse. These factors remain the main obstacles to the success of this treatment in our population.
doi:10.1155/2015/576950
PMCID: PMC4398910  PMID: 25922837

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