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1.  Intronic Variants in the NFKB1 Gene May Influence Hearing Forecast in Patients with Unilateral Sensorineural Hearing Loss in Meniere's Disease 
PLoS ONE  2014;9(11):e112171.
Meniere's disease is an episodic vestibular syndrome associated with sensorineural hearing loss (SNHL) and tinnitus. Patients with MD have an elevated prevalence of several autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis and psoriasis), which suggests a shared autoimmune background. Functional variants of several genes involved in the NF-κB pathway, such as REL, TNFAIP3, NFKB1 and TNIP1, have been associated with two or more immune-mediated diseases and allelic variations in the TLR10 gene may influence bilateral affectation and clinical course in MD. We have genotyped 716 cases of MD and 1628 controls by using the ImmunoChip, a high-density genotyping array containing 186 autoimmune loci, to explore the association of immune system related-loci with sporadic MD. Although no single nucleotide polymorphism (SNP) reached a genome-wide significant association (p<10−8), we selected allelic variants in the NF-kB pathway for further analyses to evaluate the impact of these SNPs in the clinical outcome of MD in our cohort. None of the selected SNPs increased susceptibility for MD in patients with uni or bilateral SNHL. However, two potential regulatory variants in the NFKB1 gene (rs3774937 and rs4648011) were associated with a faster hearing loss progression in patients with unilateral SNHL. So, individuals with unilateral MD carrying the C allele in rs3774937 or G allele in rs4648011 had a shorter mean time to reach hearing stage 3 (>40 dB HL) (log-rank test, corrected p values were p = 0.009 for rs3774937 and p = 0.003 for rs4648011, respectively). No variants influenced hearing in bilateral MD. Our data support that the allelic variants rs3774937 and rs4648011 can modify hearing outcome in patients with MD and unilateral SNHL.
doi:10.1371/journal.pone.0112171
PMCID: PMC4232390  PMID: 25397881
2.  Study of Hydatidosis-Attributed Mortality in Endemic Area 
PLoS ONE  2014;9(3):e91342.
Background
Cystic hydatid disease is still an important health problem in European Mediterranean areas. In spite of being traditionally considered as a “benign” pathology, cystic echinococcosis is an important cause of morbidity in these areas. Nevertheless, there are few analyses of mortality attributed to human hydatidosis.
Objective
To describe the epidemiology, the mortality rate and the causes of mortality due to E. granulosus infection in an endemic area.
Methodology
A retrospective study followed up over a period of 14 years (1998–2011).
Principal Findings
Of the 567 patients diagnosed with hydatid disease over the period 1998–2011, eleven deaths directly related to hydatid disease complications were recorded. Ten patients (90.9%) died due to infectious complications and the remaining one (9.1%) died due to mechanical complications after a massive hemoptysis. We registered a case fatality rate of 1.94% and a mortality rate of 3.1 per 100.000 inhabitants.
Conclusions
Hydatidosis is still a frequent parasitic disease that causes a considerable mortality. The main causes of mortality in patients with hydatidosis are complications related to the rupture of CE cysts with supurative collangitis. Therefore, an expectant management can be dangerous and it must be only employed in well-selected patients.
doi:10.1371/journal.pone.0091342
PMCID: PMC3954695  PMID: 24632824
3.  Effects of rs7903146 Variation in the Tcf7l2 Gene in the Lipid Metabolism of Three Different Populations 
PLoS ONE  2012;7(8):e43390.
Background
TCF7L2 rs7903146 is an important genetic factor predicting type 2 diabetes (T2DM) which has also been linked to higher cardiovascular risk. To date, there is little information about the additional impact of this single nucleotide polymorphism (SNP) beyond glucose metabolism.
Methodology/Principal Findings
We studied whether rs7903146 influenced postprandial lipid metabolism in three different populations (healthy young men, metabolic syndrome (MetS) patients and elderly persons). Eighty-eight healthy males were submitted to a single saturated fatty acid-rich test meal. Additionally, 110 middle-aged MetS patients and 20 healthy elderly persons (≥65 years) were submitted to three different dietary models followed by test meals. Minor allele homozygotes for rs7903146 showed a worse postprandial lipemia profile in young males, as seen by a lower HDL-cholesterol and Apo A1 concentration during the postprandial lipemia and a trend towards higher triglycerides (TG), than the other genotypes. In healthy elderly persons, carriers of the minor allele showed higher total cholesterol, LDL-cholesterol, Apo B and TG in the fasting state, and a higher postprandial area under the curve for total cholesterol, Apo B, small-triglyceride rich lipoprotein (TRL) cholesterol and small-(TRL) triglycerides. These results were accompanied by differential changes in adipokines. We did not observe any influence of rs7903146 on the postprandium of MetS patients.
Conclusions/Significance
Healthy young males and elderly persons who are carriers of the mutant allele for rs7903146 have an impaired postprandial lipid metabolism that may be mediated by an alteration in adipokine regulation, and may be related to the higher cardiovascular risk observed in these persons.
Trial Registration
ClinicalTrials.gov NCT00429195
doi:10.1371/journal.pone.0043390
PMCID: PMC3423356  PMID: 22916254
4.  A Customized Pigmentation SNP Array Identifies a Novel SNP Associated with Melanoma Predisposition in the SLC45A2 Gene 
PLoS ONE  2011;6(4):e19271.
As the incidence of Malignant Melanoma (MM) reflects an interaction between skin colour and UV exposure, variations in genes implicated in pigmentation and tanning response to UV may be associated with susceptibility to MM. In this study, 363 SNPs in 65 gene regions belonging to the pigmentation pathway have been successfully genotyped using a SNP array. Five hundred and ninety MM cases and 507 controls were analyzed in a discovery phase I. Ten candidate SNPs based on a p-value threshold of 0.01 were identified. Two of them, rs35414 (SLC45A2) and rs2069398 (SILV/CKD2), were statistically significant after conservative Bonferroni correction. The best six SNPs were further tested in an independent Spanish series (624 MM cases and 789 controls). A novel SNP located on the SLC45A2 gene (rs35414) was found to be significantly associated with melanoma in both phase I and phase II (P<0.0001). None of the other five SNPs were replicated in this second phase of the study. However, three SNPs in TYR, SILV/CDK2 and ADAMTS20 genes (rs17793678, rs2069398 and rs1510521 respectively) had an overall p-value<0.05 when considering the whole DNA collection (1214 MM cases and 1296 controls). Both the SLC45A2 and the SILV/CDK2 variants behave as protective alleles, while the TYR and ADAMTS20 variants seem to function as risk alleles. Cumulative effects were detected when these four variants were considered together. Furthermore, individuals carrying two or more mutations in MC1R, a well-known low penetrance melanoma-predisposing gene, had a decreased MM risk if concurrently bearing the SLC45A2 protective variant. To our knowledge, this is the largest study on Spanish sporadic MM cases to date.
doi:10.1371/journal.pone.0019271
PMCID: PMC3084811  PMID: 21559390
5.  The effect of H. pylori eradication on meal-associated changes in plasma ghrelin and leptin 
BMC Gastroenterology  2011;11:37.
Background
Appetite and energy expenditure are regulated in part by ghrelin and leptin produced in the gastric mucosa, which may be modified by H. pylori colonization. We prospectively evaluated the effect of H. pylori eradication on meal-associated changes in serum ghrelin and leptin levels, and body weight.
Methods
Veterans referred for upper GI endoscopy were evaluated at baseline and ≥8 weeks after endoscopy, and H. pylori status and body weight were ascertained. During the first visit in all subjects, and during subsequent visits in the initially H. pylori-positive subjects and controls, blood was collected after an overnight fast and 1 h after a standard high protein meal, and levels of eight hormones determined.
Results
Of 92 enrolled subjects, 38 were H. pylori-negative, 44 H. pylori-positive, and 10 were indeterminate. Among 23 H. pylori-positive subjects who completed evaluation after treatment, 21 were eradicated, and 2 failed eradication. After a median of seven months following eradication, six hormones related to energy homeostasis showed no significant differences, but post-prandial acylated ghrelin levels were nearly six-fold higher than pre-eradication (p = 0.005), and median integrated leptin levels also increased (20%) significantly (p < 0.001). BMI significantly increased (5 ± 2%; p = 0.008) over 18 months in the initially H. pylori-positive individuals, but was not significantly changed in those who were H. pylori-negative or indeterminant at baseline.
Conclusions
Circulating meal-associated leptin and ghrelin levels and BMI changed significantly after H. pylori eradication, providing direct evidence that H. pylori colonization is involved in ghrelin and leptin regulation, with consequent effects on body morphometry.
doi:10.1186/1471-230X-11-37
PMCID: PMC3089783  PMID: 21489301
6.  Augmented Reality for the Assessment of Children's Spatial Memory in Real Settings 
PLoS ONE  2014;9(12):e113751.
Short-term memory can be defined as the capacity for holding a small amount of information in mind in an active state for a short period of time. Although some instruments have been developed to study spatial short-term memory in real environments, there are no instruments that are specifically designed to assess visuospatial short-term memory in an attractive way to children. In this paper, we present the ARSM (Augmented Reality Spatial Memory) task, the first Augmented Reality task that involves a user's movement to assess spatial short-term memory in healthy children. The experimental procedure of the ARSM task was designed to assess the children's skill to retain visuospatial information. They were individually asked to remember the real place where augmented reality objects were located. The children (N = 76) were divided into two groups: preschool (5–6 year olds) and primary school (7–8 year olds). We found a significant improvement in ARSM task performance in the older group. The correlations between scores for the ARSM task and traditional procedures were significant. These traditional procedures were the Dot Matrix subtest for the assessment of visuospatial short-term memory of the computerized AWMA-2 battery and a parent's questionnaire about a child's everyday spatial memory. Hence, we suggest that the ARSM task has high verisimilitude with spatial short-term memory skills in real life. In addition, we evaluated the ARSM task's usability and perceived satisfaction. The study revealed that the younger children were more satisfied with the ARSM task. This novel instrument could be useful in detecting visuospatial short-term difficulties that affect specific developmental navigational disorders and/or school academic achievement.
doi:10.1371/journal.pone.0113751
PMCID: PMC4249957  PMID: 25438146
7.  Ameloblastic fibroma: A rare case appearing as a mixed radiographic image 
Ameloblastic fibroma (AF) is a benign tumor of mixed odontogenic origin, which affects predominantly young individuals. AF appearing as a mixed radiographic image is very rare. This report describes a case of AF in a 12-year-old male identified during a routine radiographic exam for orthodontic treatment planning. The panoramic radiography revealed a well-defined multilocular mixed image located in the mandible between the roots of the left mandibular second premolar and first molar. The lesion was excised under local anesthesia. Histopathological analysis revealed islands of epithelial cells and columnar peripheral cells showing a nucleus in inverted polarization, interspersed with spindle-shaped cells and abundant extracellular matrix deposition. No atypia was observed. The diagnosis of AF was established. No tumor recurred up to 30 months after treatment. Although rare, AF should be also considered in the differential diagnosis of mixed radiographic images of the jaws in young patients.
Key words:Ameloblastic fibroma, differential diagnosis, incidental finding, mixed image, radiographic features.
doi:10.4317/jced.51471
PMCID: PMC4312690
8.  Factors associated with postprandial lipemia and apolipoprotein A-V levels in individuals with familial combined hyperlipidemia 
BMC Endocrine Disorders  2014;14(1):90.
Background
Alterations in postprandial metabolism have been described in familial combined hyperlipidemia (FCH); however, their underlying mechanisms are not well characterized. We aimed to identify factors related to the magnitude of postprandial lipemia and apolipoprotein (apo) A-V levels in subjects with FCH.
Methods
FCH cases (n = 99) were studied using a standardized meal test. Abdominal obesity was assessed using the waist to hip ratio (WHR). A linear regression model was performed to investigate the variables associated with the triglycerides incremental area under the curve (iAUC). Independent associations between metabolic variables and apo A-V iAUC were also investigated in a randomly selected subgroup (n = 44). The study sample was classified according to the presence of fasting hypertriglyceridemia (≥150 mg/dL) and abdominal obesity (WHR ≥0.92 in men and ≥0.85 in women) to explore differences in parameters.
Results
The fasting apo B-48 levels (r = 0.404), and the WHR (r = 0.359) were independent factors contributing to the triglycerides iAUC (r2 = 0.29, P < 0.001). The triglycerides iAUC was independently associated with the apo A-V iAUC (r2 = 0.54, P < 0.01). Patients with both hypertriglyceridemia and abdominal obesity showed the most robust triglycerides and apo A-V postprandial responses.
Conclusions
In patients with FCH the fasting apo B-48 level is the main factor associated with postprandial lipemia. Abdominal obesity also contributes to the magnitude of the postprandial response.
The triglycerides postprandial increment is the principal factor associated with the apo A-V postprandial response.
doi:10.1186/1472-6823-14-90
PMCID: PMC4253986  PMID: 25425215
Postprandial lipemia; Triglycerides; Apo B-48; Apo A-V; Abdominal obesity; Waist to hip ratio
9.  HIV infection early diagnosis experience in primary care 
Journal of the International AIDS Society  2014;17(4Suppl 3):19597.
Introduction
Traditional screening system focus on classic risk factors “lost” a substantial proportion of HIV-infected patients. Several organizations such as CDC or USPS Task Force favour universal screening for HIV infection for good cost-effectiveness profile. In a previous study prevalence of HIV infection in patients attending our infectious diseases department was high (5.4%).
Objective
To determine prevalence of HIV infection in patients aged 20–55 years in primary care (PC).
Material and Methods
A propsective observational study was undertaken between February and June 2013. We performed a screening of HIV infection type “Opt-out” (offering voluntary rejection) in 4 PC centers (32 Physicians) in San Juan-Alicante. Sample size (n=318) for a prevalence of 1% and a confidence level of 97% was calculated. Nevertheless, other PC physician not recruiting patients performed HIV testing according clinical risk factors.
Results
HIV testing was offered to 508 patients. Mean age 38.9±10 years (58.5% female). Overall, 430 (83.8%) agreed to participate. Finally, 368 patients (71.7% of total) were tested for HIV. No patient had a positive result (100% ELISA HIV negative). However, following clinical practice, 3 patients were diagnosed of HIV in the same period by non-recruiting physicians. In 2 cases, serology was performed at the patient's request and in one case by constitutional syndrome. The 3 patients were MSM.
Conclusions
1) In our study, we detected no new cases of HIV infection through universal screening. 2) Our screened population could be lower-risk because of high percentage of women included (58.5%). 3) Performing HIV opt-in screening (clinical practice), we detected 3 cases in the same period, all having HIV risk factors (MSM). 4) These results suggest that opt-out screening should be developed in high-risk populations. It is still to be determined what is the best screening strategy in low-risk populations such as ours.
doi:10.7448/IAS.17.4.19597
PMCID: PMC4224898  PMID: 25394101
10.  Role of childhood infection in the sequelae of H. pylori disease 
Gut Microbes  2013;4(6):426-438.
The persistence of Helicobacter pylori infection plays a fundamental role in the development of H. pylori-associated complications. Since the majority of infected persons acquire the bacteria during early childhood, an examination of the immunobiology of H. pylori infection in children compared with that of adults may help identify host factors that contribute to persistent infection. Therefore, we begin our review of the role of persistence in H. pylori disease with an assessment of the clinical features of H. pylori infection in children. We next review the bacterial factors that promote colonization and evasion of host defense mechanisms. We then focus our attention on the early host immunological factors that promote persistence of the infection and its complications in humans and mouse models. We also highlight topics in which further research is needed. An examination of how immunological factors cause divergent manifestations of H. pylori infection in children compared with adults may provide new insight for therapeutic modification or prevention of persistent H. pylori infection and its complications.
doi:10.4161/gmic.26943
PMCID: PMC3928156  PMID: 24275060
Helicobacter pylori; cancer; infection; children
11.  Ethnicity is a strong predictor for Helicobacter pylori infection in young women in a multi-ethnic European city 
Journal of gastroenterology and hepatology  2013;28(11):10.1111/jgh.12315.
BACKGROUND AND AIM
At the same time that H. pylori prevalence is declining in Western countries, immigrants from developing countries with high H. pylori prevalence have settled in Western urban areas. Actual epidemiologic data on H. pylori in a migrant community may help in realizing a more selective approach to assess H. pylori-related diseases. We aimed to define H. pylori prevalence as well as risk groups for H. pylori in a cohort of young women living in a multi-ethnic European city.
METHODS
We measured IgG anti-H. pylori and CagA-antibodies in serum of pregnant women included in a population-based prospective cohort study. Information on demographics, and socio-economic status was collected by questionnaires. Chi-square and logistic regression were used.
RESULTS
In total, 3146 (46%) of the 6837 tested women (mean age 29.7 ± 5.3) were H. pylori-positive and 1110 (35%) of them were CagA-positive. The H. pylori prevalence in Dutch women was 24%, which was significantly lower than in non-Dutch women (64%; p<0.001). In particular, H. pylori positivity was found in 92% of Moroccan (OR 19.2; 95% CI 11.8-32.0), 80% of Cape Verdean (7.6; 5.0-11.5), 81% of Turkish (9.0; 6.7-12.1), 60% of Dutch Antillean (3.3; 2.3-4.7), and 58% of Surinamese women (3.0; 2.3-3.8). Among H. pylori-positive Dutch subjects, 19% were CagA-positive compared with 40% of the non-Dutch subjects (p<0.001).
CONCLUSIONS
Despite a general trend of declining prevalence in Western countries, H. pylori remains highly prevalent in migrant communities, which may constitute target groups for screening and eradication to prevent H. pylori-related diseases.
doi:10.1111/jgh.12315
PMCID: PMC3822168  PMID: 23808840
Helicobacter pylori; cagA protein; epidemiology
12.  Nonlinearities distribution Laplace transform-homotopy perturbation method 
SpringerPlus  2014;3:594.
This article proposes non-linearities distribution Laplace transform-homotopy perturbation method (NDLT-HPM) to find approximate solutions for linear and nonlinear differential equations with finite boundary conditions. We will see that the method is particularly relevant in case of equations with nonhomogeneous non-polynomial terms. Comparing figures between approximate and exact solutions we show the effectiveness of the proposed method.
doi:10.1186/2193-1801-3-594
PMCID: PMC4203791  PMID: 25392771
Homotopy perturbation method; Nonlinear differential equation; Approximate solutions; Laplace transform; Laplace transform homotopy perturbation method; Finite boundary conditions
13.  Fungal model systems and the elucidation of pathogenicity determinants 
Fungal Genetics and Biology  2014;70(100):42-67.
Highlights
•History of seven fungal species used as models for studying development and pathogenicity.•Outline of central stages of their life cycle and their infection processes.•Molecular toolkits used to study different aspects of pathogenicity.•Insight gained from genome sequencing projects.•Current research trends and future challenges.
Fungi have the capacity to cause devastating diseases of both plants and animals, causing significant harvest losses that threaten food security and human mycoses with high mortality rates. As a consequence, there is a critical need to promote development of new antifungal drugs, which requires a comprehensive molecular knowledge of fungal pathogenesis. In this review, we critically evaluate current knowledge of seven fungal organisms used as major research models for fungal pathogenesis. These include pathogens of both animals and plants; Ashbya gossypii, Aspergillus fumigatus, Candida albicans, Fusarium oxysporum, Magnaporthe oryzae, Ustilago maydis and Zymoseptoria tritici. We present key insights into the virulence mechanisms deployed by each species and a comparative overview of key insights obtained from genomic analysis. We then consider current trends and future challenges associated with the study of fungal pathogenicity.
doi:10.1016/j.fgb.2014.06.011
PMCID: PMC4161391  PMID: 25011008
Fungal model organism; Plant fungal pathogen; Human fungal pathogen; Genomics; Virulence
14.  Better detection of platelet aggregation in patients with metabolic syndrome using epinephrine and ADP 
Background
Patients with metabolic syndrome (MS) often have increased platelet aggregation. In order to determine which concentration detects a higher level of platelet aggregation in patients with MS, the agonists ADP and epinephrine were compared.
Methods
The study included 56 subjects with MS and 53 healthy subjects. Blood pressure, weight, body-mass index, and hip-to-waist ratio were collected from all subjects. Insulin, glucose, total serum cholesterol, HDL-C, LDL-C, total triglycerides, markers of plasma atherogenicity, and indices of insulin resistance were measured in all participants. For aggregometry assays, the Born method was used. Platelets were treated with ADP and epinephrine in decreasing concentrations of 2.34, 1.17, and 0.58 μM, as well as, 11.0, 1.1, and 0.55 μM, respectively. ROC curves were plotted to define the diagnostic efficiency of epinephrine levels for MS.
Results
Among healthy individuals and MS patients significant differences were observed in body weight, body-mass index, waist-circumference, levels of insulin, indices of insulin resistance, and levels of HDL-cholesterol, LDL-cholesterol and total triglycerides. There was a significant difference in the detection of increased platelet aggregation using 11.0 μM and 0.55 μM epinephrine and 0.58 μM ADP. With both agonists, ROC analysis showed an area under the curve of >0.8 for 11.0 μM epinephrine and 2.34 μM ADP. However, for MS patients, 11.0 μM epinephrine had a slightly better diagnostic efficiency than 2.34 μM ADP.
Conclusions
It was found that 11.0 μM epinephrine and 2.34 μM ADP detected better platelet aggregation in patients with MS than in healthy subject. Both concentrations detected increased platelet aggregation in patients with MS.
doi:10.1186/1758-5996-6-93
PMCID: PMC4169807  PMID: 25243022
Platelets; Metabolic syndrome; ADP; Epinephrine
15.  OncodriveROLE classifies cancer driver genes in loss of function and activating mode of action 
Bioinformatics  2014;30(17):i549-i555.
Motivation: Several computational methods have been developed to identify cancer drivers genes—genes responsible for cancer development upon specific alterations. These alterations can cause the loss of function (LoF) of the gene product, for instance, in tumor suppressors, or increase or change its activity or function, if it is an oncogene. Distinguishing between these two classes is important to understand tumorigenesis in patients and has implications for therapy decision making. Here, we assess the capacity of multiple gene features related to the pattern of genomic alterations across tumors to distinguish between activating and LoF cancer genes, and we present an automated approach to aid the classification of novel cancer drivers according to their role.
Result: OncodriveROLE is a machine learning-based approach that classifies driver genes according to their role, using several properties related to the pattern of alterations across tumors. The method shows an accuracy of 0.93 and Matthew's correlation coefficient of 0.84 classifying genes in the Cancer Gene Census. The OncodriveROLE classifier, its results when applied to two lists of predicted cancer drivers and TCGA-derived mutation and copy number features used by the classifier are available at http://bg.upf.edu/oncodrive-role.
Availability and implementation: The R implementation of the OncodriveROLE classifier is available at http://bg.upf.edu/oncodrive-role.
Contact: abel.gonzalez@upf.edu or nuria.lopez@upf.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btu467
PMCID: PMC4147920  PMID: 25161246
16.  A handy approximate solution for a squeezing flow between two infinite plates by using of Laplace transform-homotopy perturbation method 
SpringerPlus  2014;3:421.
This article proposes Laplace Transform Homotopy Perturbation Method (LT-HPM) to find an approximate solution for the problem of an axisymmetric Newtonian fluid squeezed between two large parallel plates. After comparing figures between approximate and exact solutions, we will see that the proposed solutions besides of handy, are highly accurate and therefore LT-HPM is extremely efficient.
doi:10.1186/2193-1801-3-421
PMCID: PMC4141937  PMID: 25157331
Laplace transform homotopy perturbation method; Nonlinear fluid problems; Power series
17.  Dissecting phenotypic traits linked to human resilience to Alzheimer’s pathology 
Brain  2013;136(8):2510-2526.
Clinico-pathological correlation studies and positron emission tomography amyloid imaging studies have shown that some individuals can tolerate substantial amounts of Alzheimer’s pathology in their brains without experiencing dementia. Few details are known about the neuropathological phenotype of these unique cases that might prove relevant to understanding human resilience to Alzheimer’s pathology. We conducted detailed quantitative histopathological and biochemical assessments on brains from non-demented individuals before death whose brains were free of substantial Alzheimer’s pathology, non-demented individuals before death but whose post-mortem examination demonstrated significant amounts of Alzheimer’s changes (‘mismatches’), and demented Alzheimer’s cases. Quantification of amyloid-β plaque burden, stereologically-based counts of neurofibrillary tangles, neurons and reactive glia, and morphological analyses of axons were performed in the multimodal association cortex lining the superior temporal sulcus. Levels of synaptic integrity markers, and soluble monomeric and multimeric amyloid-β and tau species were measured. Our results indicate that some individuals can accumulate equivalent loads of amyloid-β plaques and tangles to those found in demented Alzheimer’s cases without experiencing dementia. Analyses revealed four main phenotypic differences among these two groups: (i) mismatches had striking preservation of neuron numbers, synaptic markers and axonal geometry compared to demented cases; (ii) demented cases had significantly higher burdens of fibrillar thioflavin-S-positive plaques and of oligomeric amyloid-β deposits reactive to conformer-specific antibody NAB61 than mismatches; (iii) strong and selective accumulation of hyperphosphorylated soluble tau multimers into the synaptic compartment was noted in demented cases compared with controls but not in mismatches; and (iv) the robust glial activation accompanying amyloid-β and tau pathologies in demented cases was remarkably reduced in mismatches. Further biochemical measurements of soluble amyloid-β species—monomers, dimers and higher molecular weight oligomers—in total brain homogenates and synaptoneurosomal preparations failed to demonstrate significant differences between mismatches and demented cases. Together, these data suggest that amyloid-β plaques and tangles do not inevitably result in neural system derangement and dementia in all individuals. We identified distinct phenotypic characteristics in the profile of brain fibrillar and soluble amyloid-β and tau accrual and in the glial response that discriminated demented and non-demented individuals with high loads of Alzheimer’s pathology. Amyloid-β deposition in the form of fibrillar plaques and intimately related oligomeric amyloid-β assemblies, hyperphosphorylated soluble tau species localized in synapses, and glial activation emerged in this series as likely mediators of neurotoxicity and altered cognition, providing further insight into factors and pathways potentially involved in human susceptibility or resilience to Alzheimer’s pathological changes.
doi:10.1093/brain/awt171
PMCID: PMC3722351  PMID: 23824488
Alzheimers disease; amyloid pathology; tau pathology; resilience; astrocytes; microglia
18.  Hypertriglyceridemia Influences the Degree of Postprandial Lipemic Response in Patients with Metabolic Syndrome and Coronary Artery Disease: From the Cordioprev Study 
PLoS ONE  2014;9(5):e96297.
Objective
To determine whether metabolic syndrome traits influence the postprandial lipemia response of coronary patients, and whether this influence depends on the number of MetS criteria.
Materials and Methods
1002 coronary artery disease patients from the CORDIOPREV study were submitted to an oral fat load test meal with 0.7 g fat/kg body weight (12% saturated fatty acids, 10% polyunsaturated fatty acids, 43% monounsaturated fatty acids), 10% protein and 25% carbohydrates. Serial blood test analyzing lipid fractions were drawn at 0, 1, 2, 3 and 4 hours during the postprandial state. Total and incremental area under the curves of the different postprandial parameters were calculated following the trapezoid rule to assess the magnitude of change during the postprandial state
Results
Postprandial lipemia response was directly related to the presence of metabolic syndrome. We found a positive association between the number of metabolic syndrome criteria and the response of postprandial plasma triglycerides (p<0.001), area under the curve of triglycerides (p<0.001) and incremental area under the curve of triglycerides (p<0.001). However, the influence of them on postprandial triglycerides remained statistically significant only in those patients without basal hypertriglyceridemia. Interestingly, in stepwise multiple linear regression analysis with the AUC of triglycerides as the dependent variable, only fasting triglycerides, fasting glucose and waist circumference appeared as significant independent (P<0.05) contributors. The multiple lineal regression (R) was 0.77, and fasting triglycerides showed the greatest effect on AUC of triglycerides with a standardized coefficient of 0.75.
Conclusions
Fasting triglycerides are the major contributors to the postprandial triglycerides levels. MetS influences the postprandial response of lipids in patients with coronary heart disease, particularly in non-hypertriglyceridemic patients.
doi:10.1371/journal.pone.0096297
PMCID: PMC4011695  PMID: 24802225
19.  Quantitation and Composition of Cutaneous Microbiota in Diabetic and Nondiabetic Men 
The Journal of Infectious Diseases  2013;207(7):1105-1114.
Background. Diabetic foot infections are a leading cause of lower extremity amputations. Our study examines the microbiota of diabetic skin prior to ulcer development or infection.
Methods. In a case-control study, outpatient males were recruited at a veterans hospital. Subjects were swabbed at 4 cutaneous sites, 1 on the forearm and 3 on the foot. Quantitative polymerase chain reaction (qPCR) with primers and probes specific for bacteria, Staphylococcus species, Staphylococcus aureus, and fungi were performed on all samples. High-throughput 16S ribosomal RNA (rRNA) sequencing was performed on samples from the forearm and the plantar aspect of the foot.
Results. qPCR analysis of swab specimens from 30 diabetic subjects and 30 control subjects showed no differences in total numbers of bacteria or fungi at any sampled site. Increased log10 concentrations of Staphylococcus aureus, quantified by the number of nuc gene copies, were present in diabetic men on the plantar aspect of the foot. High-throughput 16S rRNA sequencing found that, on the foot, the microbiota in controls (n = 24) was dominated by Staphylococcus species, whereas the microbiota in diabetics (n = 23) was more diverse at the genus level. The forearm microbiota had similar diversity in diabetic and control groups.
Conclusions. The feet of diabetic men had decreased populations of Staphylococcus species, increased populations of S. aureus, and increased bacterial diversity, compared with the feet of controls. These ecologic changes may affect the risk for wound infections.
doi:10.1093/infdis/jit005
PMCID: PMC3583274  PMID: 23300163
microbiota; microbiome; diabetic foot; cutaneous; Staphylococcus; Staphylococcus aureus
20.  A handy approximation for a mediated bioelectrocatalysis process, related to Michaelis-Menten equation 
SpringerPlus  2014;3:162.
In this article, Perturbation Method (PM) is employed to obtain a handy approximate solution to the steady state nonlinear reaction diffusion equation containing a nonlinear term related to Michaelis-Menten of the enzymatic reaction. Comparing graphics between the approximate and exact solutions, it will be shown that the PM method is quite efficient.
doi:10.1186/2193-1801-3-162
PMCID: PMC3982037  PMID: 24741477
Michaelis-Menten kinetics; Perturbation method; Reaction/diffusion equation; Mediated bioelectrocatalysis
21.  Preoperative chemoradiotherapy in rectal cancer induces changes in the expression of nuclear β-catenin: prognostic significance 
BMC Cancer  2014;14:192.
Background
Preoperative chemoradiotherapy (CRT) is the cornerstone of treatment for locally advanced rectal cancer (LARC). Although high local control is achieved, overall rates of distant control remain suboptimal. Colorectal carcinogenesis is associated with critical alterations of the Wnt/β-catenin pathway involved in proliferation and survival. The aim of this study was to assess whether CRT induces changes in the expression of β-catenin/E-cadherin, and to determine whether these changes are associated with survival.
Methods
The Immunohistochemical expression of nuclear β-catenin and membranous E-cadherin was prospectively analysed in tumour blocks from 98 stage II/III rectal cancer patients treated with preoperative CRT. Tumour samples were collected before and after CRT treatment. All patients were treated with pelvic RT (46–50 Gy in 2 Gy fractions) and 5-fluorouracil (5FU) intravenous infusion (225 mg/m2) or capecitabine (825 mg/m2) during RT treatment, followed by total mesorectal excision (TME). Disease-free survival (DFS) was analysed using the Kaplan-Meier method and a multivariate Cox regression model was employed for the Multivariate analysis.
Results
CRT induced significant changes in the expression of nuclear β-catenin (49% of patients presented an increased expression after CRT, 17% a decreased expression and 34% no changes; p = 0.001). After a median follow-up of 25 months, patients that overexpressed nuclear β-catenin after CRT showed poor survival compared with patients that experienced a decrease in nuclear β-catenin expression (3-year DFS 92% vs. 43%, HR 0.17; 95% CI 0.03 to 0.8; p = 0.02). In the multivariate analysis for DFS, increased nuclear β-catenin expression after CRT almost reached the cut-off for significance (p = 0.06).
Conclusions
In our study, preoperative CRT for LARC induced significant changes in nuclear β-catenin expression, which had a major impact on survival. Finding a way to decrease CRT resistance would significantly improve LARC patient survival.
doi:10.1186/1471-2407-14-192
PMCID: PMC3995577  PMID: 24629143
Locally advanced rectal cancer; Radiotherapy; Chemotherapy; β-catenin
22.  A review of Helicobacter pylori diagnosis, treatment, and methods to detect eradication 
Helicobacter pylori (H. pylori) affects nearly half of the world’s population and, thus, is one of the most frequent and persistent bacterial infections worldwide. H. pylori is associated with peptic ulcer disease, gastric ulcers, mucosa-associated lymphoid tissue lymphoma, and gastric cancer. Various diagnostic methods exist to detect infection, and the choice of one method or another depends on several factors, such as accessibility, advantages and disadvantages of each method, cost, and the age of patients. Once H. pylori infection is diagnosed, the clinician decides whether treatment is necessity, according to the patient’s clinical condition. Typically, eradication of H. pylori is recommended for treatment and prevention of the infection. Cure rates with the standard triple therapy are acceptable, and effective quadruple therapies, sequential therapies, and concomitant therapies have been introduced as key alternatives to treat H. pylori infection. In this work, we review the main diagnostic methods used to identify H. pylori infection and to confirm eradication of infection. In addition, key factors related to treatment are reviewed.
doi:10.3748/wjg.v20.i6.1438
PMCID: PMC3925853  PMID: 24587620
Diagnosis; Helicobacter pylori; Treatment; Hybrid therapy; Concomitant therapy; Sequential therapy
23.  Postprandial antioxidant gene expression is modified by Mediterranean diet supplemented with coenzyme Q10 in elderly men and women 
Age  2011;35(1):159-170.
Postprandial oxidative stress is characterized by an increased susceptibility of the organism towards oxidative damage after consumption of a meal rich in lipids and/or carbohydrates. We have investigated whether the quality of dietary fat alters postprandial gene expression and protein levels involved in oxidative stress and whether the supplementation with coenzyme Q10 (CoQ) improves this situation in an elderly population. Twenty participants were randomized to receive three isocaloric diets each for 4 weeks: Mediterranean diet supplemented with CoQ (Med + CoQ diet), Mediterranean diet (Med diet), saturated fatty acid-rich diet (SFA diet). After 12-h fast, volunteers consumed a breakfast with a fat composition similar to that consumed in each of the diets. Nrf2, p22phox and p47phox, superoxide dismutase 1 and 2 (SOD1 and SOD2), glutathione peroxidase 1 (GPx1), thiorredoxin reductase (TrxR) gene expression and Kelch-like ECH associating protein 1 (Keap-1) and citoplasmic and nuclear Nrf2 protein levels were determined. Med and Med + CoQ diets induced lower Nrf2, p22phox, p47phox, SOD1, SOD2 and TrxR gene expression and higher cytoplasmic Nrf2 and Keap-1 protein levels compared to the SFA diet. Moreover, Med + CoQ diet produced lower postprandial Nrf2 gene expression and lower nuclear Nrf2 protein levels compared to the other diets and lower GPx1 gene expression than the SFA diet. Our results support the antioxidant effect of a Med diet and that exogenous CoQ supplementation has a protective effects against free radical overgeneration through the lowering of postprandial oxidative stress modifying the postprandial antioxidant protein levels and reducing the postprandial expression of antioxidant genes in peripheral blood mononuclear cells.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-011-9331-4) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-011-9331-4
PMCID: PMC3543746  PMID: 22057896
CoQ10; Mediterranean diet; Oxidative stress; Gene expression
25.  Starvation Increases Insulin Sensitivity and Reduces Juvenile Hormone Synthesis in Mosquitoes 
PLoS ONE  2014;9(1):e86183.
Background
The interactions between the insulin signaling pathway (ISP) and juvenile hormone (JH) controlling reproductive trade-offs are well documented in insects. JH and insulin regulate reproductive output in mosquitoes; both hormones are involved in a complex regulatory network, in which they influence each other and in which the mosquito's nutritional status is a crucial determinant of the network's output. Previous studies reported that the insulin-TOR (target of rapamacyn) signaling pathway is involved in the nutritional regulation of JH synthesis in female mosquitoes. The present studies further investigate the regulatory circuitry that controls both JH synthesis and reproductive output in response to nutrient availability.
Methods
We used a combination of diet restriction, RNA interference (RNAi) and insulin treatments to modify insulin signaling and study the cross-talk between insulin and JH in response to starvation. JH synthesis was analyzed using a newly developed assay utilizing fluorescent tags.
Conclusions
Our results reveal that starvation decreased JH synthesis via a decrease in insulin signaling in the corpora allata (CA). Paradoxically, starvation-induced up regulation of insulin receptor transcripts and therefore “primed” the gland to respond rapidly to increases in insulin levels. During this response to starvation the synthetic potential of the CA remained unaffected, and the gland rapidly and efficiently responded to insulin stimulation by increasing JH synthesis to rates similar to those of CA from non-starved females.
doi:10.1371/journal.pone.0086183
PMCID: PMC3906049  PMID: 24489697

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