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1.  A Delphi Study to Detect Deficiencies and Propose Actions in Real Life Treatment of Neovascular Age-Related Macular Degeneration 
Journal of Ophthalmology  2014;2014:595132.
Purpose. Spanish retina specialists were surveyed in order to propose actions to decrease deficiencies in real-life neovascular age macular degeneration treatment (nv-AMD). Methods. One hundred experts, members of the Spanish Vitreoretinal Society (SERV), were invited to complete an online survey of 52 statements about nv-AMD management with a modified Delphi methodology. Four rounds were performed using a 5-point Linkert scale. Recommendations were developed after analyzing the differences between the results and the SERV guidelines recommendations. Results. Eighty-seven specialists completed all the Delphi rounds. Once major potential deficiencies in real-life nv-AMD treatment were identified, 15 recommendations were developed with a high level of agreement. Consensus statements to reduce the burden of the disease included the use of treat and extend regimen and to reduce the amount of diagnostic tests during the loading phase and training technical staff to perform these tests and reduce the time between relapse detection and reinjection, as well as establishing patient referral protocols to outside general ophthalmology clinics. Conclusion. The level of agreement with the final recommendations for nv-AMD treatment among Spanish retinal specialist was high indicating that some actions could be applied in order to reduce the deficiencies in real-life nv-AMD treatment.
PMCID: PMC4283441  PMID: 25587438
2.  Gene expression profile regulated by the HPV16 E7 oncoprotein and estradiol in cervical tissue 
Virology  2013;447(0):155-165.
The HPV16 E7 oncoprotein and 17β-estradiol are important factors for the induction of premalignant lesions and cervical cancer. The study of these factors is crucial for a better understanding of cervical tumorigenesis. Here, we assessed the global gene expression profiles induced by the HPV16 E7 oncoprotein and/or 17β-estradiol in cervical tissue of FvB and K14E7 transgenic mice. We found that the most dramatic changes in gene expression occurred in K14E7 and FvB groups treated with 17β-estradiol. A large number of differentially expressed genes involved in the immune response were observed in 17β-estradiol treated groups. The E7 oncoprotein mainly affected the expression of genes involved in cellular metabolism. Our microarray data also identified differentially expressed genes that have not previously been reported in cervical cancer. The identification of genes regulated by E7 and 17β-estradiol, provides the basis for further studies on their role in cervical carcinogenesis.
PMCID: PMC3982872  PMID: 24210110
HPV16 E7; 17β-estradiol; Microarrays; Cervix; Carcinogenesis; K14E7
3.  Nuke-sparing regimens as a main simplification strategy and high level of toxicity resolution after antiretroviral switch: the SWITCHART Study 
Journal of the International AIDS Society  2014;17(4Suppl 3):19819.
The advent of combined antiretroviral therapy (ART) in the past decade has led to HIV suppression in most cases. Virological failure was the main reason for ART switch a few years ago; however, toxicity and treatment simplification have now gained importance due to the availability of more effective and convenient drugs. This study assessed the reasons for ART switch in daily practice.
Material and Methods
Observational retrospective study that included patients whose ART was switched between January 2011 and July 2012. Patients with any other switch during the follow-up period (until September 2013) were excluded.
A total of 246 patients were included. Main reasons for ART switch were simplification (33%) and toxicity (31%), followed by clinical trial inclusion (13%), virological failure (6%), drug interaction (4%), patient decision (3%), lack of adherence (2%), pregnancy (1%) and other (8%). Eighty patients switched to a simpler regimen (median age 48 [40–53], mean CD4 count 608±265 cells/cl, 89% <50 copies/ml, mean number of previous regimens 6±5, mean time on previous ART 3±2 years). In this case, previous ART mostly included 2NRTI+1PI/r (54%) (Figure 1). The simplification strategy mainly contained nuke-sparing regimens (60%) based on PI (DRV/r 48%): monotherapy 46%, dual therapy 13% (PI/r+maraviroc 9%, PI/r+NNRTI 4%) and triple therapy 1% (PI/r+maraviroc+raltegravir). The second preferred simplification option was 2NRTI+1NNRTI (24%). Seventy-seven patients switched due to toxicities (median age 47 [43–53], mean CD4 count 606±350 cells/μl, <50 copies/ml 82%, mean number of previous regimens 4±3, mean time on previous ART 3±3 years). Renal (25%) and CNS (18%) toxicities were the main reasons for ART switch, followed by diarrhoea (16%), liver enzyme elevation (ALT 10%; AST 9%; bilirubin 7%), lipid elevation (cholesterol 5%; triglycerides 8%), nausea (7%) and other (=5%) (Figure 2). All patients with renal toxicity were under TDF and in most cases this drug was removed from the new regimen (with 3TC/ABC or nuke-sparing). Among patients with CNS toxicity, 79% were taking EFV; the main new treatment was a second-generation NNRTI (ETR)+2NRTI. Toxicities were completely resolved in 66% of patients, partially resolved in 22% and not resolved in only 12%; the median time from ART switch to toxicity resolution was 4 (2–8) months.
The main reasons for ART switch in daily practice are simplification and toxicities, renal and CNS toxicities being the most prevalent. The preferred simplification strategies are nuke-sparing regimens, mainly DRV/r-based monotherapy and dual therapy. ART switch leads to a complete resolution of toxicities in most cases in the short term.
PMCID: PMC4225341  PMID: 25397563
4.  May the Evaluation of Nitrosative Stress Through Selective Increase of 3-Nitrotyrosine Proteins Other Than Nitroalbumin and Dominant Tyrosine-125/136 Nitrosylation of Serum α-Synuclein Serve for Diagnosis of Sporadic Parkinson's Disease? 
Antioxidants & Redox Signaling  2013;19(9):912-918.
Nitrosative stress, where nitrosylation of tyrosine (Tyr) leading to 3-nitrotyrosine proteins or free 3-nitrotyrosine is the most prominent change, has been proposed as a pathogenic mechanism in Parkinson's disease (PD). Levels of 3-nitrotyrosine proteins in serum and cerebrospinal fluid (CSF) of patients with PD have not been studied. Nitrosative stress-induced protein changes in serum and CSF were analyzed in patients with PD (n=54) and controls (n=40). Herein, we demonstrate the presence of nitrosative stress in serum and CSF of patients with early PD leading to selective increase of 3-nitrotyrosine proteins other than nitroalbumin, without free 3-nitrotyrosine (Hoehn-Yahr stage 1, p<0.05; stage 2, p<0.01). Among 3-nitrotyrosine proteins, nitro-α-synuclein (N-αSyn) was detected in serum, not CSF, and the sites of Tyr nitrosylation were observed to be modified in patients with early PD. Thus, the intensity of nitrosylation of Tyr125/136 residues is enhanced (stage 1, p<0.05; stage 2, p<0.01), and that of the Tyr39 site is reduced (stage 1, p<0.05), and the ratio between both parameters (α-synuclein with nitrosylated tyrosines 125 and 136 [N-αSyn-Tyr125/136]:α-synuclein with nitrosylated tyrosine 39 [N-αSyn-Tyr39] ratio) is significantly higher in patients with early PD (p<0.01). These observations lead to the hypothesis that evaluating nitrosative stress through enhanced levels of 3-nitrotyrosine proteins in serum and CSF without changes in nitroalbumin, together with the profile of tyrosine nitrosylation of serum αSyn characterized by dominant nitrosylation of Tyr125/136, could serve for the diagnosis of sporadic PD. Antioxid. Redox Signal. 19, 912–918.
PMCID: PMC3763231  PMID: 23418747
5.  Correlations between major risk factors and closely related Mycobacterium tuberculosis isolates grouped by three current enotyping procedures: a population-based study in northeast Mexico 
Memórias do Instituto Oswaldo Cruz  2014;109(6):814-819.
The characteristics of tuberculosis (TB) patients related to a chain of recent TB transmissions were investigated. Mycobacterium tuberculosis (MTB) isolates (120) were genotyped using the restriction fragment length polymorphism-IS6110 (R), spacer oligotyping (S) and mycobacterial interspersed repetitive units-variable number of tandem repeats (M) methods. The MTB isolates were clustered and the clusters were grouped according to the similarities of their genotypes. Spearman’s rank correlation coefficients between the groups of MTB isolates with similar genotypes and those patient characteristics indicating a risk for a pulmonary TB (PTB) chain transmission were ana- lysed. The isolates showing similar genotypes were distributed as follows: SMR (5%), SM (12.5%), SR (1.67%), MR (0%), S (46.67%), M (5%) and R (0%). The remaining 35 cases were orphans. SMR exhibited a significant correlation (p < 0.05) with visits to clinics, municipalities and comorbidities (primarily diabetes mellitus). S correlated with drug consumption and M with comorbidities. SMR is needed to identify a social network in metropolitan areas for PTB transmission and S and M are able to detect risk factors as secondary components of a transmission chain of TB.
PMCID: PMC4238775  PMID: 25317710
Mycobacterium tuberculosis; MTB; genotyping; risk factors; tuberculosis transmission; population; based study
6.  Dysregulated 5-HT2A receptor binding in postmortem frontal cortex of schizophrenic subjects 
Previous postmortem and neuroimaging studies have repeatedly suggested alterations in serotonin 5-HT2A receptor (5-HT2AR) binding associated with the pathophysiology of schizophrenia. These studies were performed with ligands, such as ketanserin, altanserin and LSD, that may bind with high-affinity to different structural or functional conformations of the 5-HT2AR. Interpretation of results may also be confounded by chronic antipsychotic treatment and suicidal behavior in the schizophrenia group. We quantified 5-HT2AR density by radioligand binding assays in postmortem prefrontal cortex of antipsychotic-free (n=29) and antipsychotic-treated (n=16) schizophrenics, suicide victims with other psychiatric diagnoses (n=13), and individually matched controls. [3H]Ketanserin binding, and its displacement by altanserin or the LSD-like agonist DOI, was assayed. Results indicate that the number of [3H]ketanserin binding sites to the 5-HT2AR was increased in antipsychotic-free (128±11%), but not in antipsychotic-treated (92±12%), schizophrenic subjects. In suicide victims, [3H]ketanserin binding did not differ as compared to controls. Aging correlated negatively with [3H]ketanserin binding in schizophrenia, suicide victims and controls. The fraction of high-affinity sites of DOI displacing [3H]ketanserin binding to the 5-HT2AR was increased in antipsychotic-free schizophrenic subjects. Functional uncoupling of heterotrimeric G proteins led to increased fraction of high-affinity sites of altanserin displacing [3H]ketanserin binding to the 5-HT2AR in schizophrenic subjects, but not in controls. Together, these results suggest that the active conformation of the 5-HT2AR is up-regulated in prefrontal cortex of antipsychotic-free schizophrenic subjects, and may provide a pharmacological explanation for discordant findings previously obtained.
PMCID: PMC3586752  PMID: 23176747
7.  α-Synuclein inclusions in the skin of Parkinson's disease and parkinsonism 
The presence in the brain of α-synuclein containing Lewy neurites, or bodies, is the histological hallmark of Parkinson's disease (PD). The discovery of α-synuclein aggregates in nerve endings of the heart, digestive tract, and skin has lent support to the concept of PD as a systemic disease. Our goals were, first, to demonstrate the presence of α-synuclein inclusions in the skin and, second, to detect quantitative differences between patients with PD and atypical parkinsonism (AP).
Skin biopsies were taken from 67 patients and 20 controls. The biopsies underwent immunohistochemistry (IHC) and immunofluorescence (IF) testing for α-synuclein, whereupon its presence was quantified as the percentage of positive cells. Patients were divided into those with PD and those with AP. AP patients included AP with neurodegenerative disease (proteinopathies) and secondary AP.
Sixty-seven patients (34 with PD) and 20 controls were recruited. In the PD group, α-synuclein was detected in 58% of the cells in the spinous cell layer (SCL), 62% in the pilosebaceous unit (PSU), and 58% in the eccrine glands (EG). The AP-proteinopathies group showed 7%, 7%, and 0% expression of α-synuclein, respectively. No expression was found in the skin of the control group.
The expression of α-synuclein in the skin was relatively high in the PD group, scarce in AP, and null for the individuals in the control group. While these findings require further confirmation, this minimally invasive technique may aid in the improvement of the accuracy of PD diagnoses.
PMCID: PMC4184776  PMID: 25356418
8.  Effectiveness of the Epley’s maneuver performed in primary care to treat posterior canal benign paroxysmal positional vertigo: study protocol for a randomized controlled trial 
Trials  2014;15:179.
Vertigo is a common medical condition with a broad spectrum of diagnoses which requires an integrated approach to patients through a structured clinical interview and physical examination. The main cause of vertigo in primary care is benign paroxysmal positional vertigo (BPPV), which should be confirmed by a positive D-H positional test and treated with repositioning maneuvers. The objective of this study is to evaluate the effectiveness of Epley’s maneuver performed by general practitioners (GPs) in the treatment of BPPV.
This study is a randomized clinical trial conducted in the primary care setting. The study’s scope will include two urban primary care centers which provide care for approximately 49,400 patients. All patients attending these two primary care centers, who are newly diagnosed with benign paroxysmal positional vertigo, will be invited to participate in the study and will be randomly assigned either to the treatment group (Epley’s maneuver) or to the control group (a sham maneuver). Both groups will receive betahistine. Outcome variables will be: response to the D-H test, patients’ report on presence or absence of vertigo during the previous week (dichotomous variable: yes/no), intensity of vertigo symptoms on a Likert-type scale in the previous week, total score on the Dizziness Handicap Inventory (DHI) and quantity of betahistine taken.
We will use descriptive statistics of all variables collected. Groups will be compared using the intent-to-treat approach and either parametric or nonparametric tests, depending on the nature and distribution of the variables. Chi-square test or Fisher’s exact test will be conducted to compare categorical measures and Student’s t-test or Mann–Whitney U-test will be used for intergroup comparison variables.
Positive results from our study will highlight that treatment of benign paroxysmal positional vertigo can be performed by trained general practitioners (GPs) and, therefore, its widespread practice may contribute to improve the quality of life of BPPV patients.
Trial registration Identifier: NCT01969513.
PMCID: PMC4043960  PMID: 24886338
Primary care; Canalith repositioning procedure; Benign paroxysmal positional vertigo; Randomized clinical trial; Betahistine
9.  The Relationship between the Antitumor Effect of the IL-12 Gene Therapy and the Expression of Th1 Cytokines in an HPV16-Positive Murine Tumor Model 
Mediators of Inflammation  2014;2014:510846.
Objective. The goal of the present study was to investigate the effect of IL-12 expressed in plasmid on the Th1 cytokine profile in an experimental HPV16-positive murine tumor model and the association with the IL-12's antitumor effect. Methods. Mice were injected with BMK-16/myc cells to establish HPV16-positive tumor and then pNGVL3-mIL-12 plasmid; pcDNA3 plasmid or PBS was injected directly into tumor site. The antitumor effect of the treatment was evaluated and the cytokines expression profile in each tumor tissue was analyzed. Results. Treatment with pNGVL3-mIL-12 plasmid had a significant antitumor effect, and a Th2-Th3-type cytokines prolife was detected in the murine tumor model with expression of the cytokines IL-10, IL-4, and TGF-β1. However, after the tumor was treated with three intratumoral injections of plasmid containing IL-12 cDNA, it showed a cytokine profile associated with Th1 with expression of IL-2, IL-12, and IFN-γ cytokines and reduced expression of IL-10, IL-4, and TGF-β1. Conclusions. The treatment with the IL-12 gene in the experimental HPV16-positive tumor model promoted the activation of the cellular immune response via expression of a Th1-type cytokine profile and was associated with the inhibition of tumor growth. Thus, IL-12 treatment represents a novel approach for gene therapy against cervical cancer.
PMCID: PMC3997981  PMID: 24808638
10.  Prebiotic effect during the first year of life in healthy infants fed formula containing GOS as the only prebiotic: a multicentre, randomised, double-blind and placebo-controlled trial 
Currently, there is no consensus concerning the possible beneficial colonic and systemic effects of prebiotic-containing infant formula. This study assesses whether the feeding of a galactooligosaccharides (GOS)-containing infant formula (0.44 g/dl of GOS) and the subsequent feeding of a GOS-containing follow-on formula (0.50 g/dl of GOS) have a prebiotic effect on intestinal microbiota that helps to decrease infections and allergy manifestations in healthy infants during the first year of life.
A multicentre, randomised, double-blind and placebo-controlled trial was carried out on 365 healthy term infants enrolled before 8 weeks of age and randomly assigned to a formula with or without GOS, until 12 months of age. The incidence of infections and allergy manifestations, the antibiotics prescribed and faecal characteristics were recorded up to 12 months of age, while faecal samples were collected up to 4 months for the measurement of secretory immunoglobulin A, short-chain fatty acids and microbiota.
A prebiotic effect on the faecal analysis was observed at 4 months of life. The GOS group showed a lower faecal pH (P = 0.019), a lower decreasing trend in secretory immunoglobulin A (P = 0.078), lower butyric acid concentration (P = 0.040) and an increase in Bifidobacterium counts (P = 0.010). Changes in faecal characteristics involved greater frequency (P < 0.001) and softer consistency (P < 0.05). The incidence of infections or allergic manifestations during the first year of life was similar in both groups, with no statistical differences (P > 0.05).
The feeding of GOS-containing infant formula produced a definite prebiotic effect consisting of changes in faecal composition and microbiota, and in faecal consistency and the frequency of defaecation. No changes in the incidence of infection or allergic manifestation during the first year of life were observed.
PMCID: PMC4303717  PMID: 24671237
Clinical trial; Prebiotics; Infant nutrition; Infant formula; Randomised double-blind, placebo-controlled study
11.  Is the Physician’s Behavior in Dyslipidemia Diagnosis in Accordance with Guidelines? Cross-Sectional Escarval Study 
PLoS ONE  2014;9(3):e91567.
Clinical inertia has been defined as mistakes by the physician in starting or intensifying treatment when indicated. Inertia, therefore, can affect other stages in the healthcare process, like diagnosis. The diagnosis of dyslipidemia requires ≥2 high lipid values, but inappropriate behavior in the diagnosis of dyslipidemia has only previously been analyzed using just total cholesterol (TC).
To determine clinical inertia in the dyslipidemia diagnosis using both TC and high-density lipoprotein cholesterol (HDL-c) and its associated factors.
All health center visits in the second half of 2010 in the Valencian Community (Spain).
11,386 nondyslipidemic individuals aged ≥20 years with ≥2 lipid determinations.
Measurement Variables
Gender, atrial fibrillation, hypertension, diabetes, cardiovascular disease, age, and ESCARVAL training course. Lipid groups: normal (TC<5.17 mmol/L and normal HDL-c [≥1.03 mmol/L in men and ≥1.29 mmol/L in women], TC inertia (TC≥5.17 mmol/L and normal HDL-c), HDL-c inertia (TC<5.17 mmol/L and low HDL-c), and combined inertia (TC≥5.17 mmol/L and low HDL-c).
TC inertia: 38.0% (95% CI: 37.2–38.9%); HDL-c inertia: 17.7% (95% CI: 17.0–18.4%); and combined inertia: 9.6% (95% CI: 9.1–10.2%). The profile associated with TC inertia was: female, no cardiovascular risk factors, no cardiovascular disease, middle or advanced age; for HDL-c inertia: female, cardiovascular risk factors and cardiovascular disease; and for combined inertia: female, hypertension and middle age.
Cross-sectional study, under-reporting, no analysis of some cardiovascular risk factors or other lipid parameters.
A more proactive attitude should be adopted, focusing on the full diagnosis of dyslipidemia in clinical practice. Special emphasis should be placed on patients with low HDL-c levels and an increased cardiovascular risk.
PMCID: PMC3953440  PMID: 24626597
12.  The relationship between cervical flexor endurance, cervical extensor endurance, VAS, and disability in subjects with neck pain 
Several tests have been suggested to assess the isometric endurance of the cervical flexor (NFME) and extensors (NEE) muscles. This study proposes to determine whether neck flexors endurance is related to extensor endurance, and whether cervical muscle endurance is related to disability, pain amount and pain stage in subjects with neck pain.
Thirty subjects (18 women, 12 men, mean ± SD age: 43 ± 12 years) complaining of neck pain filled out the Visual Analogue Scale (VAS) and the Neck Pain and Disability Scale-Italian version (NPDS-I). They also completed the timed endurance tests for the cervical muscles.
The mean endurance was 246.7 ± 150 seconds for the NEE test, and 44.9 ± 25.3 seconds for the NMFE test. A significant correlation was found between the results of these two tests (r = 0.52, p = 0.003). A positive relationship was also found between VAS and NPDS-I (r = 0.549, p = 0.002). The endurance rates were similar for acute/subacute and chronic subjects, whereas males demonstrated significantly higher values compared to females in NFME test.
These findings suggest that neck flexors and extensors endurance are correlated and that the cervical endurance is not significantly altered by the duration of symptoms in subjects with neck pain.
PMCID: PMC3975896  PMID: 24581272
Neck pain; Physical endurance; Neck muscles; Isometric contraction; Measure
13.  Chronic treatment with LY341495 decreases 5-HT2A receptor binding and hallucinogenic effects of LSD in mice 
Neuroscience letters  2013;536:69-73.
Hallucinogenic drugs, such as lysergic acid diethylamide (LSD), mescaline and psilocybin, alter perception and cognitive processes. All hallucinogenic drugs have in common a high affinity for the serotonin 5-HT2A receptor. Metabotropic glutamate 2/3 (mGlu2/3) receptor ligands show efficacy in modulating the cellular and behavioral responses induced by hallucinogenic drugs. Here, we explored the effect of chronic treatment with the mGlu2/3 receptor antagonist 2S-2-amino-2-(1S,2S-2-carboxycyclopropan-1-yl)-3-(xanth-9-yl)-propionic acid (LY341495) on the hallucinogenic-like effects induced by LSD (0.24 mg/kg). Mice were chronically (21 days) treated with LY341495 (1.5 mg/kg), or vehicle, and experiments were carried out one day after the last injection. Chronic treatment with LY341495 down-regulated [3H]ketanserin binding in somatosensory cortex of wild-type, but not mGlu2 knockout (KO), mice. Head-twitch behavior, and expression of c-fos, egr-1 and egr-2, which are responses induced by hallucinogenic 5-HT2A agonists, were found to be significantly decreased by chronic treatment with LY341495. These findings suggest that repeated blockade of the mGlu2 receptor by LY341495 results in reduced 5-HT2A receptor-dependent hallucinogenic effects of LSD.
PMCID: PMC3578056  PMID: 23333599
Hallucinogenic drugs; Serotonin 5-HT2A receptor; Metabotropic glutamate 2 (mGlu2) receptor; Lysergic acid diethylamide (LSD); LY341495; G protein-coupled receptor (GPCR); schizophrenia; psychosis
14.  Combining rimonabant and fentanyl in a single entity: preparation and pharmacological results 
Based on numerous pharmacological studies that have revealed an interaction between cannabinoid and opioid systems at the molecular, neurochemical, and behavioral levels, a new series of hybrid molecules has been prepared by coupling the molecular features of two wellknown drugs, ie, rimonabant and fentanyl. The new compounds have been tested for their affinity and functionality regarding CB1 and CB2 cannabinoid and μ opioid receptors. In [35S]-GTPγS (guanosine 5′-O-[gamma-thio]triphosphate) binding assays from the post-mortem human frontal cortex, they proved to be CB1 cannabinoid antagonists and μ opioid antagonists. Interestingly, in vivo, the new compounds exhibited a significant dual antagonist action on the endocannabinoid and opioid systems.
PMCID: PMC3934591  PMID: 24591816
fentanyl; rimonabant; cannabinoid; opioid; behavioral assays
15.  Analysis of a sample of type 2 diabetic patients with obesity or overweight and at cardiovascular risk: a cross sectional study in Spain 
BMC Research Notes  2014;7:48.
The multifactorial control of diabetes relies on interventions that provide patients with the best knowledge and resources available. The objective of this research was to analyze the clinical characteristics of a sample of people with type 2 diabetes at high cardiovascular risk, and establish possible links between disease control, family history and lifestyle, to improve the quality of interventions. Family history, lifestyle habits, blood pressure, anthropometric data and laboratory tests were analyzed in this descriptive and comparative cross-sectional study.
All patients had a pathological body mass index (BMI), and in those patients with a family history of diabetes, the disease was more serious and onset was earlier. Overall, 70.9% were taking drugs for arterial blood pressure management, with mean values within recommended limits; 87.1% were taking antihyperlipidemic drugs and had mean values for blood lipids within reference range; 93.5% were receiving oral antidiabetic drugs and/or insulin and had blood glucose and glycosylated hemoglobin (HbA1c) values higher than recommended limit; and 87% were taking antiplatelet drugs and had fibrinogen and ultrasensitive C-reactive protein higher than the normal range. High HbA1c values were found in a high proportion of our sample who were not following a tailored diet (84.2%), and better BMIs were associated with moderate physical activity. Coexistence of somatic disorders (97.4% of the sample with musculoskeletal diseases) could lead to the lack of physical activity.
This sample of patients with type 2 diabetes and at high cardiovascular risk, had acceptable metabolic control, facilitated by drug therapy. Family history of diabetes was associated with earlier disease onset and worse disease progression. Patients who were not following a tailored diet had worse HbA1c values compared with those who were. Individuals who practiced moderate physical activity in line with international recommendations for weight maintenance had the best BMI values, but the high prevalence of comorbidities could adversely affect exercise habits. Appropriate use of medication, dietary advice, and tailored physiotherapy physical activity suitable for people with comorbidities should be included in multifactorial treatment strategies for these patients, particularly in the presence of a family history of diabetes.
PMCID: PMC3901755  PMID: 24443817
Diabetes Mellitus; Obesity; Cardiovascular risk; Genetics; Life habits; Health education; Physiotherapy
16.  Basal/HER2 breast carcinomas 
Cell Cycle  2013;12(2):225-245.
High rates of inherent primary resistance to the humanized monoclonal antibody trastuzumab (Herceptin) are frequent among HER2 gene-amplified breast carcinomas in both metastatic and adjuvant settings. The clinical efficacy of trastuzumab is highly correlated with its ability to specifically and efficiently target HER2-driven populations of breast cancer stem cells (CSCs). Intriguingly, many of the possible mechanisms by which cancer cells escape trastuzumab involve many of the same biomarkers that have been implicated in the biology of CS-like tumor-initiating cells. In the traditional, one-way hierarchy of CSCs in which all cancer cells descend from special self-renewing CSCs, HER2-positive CSCs can occur solely by self-renewal. Therefore, by targeting CSC self-renewal and resistance, trastuzumab is expected to induce tumor shrinkage and further reduce breast cancer recurrence rates when used alongside traditional therapies. In a new, alternate model, more differentiated non-stem cancer cells can revert to trastuzumab-refractory, CS-like cells via the activation of intrinsic or microenvironmental paths-to-stemness, such as the epithelial-to-mesenchymal transition (EMT). Alternatively, stochastic transitions of trastuzumab-responsive CSCs might also give rise to non-CSC cellular states that lack major attributes of CSCs and, therefore, can remain “hidden” from trastuzumab activity. Here, we hypothesize that a better understanding of the CSC/non-CSC social structure within HER2-overexpressing breast carcinomas is critical for trastuzumab-based treatment decisions in the clinic. First, we decipher the biological significance of CSC features and the EMT on the molecular effects and efficacy of trastuzumab in HER2-positive breast cancer cells. Second, we reinterpret the genetic heterogeneity that differentiates trastuzumab-responders from non-responders in terms of CSC cellular states. Finally, we propose that novel predictive approaches aimed at better forecasting early tumor responses to trastuzumab should identify biological determinants that causally underlie the intrinsic flexibility of HER2-positive CSCs to “enter” into or “exit” from trastuzumab-sensitive states. An accurate integration of CSC cellular states and EMT-related biomarkers with the currently available breast cancer molecular taxonomy may significantly improve our ability to make a priori decisions about whether patients belonging to HER2 subtypes differentially enriched with a “mesenchymal transition signature” (e.g., luminal/HER2 vs. basal/HER2) would distinctly benefit from trastuzumab-based therapy ab initio.
PMCID: PMC3575452  PMID: 23255137
basal-like; cancer stem cells; EMT; HER2; trastuzumab; breast cancer; reprogramming
17.  Persistent effects of chronic clozapine on the cellular and behavioral responses to LSD in mice 
Psychopharmacology  2012;225(1):217-226.
In schizophrenia patients, optimal treatment with antipsychotics requires weeks to months of sustained drug therapy. However, single administration of antipsychotic drugs can reverse schizophrenia-like behavioral alterations in rodent models of psychosis. This raises questions about the physiological relevance of such antipsychotic-like activity.
This study evaluates the effects of chronic treatment with clozapine on the cellular and behavioral responses induced by the hallucinogenic serotonin 5-HT2A receptor agonist lysergic acid diethylamide (LSD) as a mouse model of psychosis.
Mice were treated chronically (21 days) with 25 mg/kg/day clozapine. Experiments were conducted 1, 7, 14, and 21 days after the last clozapine administration. [3H]Ketanserin binding and 5-HT2A mRNA expression were determined in mouse somatosensory cortex. Head-twitch behavior, expression of c-fos, which is induced by all 5-HT2A agonists, and expression of egr-1 and egr-2, which are LSD-like specific, were assayed.
Head-twitch response was decreased and [3H]ketanserin binding was downregulated in 1, 7, and 14 days after chronic clozapine. 5-HT2A mRNA was reduced 1 day after chronic clozapine. Induction of c-fos, but not egr-1 and egr-2, was rescued 7 days after chronic clozapine. These effects were not observed after short treatment (2 days) with clozapine or chronic haloperidol (1 mg/kg/day).
Our findings provide a murine model of chronic atypical antipsychotic drug action and suggest downregulation of the 5-HT2A receptor as a potential mechanism involved in these persistent therapeutic-like effects.
PMCID: PMC3552490  PMID: 22842765
Schizophrenia; Hallucinogenic drugs; LSD; Mouse models; GPCR
18.  The T309G MDM2 Gene Polymorphism Is a Novel Risk Factor for Proliferative Vitreoretinopathy 
PLoS ONE  2013;8(12):e82283.
Proliferative vitreoretinopathy (PVR) is still the major cause of failure in retinal detachment (RD) surgery. It is believed that down-regulation in the p53 pathway could be an important key in PVR pathogenesis. The purpose was to evaluate the impact of T309G MDM2 polymorphism (rs2279744) in PVR. Distribution of T309G MDM2 genotypes among European subjects undergoing RD surgery was evaluated. Proportions of genotypes between subsamples from different countries were analyzed. Also, a genetic interaction between rs2279744 in MDM2 and rs1042522 in p53 gene was analyzed. Significant differences were observed comparing MDM2 genotype frequencies at position 309 of intron 1 between cases (GG: 21.6%, TG: 54.5%, TT: 23.8%) and controls (GG: 7.3%, TG: 43.9%, TT: 48.7%). The proportions of genotypes between sub-samples from different countries showed a significant difference. Distribution of GG genotype revealed differences in Spain (35.1–53.0)/(22.6–32.9), Portugal (39.0–74.4)/(21.4–38.9), Netherlands (40.6–66.3)/(25.3–38.8) and UK (37.5–62.4)/(23.3–34.2). The OR of G carriers in the global sample was 5.9 (95% CI: 3.2 to 11.2). The OR of G carriers from Spain and Portugal was 5.4 (95% CI: 2.2–12.7), whereas in the UK and the Netherlands was 7.3 (95% CI: 2.8–19.1). Results indicate that the G allele of rs2279744 is associated with a higher risk of developing PVR in patients undergoing a RD surgery. Further studies are necessary to understand the role of this SNP in the development of PVR.
PMCID: PMC3857251  PMID: 24349246
19.  Navigating challenges and opportunities of land degradation and sustainable livelihood development in dryland social–ecological systems: a case study from Mexico 
Drylands are one of the most diverse yet highly vulnerable social–ecological systems on Earth. Water scarcity has contributed to high levels of heterogeneity, variability and unpredictability, which together have shaped the long coadaptative process of coupling humans and nature. Land degradation and desertification in drylands are some of the largest and most far-reaching global environmental and social change problems, and thus are a daunting challenge for science and society. In this study, we merged the Drylands Development Paradigm, Holling's adaptive cycle metaphor and resilience theory to assess the challenges and opportunities for livelihood development in the Amapola dryland social–ecological system (DSES), a small isolated village in the semi-arid region of Mexico. After 450 years of local social–ecological evolution, external drivers (neoliberal policies, change in land reform legislation) have become the most dominant force in livelihood development, at the cost of loss of natural and cultural capital and an increasingly dysfunctional landscape. Local DSESs have become increasingly coupled to dynamic larger-scale drivers. Hence, cross-scale connectedness feeds back on and transforms local self-sustaining subsistence farming conditions, causing loss of livelihood resilience and diversification in a globally changing world. Effective efforts to combat desertification and improve livelihood security in DSESs need to consider their cyclical rhythms. Hence, we advocate novel dryland stewardship strategies, which foster adaptive capacity, and continuous evaluation and social learning at all levels. Finally, we call for an effective, flexible and viable policy framework that enhances local biotic and cultural diversity of drylands to transform global drylands into a resilient biome in the context of global environmental and social change.
PMCID: PMC3479689  PMID: 23045713
complex adaptive systems; Drylands Development Paradigm; livelihood diversification; resilience thinking
20.  Splice variants of zinc finger protein 695 mRNA associated to ovarian cancer 
Studies of alternative mRNA splicing (AS) in health and disease have yet to yield the complete picture of protein diversity and its role in physiology and pathology. Some forms of cancer appear to be associated to certain alternative mRNA splice variants, but their role in the cancer development and outcome is unclear.
We examined AS profiles by means of whole genome exon expression microarrays (Affymetrix GeneChip 1.0) in ovarian tumors and ovarian cancer-derived cell lines, compared to healthy ovarian tissue. Alternatively spliced genes expressed predominantly in ovarian tumors and cell lines were confirmed by RT-PCR.
Among several significantly overexpressed AS genes in malignant ovarian tumors and ovarian cancer cell lines, the most significant one was that of the zinc finger protein ZNF695, with two previously unknown mRNA splice variants identified in ovarian tumors and cell lines. The identity of ZNF695 AS variants was confirmed by cloning and sequencing of the amplicons obtained from ovarian cancer tissue and cell lines.
Alternative ZNF695 mRNA splicing could be a marker of ovarian cancer with possible implications on its pathogenesis.
PMCID: PMC3847372  PMID: 24007497
Ovarian cancer; Alternative mRNA splicing; ZNF695
21.  Characterisation of pks15/1 in clinical isolates of Mycobacterium tuberculosis from Mexico 
Memórias do Instituto Oswaldo Cruz  2013;108(6):718-723.
Tuberculosis (TB) is an infectocontagious respiratory disease caused by members of the Mycobacterium tuberculosis complex. A 7 base pair (bp) deletion in the locus polyketide synthase (pks)15/1 is described as polymorphic among members of the M. tuberculosis complex, enabling the identification of Euro-American, Indo-Oceanic and Asian lineages. The aim of this study was to characterise this locus in TB isolates from Mexico. One hundred twenty clinical isolates were recovered from the states of Veracruz and Estado de Mexico. We determined the nucleotide sequence of a ± 400 bp fragment of the locus pks15/1, while genotypic characterisation was performed by spoligotyping. One hundred and fifty isolates contained the 7 bp deletion, while five had the wild type locus. Lineages X (22%), LAM (18%) and T (17%) were the most frequent; only three (2%) of the isolates were identified as Beijing and two (1%) EAI-Manila. The wild type pks15/1 locus was observed in all Asian lineage isolates tested. Our results confirm the utility of locus pks15/1 as a molecular marker for identifying Asian lineages of the M. tuberculosis complex. This marker could be of great value in the epidemiological surveillance of TB, especially in countries like Mexico, where the prevalence of such lineages is unknown.
PMCID: PMC3970685  PMID: 24037193
tuberculosis; W-Beijing; pks15/1; Mexico
22.  Virological Efficacy in Cerebrospinal Fluid and Neurocognitive Status in Patients with Long-Term Monotherapy Based on Lopinavir/Ritonavir: An Exploratory Study 
PLoS ONE  2013;8(7):e70201.
Data on suppression of HIV replication in the CNS and on the subsequent risk of neurocognitive impairment using monotherapy with boosted protease inhibitors are limited.
Ours was an exploratory cross-sectional study in patients on lopinavir/ritonavir-based monotherapy (LPV/r-MT) or standard triple therapy (LPV/r-ART) for at least 96 weeks who maintained a plasma viral load <50 copies/mL. HIV-1 RNA in CSF was determined by HIV-1 SuperLow assay (lower limit of detection, 1 copy/mL). Neurocognitive functioning was assessed using a recommended battery of neuropsychological tests covering 7 areas. Neurocognitive impairment (NCI) was determined and also a global deficit score (GDS) for study comparisons.
Seventeen patients on LPV/r-MT and 17 on LPV/r-ART were included. Fourteen (82.4%) patients on LPV/r-MT and 16 (94.1%) on LPV/r-ART had HIV-1 RNA <1 copy/mL in CSF (p = 0.601). NCI was observed in 7 patients on LPV/r-MT and in 10 on LPV/r-ART (41% vs 59%; p = 0.494). Mean (SD) GDS was 0.22 (0.20) in patients on LPV/r-MT and 0.47 (0.34) in those on LPV/r-ART (p = 0.012).
Suppression of HIV in CSF is similar in individuals with durable plasma HIV-1 RNA suppression who are receiving LPV/r-MT or LPV/r-ART for at least 96 weeks. Findings for HIV-1 replication in CSF and neurocognitive status indicate that this strategy seems to be safe for CNS functioning.
PMCID: PMC3724821  PMID: 23922957
23.  Prenatal stress induces schizophrenia-like alterations of 5-HT2A and mGlu2 receptors in the adult offspring: Role of maternal immune system 
It has been suggested that severe adverse life events during pregnancy increase the risk of schizophrenia in the offspring. The serotonin 5-HT2A and the metabotropic glutamate 2 (mGlu2) receptors both have been the target of considerable attention regarding schizophrenia and antipsychotic drug development. We tested the effects of maternal variable stress during pregnancy on expression and behavioral function of these two receptors in mice. Prenatal stress increased 5-HT2A and decreased mGlu2 expression in frontal cortex, a brain region involved in perception, cognition and mood. This pattern of expression of 5-HT2A and mGlu2 receptors was consistent with behavioral alterations, including increased head-twitch response to the hallucinogenic 5-HT2A agonist DOI, and decreased mGlu2-dependent antipsychotic-like effect of the mGlu2/3 agonist LY379268 in adult, but not prepubertal, mice born to stressed mothers during pregnancy. Cross-fostering studies determined that these alterations were not due to effects of prenatal stress on maternal care. Additionally, a similar pattern of biochemical and behavioral changes were observed in mice born to mothers injected with poly-(I:C) during pregnancy as a model of prenatal immune activation. These data strengthen pathophysiological hypotheses that propose an early neurodevelopmental origin for schizophrenia and other psychiatric disorders.
PMCID: PMC3711555  PMID: 23325246
24.  Genetic diversity of the Mycobacterium tuberculosis Complex in San Luis Potosí, México 
BMC Research Notes  2013;6:172.
Although epidemiologic and socioeconomic criteria and biomedical risk factors indicate high-priority for tuberculosis (TB) control in Mexico, molecular epidemiology studies of the disease in the country are scarce.
Complete sociodemographic and clinical data were obtained from 248 of the 432 pulmonary TB (PTB) cases confirmed from 2006 to 2010 on the population under epidemiological surveillance in the state of San Luis Potosí, México. From most PTB cases with complete data Mycobacterium tuberculosis complex (MTC) isolates were recovered and their spoligotypes, lineages and families, geographic distribution and drug resistance determined.
Pulmonary tuberculosis incidence ranged from 2.4 to 33.4 (cases per 100,000 inhabitants) in the six state sanitary jurisdictions that were grouped in regions of low (jurisdictions I-II-III), intermediate (jurisdictions IV-V) and high incidence (jurisdiction VI) with 6.2, 17.3 and 33.4 rates, respectively. Most patients were poor, 50-years-median-age males and housewives. Among the 237 MTC spoligotyped isolates, 232 corresponded to M. tuberculosis (104 spoligotypes in 24 clusters) and five to M. bovis. The predominant Euro-American lineage was distributed all over the state, the East-Asian lineage (Beijing family) in the capital city, the Indo-Oceanic (Manila family) in eastern localities, and M. bovis in rural localities.
In San Luis Potosí TB affects mainly poor male adults and is caused by M. tuberculosis and to a minor extent by M. bovis. There is great genotypic diversity among M. tuberculosis strains, the Euro-American lineage being much more prevalent than the Indo-Oceanic and East-Asian lineages. The frequency of resistant strains is relatively low and not associated to any particular lineage.
PMCID: PMC3651706  PMID: 23635381
Tuberculosis; Mycobacterium bovis; Spoligotypes; Molecular epidemiology; San Luis Potosí; Mexico; Social determinants of tuberculosis
25.  A population-based study of first and second-line drug-resistant tuberculosis in a high-burden area of the Mexico/United States border 
Memórias do Instituto Oswaldo Cruz  2013;108(2):160-166.
The resistance of 139 Mycobacterium tuberculosis (MTB) isolates from the city of Monterrey, Northeast Mexico, to first and second-line anti-TB drugs was analysed. A total of 73 isolates were susceptible and 66 were resistant to anti-TB drugs. Monoresistance to streptomycin, isoniazid (INH) and ethambutol was observed in 29 cases. Resistance to INH was found in 52 cases and in 29 cases INH resistance was combined with resistance to two or three drugs. A total of 24 isolates were multidrug-resistant (MDR) resistant to at least INH and rifampicin and 11 MDR cases were resistant to five drugs. The proportion of MDR-TB among new TB cases in our target population was 0.72% (1/139 cases). The proportion of MDR-TB among previously treated cases was 25.18% (35/139 cases). The 13 polyresistant and 24 MDR isolates were assayed against the following seven second-line drugs: amikacin (AMK), kanamycin (KAN), capreomycin (CAP), clofazimine (CLF), ethionamide (ETH), ofloxacin (OFL) and cycloserine (CLS). Resistance to CLF, OFL or CLS was not observed. Resistance was detected to ETH (10.80%) and to AMK (2.70%), KAN (2.70%) and CAP (2.70%). One isolate of MDR with primary resistance was also resistant to three second-line drugs. Monterrey has a high prevalence of MDR-TB among previously treated cases and extensively drug-resistant-MTB strains may soon appear.
PMCID: PMC3970668  PMID: 23579794
tuberculosis;  Mycobacterium tuberculosis ; first and second-line drug resistance

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