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1.  Management of primary achalasia: The role of endoscopy 
Achalasia is an oesophageal motor disorder which leads to the functional obstruction of the lower oesophageal sphincter (LES) and is currently incurable. The main objective of all existing therapies is to achieve a reduction in the obstruction of the distal oesophagus in order to improve oesophageal transit, relieve the symptomatology, and prevent long-term complications. The most common treatments used are pneumatic dilation (PD) and laparoscopic Heller myotomy, which involves partial fundoplication with comparable short-term success rates. The most economic non-surgical therapy is PD, with botulinum toxin injections reserved for patients with a higher surgical risk for whom the former treatment option is unsuitable. A new technology is peroral endoscopic myotomy, postulated as a possible non-invasive alternative to surgical myotomy. Other endoluminal treatments subject to research more recently include injecting ethanolamine into the LES and using a temporary self-expanding metallic stent. At present, there is not enough evidence permitting a routine recommendation of any of these three novel methods. Patients must undergo follow-up after treatment to guarantee that their symptoms are under control and to prevent complications. Most experts are in favour of some form of endoscopic follow-up, however no established guidelines exist in this respect. The prognosis for patients with achalasia is good, although a recurrence after treatment using any method requires new treatment.
doi:10.4253/wjge.v7.i6.593
PMCID: PMC4461934  PMID: 26078828
Achalasia; Endoscopic treatment; Dilation; Botulinum toxin; Myotomy
2.  Physical Inactivity And Low Fitness Deserve More Attention To Alter Cancer Risk And Prognosis 
Sedentary lifestyle is associated with elevated cancer risk whereas regular physical activity (PA) and high cardiorespiratory fitness (CRF) have the opposite effect, with several biological mechanisms mediating such associations. There is a need for lifestyle interventions aimed at increasing the PA levels and CRF of the general population and particularly cancer survivors. Further, provocative data suggest a dose-dependent benefit of increasing levels of PA and/or CRF against cancer risk or mortality. Thus, current PA guidelines (≥150 min/week of moderate-to-vigorous PA) may not be sufficiently rigorous for preventing cancer nor for extending cancer survivorship. Research targeting this issue is urgently needed. Promoting regular PA along with monitoring indicators of CRF and adiposity may provide powerful strategies to prevent cancer in populations, help cancer patients more effectively deal with their disease and enhance secondary prevention programs in those who are affected by cancer.
doi:10.1158/1940-6207.CAPR-14-0320
PMCID: PMC4315717  PMID: 25416409
3.  Exercise Attenuates the Major Hallmarks of Aging 
Rejuvenation Research  2015;18(1):57-89.
Abstract
Regular exercise has multi-system anti-aging effects. Here we summarize how exercise impacts the major hallmarks of aging. We propose that, besides searching for novel pharmaceutical targets of the aging process, more research efforts should be devoted to gaining insights into the molecular mediators of the benefits of exercise and to implement effective exercise interventions for elderly people.
doi:10.1089/rej.2014.1623
PMCID: PMC4340807  PMID: 25431878
4.  FNDC5 (irisin) gene and exceptional longevity: a functional replication study with rs16835198 and rs726344 SNPs 
Age  2014;36(6):9733.
Irisin might play an important role in reducing the risk of obesity, insulin resistance, or several related diseases, and high irisin levels may contribute to successful aging. Thus, the irisin precursor (FNDC5) gene is a candidate to influence exceptional longevity (EL), i.e., being a centenarian. It has been recently shown that two single-nucleotide polymorphisms (SNPs) in the FNDC5 gene, rs16835198 and rs726344, are associated with in vivo insulin sensitivity in adults. We determined luciferase gene reporter activity in the two above-mentioned SNPs and studied genotype distributions among centenarians (n = 175, 144 women) and healthy controls (n = 347, 142 women) from Spain. We also studied an Italian [79 healthy centenarians (40 women) and 316 healthy controls (156 women)] and a Japanese cohort [742 centenarians (623 women) and 499 healthy controls (356 women)]. The rs726344 SNP had functional significance, as shown by differences in luciferase activity between the constructs of this SNP (all P ≤ 0.05), with the variant A-allele having higher luciferase activity compared with the G-allele (P = 0.04). For the rs16835198 SNP, the variant T-allele tended to show higher luciferase activity compared with the G-allele (P = 0.07). However, we found no differences between genotype/allele frequencies of the two SNPs in centenarians versus controls in any cohort, and no significant association (using logistic regression adjusted by sex) between the two SNPs and EL. Further research is needed with different cohorts as well as with additional variants in the FNDC5 gene or in other genes involved in irisin signaling.
doi:10.1007/s11357-014-9733-1
PMCID: PMC4245403  PMID: 25427998
Myokines; Cardiometabolic; Disorders; Allele; Longevity; Centenarians
5.  Niemann-Pick disease treatment: a systematic review of clinical trials 
The aim of this systematic review was to analyse all the published clinical trials assessing treatments for Niemann-Pick (NP) disease. At present there are only trials investigating the treatment of NP disease type C. Furthermore, there is no uniformity among studies in treatment outcomes or in data analysis and presentation of results. Miglustat is able to delay neurodegeneration, with greater benefits in patients with a late onset of the disease and β-cyclodextrin-hydroxypropyl (HBP-CD) can attenuate clinical symptoms. As for cholesterol-lowering drugs, the combination of lovastatin, cholestyramine and nicotinic acid is the most effective one for lowering cholesterolemia. Further research is much needed, and ongoing trials using enzyme replacement therapy might hopefully show promising results in the foreseeable future.
doi:10.3978/j.issn.2305-5839.2015.12.04
PMCID: PMC4701532  PMID: 26807415
Niemann-Pick (NP) disease; miglustat; clinical trial; treatment
7.  BubbleGUM: automatic extraction of phenotype molecular signatures and comprehensive visualization of multiple Gene Set Enrichment Analyses 
BMC Genomics  2015;16:814.
Background
Recent advances in the analysis of high-throughput expression data have led to the development of tools that scaled-up their focus from single-gene to gene set level. For example, the popular Gene Set Enrichment Analysis (GSEA) algorithm can detect moderate but coordinated expression changes of groups of presumably related genes between pairs of experimental conditions. This considerably improves extraction of information from high-throughput gene expression data. However, although many gene sets covering a large panel of biological fields are available in public databases, the ability to generate home-made gene sets relevant to one’s biological question is crucial but remains a substantial challenge to most biologists lacking statistic or bioinformatic expertise. This is all the more the case when attempting to define a gene set specific of one condition compared to many other ones. Thus, there is a crucial need for an easy-to-use software for generation of relevant home-made gene sets from complex datasets, their use in GSEA, and the correction of the results when applied to multiple comparisons of many experimental conditions.
Result
We developed BubbleGUM (GSEA Unlimited Map), a tool that allows to automatically extract molecular signatures from transcriptomic data and perform exhaustive GSEA with multiple testing correction. One original feature of BubbleGUM notably resides in its capacity to integrate and compare numerous GSEA results into an easy-to-grasp graphical representation. We applied our method to generate transcriptomic fingerprints for murine cell types and to assess their enrichments in human cell types. This analysis allowed us to confirm homologies between mouse and human immunocytes.
Conclusions
BubbleGUM is an open-source software that allows to automatically generate molecular signatures out of complex expression datasets and to assess directly their enrichment by GSEA on independent datasets. Enrichments are displayed in a graphical output that helps interpreting the results. This innovative methodology has recently been used to answer important questions in functional genomics, such as the degree of similarities between microarray datasets from different laboratories or with different experimental models or clinical cohorts. BubbleGUM is executable through an intuitive interface so that both bioinformaticians and biologists can use it. It is available at http://www.ciml.univ-mrs.fr/applications/BubbleGUM/index.html.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-2012-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s12864-015-2012-4
PMCID: PMC4617899  PMID: 26481321
Gene set enrichment analysis; Transcriptomic signatures; Comparative transcriptomics; Integrative representation
8.  PTK2 rs7460 and rs7843014 Polymorphisms and Exceptional Longevity: A Functional Replication Study 
Rejuvenation Research  2014;17(5):430-438.
Abstract
Focal adhesion is critical for cell survival. The focal adhesion kinase (FAK, or PTK2) is an important component of the human interactome and thus is a potential longevity-related protein. Here we studied the association between two PTK2 gene single-nucleotide polymorphisms (SNPs) (rs7843014, rs7460) and exceptional longevity (EL). In addition to gaining insight into their functionality by determining luciferase gene reporter activity, we studied the genotype/allele frequency of these two SNPs among three different cohorts: (1) Spanish centenarians (n=175, 100–111 years, 144 women) and healthy controls (n=355, 20–50 years, 284 women); (2) Italian centenarians (n=79, 100–104 years, 40 women) and controls (n=316, 29–50 years, 156 women); and (3) Japanese centenarians (n=742, 100–116 years, 623 women) and healthy controls (n=499, 23–59 years, 356 women). Both SNPs had functional significance, with the A allele up-regulating luciferase activity compared to the other allele (rs7460 T allele and rs7843014 C allele, respectively). The A allele of both SNPs was negatively associated with EL in the Spanish cohort (rs7460, odds ratio [OR] adjusted by sex=0.40, 95% confidence intervals [CI] 0.3, 0.6, p<0.001); rs7843014, OR=0.37, 95% CI 0.3, 0.5, p<0.001). The OR of being a centenarian if having the rs7460-TT genotype was 6.68 (95% CI 4.1, 10.8, p<0.001). The rs7843014 CC genotype was also positively associated with EL (OR=7.58, 95% CI 4.6, 12.3, p<0.001]. No association was, however, found for the Italian or Japanese cohorts. Thus, two genotypes of the FAK gene, rs7460 TT and rs7843014 CC, are possibly associated with lower gene expression and might favor the likelihood of reaching EL in the Spanish population. Further research is needed to unveil the mechanisms by which FAK expression could perhaps influence the rate of aging.
doi:10.1089/rej.2014.1570
PMCID: PMC4203112  PMID: 24930376
9.  A Novel Association between Femoroacetabular Impingement and Anterior Knee Pain 
Pain Research and Treatment  2015;2015:937431.
Background. For a long time it has been accepted that the main problem in the anterior knee pain (AKP) patient is in the patella. Currently, literature supports the link between abnormal hip function and AKP. Objective. Our objective is to investigate if Cam femoroacetabular impingement (FAI) resolution is related to the outcome in pain and disability in patients with chronic AKP recalcitrant to conservative treatment associated with Cam FAI. Material and Methods. A retrospective study on 7 patients with chronic AKP associated with FAI type Cam was performed. Knee and hip pain were measured with the visual analogue scale (VAS), knee disability with the Kujala scale, and hip disability with the Nonarthritic Hip Score (NAHS). Results. The VAS knee pain score and VAS hip pain score had a significant improvement postoperatively. At final follow-up, there was significant improvement in all functional scores (Kujala score and NAHS). Conclusion. Our finding supports the link between Cam FAI and AKP in some young patients. Assessment of Cam FAI should be considered as a part of the physical examination of patients with AKP, mainly in cases with pain recalcitrant to conservative treatment.
doi:10.1155/2015/937431
PMCID: PMC4584218  PMID: 26451254
10.  Quantitative Anatomical Studies 
BioMed Research International  2015;2015:781590.
doi:10.1155/2015/781590
PMCID: PMC4568322  PMID: 26417602
11.  Relationship between Urinary Level of Phytate and Valvular Calcification in an Elderly Population: A Cross-Sectional Study 
PLoS ONE  2015;10(8):e0136560.
Pathological calcification generally consists of the formation of solid deposits of hydroxyapatite (calcium phosphate) in soft tissues. Supersaturation is the thermodynamic driving force for crystallization, so it is believed that higher blood levels of calcium and phosphate increase the risk of cardiovascular calcification. However several factors can promote or inhibit the natural process of pathological calcification. This cross-sectional study evaluated the relationship between physiological levels of urinary phytate and heart valve calcification in a population of elderly out subjects. A population of 188 elderly subjects (mean age: 68 years) was studied. Valve calcification was measured by echocardiography. Phytate determination was performed from a urine sample and data on blood chemistry, end-systolic volume, concomitant diseases, cardiovascular risk factors, medication usage and food were obtained. The study population was classified in three tertiles according to level of urinary phytate: low (<0.610 μM), intermediate (0.61–1.21 μM), and high (>1.21 μM). Subjects with higher levels of urinary phytate had less mitral annulus calcification and were less likely to have diabetes and hypercholesterolemia. In the multivariate analysis, age, serum phosphorous, leukocytes total count and urinary phytate excretion appeared as independent factors predictive of presence of mitral annulus calcification. There was an inverse correlation between urinary phytate content and mitral annulus calcification in our population of elderly out subjects. These results suggest that consumption of phytate-rich foods may help to prevent cardiovascular calcification evolution.
doi:10.1371/journal.pone.0136560
PMCID: PMC4554994  PMID: 26322979
12.  Ortho-methylated 3-hydroxypyridines hinder hen egg-white lysozyme fibrillogenesis 
Scientific Reports  2015;5:12052.
Protein aggregation with the concomitant formation of amyloid fibrils is related to several neurodegenerative diseases, but also to non-neuropathic amyloidogenic diseases and non-neurophatic systemic amyloidosis. Lysozyme is the protein involved in the latter, and it is widely used as a model system to study the mechanisms underlying fibril formation and its inhibition. Several phenolic compounds have been reported as inhibitors of fibril formation. However, the anti-aggregating capacity of other heteroaromatic compounds has not been studied in any depth. We have screened the capacity of eleven different hydroxypyridines to affect the acid-induced fibrillization of hen lysozyme. Although most of the tested hydroxypyridines alter the fibrillation kinetics of HEWL, only 3-hydroxy-2-methylpyridine, 3-hydroxy-6-methylpyridine and 3-hydroxy-2,6-dimethylpyridine completely abolish fibril formation. Different biophysical techniques and several theoretical approaches are combined to elucidate their mechanism of action. O-methylated 3-hydroxypyridines bind non-cooperatively to two distinct but amyloidogenic regions of monomeric lysozyme. This stabilises the protein structure, as evidenced by enhanced thermal stability, and results in the inhibition of the conformational transition that precedes fibril assembly. Our results point to o-methylated 3-hydroxypyridines as a promising molecular scaffold for the future development of novel fibrillization inhibitors.
doi:10.1038/srep12052
PMCID: PMC4500996  PMID: 26169912
13.  Effects of allopurinol on exercise-induced muscle damage: new therapeutic approaches? 
Cell Stress & Chaperones  2014;20(1):3-13.
Intensive muscular activity can trigger oxidative stress, and free radicals may hence be generated by working skeletal muscle. The role of the enzyme xanthine oxidase as a generating source of free radicals is well documented and therefore is involved in the skeletal muscle damage as well as in the potential transient cardiovascular damage induced by high-intensity physical exercise. Allopurinol is a purine hypoxanthine-based structural analog and a well-known inhibitor of xanthine oxidase. The administration of the xanthine oxidase inhibitor allopurinol may hence be regarded as promising, safe, and an economic strategy to decrease transient skeletal muscle damage (as well as heart damage, when occurring) in top-level athletes when administered before a competition or a particularly high-intensity training session. Although continuous administration of allopurinol in high-level athletes is not recommended due to its possible role in hampering training-induced adaptations, the drug might be useful in non-athletes. Exertional rhabdomyolysis is the most common form of rhabdomyolysis and affects individuals participating in a type of intense exercise to which they are not accustomed. This condition can cause exercise-related myoglobinuria, thus increasing the risk of acute renal failure and is also associated with sickle cell trait. In this manuscript, we have reviewed the recent evidence about the effects of allopurinol on exercise-induced muscle damage. More research is needed to determine whether allopurinol may be useful for preventing not only exertional rhabdomyolysis and acute renal damage but also skeletal muscle wasting in critical illness as well as in immobilized, bedridden, sarcopenic or cachectic patients.
doi:10.1007/s12192-014-0543-2
PMCID: PMC4255256  PMID: 25181966
Xanthine oxidase; Free radicals; Muscle injury; Rhabdomyolysis; Sarcopenia; Cachexy
14.  Executioner Caspase-3 and 7 Deficiency Reduces Myocyte Number in the Developing Mouse Heart 
PLoS ONE  2015;10(6):e0131411.
Executioner caspase-3 and -7 are proteases promoting cell death but non-apoptotic roles are being discovered. The heart expresses caspases only during development, suggesting they contribute to the organ maturation process. Therefore, we aimed at identifying novel functions of caspases in heart development. We induced simultaneous deletion of executioner caspase-3 and -7 in the mouse myocardium and studied its effects. Caspase knockout hearts are hypoplastic at birth, reaching normal weight progressively through myocyte hypertrophy. To identify the molecular pathways involved in these effects, we used microarray-based transcriptomics and multiplexed quantitative proteomics to compare wild type and executioner caspase-deficient myocardium at different developmental stages. Transcriptomics showed reduced expression of genes promoting DNA replication and cell cycle progression in the neonatal caspase-deficient heart suggesting reduced myocyte proliferation, and expression of non-cardiac isoforms of structural proteins in the adult null myocardium. Proteomics showed reduced abundance of proteins involved in oxidative phosphorylation accompanied by increased abundance of glycolytic enzymes underscoring retarded metabolic maturation of the caspase-null myocardium. Correlation between mRNA expression and protein abundance of relevant genes was confirmed, but transcriptomics and proteomics indentified complementary molecular pathways influenced by caspases in the developing heart. Forced expression of wild type or proteolytically inactive caspases in cultured cardiomyocytes induced expression of genes promoting cell division. The results reveal that executioner caspases can modulate heart’s cellularity and maturation during development, contributing novel information about caspase biology and heart development.
doi:10.1371/journal.pone.0131411
PMCID: PMC4487935  PMID: 26121671
15.  Primary Cutaneous Mucormycosis Produced by the New Species Apophysomyces mexicanus 
Journal of Clinical Microbiology  2014;52(12):4428-4431.
A case of fungal necrotizing fasciitis that appeared in an immunocompetent Mexican woman after a car accident is described. The patient did not respond to antifungal treatment and died 4 days later. The fungus was molecularly identified as a new species of Apophysomyces, namely, Apophysomyces mexicanus.
doi:10.1128/JCM.02138-14
PMCID: PMC4313335  PMID: 25297328
16.  Deep Transverse Lateral Retinaculum Reconstruction for Medial Patellar Instability 
Arthroscopy Techniques  2015;4(3):e245-e249.
Medial patellar instability can be a disabling complication of an extensive lateral retinaculum release. It is often overlooked, and for the diagnosis, it is necessary to have a high index of suspicion. Typically, the patient feels a new pain and new instability after the lateral retinaculum release that are distinct from, and much worse than, those before surgery. All of our patients had significant relief from their pain with “reverse” McConnell taping. If there is a significant improvement in symptoms after this taping and stress radiographs or stress axial computed tomography scans show an objective pathologic medial patellar displacement, reconstruction of the lateral retinaculum should be considered. This article details our technique for reconstruction of the deep transverse layer of the lateral retinaculum using an anterior strip of the iliotibial band. This strip is detached from its insertion onto the Gerdy tubercle and then reflected proximally beyond the level of the lateral femoral epicondyle. Finally, it is attached either by direct suture to the remaining prepatellar and peripatellar retinaculum if there is adequate tissue present or by a suture anchor.
doi:10.1016/j.eats.2015.02.003
PMCID: PMC4523718  PMID: 26258038
17.  Babelomics 5.0: functional interpretation for new generations of genomic data 
Nucleic Acids Research  2015;43(Web Server issue):W117-W121.
Babelomics has been running for more than one decade offering a user-friendly interface for the functional analysis of gene expression and genomic data. Here we present its fifth release, which includes support for Next Generation Sequencing data including gene expression (RNA-seq), exome or genome resequencing. Babelomics has simplified its interface, being now more intuitive. Improved visualization options, such as a genome viewer as well as an interactive network viewer, have been implemented. New technical enhancements at both, client and server sides, makes the user experience faster and more dynamic. Babelomics offers user-friendly access to a full range of methods that cover: (i) primary data analysis, (ii) a variety of tests for different experimental designs and (iii) different enrichment and network analysis algorithms for the interpretation of the results of such tests in the proper functional context. In addition to the public server, local copies of Babelomics can be downloaded and installed. Babelomics is freely available at: http://www.babelomics.org.
doi:10.1093/nar/gkv384
PMCID: PMC4489263  PMID: 25897133
18.  Prognostic Value of the Interaction between Galectin-3 and Antigen Carbohydrate 125 in Acute Heart Failure 
PLoS ONE  2015;10(4):e0122360.
Aims
Galectin-3 (Gal-3) and carbohydrate antigen 125 (CA125) have emerged as robust prognostic biomarkers in heart failure. Experimental data have also suggested a potential molecular interaction between CA125 and Gal-3; however, the biological and clinical relevance of this interaction is still uncertain. We sought to evaluate, in patients admitted for acute heart failure, the association between plasma Gal-3 with all-cause mortality and the risk for rehospitalizations among high and low levels of CA125.
Methods and Results
We included 264 consecutive patients admitted for acute heart failure to the Cardiology Department in a third-level center. Both biomarkers were measured on admission. Negative binomial and Cox regression models were used to evaluate the prognostic effect of the interaction between Gal-3 and CA125 (dichotomized by its median) with hospital readmission and all-cause mortality, respectively. During a median follow-up of 2 years (IQR = 1-2.8), 108 (40.9%) patients deaths and 365 rehospitalizations in 171 (69.5%) patients were registered. In a multivariable setting, the effect of Gal-3 on mortality and rehospitalization was differentially mediated by CA125 (p = 0.007 and p<0.001, respectively). Indeed, in patients with CA125 above median (>67 U/ml), values across the continuum of Gal-3 showed a positive and almost linear relationship with either the risk of death or rehospitalization. Conversely, when CA125 was below median (≤67 U/ml), Gal-3 lacked any prognostic effect on both endpoints.
Conclusion
In patients with acute heart failure, Gal-3 was strongly associated with higher risk of long-term mortality and repeated rehospitalizations, but only in those patients exhibiting higher values of CA125 (above 67 U/ml).
doi:10.1371/journal.pone.0122360
PMCID: PMC4395409  PMID: 25875367
19.  Experimental Therapy with Azoles against Candida guilliermondii 
Antimicrobial Agents and Chemotherapy  2014;58(10):6255-6257.
We evaluated the in vitro killing activity of voriconazole (VRC) and posaconazole (PSC) against two clinical isolates of Candida guilliermondii. The two drugs showed fungistatic activity against both isolates and were effective in reducing kidney fungal burden in a neutropenic murine model of disseminated candidiasis in infected mice. PSC was significantly more effective than VRC against one of the strains. The serum levels of PSC and VRC were above the corresponding MICs for these isolates.
doi:10.1128/AAC.03051-14
PMCID: PMC4187986  PMID: 25049245
20.  Changes in nerve-mediated contractility of the lower urinary tract in a mouse model of premature ageing 
British Journal of Pharmacology  2014;171(7):1687-1705.
Background and Purpose
A high incidence of lower urinary tract disorders is associated with ageing. In the senescent-accelerated prone (SAMP8) mouse strain and the senescent-accelerated resistant (SAMR1) strain, we compared smooth muscle contractility in responses to intrinsic neurotransmitters, both in the bladder and urethra.
Experimental Approach
We analysed micturition frequency, the changes in muscle tension induced by electrical field stimulation or agonist administration, the density of nerves (adrenergic, cholinergic and nitrergic) and interstitial cells (ICs), as well as cGMP accumulation in bladder and urethral preparations.
Key Results
Senescent mice of the SAMP8 strain displayed increased micturition frequency and excitatory contractility of neurogenic origin in the bladder. While cholinergic nerve density remained unchanged, there was a mild sensitization to ACh in male mice. Potentiation in the detrusor may be also provoked by the stronger contribution of ATP, together with reduced adrenergic innervation in males and COX-derived prostanoid production in females. The greater excitatory contractility in the urethra was probably due to the sensitization to noradrenaline, in conjunction with attenuated nitrergic relaxation. There were also fewer neuronal NOS immunoreactive (ir) nerves and vimentin-positive ICs, although the sildenafil-and diethylamine-NONOate-induced relaxations and cGMP-ir remained unchanged.
Conclusions and Implications
Premature senescent mice exhibit bladder and urethral hyperexcitability, coupled with reduced urethral relaxation of neurogenic origin, which could model the impaired urinary function in elderly humans. We propose that senescence-accelerated mice provide a useful tool to analyse the basic mechanisms of age-related changes in bladder and urethral function.
doi:10.1111/bph.12567
PMCID: PMC3966749  PMID: 24372152
ageing; SAMP8 mouse; bladder; urethra; cholinergic; adrenergic; nitrergic; nerve-mediated contractility; bladder hyperactivity
21.  Factors Associated With Scoliosis in Schoolchildren: a Cross-Sectional Population-Based Study 
Journal of Epidemiology  2015;25(3):212-220.
Background
The present study aimed to investigate the prevalence of scoliosis and to analyze the factors associated with scoliosis in schoolchildren aged between 7 and 17 years.
Methods
This is a cross-sectional and quantitative study with stratified random selection of public school students in the city of Santa Cruz, Brazil. The presence of scoliosis was examined, as well as the flexibility of the posterior muscle chain, socioeconomic characteristics, anthropometry, lifestyle habits, sexual maturation, and ergonomics of school furniture. In order to identify factors associated with scoliosis, the variables were divided in biological, socioeconomic, lifestyle, and ergonomic factors, and crude and adjusted prevalence ratios (PRs) were estimated by means of Poisson regression analysis.
Results
Two hundred and twelve pupils participated in this study (mean age 11.61 years, 58% female). The prevalence of scoliosis was 58.1% (n = 123) and associated with female sex (PR 2.54; 95% CI, 1.33–4.86) and age between 13 and 15 years (PR 5.35; 95% CI, 2.17–13.21). Sleeping in a hammock was inversely associated with scoliosis (PR 0.44; 95% CI, 0.23–0.81).
Conclusions
Scoliosis seems to be positively associated with female sex and age between 13 and 15 years, whereas the habit of sleeping in a hammock is negatively associated with the onset of scoliosis.
doi:10.2188/jea.JE20140061
PMCID: PMC4340998  PMID: 25716134
scoliosis; children; risk factors
22.  Exceptional longevity and muscle and fitness related genotypes: a functional in vitro analysis and case-control association replication study with SNPs THRH rs7832552, IL6 rs1800795, and ACSL1 rs6552828 
There are several gene variants that are candidates to influence functional capacity in long-lived individuals. As such, their potential association with exceptional longevity (EL, i.e., reaching 100+ years) deserves analysis. Among them are rs7832552 in the thyrotropin-releasing hormone receptor (TRHR) gene, rs1800795 in the interleukin-6 (IL6) gene and rs6552828 in the coenzyme A synthetase long-chain 1 (ACSL1) gene. To gain insight into their functionality (which is yet unknown), here we determined for the first time luciferase gene reporter activity at the muscle tissue level in rs7832552 and rs6552828. We then compared allele/genotype frequencies of the 3 abovementioned variants among centenarians [n = 138, age range 100–111 years (114 women)] and healthy controls [n = 334, 20–50 years (141 women)] of the same ethnic and geographic origin (Spain). We also studied healthy centenarians [n = 79, 100–104 years (40 women)] and controls [n = 316, 27–81 years (156 women)] from Italy, and centenarians [n = 742, 100–116 years (623 women)] and healthy controls [n = 499, 23–59 years (356 women)] from Japan. The THRH rs7832552 T-allele and ACSL1 rs6552828 A-allele up-regulated luciferase activity compared to the C and G-allele, respectively (P = 0.001). Yet we found no significant association of EL with rs7832552, rs1800795 or rs6552828 in any of the 3 cohorts. Further research is needed with larger cohorts of centenarians of different origin as well as with younger old people.
doi:10.3389/fnagi.2015.00059
PMCID: PMC4422078  PMID: 25999849
centenarians; polymorphisms; luciferase reporter; gene association study; muscle and sarcopenia
25.  Histone deacetylase inhibitors promote glioma cell death by G2 checkpoint abrogation leading to mitotic catastrophe 
Cell Death & Disease  2014;5(10):e1435-.
Glioblastoma multiforme is resistant to conventional anti-tumoral treatments due to its infiltrative nature and capability of relapse; therefore, research efforts focus on characterizing gliomagenesis and identifying molecular targets useful on therapy. New therapeutic strategies are being tested in patients, such as Histone deacetylase inhibitors (HDACi) either alone or in combination with other therapies. Here two HDACi included in clinical trials have been tested, suberanilohydroxamic acid (SAHA) and valproic acid (VPA), to characterize their effects on glioma cell growth in vitro and to determine the molecular changes that promote cancer cell death. We found that both HDACi reduce glioma cell viability, proliferation and clonogenicity. They have multiple effects, such as inducing the production of reactive oxygen species (ROS) and activating the mitochondrial apoptotic pathway, nevertheless cell death is not prevented by the pan-caspase inhibitor Q-VD-OPh. Importantly, we found that HDACi alter cell cycle progression by decreasing the expression of G2 checkpoint kinases Wee1 and checkpoint kinase 1 (Chk1). In addition, HDACi reduce the expression of proteins involved in DNA repair (Rad51), mitotic spindle formation (TPX2) and chromosome segregation (Survivin) in glioma cells and in human glioblastoma multiforme primary cultures. Therefore, HDACi treatment causes glioma cell entry into mitosis before DNA damage could be repaired and to the formation of an aberrant mitotic spindle that results in glioma cell death through mitotic catastrophe-induced apoptosis.
doi:10.1038/cddis.2014.412
PMCID: PMC4237242  PMID: 25275596

Results 1-25 (126)