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1.  Physical activity - an important preanalytical variable 
Biochemia Medica  2014;24(1):68-79.
The concentration of several biochemical and hematological biomarkers is strongly influenced by a number of preanalytical variables. Several lines of evidence attest that short, middle, and long-term exercise, as well as the relative intensity of physical effort (from mild to strenuous), may influence a broad array of laboratory variables. The amount of extracellular release and clearance from blood of most of these biomarkers is markedly influenced by the biological characteristics of the molecule(s), level of training, type, intensity and duration of exercise, and time of recovery after training. It is hence noteworthy that test results that fall outside the conventional reference ranges in athletes not only may reflect the presence of a given disease, but may frequently mirror an adaptation to regular training or changes that have occurred during and/or following strenuous exercise, and which should be clearly acknowledged to prevent misinterpretation of laboratory data. The aim of this narrative review is to provide an update about the most significant changes of some biochemical and hematological biomarkers in response to physical exercise, for appropriate interpretation of these changes in the context of physically active subjects.
PMCID: PMC3936967  PMID: 24627716
biomarkers; training; plasma volume; metabolism; cellular damage
2.  Effects of nitrogen nutrition on the synthesis and deposition of the ω-gliadins of wheat 
Annals of Botany  2013;113(4):607-615.
Background and Aims
The ω-gliadin storage proteins of wheat are of interest in relation to their impact on grain processing properties and their role in food allergy, particularly the ω-5 sub-group and wheat-dependent exercise-induced anaphylaxis. The ω-gliadins are also known to be responsive to nitrogen application. This study therefore compares the effects of cultivar and nitrogen availability on the synthesis and deposition of ω-gliadins in wheat grown under field conditions in the UK, including temporal and spatial analyses at the protein and transcript levels.
SDS–PAGE, western blotting and N-terminal amino acid sequencing were used to compare the patterns of ω-gliadin components in mature grain of six British wheat (Triticum aestivum) cultivars and their accumulation during the development of grain grown in field plots with varying nitrogen supply. Changes in gene expression during development were determined using real-time reverse transcription–PCR (RT–PCR). Spatial patterns of gene expression and protein accumulation were determined by in situ hybridization and immunofluorescence microscopy, respectively.
Key Results
Two patterns of ω-gliadins were identified in the six cultivars, including both monomeric ‘gliadin’ proteins and subunits present in polymeric ‘glutenin’ fractions. Increasing the level of nitrogen fertilizer in field plots resulted in increased expression of ω-gliadin transcripts and increased proportions of ω-5 gliadins. Nitrogen supply also affected the spatial patterns of ω-gliadin synthesis and deposition, which were differentially increased in the outer layers of the starchy endosperm with high levels of nitrogen.
Wheat ω-gliadins vary in amount and composition between cultivars, and in their response to nitrogen supply. Their spatial distribution is also affected by nitrogen supply, being most highly concentrated in the sub-aleurone cells of the starchy endosperm under higher nitrogen availability.
PMCID: PMC3936585  PMID: 24344140
Wheat; Triticum aestivum; storage protein; nitrogen; ω-gliadin; RNA in situ hybridization; immunolocalization; protein bodies; wheat allergy
3.  The p38–PGC-1α–irisin–betatrophin axis 
Adipocyte  2013;3(1):67-68.
The discovery of irisin as a novel and promising peptidic hormone has raised hopes regarding the hypothesis that irisin may provide additional benefits, not only for obesity and diabetes, but also for a wide range of pathological conditions since this hormone may prove to be therapeutically and clinically beneficial. In addition, a new hormone, betatrophin, has recently been identified by Yi and coworkers. Both hormones are connected by a new pathway clearly involved in insulin resistance. We hypothesize here how these hormones may be linked and their possible implications in both aged-reduced restricted regenerative capacity and dedifferentiated β cells of diabetic patients.
PMCID: PMC3917937  PMID: 24575373
diabetes; metabolism; obesity; oxidative stress; β cells
4.  Integrin-assisted drug delivery of nano-scaled polymer therapeutics bearing paclitaxel 
Biomaterials  2011;32(15):10.1016/j.biomaterials.2011.01.073.
Angiogenesis plays a prominent role in cancer progression. Anti-angiogenic therapy therefore, either alone or in combination with conventional cytotoxic therapy, offers a promising therapeutic approach. Paclitaxel (PTX) is a widely-used potent cytotoxic drug that also exhibits anti-angiogenic effects at low doses. However, its use, at its full potential, is limited by severe side effects. Here we designed and synthesized a targeted conjugate of PTX, a polymer and an integrin-targeted moiety resulting in a polyglutamic acid (PGA)-PTX-E-[c(RGDfK)2] nano-scaled conjugate. Polymer conjugation converted PTX to a macromolecule, which passively targets the tumor tissue exploiting the enhanced permeability and retention effect, while extravasating via the leaky tumor neovasculature. The cyclic RGD peptidomimetic enhanced the effects previously seen for PGA-PTX alone, utilizing the additional active targeting to the αvβ3 integrin overexpressed on tumor endothelial and epithelial cells. This strategy is particularly valuable when tumors are well-vascularized, but they present poor vascular permeability. We show that PGA is enzymatically-degradable leading to PTX release under lysosomal acidic pH. PGA-PTX-E-[c(RGDfK)2] inhibited the growth of proliferating αvβ3-expressing endothelial cells and several cancer cells. We also showed that PGA-PTX-E-[c(RGDfK)2] blocked endothelial cells migration towards vascular endothelial growth factor; blocked capillary-like tube formation; and inhibited endothelial cells attachment to fibrinogen. Orthotopic studies in mice demonstrated preferential tumor accumulation of the RGD-bearing conjugate, leading to enhanced antitumor efficacy and a marked decrease in toxicity as compared with free PTX-treated mice.
PMCID: PMC3857101  PMID: 21376390
Angiogenesis; polymer therapeutics; Polyglutamic acid; paclitaxel; RGD peptidomimetic; integrin
5.  Vitamin C Supplementation Does not Improve Hypoxia-Induced Erythropoiesis 
High Altitude Medicine & Biology  2012;13(4):269-274.
Martinez-Bello,Vladimir E., Fabian Sanchis-Gomar, Daniel Martinez-Bello, Gloria Olaso-Gonzalez, Mari Carmen Gomez-Cabrera, and Jose Viña. Vitamin C Supplementation Does Not Improve Hypoxia-Induced Erythropoiesis. High Alt Med Biol 13:269–274, 2012.—Hypoxia induces reactive oxygen species production. Supplements with antioxidant mixtures can compensate for the decline in red cell membrane stability following intermittent hypobaric hypoxia by decreasing protein and lipid oxidation. We aimed to determine whether supplementation with vitamin C is implicated in the regulation of erythropoiesis and in the oxygen-carrying capacity of the blood, and also whether antioxidant supplementation prevents the oxidative stress associated to intermittent hypoxia. Twenty-four male Wistar rats were randomly divided into four experimental groups: normoxia control (n=6), normoxia + vitamin C (n=6), hypoxia control (12 h pO2 12%/12 h pO2 21%) (n=6), and hypoxia + vitamin C (n=6). Animals were supplemented with vitamin C at a dose of 250 mg·kg−1·day−1 for 21 days. Red blood cell count, hemoglobin, hematocrit, reticulocytes, erythropoietin, and oxidative stress parameters such as malondialdehyde and protein oxidation in plasma were analyzed at two different time points: basal sample (day zero) and final sample (day 21). Similar RBC, Hb, Hct, and Epo increments were observed in both hypoxic groups regardless of the vitamin C supplementation. There was no change on MDA levels after intermittent hypoxic exposure in any experimental group. However, we found an increase in plasma protein oxidation in both hypoxic groups. Vitamin C does not affect erythropoiesis and protein oxidation in rats submitted to intermittent hypoxic exposure.
PMCID: PMC3533831  PMID: 23270444
hematocrit; hemoglobin; red blood cells; oxidative stress; antioxidants
6.  Phase II Open-Label Study to Assess Efficacy and Safety of Lenalidomide in Combination with Cetuximab in KRAS-Mutant Metastatic Colorectal Cancer 
PLoS ONE  2013;8(11):e62264.
This study aimed to assess the efficacy and safety of combination treatment with lenalidomide and cetuximab in KRAS-mutant metastatic colorectal cancer patients. This was a phase II multicenter, open-label trial comprising a safety lead-in phase (phase IIa) to determine the maximum tolerated dose, and a randomized proof of concept phase (phase IIb) to determine the response rate of lenalidomide plus cetuximab combination therapy. Phase IIa treatment comprised oral lenalidomide (starting dose 25 mg/day) and intravenous cetuximab (400 mg/m2 followed by weekly 250 mg/m2) in 28-day cycles. In phase IIb patients were randomized to either the phase IIa treatment schedule of lenalidomide plus cetuximab combination therapy or lenalidomide 25 mg/day monotherapy. Eight patients were enrolled into phase IIa. One patient developed a dose-limiting toxicity and the maximum tolerated dose of lenalidomide was determined at 25 mg/day. Forty-three patients were enrolled into phase IIb proof of concept. Best response was stable disease in 9 patients and study enrollment was terminated prematurely due to lack of efficacy in both treatment arms and failure to achieve the planned response objective. The majority of adverse events were grade 1 and 2. In both phases, the adverse events most commonly attributed to any study drugs were fatigue, rash and other skin disorders, diarrhea, nausea, and stomatitis. Thirty-nine deaths occurred; none was related to study drug. The combination of lenalidomide and cetuximab appeared to be well tolerated but did not have clinically meaningful activity in KRAS-mutant metastatic colorectal cancer patients.
Trial Registration NCT01032291
PMCID: PMC3823943  PMID: 24244261
7.  Acute Coronary Syndromes in 2011 and 2012 
PMCID: PMC4081172  PMID: 24343553
Acute Coronary Syndrome; Coronary Balloon Angioplasty; Myocardial Infarction
8.  Intraoral Schwannomas: Presentation of a series of 12 cases 
Introduction: Schwannomas are benign and not very frequent tumors of the peripheral nerves, derived from the nerve supporting Schwann cells. Study Design: Data were collected on the clinical manifestations (sex, age), location, size and symptonts of the lesions as well as the evolution time and the initial (presumption) diagnosis. Results: Twelve patients were documented, with a mean age of 29,5 ± 12,1 years (range 16-50) and a balanced gender distribution. The mean duration of the lesions was 42,17± 45,3 months. The lesion located in the floor of the mouth was the largest tumor, measuring about 4 cm in maximum diameter, while the average size of the 12 schwannomas was 2.04± 1.1 cm. Conclusion: We present 12 oral schwannomas diagnosed and treated over a period of 10 years.
Key words:Schwannomas, oral benign tumor, neurilemmoma.
PMCID: PMC3892247  PMID: 24455080
9.  Framingham Risk Score for Prediction of Cardiovascular Diseases: A Population-Based Study from Southern Europe 
PLoS ONE  2013;8(9):e73529.
The question about what risk function should be used in primary prevention remains unanswered. The Framingham Study proposed a new algorithm based on three key ideas: use of the four risk factors with the most weight (cholesterol, blood pressure, diabetes and smoking), prediction of overall cardiovascular diseases and incorporating the concept of vascular age. The objective of this study was to apply this new function in a cohort of the general non Anglo-Saxon population, with a 10-year follow-up to determine its validity.
The cohort was studied in 1992-94 and again in 2004-06. The sample comprised 959 randomly-selected persons, aged 30-74 years, who were representative of the population of Albacete, Spain. At the first examination cycle, needed data for the new function were collected and at the second examination, data on all events were recorded during the follow-up period. Discrimination was studied with ROC curves. Comparisons of prediction models and reality in tertiles (Hosmer-Lemeshow) were performed, and the individual survival functions were calculated.
The mean risks for women and men, respectively, were 11.3% and 19.7% and the areas under the ROC curve were 0.789 (95%CI, 0.716-0.863) and 0.780 (95%CI, 0.713-0.847) (P<0.001, both). Cardiovascular disease events occurred in the top risk tertiles. Of note were the negative predictive values in both sexes, and a good specificity in women (85.6%) and sensitivity in men (79.1%) when their risk for cardiovascular disease was high. This model overestimates the risk in older women and in middle-aged men. The cumulative probability of individual survival by tertiles was significant in both sexes (P<0.001).
The results support the proposal for “reclassification” of Framingham. This study, with a few exceptions, passed the test of discrimination and calibration in a random sample of the general population from southern Europe.
PMCID: PMC3764050  PMID: 24039972
10.  Differential mortality association of loop diuretic dosage according to blood urea nitrogen and carbohydrate antigen 125 following a hospitalization for acute heart failure 
European Journal of Heart Failure  2012;14(9):974-984.
Recent observations in chronic stable heart failure suggest that high-dose loop diuretics (HDLDs) have detrimental prognostic effects in patients with high blood urea nitrogen (BUN), but recent findings have also indicated that diuretics may improve renal function. Carbohydrate antigen 125 (CA125) has been shown to be a surrogate of systemic congestion. We sought to explore whether BUN and CA125 modulate the mortality risk associated with HDLDs following a hospitalization for acute heart failure (AHF).
Methods and results
We analysed 1389 consecutive patients discharged for AHF. CA125 and BUN were measured at a mean of 72 ± 12 h after admission. HDLDs (≥120 mg/day in furosemide equivalent dose) were interacted to a four-level variable according to CA125 (>35 U/mL) and BUN (above the median), and related to all-cause mortality. At a median follow-up of 21 months, 561 (40.4%) patients died. The use of HDLDs was independently associated with increased mortality [hazard ratio (HR) 1.23, 95% confidence interval (CI) 1.01–1.50], but this association was not homogeneous across CA125–BUN categories (P for interaction <0.001). In patients with normal CA125, use of HDLDs was associated with high mortality if BUN was above the median (HR 2.29, 95% 1.51–3.46), but not in those with BUN below the median (HR 1.22, 95% CI 0.73–2.04). Conversely, in patients with high CA125, HDLDs showed an association with increased survival if BUN was above the median (HR 0.73, 95% CI 0.55–0.98) but was associated with increased mortality in those with BUN below the median (HR 1.94, 95% CI 1.36–2.76).
The risk associated with HDLDs in patients after hospitalization for AHF was dependent on the levels of BUN and CA125. The information provided by these two biomarkers may be helpful in tailoring the dose of loop diuretics at discharge for AHF.
PMCID: PMC3423949  PMID: 22700856
Loop diuretics; Mortality; Acute heart failure; Carbohydrate antigen 125; Blood urea nitrogen
11.  Towards germline gene therapy of inherited mitochondrial diseases 
Nature  2012;493(7434):627-631.
Mutations in mitochondrial DNA (mtDNA) are associated with serious human diseases and inherited from mother's eggs. Here we investigated the feasibility of mtDNA replacement in human oocytes by spindle transfer (ST). Of 106 human oocytes donated for research, 65 were subjected to reciprocal ST and 33 served as controls. Fertilization rate in ST oocytes (73%) was similar to controls (75%). However, a significant portion of ST zygotes (52%) displayed abnormal fertilization as determined by irregular number of pronuclei. Among normally fertilized ST zygotes, blastocyst development (62%) and embryonic stem cell (ESC) isolation (38%) rates were comparable to controls. All ESC lines derived from ST zygotes displayed normal euploid karyotypes and contained exclusively donor mtDNA. The mtDNA can be efficiently replaced in human oocytes. Although some ST oocytes displayed abnormal fertilization, remaining embryos were capable of developing to blastocysts and producing ESCs similar to controls.
PMCID: PMC3561483  PMID: 23103867
12.  Pathogenic Potential of Bacillus cereus Strains as Revealed by Phenotypic Analysis 
Journal of Clinical Microbiology  2013;51(1):320-323.
The Bacillus cereus pathogenic spectrum ranges from strains used as probiotics to human-lethal strains. However, prediction of the pathogenic potential of a strain remains difficult. Here, we show that food poisoning and clinical strains can be differentiated from harmless strains on the basis of host colonization phenotypes.
PMCID: PMC3536244  PMID: 23135929
13.  Age associated low mitochondrial biogenesis may be explained by lack of response of PGC-1α to exercise training 
Age  2011;34(3):669-679.
Low mitochondriogenesis is critical to explain loss of muscle function in aging and in the development of frailty. The aim of this work was to explain the mechanism by which mitochondriogenesis is decreased in aging and to determine to which extent it may be prevented by exercise training. We used aged rats and compared them with peroxisome proliferator-activated receptor-γ coactivator-1α deleted mice (PGC-1α KO). PGC-1α KO mice showed a significant decrease in the mitochondriogenic pathway in muscle. In aged rats, we found a loss of exercise-induced expression of PGC-1α, nuclear respiratory factor-1 (NRF-1), and of cytochrome C. Thus muscle mitochondriogenesis, which is activated by exercise training in young animals, is not in aged or PGC-1α KO ones. Other stimuli to increase PGC-1α synthesis apart from exercise training, namely cold induction or thyroid hormone treatment, were effective in young rats but not in aged ones. To sum up, the low mitochondrial biogenesis associated with aging may be due to the lack of response of PGC-1α to different stimuli. Aged rats behave as PGC-1α KO mice. Results reported here highlight the role of PGC-1α in the loss of mitochondriogenesis associated with aging and point to this important transcriptional coactivator as a target for pharmacological interventions to prevent age-associated sarcopenia.
PMCID: PMC3337936  PMID: 21590341
Sarcopenia; Exercise; Oxidative stress; Aging; Cytochrome C; Gene knockout; Life Sciences; Molecular Medicine; Geriatrics/Gerontology; Cell Biology
14.  The Pore-Forming Haemolysins of Bacillus Cereus: A Review 
Toxins  2013;5(6):1119-1139.
The Bacillus cereus sensu lato group contains diverse Gram-positive spore-forming bacteria that can cause gastrointestinal diseases and severe eye infections in humans. They have also been incriminated in a multitude of other severe, and frequently fatal, clinical infections, such as osteomyelitis, septicaemia, pneumonia, liver abscess and meningitis, particularly in immuno-compromised patients and preterm neonates. The pathogenic properties of this organism are mediated by the synergistic effects of a number of virulence products that promote intestinal cell destruction and/or resistance to the host immune system. This review focuses on the pore-forming haemolysins produced by B. cereus: haemolysin I (cereolysin O), haemolysin II, haemolysin III and haemolysin IV (CytK). Haemolysin I belongs to the cholesterol-dependent cytolysin (CDC) family whose best known members are listeriolysin O and perfringolysin O, produced by L. monocytogenes and C. perfringens respectively. HlyII and CytK are oligomeric ß-barrel pore-forming toxins related to the α-toxin of S. aureus or the ß-toxin of C. perfringens. The structure of haemolysin III, the least characterized haemolytic toxin from the B. cereus, group has not yet been determined.
PMCID: PMC3717773  PMID: 23748204
B. cereus; haemolysins; cereolysin O; haemolysin II; haemolysin III; cytotoxin K; PlcR
15.  Pseudotumors and tumors of the temporomandibular joint. A review 
Objective: To review the pseudotumors and tumors of the temporomandibular joint (TMJ) published in journals included in Journal Citation Reports (JCR), and to evaluate whether there are clinical and radiological signs capable of differentiating between pseudotumors and tumors and between malignant and benign tumors. Material and Methods: A systematic Medline search was made of clinical cases of tumors and pseudotumors of the TMJ covering a 20-year period and published in journals included in JCR. Only cases with histological confirmation were included. A description is provided of the general characteristics of TMJ tumors, with comparison of the clinical, diagnostic, therapeutic and evolutive variables referred to pseudotumors, benign tumors and malignant tumors. Results: We identified 285 TMJ tumors published in 181 articles of 15 journals. The most frequent lesions were pseudotumors (synovial chondromatosis, pigmented villonodular synovitis, eosinophilic granuloma and osteochondroma). The mean age was 42 years and one month ± 16 years and two months. Tumors were more common in females. The mean time from symptoms onset to consultation was 30 months and 8 days ± 41 months and 9 days, and almost 19.6% of the cases initially had been diagnosed and treated as TMJ dysfunction. The most frequent clinical manifestations were pain, swelling and the limitation of joint movements. The most common radiological findings in the case of benign and malignant lesions were radiopacities and radiotransparencies, respectively. No panoramic X-ray alterations were observed in 14.6% of the benign tumors and in 7.7% of the malignant lesions. Surgery was the usual form of treatment. Sequelae were recorded in 18.2% of the cases, with tumor relapse in 9.1%. The four-year survival rate in the case of malignant tumors was 72.2%.
Key words:Tumor, temporomandibular joint, metaplasia, pseudotumor, condyle.
PMCID: PMC3668863  PMID: 23385515
16.  Activity Recognition Using Hybrid Generative/Discriminative Models on Home Environments Using Binary Sensors 
Sensors (Basel, Switzerland)  2013;13(5):5460-5477.
Activities of daily living are good indicators of elderly health status, and activity recognition in smart environments is a well-known problem that has been previously addressed by several studies. In this paper, we describe the use of two powerful machine learning schemes, ANN (Artificial Neural Network) and SVM (Support Vector Machines), within the framework of HMM (Hidden Markov Model) in order to tackle the task of activity recognition in a home setting. The output scores of the discriminative models, after processing, are used as observation probabilities of the hybrid approach. We evaluate our approach by comparing these hybrid models with other classical activity recognition methods using five real datasets. We show how the hybrid models achieve significantly better recognition performance, with significance level p < 0.05, proving that the hybrid approach is better suited for the addressed domain.
PMCID: PMC3690009  PMID: 23615583
activity recognition; hidden Markov model; hybrid schemes; wireless sensor networks
17.  Erythropoietin Receptor (EpoR) Agonism Is Used to Treat a Wide Range of Disease 
Molecular Medicine  2013;19(1):62-64.
The erythropoietin receptor (EpoR) was discovered and described in red blood cells (RBCs), stimulating its proliferation and survival. The target in humans for EpoR agonists drugs appears clear—to treat anemia. However, there is evidence of the pleitropic actions of erythropoietin (Epo). For that reason, rhEpo therapy was suggested as a reliable approach for treating a broad range of pathologies, including heart and cardiovascular diseases, neurodegenerative disorders (Parkinson’s and Alzheimer’s disease), spinal cord injury, stroke, diabetic retinopathy and rare diseases (Friedreich ataxia). Unfortunately, the side effects of rhEpo are also evident. A new generation of nonhematopoietic EpoR agonists drugs (asialoEpo, Cepo and ARA 290) have been investigated and further developed. These EpoR agonists, without the erythropoietic activity of Epo, while preserving its tissue-protective properties, will provide better outcomes in ongoing clinical trials. Nonhematopoietic EpoR agonists represent safer and more effective surrogates for the treatment of several diseases such as brain and peripheral nerve injury, diabetic complications, renal ischemia, rare diseases, myocardial infarction, chronic heart disease and others.
PMCID: PMC3646093  PMID: 23615965
18.  Ex vivo erythrocyte generation and blood doping 
Blood Transfusion  2013;11(2):161-163.
PMCID: PMC3626461  PMID: 23114519
19.  Comparative split-mouth study of the anesthetic efficacy of 4% articaine versus 0.5% bupivacaine in impacted mandibular third molar extraction 
Objective: The purpose of this study was to compare the clinical efficacy of articaine at 4% (epinephrine 1:100,000) with bupivacaine at 0.5% (epinephrine 1:200,000) for surgical extraction of impacted mandibular third molars. Study Design: This was a randomized, double blind, split-mouth, clinical trial. Thirty-six patients took part and underwent extraction of 72 lower third molars. The variables studied were: anesthetic latency time, intra-operative bleeding, anesthetic quality, hemodynamic changes during the surgical intervention, anesthetic duration in the soft tissues, post-operative analgesia and post-operative pain at 2, 6, 12 and 24 hours using a visual analogue scale, as well as any need for additional rescue medication. Results: Latency time was 2.0 minutes for articaine and 3.1 minutes for bupivacaine, with statistically significant difference (p<0.05). Bleeding was greater when bupivacaine was used (p<0.05) and anesthetic quality was greater with articaine (p<0.05). The duration of soft tissue anesthesia was longer with bupivacaine (p<0.05). Differences in post-operative analgesia, haemodynamic changes, post-operative pain and the quantity of rescue medication consumed were not statistically significant (p>0.05). Conclusions: Articaine showed greater clinical efficacy than bupivacaine, reducing latency time, bleeding, anesthetic duration in the soft tissues and achieving higher anesthetic quality, requiring less reinforcement during surgery than bupivacaine.
Key words:Articaine, bupivacaine, anesthetic efficacy, impacted mandibular third molar.
PMCID: PMC3892217  PMID: 24455059
21.  Centenarians, but not octogenarians, up-regulate the expression of microRNAs 
Scientific Reports  2012;2:961.
Centenarians exhibit extreme longevity and a remarkable compression of morbidity. They have a unique capacity to maintain homeostatic mechanisms. Since small non-coding RNAs (including microRNAs) are implicated in the regulation of gene expression, we hypothesised that longevity of centenarians may reflect alterations in small non-coding RNA expression. We report the first comparison of microRNAs expression profiles in mononuclear cells from centenarians, octogenarians and young individuals resident near Valencia, Spain. Principal Component Analysis of the expression of 15,644 mature microRNAs and, 2,334 snoRNAs and scaRNAs in centenarians revealed a significant overlap with profiles in young individuals but not with octogenarians and a significant up-regulation of 7 small non-coding RNAs in centenarians compared to young persons and notably 102 small non-coding RNAs when compared with octogenarians. We suggest that the small non-coding RNAs signature in centenarians may provide insights into the underlying molecular mechanisms endowing centenarians with extreme longevity.
PMCID: PMC3518811  PMID: 23233880
22.  Inhibition of Xanthine Oxidase by Allopurinol Prevents Skeletal Muscle Atrophy: Role of p38 MAPKinase and E3 Ubiquitin Ligases 
PLoS ONE  2012;7(10):e46668.
Alterations in muscle play an important role in common diseases and conditions. Reactive oxygen species (ROS) are generated during hindlimb unloading due, at least in part, to the activation of xanthine oxidase (XO). The major aim of this study was to determine the mechanism by which XO activation causes unloading-induced muscle atrophy in rats, and its possible prevention by allopurinol, a well-known inhibitor of this enzyme. For this purpose we studied one of the main redox sensitive signalling cascades involved in skeletal muscle atrophy i.e. p38 MAPKinase, and the expression of two well known muscle specific E3 ubiquitin ligases involved in proteolysis, the Muscle atrophy F-Box (MAFbx; also known as atrogin-1) and Muscle RING (Really Interesting New Gene) Finger-1 (MuRF-1). We found that hindlimb unloading induced a significant increase in XO activity and in the protein expression of the antioxidant enzymes CuZnSOD and Catalase in skeletal muscle. The most relevant new fact reported in this paper is that inhibition of XO with allopurinol, a drug widely used in clinical practice, prevents soleus muscle atrophy by ∼20% after hindlimb unloading. This was associated with the inhibition of the p38 MAPK-MAFbx pathway. Our data suggest that XO was involved in the loss of muscle mass via the activation of the p38MAPK-MAFbx pathway in unloaded muscle atrophy. Thus, allopurinol may have clinical benefits to combat skeletal muscle atrophy in bedridden, astronauts, sarcopenic, and cachexic patients.
PMCID: PMC3465256  PMID: 23071610
23.  Temperature-Dependent Production of Various PlcR-Controlled Virulence Factors in Bacillus weihenstephanensis Strain KBAB4 
The Bacillus cereus sensu lato complex has recently been divided into several phylogenetic groups with clear differences in growth temperature range. However, only a few studies have investigated the actual pathogenic potential of the psychrotolerant strains of the B. cereus group at low temperature, and little information is available concerning gene expression at low temperature. We found that vegetative cells of the psychrotolerant B. weihenstephanensis strain KBAB4 were pathogenic against the model insect Galleria mellonella at 15°C but not at 30°C. A similar temperature-dependent difference also was observed for the supernatant, which was cytotoxic to Vero epithelial cell lines and to murine macrophage J774 cells at 15°C but not at 30°C. We therefore determined the effect of low temperature on the production of various proteins putatively involved in virulence using two-dimensional protein gel electrophoresis, and we showed that the production of the Hbl enterotoxin and of two proteases, NprB and NprP2, was greater at a growth temperature of 15°C than at 30°C. The quantification of the mRNA levels for these virulence genes by real-time quantitative PCR at both temperatures showed that there was also more mRNA present at 15°C than at 30°C. We also found that at 15°C, hbl mRNA levels were maximal in the mid- to late exponential growth phase. In conclusion, we found that the higher virulence of the B. cereus KBAB4 strain at low temperature was accompanied by higher levels of the production of various known PlcR-controlled virulence factors and by a higher transcriptional activity of the corresponding genes.
PMCID: PMC3318839  PMID: 22307282
24.  Effect of Feed Restriction and Realimentation with Monensin Supplementation on Placental Structure and Ultrastructure in Anglo-Nubian Goats 
ISRN Veterinary Science  2012;2012:490530.
The aim of this study was to evaluate the effect of feed restriction followed by a realimentation with monensin supplementation on morphological, ultrastructural, and apoptotic characteristics in the term placenta of Anglo-Nubian does. Treatments were a control group (C = 5), a group fed at 0.70 of that consumed by controls (R = 7), and the same as R with monensin (M = 7). After parturition, 27 placentas were gathered, C: 7, M: 10, and R: 10. No differences were detected between treatments in relation to morphological and ultrastructural analysis. The greatest values of binucleate cells were detected in placentas from R, and it could be due to the need to compensate and satisfy nutritional differences of restriction. We detected the highest apoptotic index in R as a consequence of nutritional treatment. We describe for the first time the structural and ultrastructural morphology and remodeling by apoptosis of Anglo-Nubian placenta at term of goats subjected to nutritional restriction during peripubertal period and the use of monensin as a growth promoter.
PMCID: PMC3671730  PMID: 23762584
25.  Posterior arch defect in a dry atlas 
European Spine Journal  2011;20(9):1574-1575.
PMCID: PMC3175901  PMID: 21327812

Results 1-25 (89)