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1.  Global human frequencies of predicted nuclear pathogenic variants and the role played by protein hydrophobicity in pathogenicity potential 
Scientific Reports  2014;4:7155.
Mitochondrial proteins are coded by nuclear (nDNA) and mitochondrial (mtDNA) genes, implying a complex cross-talk between the two genomes. Here we investigated the diversity displayed in 104 nuclear-coded mitochondrial proteins from 1,092 individuals from the 1000 Genomes dataset, in order to evaluate if these genes are under the effects of purifying selection and how that selection compares with their mitochondrial encoded counterparts. Only the very rare variants (frequency < 0.1%) in these nDNA genes are indistinguishable from a random set from all possible variants in terms of predicted pathogenicity score, but more frequent variants display distinct signs of purifying selection. Comparisons of selection strength indicate stronger selection in the mtDNA genes compared to this set of nDNA genes, accounted for by the high hydrophobicity of the proteins coded by the mtDNA. Most of the predicted pathogenic variants in the nDNA genes were restricted to a single continental population. The proportion of individuals having at least one potential pathogenic mutation in this gene set was significantly lower in Europeans than in Africans and Asians. This difference may reflect demographic asymmetries, since African and Asian populations experienced main expansions in middle Holocene, while in Europeans the main expansions occurred earlier in the post-glacial period.
PMCID: PMC4239565  PMID: 25412673
2.  Integrated Analysis of Climate, Soil, Topography and Vegetative Growth in Iberian Viticultural Regions 
PLoS ONE  2014;9(9):e108078.
The Iberian viticultural regions are convened according to the Denomination of Origin (DO) and present different climates, soils, topography and management practices. All these elements influence the vegetative growth of different varieties throughout the peninsula, and are tied to grape quality and wine type. In the current study, an integrated analysis of climate, soil, topography and vegetative growth was performed for the Iberian DO regions, using state-of-the-art datasets. For climatic assessment, a categorized index, accounting for phenological/thermal development, water availability and grape ripening conditions was computed. Soil textural classes were established to distinguish soil types. Elevation and aspect (orientation) were also taken into account, as the leading topographic elements. A spectral vegetation index was used to assess grapevine vegetative growth and an integrated analysis of all variables was performed. The results showed that the integrated climate-soil-topography influence on vine performance is evident. Most Iberian vineyards are grown in temperate dry climates with loamy soils, presenting low vegetative growth. Vineyards in temperate humid conditions tend to show higher vegetative growth. Conversely, in cooler/warmer climates, lower vigour vineyards prevail and other factors, such as soil type and precipitation acquire more important roles in driving vigour. Vines in prevailing loamy soils are grown over a wide climatic diversity, suggesting that precipitation is the primary factor influencing vigour. The present assessment of terroir characteristics allows direct comparison among wine regions and may have great value to viticulturists, particularly under a changing climate.
PMCID: PMC4176712  PMID: 25251495
3.  Spinal Cord Infarction and Patent Foramen Ovale: Is There a Link? 
Case Reports in Neurology  2014;6(2):188-192.
Spinal cord infarction (SCI) is an uncommon but important cause of acute myelopathy. Nevertheless, contrary to cerebral stroke, the discussion about paradoxical embolism as a cause of cryptogenic SCI remains dubious. We describe the case of a 24-year-old woman who developed sudden-onset back pain followed by upper limb paralysis. T2-weighted MRI demonstrated hyperintense signal, extending from C5 to D1 with corresponding restricted diffusion on diffusion-weighted MRI and reduction of the apparent diffusion coefficient. Diagnostic workup, including lumbar puncture, showed no changes. Transcranial Doppler showed a right-to-left shunt with an uncountable number of microembolic signals after Valsalva maneuvers, and a patent foramen ovale (PFO) with an atrial septum aneurysm was identified. We discuss the paucity of evidence of right-to-left shunting in spinal diseases compared to cerebral events and the potential role of paradoxical embolism through PFO as a possible mechanism of SCI.
PMCID: PMC4105946  PMID: 25076895
Spinal cord infarction; Stroke; Patent foramen ovale; Right-to-left shunting; Atrial septal aneurysm
4.  Time-Dependent Effects of Training on Cardiovascular Control in Spontaneously Hypertensive Rats: Role for Brain Oxidative Stress and Inflammation and Baroreflex Sensitivity 
PLoS ONE  2014;9(5):e94927.
Baroreflex dysfunction, oxidative stress and inflammation, important hallmarks of hypertension, are attenuated by exercise training. In this study, we investigated the relationships and time-course changes of cardiovascular parameters, pro-inflammatory cytokines and pro-oxidant profiles within the hypothalamic paraventricular nucleus of the spontaneously hypertensive rats (SHR). Basal values and variability of arterial pressure and heart rate and baroreflex sensitivity were measured in trained (T, low-intensity treadmill training) and sedentary (S) SHR at weeks 0, 1, 2, 4 and 8. Paraventricular nucleus was used to determine reactive oxygen species (dihydroethidium oxidation products, HPLC), NADPH oxidase subunits and pro-inflammatory cytokines expression (Real time PCR), p38 MAPK and ERK1/2 expression (Western blotting), NF-κB content (electrophoretic mobility shift assay) and cytokines immunofluorescence. SHR-S vs. WKY-S (Wistar Kyoto rats as time control) showed increased mean arterial pressure (172±3 mmHg), pressure variability and heart rate (358±7 b/min), decreased baroreflex sensitivity and heart rate variability, increased p47phox and reactive oxygen species production, elevated NF-κB activity and increased TNF-α and IL-6 expression within the paraventricular nucleus of hypothalamus. Two weeks of training reversed all hypothalamic changes, reduced ERK1/2 phosphorylation and normalized baroreflex sensitivity (4.04±0.31 vs. 2.31±0.19 b/min/mmHg in SHR-S). These responses were followed by increased vagal component of heart rate variability (1.9-fold) and resting bradycardia (−13%) at the 4th week, and, by reduced vasomotor component of pressure variability (−28%) and decreased mean arterial pressure (−7%) only at the 8th week of training. Our findings indicate that independent of the high pressure levels in SHR, training promptly restores baroreflex function by disrupting the positive feedback between high oxidative stress and increased pro-inflammatory cytokines secretion within the hypothalamic paraventricular nucleus. These early adaptive responses precede the occurrence of training-induced resting bradycardia and blood pressure fall.
PMCID: PMC4006803  PMID: 24788542
5.  The First Modern Human Dispersals across Africa 
PLoS ONE  2013;8(11):e80031.
The emergence of more refined chronologies for climate change and archaeology in prehistoric Africa, and for the evolution of human mitochondrial DNA (mtDNA), now make it feasible to test more sophisticated models of early modern human dispersals suggested by mtDNA distributions. Here we have generated 42 novel whole-mtDNA genomes belonging to haplogroup L0, the most divergent clade in the maternal line of descent, and analysed them alongside the growing database of African lineages belonging to L0’s sister clade, L1’6. We propose that the last common ancestor of modern human mtDNAs (carried by “mitochondrial Eve”) possibly arose in central Africa ~180 ka, at a time of low population size. By ~130 ka two distinct groups of anatomically modern humans co-existed in Africa: broadly, the ancestors of many modern-day Khoe and San populations in the south and a second central/eastern African group that includes the ancestors of most extant worldwide populations. Early modern human dispersals correlate with climate changes, particularly the tropical African “megadroughts” of MIS 5 (marine isotope stage 5, 135–75 ka) which paradoxically may have facilitated expansions in central and eastern Africa, ultimately triggering the dispersal out of Africa of people carrying haplogroup L3 ~60 ka. Two south to east migrations are discernible within haplogroup LO. One, between 120 and 75 ka, represents the first unambiguous long-range modern human dispersal detected by mtDNA and might have allowed the dispersal of several markers of modernity. A second one, within the last 20 ka signalled by L0d, may have been responsible for the spread of southern click-consonant languages to eastern Africa, contrary to the view that these eastern examples constitute relicts of an ancient, much wider distribution.
PMCID: PMC3827445  PMID: 24236171
6.  A substantial prehistoric European ancestry amongst Ashkenazi maternal lineages 
Nature Communications  2013;4:2543.
The origins of Ashkenazi Jews remain highly controversial. Like Judaism, mitochondrial DNA is passed along the maternal line. Its variation in the Ashkenazim is highly distinctive, with four major and numerous minor founders. However, due to their rarity in the general population, these founders have been difficult to trace to a source. Here we show that all four major founders, ~40% of Ashkenazi mtDNA variation, have ancestry in prehistoric Europe, rather than the Near East or Caucasus. Furthermore, most of the remaining minor founders share a similar deep European ancestry. Thus the great majority of Ashkenazi maternal lineages were not brought from the Levant, as commonly supposed, nor recruited in the Caucasus, as sometimes suggested, but assimilated within Europe. These results point to a significant role for the conversion of women in the formation of Ashkenazi communities, and provide the foundation for a detailed reconstruction of Ashkenazi genealogical history.
Ashkenazi mitochondrial DNA variation has four major founders whose sources are difficult to trace due to the rarity of Ashkenazi Jews in the general population. Here, the authors provide evidence that all four major founders originated from Europe and provide a genealogical record of the Ashkenazi.
PMCID: PMC3806353  PMID: 24104924
7.  1-Aryl-3-[4-(thieno[3,2-d]pyrimidin-4-yloxy)phenyl]ureas as VEGFR-2 Tyrosine Kinase Inhibitors: Synthesis, Biological Evaluation, and Molecular Modelling Studies 
BioMed Research International  2013;2013:154856.
The vascular endothelial growth factor receptor-2 (VEGFR-2) is a tyrosine kinase receptor involved in the growth and differentiation of endothelial cells that are implicated in tumor-associated angiogenesis. In this study, novel 1-aryl-3-[4-(thieno[3,2-d]pyrimidin-4-yloxy)phenyl]ureas were synthesized and evaluated for the VEGFR-2 tyrosine kinase inhibition. Three of these compounds showed good VEGFR-2 inhibition presenting low IC50 values (150–199 nM) in enzymatic assays, showing also a significant proliferation inhibition of VEGF-stimulated human umbilical vein endothelial cells (HUVECs) at low concentrations (0.5–1 µM), using the Bromodeoxyuridine (BrdU) assay, not affecting cell viability. The determination of the total and phosphorylated (active) VEGFR-2 was performed by western blot, and it was possible to conclude that the compounds significantly inhibit the phosphorylation of the receptor at 1 µM pointing to their antiproliferative mechanism of action in HUVECs. The molecular rationale for inhibiting the tyrosine kinase domain of VEGFR-2 was also performed and discussed using molecular docking studies.
PMCID: PMC3722775  PMID: 23936775
8.  Evaluating Purifying Selection in the Mitochondrial DNA of Various Mammalian Species 
PLoS ONE  2013;8(3):e58993.
Mitochondrial DNA (mtDNA), the circular DNA molecule inside the mitochondria of all eukaryotic cells, has been shown to be under the effect of purifying selection in several species. Traditional testing of purifying selection has been based simply on ratios of nonsynonymous to synonymous mutations, without considering the relative age of each mutation, which can be determined by phylogenetic analysis of this non-recombining molecule. The incorporation of a mutation time-ordering from phylogeny and of predicted pathogenicity scores for nonsynonymous mutations allow a quantitative evaluation of the effects of purifying selection in human mtDNA. Here, by using this additional information, we show that purifying selection undoubtedly acts upon the mtDNA of other mammalian species/genera, namely Bos sp., Canis lupus, Mus musculus, Orcinus orca, Pan sp. and Sus scrofa. The effects of purifying selection were comparable in all species, leading to a significant major proportion of nonsynonymous variants with higher pathogenicity scores in the younger branches of the tree. We also derive recalibrated mutation rates for age estimates of ancestors of these various species and proposed a correction curve in order to take into account the effects of selection. Understanding this selection is fundamental to evolutionary studies and to the identification of deleterious mutations.
PMCID: PMC3606437  PMID: 23533597
9.  A Sulfated-Polysaccharide Fraction from Seaweed Gracilaria birdiae Prevents Naproxen-Induced Gastrointestinal Damage in Rats 
Marine Drugs  2012;10(12):2618-2633.
Red seaweeds synthesize a great variety of sulfated galactans. Sulfated polysaccharides (PLSs) from seaweed are comprised of substances with pharmaceutical and biomedical potential. The aim of the present study was to evaluate the protective effect of the PLS fraction extracted from the seaweed Gracilaria birdiae in rats with naproxen-induced gastrointestinal damage. Male Wistar rats were pretreated with 0.5% carboxymethylcellulose (control group—vehicle) or PLS (10, 30, and 90 mg/kg, p.o.) twice daily (at 09:00 and 21:00) for 2 days. After 1 h, naproxen (80 mg/kg, p.o.) was administered. The rats were killed on day two, 4 h after naproxen treatment. The stomachs were promptly excised, opened along the greater curvature, and measured using digital calipers. Furthermore, the guts of the animals were removed, and a 5-cm portion of the small intestine (jejunum and ileum) was used for the evaluation of macroscopic scores. Samples of the stomach and the small intestine were used for histological evaluation, morphometric analysis and in assays for glutathione (GSH) levels, malonyldialdehyde (MDA) concentration, and myeloperoxidase (MPO) activity. PLS treatment reduced the macroscopic and microscopic naproxen-induced gastrointestinal damage in a dose-dependent manner. Our results suggest that the PLS fraction has a protective effect against gastrointestinal damage through mechanisms that involve the inhibition of inflammatory cell infiltration and lipid peroxidation.
PMCID: PMC3528114  PMID: 23342384
sulfated polysaccharide; gastrointestinal damage; naproxen; antioxidant activity
10.  Monocrotaline: Histological Damage and Oxidant Activity in Brain Areas of Mice 
This work was designed to study MCT effect in histopathological analysis of hippocampus (HC) and parahippocampal cortex (PHC) and in oxidative stress (OS) parameters in brain areas such as hippocampus (HC), prefrontal cortex (PFC), and striatum (ST). Swiss mice (25–30 g) were administered a single i.p. dose of MCT (5, 50, or 100 mg/kg) or 4% Tween 80 in saline (control group). After 30 minutes, the animals were sacrificed by decapitation and the brain areas (HC, PHC, PFC, or ST) were removed for histopathological analysis or dissected and homogenized for measurement of OS parameters (lipid peroxidation, nitrite, and catalase) by spectrophotometry. Histological evaluation of brain structures of rats treated with MCT (50 and 100 mg/kg) revealed lesions in the hippocampus and parahippocampal cortex compared to control. Lipid peroxidation was evident in all brain areas after administration of MCT. Nitrite/nitrate content decreased in all doses administered in HC, PFC, and ST. Catalase activity was increased in the MCT group only in HC. In conclusion, monocrotaline caused cell lesions in the hippocampus and parahippocampal cortex regions and produced oxidative stress in the HC, PFC, and ST in mice. These findings may contribute to the neurological effects associated with this compound.
PMCID: PMC3517861  PMID: 23251721
11.  Study protocol: using the Q-STEPS to assess and improve the quality of physical activity programmes for the elderly 
BMC Research Notes  2012;5:171.
Aging is one of the most important and obvious phenomenon observed in our society. In the past years, there has been a growing concern in designing physical activity (PA) programmes for elderly people, because evidence suggests that such health promotion interventions may reduce the deleterious effects of the ageing process. Accordingly, a growing body of literature points to the importance of a sound approach to planning and evaluation in order to improve the quality of PA programmes. However, while numerous PA programmes have been designed for the elderly in recent years, their evaluation has been scarce. Quality management processes and tools provide a practical way for organisations to assess, identify and shed light on the areas requiring improvement. The Quality Self-assessment Tool for Exercise Programmes for Seniors (Q-STEPS) seems to provide a framework tailored to evaluate PA programmes for the elderly.
The primary purpose of this study is 1) to determine feasibility, acceptability and usability of the Q-STEPS. Secondary purposes of the study are: 2) to examine the quality of the PA programmes for elderly people developed by the Portuguese Local Administration over a three-year period of self-assessments in terms of: a) Enabler domains (Leadership, Policy and Strategy, People, Partnership and Resources, Processes); b) Result domains (Customer Results, People Results, Society Results and Key Performance Results); 3) to estimate the association between the use of Q-STEPS and some indicators relating to the elderly participants, during the three self-assessments, such as: attendance rates, physical fitness, health-related quality of life and the elderly’s perceived quality of the programme. The study will be conducted in PA programmes for elderly adults from mainland Portuguese municipalities over a three-year period. The project will adopt a participative quality improvement approach that features annual learning cycles of: 1) self-assessment with the Q-STEPS; 2) feedback to and interpretation of results involving programme’s staff; 3) action planning to achieve system changes; 4) implementation of strategies for change; and 5) review process through further self-assessment. The study will collect a range of process and outcome data that will be used to achieve the research aims.
It is our understanding that the results of the Q-STEPS study will contribute directly to the evidence based on effectiveness of continuous quality improvement approaches, in order to improve customer satisfaction and adherence to PA programmes targeting the ageing population. This comprehensive evaluation will also add significant new knowledge regarding the characteristics associated with a sustainable public service.
PMCID: PMC3474180  PMID: 22471954
Q-STEPS; Feasibility; Physical activity programmes; Elderly; Evaluation; Quality
12.  Population Genetic Structure in Indian Austroasiatic Speakers: The Role of Landscape Barriers and Sex-Specific Admixture 
Molecular biology and evolution  2010;28(2):1013-1024.
The geographic origin and time of dispersal of Austroasiatic (AA) speakers, presently settled in south and southeast Asia, remains disputed. Two rival hypotheses, both assuming a demic component to the language dispersal, have been proposed. The first of these places the origin of Austroasiatic speakers in southeast Asia with a later dispersal to south Asia during the Neolithic, whereas the second hypothesis advocates pre-Neolithic origins and dispersal of this language family from south Asia. To test the two alternative models, this study combines the analysis of uniparentally inherited markers with 610,000 common single nucleotide polymorphism loci from the nuclear genome. Indian AA speakers have high frequencies of Y chromosome haplogroup O2a; our results show that this haplogroup has significantly higher diversity and coalescent time (17–28 thousand years ago) in southeast Asia, strongly supporting the first of the two hypotheses. Nevertheless, the results of principal component and “structure-like” analyses on autosomal loci also show that the population history of AA speakers in India is more complex, being characterized by two ancestral components—one represented in the pattern of Y chromosomal and EDAR results and the other by mitochondrial DNA diversity and genomic structure. We propose that AA speakers in India today are derived from dispersal from southeast Asia, followed by extensive sex-specific admixture with local Indian populations.
PMCID: PMC3355372  PMID: 20978040
Austroasiatic; mtDNA; Y chromosome; autosomes; admixture
13.  Somatic mitochondrial DNA mutations in cancer escape purifying selection and high pathogenicity mutations lead to the oncocytic phenotype: pathogenicity analysis of reported somatic mtDNA mutations in tumors 
BMC Cancer  2012;12:53.
The presence of somatic mitochondrial DNA (mtDNA) mutations in cancer cells has been interpreted in controversial ways, ranging from random neutral accumulation of mutations, to positive selection for high pathogenicity, or conversely to purifying selection against high pathogenicity variants as occurs at the population level.
Here we evaluated the predicted pathogenicity of somatic mtDNA mutations described in cancer and compare these to the distribution of variations observed in the global human population and all possible protein variations that could occur in human mtDNA. We focus on oncocytic tumors, which are clearly associated with mitochondrial dysfunction. The protein variant pathogenicity was predicted using two computational methods, MutPred and SNPs&GO.
The pathogenicity score of the somatic mtDNA variants were significantly higher in oncocytic tumors compared to non-oncocytic tumors. Variations in subunits of Complex I of the electron transfer chain were significantly more common in tumors with the oncocytic phenotype, while variations in Complex V subunits were significantly more common in non-oncocytic tumors.
Our results show that the somatic mtDNA mutations reported over all tumors are indistinguishable from a random selection from the set of all possible amino acid variations, and have therefore escaped the effects of purifying selection that act strongly at the population level. We show that the pathogenicity of somatic mtDNA mutations is a determining factor for the oncocytic phenotype. The opposite associations of the Complex I and Complex V variants with the oncocytic and non-oncocytic tumors implies that low mitochondrial membrane potential may play an important role in determining the oncocytic phenotype.
PMCID: PMC3342922  PMID: 22299657
14.  A proposed adaptation of the European Foundation for Quality Management Excellence Model to physical activity programmes for the elderly - development of a quality self-assessment tool using a modified Delphi process 
There has been a growing concern in designing physical activity (PA) programmes for elderly people, since evidence suggests that such health promotion interventions may reduce the deleterious effects of the ageing process. Complete programme evaluations are a necessary prerequisite to continuous quality improvements. Being able to refine, adapt and create tools that are suited to the realities and contexts of PA programmes for the elderly in order to support its continuous improvement is, therefore, crucial. Thus, the aim of this study was to develop a self-assessment tool for PA programmes for the elderly.
A 3-round Delphi process was conducted via the Internet with 43 national experts in PA for the elderly, management and delivery of PA programmes for the elderly, sports management, quality management and gerontology, asking experts to identify the propositions that they considered relevant for inclusion in the self-assessment tool. Experts reviewed a list of proposed statements, based on the criteria and sub-criteria from the European Foundation for Quality Management Excellence Model (EFQM) and PA guidelines for older adults and rated each proposition from 1 to 8 (disagree to agree) and modified and/or added propositions. Propositions receiving either bottom or top scores of greater than 70% were considered to have achieved consensus to drop or retain, respectively.
In round 1, of the 196 originally-proposed statements (best practice principles), the experts modified 41, added 1 and achieved consensus on 93. In round 2, a total of 104 propositions were presented, of which experts modified 39 and achieved consensus on 53. In the last round, of 51 proposed statements, the experts achieved consensus on 19. After 3 rounds of rating, experts had not achieved consensus on 32 propositions. The resulting tool consisted of 165 statements that assess nine management areas involved in the development of PA programmes for the elderly.
Based on experts' opinions, a self-assessment tool was found in order to access quality of PA programmes for the elderly. Information obtained with evaluations would be useful to organizations seeking to improve their services, customer satisfaction and, consequently, adherence to PA programmes, targeting the ageing population.
PMCID: PMC3278362  PMID: 21958203
physical activity; programmes; elderly; tool; evaluation; quality; adherence
15.  Evaluation of physical activity programmes for the elderly - exploring the lessons from other sectors and examining the general characteristics of the programmes 
BMC Research Notes  2011;4:368.
In Portugal, there are several physical activity (PA) programmes for elderly people developed by the local government. The importance of these programmes has been increasing since the evidence has shown that this type of health promotion interventions may reduce the deleterious effects of the ageing process. However, no study has already identified the general characteristics of these programmes nor if they use any scheme to assess the quality of the service provided. A widely-used scheme is the EFQM Excellence Model, which will be in the core of our present work. Thus, the main aims of this preliminary study were 1) to identify the general characteristics of the PA programmes developed by the Portuguese Local Public Administration 2) to determine the extent of implementation of quality initiatives in these programmes.
Data were collected by an on-line questionnaire sent to all Continental Municipalities (n = 278). Categorical data were expressed as absolute counts and percentages. Continuous data were expressed as the mean and SD. An open-ended question was analysed using qualitative content analysis with QSR NVivo software. Associations between categorical variables were tested by the use of contingency tables and the calculation of chi-square tests. Significance level was set at p ≤ 0.05.
Results showed: i) a total of 125 PA programmes were identified in the 18 districts of the Portugal mainland; ii) the main goal of the majority (95.2%) was the participants' health promotion; iii) different characteristics of the programmes were found according to different regions of the country; iv) certain characteristics of the programmes were associated to the existence of other features; v) only one PA programme developed quality initiatives.
In conclusion, although there are many PA programmes for elderly people spread throughout the country, aiming at improving the health of participants, the overwhelming majority does not adopt quality control initiatives. Considering that the quality of a service increases customer satisfaction, the continuous quality improvement of the PA programmes for elderly people should therefore be implemented since they can be useful and critical for elderly satisfaction and adherence.
PMCID: PMC3197507  PMID: 21943398
physical activity; elderly people; quality; assessment; EFQM
16.  Cardiovascular responses to passive static flexibility exercises are influenced by the stretched muscle mass and the Valsalva maneuver 
Clinics  2011;66(3):459-464.
The respiratory pattern is often modified or even blocked during flexibility exercises, but little is known about the cardiovascular response to concomitant stretching and the Valsalva maneuver (VM) in healthy subjects.
This study evaluated the heart rate (HR), systolic blood pressure (SBP), and rate-pressure product (RPP) during and after large and small muscle group flexibility exercises performed simultaneously with the VM.
Asymptomatic volunteers (N  =  22) with the following characteristics were recruited: age, 22 ± 3 years; weight, 73 ± 6 kg; height, 175 ± 5 cm; HR at rest, 66 ± 9 BPM; and SBP at rest, 113 ± 10 mmHg. They performed two exercises: four sets of passive static stretching for 30 s of the dorsi-flexion (DF) of the gastrocnemius and the hip flexion (HF) of the ischio-tibialis. The exercises were performed with (V+) or without (V-) the VM in a counterbalanced order. The SBP and HR were measured, and the RPP was calculated before the exercise session, at the end of each set, and during a 30-min post-exercise recovery period.
The within-group comparisons showed that only the SBP and RPP increased throughout the sets (p<0.05), but no post-exercise hypotension was detected. The between-group comparisons showed that greater SBP increases were related to the VM and to a larger stretched muscle mass. Differences for a given set were identified for the HR (the HFV+ and HFV- values were higher than the DFV+ and DFV- values by approximately 12 BPM), SBP (the HFV+ value was higher than the DFV+ and DFV- values by approximately 12 to 15 mmHg), and RPP (the HFV+ value was higher than the HFV- value by approximately 2000 mmHGxBPM, and the HFV+ value was higher than the DFV+ and DFV- values by approximately 4000 mmHGxBPM).
Both the stretched muscle mass and the VM influence acute cardiovascular responses to multiple-set passive stretching exercise sessions.
PMCID: PMC3072008  PMID: 21552673
Flexibility; Cardiovascular physiology; Health; Exercise; Physical fitness
17.  Evaluation of physical activity programmes for elderly people - a descriptive study using the EFQM' criteria 
BMC Public Health  2011;11:123.
In the past years, there has been a growing concern in designing physical activity (PA) programmes for elderly people, because evidence suggests that such health promotion interventions may reduce the deleterious effects of the ageing process. Quality is an important issue when designing a PA programme for older people. Some studies support the Excellence Model of the European Foundation for Quality Management (EFQM) as an operational framework for evaluating the quality of an organization. Within this context, the aim of this study was to characterize the quality management models of the PA programmes developed by Portuguese Local Administration to enhance quality of life for elderly people, according to the criteria of the EFQM Excellence Model.
A methodological triangulation was conducted in 26 PA programmes using questionnaire surveys, semi-structured interviews and document analysis. We used standard approaches to the statistical analysis of data including frequencies and percentages for the categorical data.
Results showed that Processes (65,38%), Leadership (61,03%), Customer results (58,46) and People (51,28%) had high percentage occurrences of quality practices. In contrast, Partnerships and resources (45,77%), People results (41,03%), Policy and strategy (37,91%), Key performance results (19,23%) and Society results (19,23%) had lower percentage occurrences.
Our findings suggest that although there are some good practices in PA programmes, there are still relevant areas that require improvement.
PMCID: PMC3050751  PMID: 21338497
18.  Population expansion in the North African Late Pleistocene signalled by mitochondrial DNA haplogroup U6 
The archaeology of North Africa remains enigmatic, with questions of population continuity versus discontinuity taking centre-stage. Debates have focused on population transitions between the bearers of the Middle Palaeolithic Aterian industry and the later Upper Palaeolithic populations of the Maghreb, as well as between the late Pleistocene and Holocene.
Improved resolution of the mitochondrial DNA (mtDNA) haplogroup U6 phylogeny, by the screening of 39 new complete sequences, has enabled us to infer a signal of moderate population expansion using Bayesian coalescent methods. To ascertain the time for this expansion, we applied both a mutation rate accounting for purifying selection and one with an internal calibration based on four approximate archaeological dates: the settlement of the Canary Islands, the settlement of Sardinia and its internal population re-expansion, and the split between haplogroups U5 and U6 around the time of the first modern human settlement of the Near East.
A Bayesian skyline plot placed the main expansion in the time frame of the Late Pleistocene, around 20 ka, and spatial smoothing techniques suggested that the most probable geographic region for this demographic event was to the west of North Africa. A comparison with U6's European sister clade, U5, revealed a stronger population expansion at around this time in Europe. Also in contrast with U5, a weak signal of a recent population expansion in the last 5,000 years was observed in North Africa, pointing to a moderate impact of the late Neolithic on the local population size of the southern Mediterranean coast.
PMCID: PMC3016289  PMID: 21176127
19.  A common MYBPC3 (cardiac myosin binding protein C) variant associated with cardiomyopathies in South Asia 
Nature genetics  2009;41(2):187-191.
Heart failure is a leading cause of mortality in South Asians. However, its genetic etiology remains largely unknown1. Cardiomyopathies due to sarcomeric mutations are a major monogenic cause for heart failure (MIM600958). Here, we describe a deletion of 25 bp in the gene encoding cardiac myosin binding protein C (MYBPC3) that is associated with heritable cardiomyopathies and an increased risk of heart failure in Indian populations (initial study OR = 5.3 (95% CI = 2.3–13), P = 2 × 10−6; replication study OR = 8.59 (3.19–25.05), P = 3 × 10−8; combined OR = 6.99 (3.68–13.57), P = 4 × 10−11) and that disrupts cardiomyocyte structure in vitro. Its prevalence was found to be high (~4%) in populations of Indian subcontinental ancestry. The finding of a common risk factor implicated in South Asian subjects with cardiomyopathy will help in identifying and counseling individuals predisposed to cardiac diseases in this region.
PMCID: PMC2697598  PMID: 19151713
20.  Coronary artery bypass surgery and longitudinal evaluation of the autonomic cardiovascular function 
Critical Care  2005;9(2):R124-R131.
Imbalance in autonomic cardiovascular function increases the risk for sudden death in patients with coronary artery disease (CAD), but the time course of the impact of coronary artery bypass grafting (CABG) on autonomic function has been little studied. Thus, the purpose of the present study was to determine the effects of the CABG on the cardiovascular autonomic function.
Patients undergoing CABG (n = 13) and two matched control groups (patients with CAD who refused surgical treatment [n = 9], and healthy volunteers [n = 9]) underwent a prospective longitudinal study consisting of autonomic evaluation before and after (3, 6, 15, 30, 60, and 90 days) surgery, including measurement of heart rate variability (HRV), respiratory sinus arrhythmia (RSA), and Valsalva maneuver.
After CABG there was a decrease in, and a later recovery of, (1) the HRV in the time domain and in the frequency domain, (2) RSA, and (3) Valsalva maneuver.
CABG caused an impairment, reversible after 60 days, of cardiovascular autonomic function, with a maximal decrease on about the sixth day after surgery.
PMCID: PMC1175925  PMID: 15774044
21.  Structure-Guided Design and Optimization of Small Molecules Targeting the Protein–Protein Interaction between the von Hippel–Lindau (VHL) E3 Ubiquitin Ligase and the Hypoxia Inducible Factor (HIF) Alpha Subunit with in Vitro Nanomolar Affinities 
Journal of Medicinal Chemistry  2014;57(20):8657-8663.
E3 ubiquitin ligases are attractive targets in the ubiquitin–proteasome system, however, the development of small-molecule ligands has been rewarded with limited success. The von Hippel–Lindau protein (pVHL) is the substrate recognition subunit of the VHL E3 ligase that targets HIF-1α for degradation. We recently reported inhibitors of the pVHL:HIF-1α interaction, however they exhibited moderate potency. Herein, we report the design and optimization, guided by X-ray crystal structures, of a ligand series with nanomolar binding affinities.
PMCID: PMC4207132  PMID: 25166285

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