Pharmacological characterization of GLPG1972/S201086, a potent and selective small-molecule inhibitor of ADAMTS5.

OBJECTIVE: A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) is a key enzyme in degradation of cartilage in osteoarthritis (OA). We report the pharmacological characterization of GLPG1972/S201086, a new, potent and selective small-molecule ADAMTS5 inhibitor. METHODS: Potency and selectivity of GLPG1972/S201086 for ADAMTS5 were determined using fluorescently labeled peptide substrates. Inhibitory effects of GLPG1972/S201086 on interleukin-1α-stimulated glycosaminoglycan release in mouse femoral head cartilage explants and on interleukin-1ß-stimulated release of an ADAMTS5-derived aggrecan neoepitope (quantified with ELISA) in human articular cartilage explants were determined. In the destabilization of the medial meniscus (DMM) mouse and menisectomized (MNX) rat models, effects of oral GLPG1972/S201086 on relevant OA histological and histomorphometric parameters were evaluated. RESULTS: GLPG1972/S201086 inhibited human and rat ADAMTS5 (IC50 ± SD: 19 ± 2 nM and <23 ± 1 nM, respectively), with 8-fold selectivity over ADAMTS4, and 60->5,000-fold selectivity over other related proteases in humans. GLPG1972/S201086 dose-dependently inhibited cytokine-stimulated aggrenolysis in mouse and human cartilage explants (100% at 20 µM and 10 µM, respectively). In DMM mice, GLPG1972/S201086 (30-120 mg/kg b.i.d) vs vehicle reduced femorotibial cartilage proteoglycan loss (23-37%), cartilage structural damage (23-39%) and subchondral bone sclerosis (21-36%). In MNX rats, GLPG1972/S201086 (10-50 mg/kg b.i.d) vs vehicle reduced cartilage damage (OARSI score reduction, 6-23%), and decreased proteoglycan loss (∼27%) and subchondral bone sclerosis (77-110%). CONCLUSIONS: GLPG1972/S201086 is a potent, selective and orally available ADAMTS5 inhibitor, demonstrating significant protective efficacy on both cartilage and subchondral bone in two relevant in vivo preclinical OA models.

Author Correction: Sex-biased patterns shaped the genetic history of Roma.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Sex-biased patterns shaped the genetic history of Roma.

The Roma population is a European ethnic minority characterized by recent and multiple dispersals and founder effects. After their origin in South Asia around 1,500 years ago, they migrated West. In Europe, they diverged into ethnolinguistically distinct migrant groups that spread across the continent. Previous genetic studies based on genome-wide data and uniparental markers detected Roma founder events and West-Eurasian gene flow. However, to the best of our knowledge, it has not been assessed whether these demographic processes have equally affected both sexes in the population. The present study uses the largest and most comprehensive dataset of complete mitochondrial and Y chromosome Roma sequences to unravel the sex-biased patterns that have shaped their genetic history. The results show that the Roma maternal genetic pool carries a higher lineage diversity from South Asia, as opposed to a single paternal South Asian lineage. Nonetheless, the European gene flow events mainly occurred through the maternal lineages; however, a signal of this gene flow is also traceable in the paternal lineages. We also detect a higher female migration rate among European Roma groups. Altogether, these results suggest that sociocultural factors influenced the emergence of sex-biased genetic patterns at global and local scales in the Roma population through time.

Patterns of genetic structure and adaptive positive selection in the Lithuanian population from high-density SNP data.

The analysis of geographically specific regions and the characterization of fine-scale patterns of genetic diversity may facilitate a much better understanding of the microevolutionary processes affecting local human populations. Here we generated genome-wide high-density SNP genotype data in 425 individuals from six geographical regions in Lithuania and combined our dataset with available ancient and modern data to explore genetic population structure, ancestry components and signatures of natural positive selection in the Lithuanian population. Our results show that Lithuanians are a homogenous population, genetically differentiated from neighbouring populations but within the general expected European context. Moreover, we not only confirm that Lithuanians preserve one of the highest proportions of western, Scandinavian and eastern hunter-gather ancestry components found in European populations but also that of an steppe Early to Middle Bronze Age pastoralists, which together configure the genetic distinctiveness of the Lithuanian population. Finally, among the top signatures of positive selection detected in Lithuanians, we identified several candidate genes related with diet (PNLIP, PPARD), pigmentation (SLC24A5, TYRP1 and PPARD) and the immune response (BRD2, HLA-DOA, IL26 and IL22).

Care, Autonomy, and Gender in Nursing Practice: A Historical Study of Nurses' Experiences.

BACKGROUND: Care is the essence of the nursing role and is closely related to the concept of professional autonomy. Autonomy is implicated in power relations between doctors and nurses and between men and women. These relationships are closely linked to care practices and the inequality of nursing and medicine. PURPOSE: The aim of this study was to analyze nursing discourse regarding the concept of care and its relationship to the concept of autonomy and gender. METHODS: This is a historical study based on oral interviews that took place between November 2008 and February 2011. We interviewed 19 nursing professionals who currently worked at the Hospital of the Holy Spirit (near Barcelona) or had worked there between 1961 and 2010. Semistructured interviews were recorded, transcribed, and analyzed. RESULTS: We highlight four main themes: "a real nurse"; "more technology, less care"; "the fragility of autonomy"; and "the invisibility of nursing work." These themes show the contradictions in the nursing profession that are based on the concept of care. However, in daily practice, the concept of care varies. Time pressure distances the nursing practice from its theoretical context. Changes in the concept of care are related to transformations in the health system and nursing work. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: Changes related to the autonomy of nursing are related to changes in the concept of care. In practice, care has a biomedical orientation. Care has become technologized and bureaucratized, which reduces the time that is spent with the patient. In a context in which medical authority predominates, nursing's struggle for autonomy is based on the recognition of the value of care. When care becomes invisible, the autonomy of nursing as a profession is threatened. This conclusion allows reflections about shifts in the concept of care and how they affect clinical practice and the autonomy of the nursing profession.

Complement factor 5 (C5) p.A252T mutation is prevalent in, but not restricted to, sub-Saharan Africa: implications for the susceptibility to meningococcal disease.

Complement C5 deficiency (C5D) is a rare primary immunodeficiency associated with recurrent infections, particularly meningitis, by Neisseria species. To date, studies to elucidate the molecular basis of hereditary C5D have included fewer than 40 families, and most C5 mutations (13 of 17) have been found in single families. However, the recently described C5 p.A252T mutation is reported to be associated with approximately 7% of meningococcal disease cases in South Africa. This finding raises the question of whether the mutation may be prevalent in other parts of Africa or other continental regions. The aim of this study was to investigate the prevalence of C5 p.A252T in Africa and other regions and discuss the implications for prophylaxis against meningococcal disease. In total, 2710 samples from healthy donors within various populations worldwide were analysed by quantitative polymerase chain reaction (qPCR) assay to detect the C5 p.A252T mutation. Eleven samples were found to be heterozygous for p.A252T, and nine of these samples were from sub-Saharan African populations (allele frequency 0·94%). Interestingly, two other heterozygous samples were from individuals in populations outside Africa (Israel and Pakistan). These findings, together with data from genomic variation databases, indicate a 0·5-2% prevalence of the C5 p.A252T mutation in heterozygosity in sub-Saharan Africa. Therefore, this mutation may have a relevant role in meningococcal disease susceptibility in this geographical area.

Discursos de profesionales de la salud y de mujeres sobre el aborto voluntario / Discourses of health professionals and voluntary women about abortion

El presente artículo indaga los significados del aborto voluntario desde el discurso de los profesionales sanitarios involucrados en ello y de mujeres que han experimentado una interrupción voluntaria del embarazo. Se toma como referencia la ley aprobada en España en el año 2010 y el objetivo es conocer como los sujetos implicados en este proceso social y de salud resignifican la ley con sus propios discursos en función de sus parámetros culturales y su rol en dicho proceso. Surgen así nomenclaturas, adjetivos y condicionantes sociales variados a pesar de encontrarnos ante un proceso que parece estar unificado, consensuado y aceptado ante la legislación, la sociedad y el modelo médico hegemónico (AU)

This article examines the different meanings of voluntary abortion which are given not only by the health professionals but also by women who have been involved in this situation. In this way, the last law approved in Spain in 2010 is taken as a reference. The aim is to know how the subjects involved in this social and health process resignify the law via their own point of view related to their cultural parameters and their role in the abortion process. For instance, it seems to be unified and approved by consensus with the legislation, society and the hegemonic medical model. However, although this matter is involved in a standard process, this issue arises many nomenclatures, adjectives and varied social conditions (AU)

GHEP-ISFG proficiency test 2011: Paper challenge on evaluation of mitochondrial DNA results.

The GHEP-ISFG Working Group performed a collaborative exercise to monitor the current practice of mitochondrial (mt)DNA reporting. The participating laboratories were invited to evaluate a hypothetical case example and assess the statistical significance of a match between the haplotypes of a case (hair) sample and a suspect. A total of 31 forensic laboratories participated of which all but one used the EMPOP database. Nevertheless, we observed a tenfold range of reported LR values (32-333.4), which was mainly due to the selection of different reference datasets in EMPOP but also due to different applied formulae. The results suggest the need for more standardization as well as additional research to harmonize the reporting of mtDNA evidence.

2006 GEP-ISFG collaborative exercise on mtDNA: reflections about interpretation, artefacts, and DNA mixtures.

We report the results of the seventh edition of the GEP-ISFG mitochondrial DNA (mtDNA) collaborative exercise. The samples submitted to the participant laboratories were blood stains from a maternity case and simulated forensic samples, including a case of mixture. The success rate for the blood stains was moderate ( approximately 77%); even though four inexperienced laboratories concentrated about one-third of the total errors. A similar success was obtained for the analysis of mixed samples (78.8% for a hair-saliva mixture and 69.2% for a saliva-saliva mixture). Two laboratories also dissected the haplotypes contributing to the saliva-saliva mixture. Most of the errors were due to reading problems and misinterpretation of electropherograms, demonstrating once more that the lack of a solid devised experimental approach is the main cause of error in mtDNA testing.

Population structure in copy number variation and SNPs in the CCL4L chemokine gene.

The recent description of a large amount of copy number variation (CNV) in the human genome has extended the concept of genome diversity. In this study we integrate the analysis of CNV and single nucleotide polymorphisms (SNPs) in the human CCL4L chemokine gene. CCL4L is a nonallelic copy of CCL4/MIP-1beta chemokine and displays a CNV that also includes the CCL3L gene, a nonallelic copy of CCL3/MIP-1alpha. This CNV and two functionally relevant CCL4L SNPs (rs4796195 and rs3744595) have been recently associated to HIV pathology in three independent studies. We have quantified the CCL4L copy number and genotyped both SNPs in samples from HGDP-CEPH Diversity Panel. A strong correlation between CCL4L CNV and one of the SNPs analyzed is found, whereas no significant linkage disequilibrium is found between the two SNPs despite their close distance (647 bp), suggesting a recent appearance of the second SNP when the diversity in the first one and CNV had already been generated. The present study points out that in genes with CNV, it may be a key issue to combine the assessment of gene copy number with the genotyping of relevant SNPs to understand the phenotypic impact of genome variation in the immune response.

Family-based association study of neuregulin-1 gene and psychosis in a Spanish sample.

Neuregulin 1 (NRG1) is one of the most exciting candidate genes for schizophrenia since its first association with the disorder in an Icelandic population. Since then, many studies have analyzed allele and haplotype frequencies in European and Asian populations in cases and controls yielding varying results. We investigated the association of NRG1 with psychosis in a total sample set of 575 individuals from 151 Spanish nuclear families. We tested eight SNPs across 1.2 Mb along NRG1 including regions previously associated to schizophrenia in association studies. After correction for multiple testing, the TDT analysis for each marker did not show a significant over-transmission of alleles from the parents to the affected offspring for any of the markers (P > 0.05). The haplotypic analysis with TRANSMIT and PDT did not show preferential transmission for any of the haplotypes analyzed in our sample. These results do not seem to suggest that the investigated NRG1 markers play a role in schizophrenia in the Spanish population, although the finding of a trend for association with one SNP in the 3'of the gene warrants further investigation.

Paternal and maternal lineages in the Balkans show a homogeneous landscape over linguistic barriers, except for the isolated Aromuns.

The Balkan Peninsula is a complex cultural mosaic comprising populations speaking languages from several branches of the Indo-European family and Altaic, as well as culturally-defined minorities such as the Aromuns who speak a Romance language. The current cultural and linguistic landscape is a palimpsest in which different peoples have contributed their cultures in a historical succession. We have sought to find any evidence of genetic stratification related to those cultural layers by typing both mtDNA and Y chromosomes, in Albanians, Romanians, Macedonians, Greeks, and five Aromun populations. We have paid special attention to the Aromuns, and sought to test genetically various hypotheses on their origins. MtDNA and Y-chromosome haplogroup frequencies in the Balkans were found to be similar to those elsewhere in Europe. MtDNA sequences and Y-chromosome STR haplotypes revealed decreased variation in some Aromun populations. Variation within Aromun populations was the primary source of genetic differentiation. Y-chromosome haplotypes tended to be shared across Aromuns, but not across non-Aromun populations. These results point to a possible common origin of the Aromuns, with drift acting to differentiate the separate Aromun communities. The homogeneity of Balkan populations prevented testing for the origin of the Aromuns, although a significant Roman contribution can be ruled out.

Extreme population differences across Neuregulin 1 gene, with implications for association studies.

Neuregulin 1 (NRG1) is one of the most exciting candidate genes for schizophrenia in recent years since its first association with the disease in an Icelandic population. Since then, many association studies have analysed allele and haplotype frequencies in distinct populations yielding varying results: some have replicated the association, although with different alleles or haplotypes being associated, whereas others have failed to replicate the association. These contradictory results might be attributed to population differences in allele and haplotype frequencies. In order to approach this issue, we have typed 13 SNPs across this large 1.4 Mb gene, including two of the SNPs originally found associated with schizophrenia in the Icelandic population, the objective being to discover if the underlying cause of the association discrepancies to date may be due to population-specific genetic variation. The analyses have been performed in a total of 1088 individuals from 39 populations, covering most of the genetic diversity in the human species. Most of the SNPs analysed displayed differing frequencies according to geographical region. These allele differences are especially relevant in two SNPs located in a large intron of the gene, as shown by the extreme F(ST) values, which reveal genetic stratification correlated to broad continental areas. This finding may be indicative of the influence of some local selective forces on this gene. Furthermore, haplotype analysis reveals a clear clustering according to geographical areas. In summary, our findings suggest that NRG1 presents extreme population differences in allele and haplotype frequencies. We have given recommendations for taking this into account in future association studies since this diversity could give rise to erroneous results.

The genetics of the pre-Roman Iberian Peninsula: a mtDNA study of ancient Iberians.

The Iberians developed a surprisingly sophisticated culture in the Mediterranean coast of the Iberian Peninsula from the 6th century BC until their conquest by the Romans in the 2nd century BC. They spoke and wrote a non-Indo-European language that still cannot be understood; their origins and relationships with other non-Indo-European peoples, like the Etruscans, are unclear, since their funerary practices were based on the cremation of bodies, and therefore anthropology has been unable to approach the study of this people. We have retrieved mitochondrial DNA (mtDNA) from a few of the scarce skeletal remains that have been preserved, some of them belonging to ritualistically executed individuals. The most stringent authentication criteria proposed for ancient DNA, such as independent replication, amino-acid analysis, quantitation of template molecules, multiple extractions and cloning of PCR products, have been followed to obtain reliable sequences from the mtDNA hypervariable region 1 (HVR1), as well as some haplogroup diagnostic SNPs. Phylogeographic analyses show that the haplogroup composition of the ancient Iberians was very similar to that found in modern Iberian Peninsula populations, suggesting a long-term genetic continuity since pre-Roman times. Nonetheless, there is less genetic diversity in the ancient Iberians than is found among modern populations, a fact that could reflect the small population size at the origin of the population sampled, and the heterogenic tribal structure of the Iberian society. Moreover, the Iberians were not especially closely related to the Etruscans, which points to considerable genetic heterogeneity in Pre-Roman Western Europe.

Haplotype tagging efficiency in worldwide populations in CTLA4 gene.

The cytotoxic T lymphocyte antigen 4 (CTLA4) acts as a potent negative regulator of T-cell response, and has been suggested as a pivotal candidate gene for autoimmune disorders such as Graves' disease, type 1 diabetes and autoimmune hypothyroidism, among others. Several single-nucleotide polymorphisms (SNPs) have been proposed as the susceptibility variants, or to be in strong linkage disequilibrium (LD) with the variant. Nevertheless, contradictory results have been found, which may be due to lack of knowledge of the genetic structure of CTLA4 and its geographic variation. We have typed 17 SNPs throughout the CTLA4 gene region in order to analyze the haplotype diversity and LD structure in a worldwide population set (1262 individuals from 44 populations) to understand the variation pattern of the region. Allele and haplotype frequency differentiation between populations is consistent with genomewide averages and points to a lack of strong population-specific selection pressures. LD is high and its pattern is not significantly different within or between continents. However, haplotype composition is significantly different between geographical groups. A continent-specific set of haplotype tagging SNPs has been designed to be used for future association studies. These are portable among populations, although their efficiency might vary depending on the population haplotype spectrum.

Mitochondrial DNA heterogeneity in Tunisian Berbers.

Berbers live in groups scattered across North Africa whose origins and genetic relationships with their neighbours are not well established. The first hypervariable segment of the mitochondrial DNA (mtDNA) control region was sequenced in a total of 155 individuals from three Tunisian Berber groups and compared to other North Africans. The mtDNA lineages found belong to a common set of mtDNA haplogroups already described in North Africa. Besides the autochthonous North African U6 haplogroup, a group of L3 lineages characterized by the transition at position 16041 seems to be restricted to North Africans, suggesting that an expansion of this group of lineages took place around 10500 years ago in North Africa, and spread to neighbouring populations. Principal components and the coordinate analyses show that some Berber groups (the Tuareg, the Mozabite, and the Chenini-Douiret) are outliers within the North African genetic landscape. This outlier position is consistent with an isolation process followed by genetic drift in haplotype frequencies, and with the high heterogeneity displayed by Berbers compared to Arab samples as shown in the AMOVA. Despite this Berber heterogeneity, no significant differences were found between Berber and Arab samples, suggesting that the Arabization was mainly a cultural process rather than a demographic replacement.

Estudio comparativo de quinapril frente a la combinación de quinapril e hidroclorotiazida en el tratamiento de la hipertensión arterial ligera-moderada / Comparative study of quinapril versus quinapril/hydrochlorothiazide in the treatment of mild-to-moderate hypertension

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Alu insertion polymorphisms in the Balkans and the origins of the Aromuns.

We have analysed 11 human-specific Alu insertion polymorphisms in the Balkans to elucidate the origins of the Aromuns, a linguistic isolate inhabiting scattered areas in the Balkan Peninsula. Four Aromun samples (two from the Republic of Macedonia, one from Albania, and one from Romania) and five neighbouring populations (Macedonians, Albanians, Romanians, Greeks, and Turks) were analysed by means of genetic distances, principal components and analyses of the molecular variance (AMOVA). Three hypotheses were tested: Aromuns are Romanophonic Greeks; the result of a Romanian southward migration; or local descendants of the Thracians. The analyses show that the Aromuns do not constitute a homogeneous group separated from the rest of the Balkan populations. Grouping by language or geography does not explain the genetic differences observed in the region, suggesting a lack of genetic structure in the area. Aromuns do not seem to be particularly related to Greeks, Romanians, or to other Romance speakers. The Aromuns might have their origin to the south of the Danube river, with extensive gene flow with the neighbouring populations. The present results suggest a common ancestry of all Balkan populations, including Aromuns, with a lack of correlation between genetic differentiation and language or ethnicity, stressing that no major migration barriers have existed in the making of the complex Balkan human puzzle.

Joining the pillars of Hercules: mtDNA sequences show multidirectional gene flow in the western Mediterranean.

Phylogenetic analysis of mitochondrial DNA (mtDNA) performed in Western Mediterranean populations has shown that both shores share a common set of mtDNA haplogroups already found in Europe and the Middle East. Principal co-ordinates of genetic distances and principal components analyses based on the haplotype frequencies show that the main genetic difference is attributed to the higher frequency of sub-Saharan L haplogroups in NW Africa, showing some gene flow across the Sahara desert, with a major impact in the southern populations of NW Africa. The AMOVA demonstrates that SW European populations are highly homogeneous whereas NW African populations display a more heterogeneous genetic pattern, due to an east-west differentiation as a result of gene flow coming from the East. Despite the shared haplogroups found in both areas, the European V and the NW African U6 haplogroups reveal the traces of the Mediterranean Sea permeability to female migrations, and allowed for determination and quantification of the genetic contribution of both shores to the genetic landscape of the geographic area. Comparison of mtDNA data with autosomal markers and Y-chromosome lineages, analysed in the same populations, shows a congruent pattern, although female-mediated gene flow seems to have been more intense than male-mediated gene flow.