This epic history compares the empires built by Spain and Britain in the Americas, from Columbus's arrival in the New World to the end of Spanish colonial rule in the early nineteenth century. J. H. ...Elliott, one of the most distinguished and versatile historians working today, offers us history on a grand scale, contrasting the worlds built by Britain and by Spain on the ruins of the civilizations they encountered and destroyed in North and South America.Elliott identifies and explains both the similarities and differences in the two empires' processes of colonization, the character of their colonial societies, their distinctive styles of imperial government, and the independence movements mounted against them. Based on wide reading in the history of the two great Atlantic civilizations, the book sets the Spanish and British colonial empires in the context of their own times and offers us insights into aspects of this dual history that still influence the Americas.
Genetics and Genomics of Pulmonary Arterial Hypertension Soubrier, Florent, MD, PhD; Chung, Wendy K., MD, PhD; Machado, Rajiv, PhD ...
Journal of the American College of Cardiology,
12/2013, Letnik:
62, Številka:
25
Journal Article, Conference Proceeding
Recenzirano
Odprti dostop
Major discoveries have been obtained within the last decade in the field of hereditary predisposition to pulmonary arterial hypertension (PAH). Among them, the identification of bone morphogenetic ...protein receptor type 2 ( BMPR2 ) as the major predisposing gene and activin A receptor type II-like kinase-1 ( ACVRL1 , also known as ALK1 ) as the major gene when PAH is associated with hereditary hemorrhagic telangiectasia. The mutation detection rate for the known genes is approximately 75% in familial PAH, but the mutation shortfall remains unexplained even after careful molecular investigation of these genes. To identify additional genetic variants predisposing to PAH, investigators harnessed the power of next-generation sequencing to successfully identify additional genes that will be described in this report. Furthermore, common genetic predisposing factors for PAH can be identified by genome-wide association studies and are detailed in this paper. The careful study of families and routine genetic diagnosis facilitated natural history studies based on large registries of PAH patients to be set up in different countries. These longitudinal or cross-sectional studies permitted the clinical characterization of PAH in mutation carriers to be accurately described. The availability of molecular genetic diagnosis has opened up a new field for patient care, including genetic counseling for a severe disease, taking into account that the major predisposing gene has a highly variable penetrance between families. Molecular information can be drawn from the genomic study of affected tissues in PAH, in particular, pulmonary vascular tissues and cells, to gain insight into the mechanisms leading to the development of the disease. High-throughput genomic techniques, on the basis of next-generation sequencing, now allow the accurate quantification and analysis of ribonucleic acid, species, including micro-ribonucleic acids, and allow for a genome-wide investigation of epigenetic or regulatory mechanisms, which include deoxyribonucleic acid methylation, histone methylation, and acetylation, or transcription factor binding.
Genetics and Genomics of Pulmonary Arterial Hypertension Machado, Rajiv D., PhD; Eickelberg, Oliver, MD; Elliott, C. Gregory, MD ...
Journal of the American College of Cardiology,
06/2009, Letnik:
54, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Pulmonary arterial hypertension (PAH) is a rare disorder that may be hereditable (HPAH), idiopathic (IPAH), or associated with either drug-toxin exposures or other medical conditions. Familial cases ...have long been recognized and are usually due to mutations in the bone morphogenetic protein receptor type 2 gene ( BMPR2 ), or, much less commonly, 2 other members of the transforming growth factor-β superfamily, activin-like kinase-type 1 ( ALK1 ) and endoglin ( ENG ), which are associated with hereditary hemorrhagic telangiectasia. In addition, approximately 20% of patients with IPAH carry mutations in BMPR2 . We provide a summary of BMPR2 mutations associated with HPAH, most of which are unique to each family and are presumed to result in loss of function. We review the finding of missense variants and variants of unknown significance in BMPR2 in IPAH/HPAH, fenfluramine exposure, and PAH associated with congenital heart disease. Clinical testing for BMPR2 mutations is available and may be offered to HPAH and IPAH patients but should be preceded by genetic counseling, since lifetime penetrance is only 10% to 20%, and there are currently no known effective preventative measures. Identification of a familial mutation can be valuable in reproductive planning and identifying family members who are not mutation carriers and thus will not require lifelong surveillance. With advances in genomic technology and with international collaborative efforts, genome-wide association studies will be conducted to identify additional genes for HPAH, genetic modifiers for BMPR2 penetrance and genetic susceptibility to IPAH. In addition, collaborative studies of BMPR2 mutation carriers should enable identification of environmental modifiers, biomarkers for disease development and progression, and surrogate markers for efficacy end points in clinical drug development, thereby providing an invaluable resource for trials of PAH prevention.
Abstract
We present high-resolution speckle interferometric imaging observations of TESS exoplanet host stars using the NN-EXPLORE Exoplanet and Stellar Speckle Imager instrument at the 3.5 m WIYN ...telescope. Eight TESS objects of interest that were originally discovered by Kepler were previously observed using the Differential Speckle Survey Instrument. Speckle observations of 186 TESS stars were carried out, and 45 (24%) likely bound companions were detected. This is approximately the number of companions we would expect to observe given the established 46% binarity rate in exoplanet host stars. For the detected binaries, the distribution of stellar mass ratio is consistent with that of the standard Raghavan distribution and may show a decrease in high-
q
systems as the binary separation increases. The distribution of binary orbital periods, however, is not consistent with the standard Ragahavan model, and our observations support the premise that exoplanet-hosting stars with binary companions have, in general, wider orbital separations than field binaries. We find that exoplanet-hosting binary star systems show a distribution peaking near 100 au, higher than the 40–50 au peak that is observed for field binaries. This fact led to earlier suggestions that planet formation is suppressed in close binaries.
ABSTRACT
Pulmonary arterial hypertension (PAH) is an often fatal disorder resulting from several causes including heterogeneous genetic defects. While mutations in the bone morphogenetic protein ...receptor type II (BMPR2) gene are the single most common causal factor for hereditary cases, pathogenic mutations have been observed in approximately 25% of idiopathic PAH patients without a prior family history of disease. Additional defects of the transforming growth factor beta pathway have been implicated in disease pathogenesis. Specifically, studies have confirmed activin A receptor type II‐like 1 (ACVRL1), endoglin (ENG), and members of the SMAD family as contributing to PAH both with and without associated clinical phenotypes. Most recently, next‐generation sequencing has identified novel, rare genetic variation implicated in the PAH disease spectrum. Of importance, several identified genetic factors converge on related pathways and provide significant insight into the development, maintenance, and pathogenetic transformation of the pulmonary vascular bed. Together, these analyses represent the largest comprehensive compilation of BMPR2 and associated genetic risk factors for PAH, comprising known and novel variation. Additionally, with the inclusion of an allelic series of locus‐specific variation in BMPR2, these data provide a key resource in data interpretation and development of contemporary therapeutic and diagnostic tools.
Pulmonary arterial hypertension is an often fatal vascular disorder.
The figure illustrates the key pathways implicated in disease pathogenesis, both convergent and distinct. Key elements harbouring deleterious mutations are indicated by asterisks. This report is the first of its kind to provide a comprehensive record of all identified mutations in causal genes including novel variation.
Major discoveries have been obtained within the last decade in the field of hereditary predisposition to pulmonary arterial hypertension (PAH). Among them, the identification of bone morphogenetic ...protein receptor type 2 (BMPR2) as the major predisposing gene and activin A receptor type II-like kinase-1 (ACVRL1, also known as ALK1) as the major gene when PAH is associated with hereditary hemorrhagic telangiectasia. The mutation detection rate for the known genes is approximately 75% in familial PAH, but the mutation shortfall remains unexplained even after careful molecular investigation of these genes. To identify additional genetic variants predisposing to PAH, investigators harnessed the power of next-generation sequencing to successfully identify additional genes that will be described in this report. Furthermore; common genetic predisposing factors for PAH can be identified by genome-wide association studies and are detailed in this paper. The careful study of families and routine genetic diagnosis facilitated natural-history studies based on large registries of PAH patients to be set up in different countries. These longitudinal or cross-sectional studies permitted the clinical characterization of PAH in mutation carriers to be accurately described. The availability of molecular genetic diagnosis has opened up a new field for patient care, including genetic counseling for a severe disease, taking into account that the major predisposing gene has a highly variable penetrance between families. Molecular information can be drawn from the genomic study of affected tissues in PAH, in particular, pulmonary vascular tissues and cells, to gain insight into the mechanisms leading to the development of the disease. High-throughput genomic techniques, on the basis of next-generation sequencing, now allow the accurate quantification and analysis of ribonucleic acid, species, including micro-ribonucleic acids, and allow for a genome-wide investigation of epigenetic or regulatory mechanisms, which include deoxyribonucleic acid methylation, histone methylation, and acetylation, or transcription factor binding. (J Am Coll Cardiol 2013;62:D13-21) a 2013 by the American College of Cardiology Foundation.
The extracellular matrix (ECM) plays a crucial role in all parts of the eye, from maintaining clarity and hydration of the cornea and vitreous to regulating angiogenesis, intraocular pressure ...maintenance, and vascular signaling. This review focuses on the interactions of the ECM for homeostasis of normal physiologic functions of the cornea, vitreous, retina, retinal pigment epithelium, Bruch's membrane, and choroid as well as trabecular meshwork, optic nerve, conjunctiva and tenon's layer as it relates to glaucoma. A variety of pathways and key factors related to ECM in the eye are discussed, including but not limited to those related to transforming growth factor-β, vascular endothelial growth factor, basic-fibroblastic growth factor, connective tissue growth factor, matrix metalloproteinases (including MMP-2 and MMP-9, and MMP-14), collagen IV, fibronectin, elastin, canonical signaling, integrins, and endothelial morphogenesis consistent of cellular activation-tubulogenesis and cellular differentiation-stabilization. Alterations contributing to disease states such as wound healing, diabetes-related complications, Fuchs endothelial corneal dystrophy, angiogenesis, fibrosis, age-related macular degeneration, retinal detachment, and posteriorly inserted vitreous base are also reviewed.
Aims/hypothesis
While the risk factors for diabetic peripheral neuropathy (DPN) are now well recognised, the risk factors for painful DPN remain unknown. We performed analysis of the EURODIAB ...Prospective Complications Study data to elucidate the incidence and risk factors of painful DPN.
Methods
The EURODIAB Prospective Complications Study recruited 3250 participants with type 1 diabetes who were followed up for 7.3±0.6 (mean ± SD) years. To evaluate DPN, a standardised protocol was used, including clinical assessment, quantitative sensory testing and autonomic function tests. Painful DPN (defined as painful neuropathic symptoms in the legs in participants with confirmed DPN) was assessed at baseline and follow-up.
Results
At baseline, 234 (25.2%) out of 927 participants with DPN had painful DPN. At follow-up, incident DPN developed in 276 (23.5%) of 1172 participants. Of these, 41 (14.9%) had incident painful DPN. Most of the participants who developed incident painful DPN were female (73% vs 48% painless DPN
p
=0.003) and this remained significant after adjustment for duration of diabetes and HbA
1c
(OR 2.69 95% CI 1.41, 6.23,
p
=0.004). The proportion of participants with macro- or microalbuminuria was lower in those with painful DPN compared with painless DPN (15% vs 34%,
p
=0.02), and this association remained after adjusting for HbA
1c
, diabetes duration and sex (
p
=0.03).
Conclusions/interpretation
In this first prospective study to investigate the risk factors for painful DPN, we definitively demonstrate that female sex is a risk factor for painful DPN. Additionally, there is less evidence of diabetic nephropathy in incident painful, compared with painless, DPN. Thus, painful DPN is not driven by cardiometabolic factors traditionally associated with microvascular disease. Sex differences may therefore play an important role in the pathophysiology of neuropathic pain in diabetes. Future studies need to look at psychosocial, genetic and other factors in the development of painful DPN.
Graphical Abstract
When J. H. Elliott publishedSpain and Its World, 1500-1700some twenty years ago, one of many enthusiasts declared, "For anyone interested in the history of empire, of Europe and of Spain, here is a ...book to keep within reach, to read, to study and to enjoy" (Times Literary Supplement). Since then Elliott has continued to explore the history of Spain and the Hispanic world with originality and insight, producing some of the most influential work in the field. In this new volume he gathers writings that reflect his recent research and thinking on politics, art, culture, and ideas in Europe and the colonial worlds between 1500 and 1800.
The volume includes fourteen essays, lectures, and articles of remarkable breadth and freshness, written with Elliott's characteristic brio. It includes an unpublished lecture in honor of the late Hugh Trevor-Roper. Organized around three themes-early modern Europe, European overseas expansion, and the works and historical context of El Greco, Velázquez, Rubens, and Van Dyck-the book offers a rich survey of the themes at the heart of Elliott's interests throughout a career distinguished by excellence and innovation.
PDF
