Abstract Despite its crucial role in the health of both the fetus and the pregnant woman, the placenta is the least understood human organ. Since a growing body of evidence also underscores the ...importance of placental development in the lifelong health of both mother and offspring, this lack of knowledge about placental structure and function is particularly concerning. Given modern approaches and technologies and the ability to develop new methods, we propose a coordinated “Human Placenta Project”, with the ultimate goal of understanding human placental structure, development, and function in real time.
The completion of a high-quality, comprehensive sequence of the human genome, in this fiftieth anniversary year of the discovery of the double-helical structure of DNA, is a landmark event. The ...genomic era is now a reality.
Welcome to the genomic era Guttmacher, Alan E; Collins, Francis S
New England journal of medicine/The New England journal of medicine,
09/2003, Letnik:
349, Številka:
10
Journal Article
HHT is an autosomal dominant disease with an estimated prevalence of at least 1/5000 which can frequently be complicated by the presence of clinically significant arteriovenous malformations in the ...brain, lung, gastrointestinal tract and liver. HHT is under-diagnosed and families may be unaware of the available screening and treatment, leading to unnecessary stroke and life-threatening hemorrhage in children and adults.
The goal of this international HHT guidelines process was to develop evidence-informed consensus guidelines regarding the diagnosis of HHT and the prevention of HHT-related complications and treatment of symptomatic disease.
The overall guidelines process was developed using the AGREE framework, using a systematic search strategy and literature retrieval with incorporation of expert evidence in a structured consensus process where published literature was lacking. The Guidelines Working Group included experts (clinical and genetic) from eleven countries, in all aspects of HHT, guidelines methodologists, health care workers, health care administrators, HHT clinic staff, medical trainees, patient advocacy representatives and patients with HHT. The Working Group determined clinically relevant questions during the pre-conference process. The literature search was conducted using the OVID MEDLINE database, from 1966 to October 2006. The Working Group subsequently convened at the Guidelines Conference to partake in a structured consensus process using the evidence tables generated from the systematic searches.
The outcome of the conference was the generation of 33 recommendations for the diagnosis and management of HHT, with at least 80% agreement amongst the expert panel for 30 of the 33 recommendations.
Abstract Introduction Cardiac phenotypes should be pronounced in hereditary hemorrhagic telangiectasia (HHT) due to frequent systemic arteriovenous malformations (AVMs), iron deficiency anemia, ...hypoxemia, hyperdynamic circulations, venous thromboemboli, and paradoxical emboli through pulmonary AVMs. Methods/results In an international survey, 1025 respondents (median age 55 years) met HHT diagnostic criteria: 942 (91.9%) reported nosebleeds, 452 (44.1%) at least daily. AVMs were commonly reported in pulmonary (544, 53%), hepatic (194, 18.9%) and/or cerebral (92, 9.0%) circulations. 770/1025 (75%) had used iron tablets, 256 (25.0%) intravenous iron, and 374 (36.5%) received blood transfusions. Arrhythmias were reported by 113/1025 (11%, including 44 (4.3%) with atrial fibrillation), angina by 36 (3.5%), and cardiac failure by 26 (2.5%). In multivariate logistic regression, these phenotypes were associated with hepatic AVMs/pulmonary hypertension (relatively interchangeable variables), blood transfusions, and intravenous iron. Cardiac insufficiency/failure often provokes intensive anemia treatments, but associations with arrhythmias, particularly with a greater transfusion burden, were less easy to explain. Myocardial infarction (23/1025; 2.2%), and abnormal coronary angiogram (≤ 31/76, ≤ 54%) rates appeared low. Provocative preliminary data were obtained including HHT-affected respondents' parents and grandparents in whom HHT could be confidently assigned, or excluded based on autosomal dominant inheritance patterns: in crude and survival analyses, myocardial infarctions were reported less frequently for individuals with HHT, particularly for males (p = 0.001). Conclusion Arrhythmias are the most common cardiac phenotype in HHT, and likely to be aggravated by iron deficiency anemia, its treatments, and/or high output states due to AVMs. Myocardial infarction rates may be reduced in this apparently high risk population.
The family history--more important than ever Guttmacher, Alan E; Collins, Francis S; Carmona, Richard H
New England journal of medicine/The New England journal of medicine,
2004-Nov-25, Letnik:
351, Številka:
22
Journal Article
Genomic medicine--a primer Guttmacher, Alan E; Collins, Francis S
New England journal of medicine/The New England journal of medicine,
11/2002, Letnik:
347, Številka:
19
Journal Article
Hereditary haemorrhagic telangiectasia, or Osler-Rendu-Weber (ORW) syndrome, is an autosomal dominant vascular dysplasia. So far, two loci have been demonstrated for ORW. Linkage studies established ...an ORW locus at chromosome 9q3; endoglin was subsequently identified as the ORW1 gene. A second locus, designated ORW2, was mapped to chromosome 12. Here we report a new 4 cM interval for ORW2 that does not overlap with any previously defined. A 1.38-Mb YAC contig spans the entire interval. It includes the activin receptor like kinase 1 gene (ACVRLK1 or ALK1), a member of the serine-threonine kinase receptor family expressed in endothelium. We report three mutations in the coding sequence of the ALK1 gene in those families which show linkage of the ORW phenotype to chromosome 12. Our data suggest a critical role for ALK1 in the control of blood vessel development or repair.
Hereditary hemorrhagic telangiectasia Guttmacher, A E; Marchuk, D A; White, Jr, R I
The New England journal of medicine,
10/1995, Letnik:
333, Številka:
14
Journal Article
The underlying basis of many forms of syndromic craniosynostosis has been defined on a molecular level. However, many patients with familial or sporadic craniosynostosis do not have the classical ...findings of those craniosynostosis syndromes. Here we present 61 individuals from 20 unrelated families where coronal synostosis is due to an amino acid substitution (Pro250Arg) that results from a single point mutation in the fibroblast growth factor receptor 3 gene on chromosome 4p. In this instance, a new clinical syndrome is being defined on the basis of the molecular finding. In addition to the skull findings, some patients had abnormalities on radiographs of hands and feet, including thimble-like middle phalanges, coned epiphyses, and carpal and tarsal fusions. Brachydactyly was seen in some cases; none had clinically significant syndactyly or deviation of the great toe. Sensorineural hearing loss was present in some, and developmental delay was seen in a minority. While the radiological findings of hands and feet can be very helpful in diagnosing this syndrome, it is not in all cases clearly distinguishable on a clinical basis from other craniosynostosis syndromes. Therefore, this mutation should be tested for in patients with coronal synostosis.
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