Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Chemical vapor deposition of GaP and GaAs thin films from [ⁿBu₂Ga(µ-E^tBu₂)₂GaⁿBu₂] (E= P or As) and Ga(PtBu₂)₃

Low pressure chemical vapor deposition (LPCVD) using the single-source precursors [nBu2Ga(µ-EtBu2)2GanBu2] (E = P or As) in the temperature range 723–823 K (0.05 mmHg), gives shiny yellow or silvery gray films of GaP and GaAs, respectively, on silica. The composition and morphology of the deposited materials have been probed via X-ray diffraction (XRD), scanning electron microscopy/energy-dispersive X-ray (SEM/EDX), X-ray photoelectron spectroscopy (XPS), atomic force microscopy (AFM), and Raman spectroscopy, revealing crystalline (cubic) GaE with 1:1 Ga/E ratios. The GaP forms nanorods growing perpendicular to the substrate surface and is rougher than the GaAs, which appears to form smaller, densely packed microcrystallites. While the GaAs films produced in this way did not exhibit any significant luminescence, the reflective GaP films obtained by LPCVD were of good electronic quality, revealing photoluminescence comparable to that of a single crystalline GaP reference. LPCVD using Ga(PtBu2)3 gives GaP, although this appears to be an inferior reagent compared to the dimer. Unlike the corresponding [nBu2In(µ-EtBu2)2InnBu2] dimers (see Aksomaityte et al., Chem. Mater.2010, 22, 4246) which gave InE films and nanowires from supercritical chemical fluid deposition in sc-CO2/hexane, under the same conditions (773 K, 12 MPa), the gallium dimer precursors mostly failed to give GaE. Instead significant carbon deposition occurred, indicating solvent degradation

Strong and specific associations between cardiovascular risk factors and white matter micro- and macrostructure in healthy aging

Cardiovascular health declines with age, increasing the risk of hypertension and elevated heart rate in middle and old age. Here, we used multivariate techniques to investigate the associations between cardiovascular health (diastolic blood pressure, systolic blood pressure, and heart rate) and white matter macrostructure (lesion volume and number) and microstructure (as measured by diffusion-weighted imaging) in the cross-sectional, population-based Cam-CAN cohort (N = 667, aged 18–88). We found that cardiovascular health and age made approximately similar contributions to white matter health and explained up to 56% of variance therein. Lower diastolic blood pressure, higher systolic blood pressure, and higher heart rate were each strongly, and independently, associated with white matter abnormalities on all indices. Body mass and exercise were associated with white matter health, both directly and indirectly via cardiovascular health. These results highlight the importance of cardiovascular risk factors for white matter health across the adult lifespan and suggest that systolic blood pressure, diastolic blood pressure, and heart rate affect white matter health via separate mechanisms