Molecular analysis of Sanfilippo syndrome type C in Spain: seven novel HGSNAT mutations and characterization of the mutant alleles

Canals I, Elalaoui SC, Pineda M, Delgadillo V, Szlago M, Jaouad IC, Sefiani A, Chabás A, Coll MJ, Grinberg D, Vilageliu L. Molecular analysis of Sanfilippo syndrome type C in Spain: seven novel HGSNAT mutations and characterization of the mutant alleles. The Sanfilippo syndrome type C [mucopolysaccharidosis IIIC (MPS IIIC)] is caused by mutations in the HGSNAT gene, encoding an enzyme involved in heparan sulphate degradation. We report the first molecular study on several Spanish Sanfilippo syndrome type C patients. Seven Spanish patients, one Argentinean and three Moroccan patients were analysed. All mutant alleles were identified and comprised nine distinct mutant alleles, seven of which were novel, including four missense mutations (p.A54V, p.L113P, p.G424V and p.L445P) and three splicing mutations due to two point mutations (c.633+1G>A and c.1378‐1G>A) and an intronic deletion (c.821‐31_821‐13del). Furthermore, we found a new single nucleotide polymorphism (SNP) (c.564‐98T>C). The two most frequent changes were the previously described c.372‐2A>G and c.234+1G>A mutations. All five splicing mutations were experimentally confirmed by studies at the RNA level, and a minigene experiment was carried out in one case for which no fibroblasts were available. Expression assays allowed us to show the pathogenic effect of the four novel missense mutations and to confirm that the already known c.710C>A (p.P237Q) is a non‐pathogenic SNP. Haplotype analyses suggested that the two mutations (c.234+1G>A and c.372‐2A>G) that were present in more than one patient have a common origin, including one (c.234+1G>A) that was found in Spanish and Moroccan patients.     

Comprehensive long-span paired-end-tag mapping reveals characteristic patterns of structural variations in epithelial cancer genomes

Somatic genome rearrangements are thought to play important roles in cancer development. We optimized a long-span paired-end-tag (PET) sequencing approach using 10-Kb genomic DNA inserts to study human genome structural variations (SVs). The use of a 10-Kb insert size allows the identification of breakpoints within repetitive or homology-containing regions of a few kilobases in size and results in a higher physical coverage compared with small insert libraries with the same sequencing effort. We have applied this approach to comprehensively characterize the SVs of 15 cancer and two noncancer genomes and used a filtering approach to strongly enrich for somatic SVs in the cancer genomes. Our analyses revealed that most inversions, deletions, and insertions are germ-line SVs, whereas tandem duplications, unpaired inversions, interchromosomal translocations, and complex rearrangements are over-represented among somatic rearrangements in cancer genomes. We demonstrate that the quantitative and connective nature of DNA-PET data is precise in delineating the genealogy of complex rearrangement events, we observe signatures that are compatible with breakage-fusion-bridge cycles, and we discover that large duplications are among the initial rearrangements that trigger genome instability for extensive amplification in epithelial cancers.     

初次诊断为慢性阻塞性肺疾病患者吸入激素治疗和发生肺炎危险性的关系

目前大多数COPD患者在接受吸入激素(ICS)治疗,但与支气管哮喘患者不同,ICS在COPD治疗中的地位尚不明确.临床研究结果显示,ICS可减少COPD患者急性加重的发作次数,但同时可增加患者肺炎的发生率.一项关于COPD患者健康调查的研究结果显示,单独吸入氟替卡松的COPD患者肺炎的发生率为18.3%,吸入氟替卡松/沙美特罗患者的肺炎发生率为19.6%,均明显高于安慰剂组(12.3%).     

VIIIth International Workshop on Radiation Damage to DNA

Summary

RNA synthesis was investigated after irradiation in resistant and sensitive lines of the slime-mould Dictyostelium Discoideum. When ³H adenine was used as a precursor to RNA, incorporation increased after irradiation in the resistant WT line but not in the sensitive line (γs-13). The extent of RNA synthesis after irradiation was correlated with the shoulder width on the survival curve of the resistant line. When this was reduced by irradiating with neutrons, or treatment with caffeine RNA synthesis was also reduced. No preferential synthesis of one RNA species occurred; there was increased labelling in all RNA species after irradiation. Sucrose gradient analysis of ribosomal RNA extracted from irradiated cells and free of messenger RNA revealed no apparent difference in composition from that extracted from unirradiated cells. Increased RNA synthesis after irradiation may form part of the recovery process in the resistant cells.     

Enhanced depth imaging of the choroid in patients with neovascular age-related macular degeneration treated with anti-VEGF therapy versus untreated patients

Purpose

To compare the subfoveal choroidal thickness (SFCT) between patients with neovascular age-related macular degeneration (nAMD) who had multiple intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) agents and those with treatment-naïve nAMD.

Methods

This retrospective case–control study included 15 patients in group 1 (nAMD in one eye which had received at least three anti-VEGF injections and early AMD in the fellow eye) and 15 patients in group 2 (newly diagnosed nAMD in one eye which had not received any treatment and early AMD in the fellow eye). They underwent enhanced depth imaging optical coherence tomography (OCT), and two OCT readers manually measured the SFCT. Inter-ocular difference in SFCT (nAMD eye minus fellow eye) was calculated for each patient.

Results

The nAMD eyes in group 1 had received a median (range) of four (3–8) intravitreal injections of anti-VEGF agents, and the OCT scans were performed at a median (range) of 9 (4–17) months after the first injection. The median inter-ocular difference in SFCT in groups 1 and 2 were not significantly different (13.5 and 3.0 μm in groups 1 and 2 respectively, p?=?0.60). There was also no statistically significant difference in SFCT between nAMD and fellow eyes (p?=?0.16), although there was a trend for greater median SFCT in the nAMD eyes.

Conclusion

The data from this small cohort suggests that no gross reduction in SFCT appears in nAMD patients after a time interval of at least 4 months between initiating repeated treatment with anti-VEGF therapy and OCT imaging. However, a study with a much larger sample size or longitudinal design is required to detect possible small fluctuations in SFCT in nAMD eyes receiving anti-VEGF therapy.     

The risk of fracture in patients with multiple sclerosis: The UK general practice research

Patients with multiple sclerosis (MS) may be at an increased risk of fracture owing to a greater risk of falling and decreased bone mineral density when compared with the general population. This study was designed to estimate the relative and absolute risk of fracture in patients with MS. We conducted a population‐based cohort study using data from the UK General Practice Research Database linked to the National Hospital Registry (1997–2008). Incident MS patients (n = 5565) were matched 1:6 by year of birth, sex, and practice with patients without MS (controls). Cox proportional‐hazards models were used to derive adjusted hazard ratios (HRs) for fracture associated with MS. Time‐dependent adjustments were made for age, comorbidity, and drug use. Absolute 5‐ and 10‐year risks of fracture were estimated for MS patients as a function of age. Compared with controls, MS patients had an almost threefold increased risk of hip fracture [HR = 2.79, 95% confidence interval (CI) 1.83–4.26] and a risk of osteoporotic fracture that was increased 1.4‐fold (HR = 1.35, 95% CI 1.13–1.62). Risk was greater in patients who had been prescribed oral/intravenous glucocorticoids (GCs; HR = 1.85, 95% CI 1.14–2.98) or antidepressants (HR = 1.79, 95% CI 1.37–2.35) in the previous 6 months. Absolute fracture risks were low in younger MS patients but became substantial when patients were older than 60 years of age. It is concluded that MS is associated with an increased risk of fracture. Fracture risk assessment may be indicated in patients with MS, especially those prescribed GCs or antidepressants. © 2011 American Society for Bone and Mineral Research     

健康档案银行的一个概念模型

阐明了健康档案银行（Health Record Banking,HRB）系统功能与商业银行系统之间的异同,强调了健康档案银行只存储特定类型的数据（如基因数据）或只维护特定的帐户类型（如个体医师或团体从业者帐户）;允许消费者在安全的虚拟帐户（即电子个人健康档案）中存储所有个人保健信息,档案为消费者掌握和控制,消费者可以在健康档案帐户中向不同的保健提供者和数据源授以不同的存取权限。阐述了HRB系统的实现方法、健康档案加工、存储使用规范等。     

Interferon-gamma exacerbates liver damage, the hepatic progenitor cell response and fibrosis in a mouse model of chronic liver injury

BACKGROUND/AIMS: Several previous studies have suggested that interferon gamma (IFNgamma) may play a key role during hepatic progenitor cell (HPC) mediated liver regeneration. However to date, no studies have directly tested the ability of IFNgamma to mediate the HPC response in an in vivo model. METHODS/RESULTS: Administration of IFNgamma to mice receiving a choline deficient, ethionine (CDE) supplemented diet to induce chronic injury resulted in an augmented HPC response. This was accompanied by increased inflammation, altered cytokine expression and hepatic fibrosis. Serum alanine aminotransferase activity, hepatocyte apoptosis and Bak staining were significantly increased in IFNgamma-treated, CDE-fed mice, demonstrating that liver damage was exacerbated in these animals. Administration of IFNgamma to control diet fed mice did not induce liver damage, however it did stimulate hepatic inflammation. CONCLUSIONS: Our results suggest that IFNgamma increases the HPC response to injury by stimulating hepatic inflammation and aggravating liver damage. This is accompanied by an increase in hepatic fibrogenesis, supporting previous reports which suggest that the HPC response may drive fibrogenesis during chronic liver injury.