Surgical treatment of aortobronchial fistula after thoracic endograft failure

Endovascular stent grafting has been recently considered as a less invasive alternative to either medical therapy or open surgical treatment for many patients with descending thoracic aortic disease. Late complications are rarely described in literature. Herein, we described the occurrence of an aorto-bronchial fistula and a retro-A dissection in a 73-year-old man after stent-grafting for a penetrating atherosclerotic ulcer (PAU) of the descending thoracic aorta and the successful surgical technique adopted in order to remove the stent-graft

Development of a Single Vector System that Enhances Trans-Splicing of SMN2 Transcripts

RNA modalities are developing as a powerful means to re-direct pathogenic pre-mRNA splicing events. Improving the efficiency of these molecules in vivo is critical as they move towards clinical applications. Spinal muscular atrophy (SMA) is caused by loss of SMN1. A nearly identical copy gene called SMN2 produces low levels of functional protein due to alternative splicing. We previously reported a trans-splicing RNA (tsRNA) that re-directed SMN2 splicing. Now we show that reducing the competition between endogenous splices sites enhanced the efficiency of trans-splicing. A single vector system was developed that expressed the SMN tsRNA and a splice-site blocking antisense (ASO-tsRNA). The ASO-tsRNA vector significantly elevated SMN levels in primary SMA patient fibroblasts, within the central nervous system of SMA mice and increased SMN-dependent in vitro snRNP assembly. These results demonstrate that the ASO-tsRNA strategy provides insight into the trans-splicing mechanism and a means of significantly enhancing trans-splicing activity in vivo

Exon Exchange Approach to Repair Duchenne Dystrophin Transcripts

Background: Trans-splicing strategies for mRNA repair involve engineered transcripts designed to anneal target mRNAs in order to interfere with their natural splicing, giving rise to mRNA chimeras where endogenous mutated exons have been replaced by exogenous replacement sequences. A number of trans-splicing molecules have already been proposed for replacing either the 59 or the 39 part of transcripts to be repaired. Here, we show the feasibility of RNA surgery by using a double trans-splicing approach allowing the specific substitution of a given mutated exon. Methodology/Principal Findings: As a target we used a minigene encoding a fragment of the mdx dystrophin gene enclosing the mutated exon (exon 23). This minigene was cotransfected with a variety of exon exchange constructions, differing in their annealing domains. We obtained accurate and efficient replacement of exon 23 in the mRNA target. Adding up a downstream intronic splice enhancer DISE in the exon exchange molecule enhanced drastically its efficiency up to 25–45 % of repair depending on the construction in use. Conclusions/Significance: These results demonstrate the possibility to fix up mutated exons, refurbish deleted exons and introduce protein motifs, while keeping natural untranslated sequences, which are essential for mRNA stability and translation regulation. Conversely to the well-known exon skipping, exon exchange has the advantage to be compatible with almost any type of mutations and more generally to a wide range of genetic conditions. In particular, it allows addressing disorders caused by dominant mutations

Gene Expression Signature in Peripheral Blood Detects Thoracic Aortic Aneurysm

BACKGROUND: Thoracic aortic aneurysm (TAA) is usually asymptomatic and associated with high mortality. Adverse clinical outcome of TAA is preventable by elective surgical repair; however, identifying at-risk individuals is difficult. We hypothesized that gene expression patterns in peripheral blood cells may correlate with TAA disease status. Our goal was to identify a distinct gene expression signature in peripheral blood that may identify individuals at risk for TAA. METHODS AND FINDINGS: Whole genome gene expression profiles from 94 peripheral blood samples (collected from 58 individuals with TAA and 36 controls) were analyzed. Significance Analysis of Microarray (SAM) identified potential signature genes characterizing TAA vs. normal, ascending vs. descending TAA, and sporadic vs. familial TAA. Using a training set containing 36 TAA patients and 25 controls, a 41-gene classification model was constructed for detecting TAA status and an overall accuracy of 78+/-6% was achieved. Testing this classifier on an independent validation set containing 22 TAA samples and 11 controls yielded an overall classification accuracy of 78%. These 41 classifier genes were further validated by TaqMan real-time PCR assays. Classification based on the TaqMan data replicated the microarray results and achieved 80% classification accuracy on the testing set. CONCLUSIONS: This study identified informative gene expression signatures in peripheral blood cells that can characterize TAA status and subtypes of TAA. Moreover, a 41-gene classifier based on expression signature can identify TAA patients with high accuracy. The transcriptional programs in peripheral blood leading to the identification of these markers also provide insights into the mechanism of development of aortic aneurysms and highlight potential targets for therapeutic intervention. The classifier genes identified in this study, and validated by TaqMan real-time PCR, define a set of promising potential diagnostic markers, setting the stage for a blood-based gene expression test to facilitate early detection of TAA

Mechanical behaviour and rupture of normal and pathological human ascending aortic wall

The mechanical properties of aortic wall, both healthy and pathological, are needed in order to develop and improve diagnostic and interventional criteria, and for the development of mechanical models to assess arterial integrity. This study focuses on the mechanical behaviour and rupture conditions of the human ascending aorta and its relationship with age and pathologies. Fresh ascending aortic specimens harvested from 23 healthy donors, 12 patients with bicuspid aortic valve (BAV) and 14 with aneurysm were tensile-tested in vitro under physiological conditions. Tensile strength, stretch at failure and elbow stress were measured. The obtained results showed that age causes a major reduction in the mechanical parameters of healthy ascending aortic tissue, and that no significant differences are found between the mechanical strength of aneurysmal or BAV aortic specimens and the corresponding age-matched control group. The physiological level of the stress in the circumferential direction was also computed to assess the physiological operation range of healthy and diseased ascending aortas. The mean physiological wall stress acting on pathologic aortas was found to be far from rupture, with factors of safety (defined as the ratio of tensile strength to the mean wall stress) larger than six. In contrast, the physiological operation of pathologic vessels lays in the stiff part of the response curve, losing part of its function of damping the pressure waves from the heart

Sodium/myo-Inositol Transporters: Substrate Transport Requirements and Regional Brain Expression in the TgCRND8 Mouse Model of Amyloid Pathology

Inositol stereoisomers, myo- and scyllo-inositol, are known to enter the brain and are significantly elevated following oral administration. Elevations in brain inositol levels occur across a concentration gradient as a result of active transport from the periphery. There are two sodium/myo-inositol transporters (SMIT1, SMIT2) that may be responsible for regulating brain inositol levels. The goals of this study were to determine the effects of aging and Alzheimer's disease (AD)-like amyloid pathology on transporter expression, to compare regional expression and to analyze substrate requirements of the inositol transporters. QPCR was used to examine expression of the two transporters in the cortex, hippocampus and cerebellum of TgCRND8 mice, a mouse model of amyloid pathology, in comparison to non-transgenic littermates. In addition, we examined the structural features of inositol required for active transport, utilizing a cell-based competitive uptake assay. Disease pathology did not alter transporter expression in the cortex or hippocampus (p>0.005), with only minimal effects of aging observed in the cerebellum (SMIT1: F2,26 = 12.62; p = 0.0002; SMIT2: F2,26 = 8.71; p = 0.0015). Overall, brain SMIT1 levels were higher than SMIT2, however, regional differences were observed. For SMIT1, at 4 and 6 months cerebellar SMIT1 levels were significantly higher than cortical and hippocampal levels (p<0.05). For SMIT2, at all three ages both cortical and cerebellar SMIT2 levels were significantly higher than hippocampal levels (p<0.05) and at 4 and 6 months of age, cerebellar SMIT2 levels were also significantly higher than cortical levels (p<0.05). Inositol transporter levels are stably expressed as a function of age, and expression is unaltered with disease pathology in the TgCRND8 mouse. Given the fact that scyllo-inositol is currently in clinical trials for the treatment of AD, the stable expression of inositol transporters regardless of disease pathology is an important finding

Genetic Variants in FBN-1 and Risk for Thoracic Aortic Aneurysm and Dissection.

OBJECTIVES: A recent genome wide association study (GWAS) by LeMaire et al. found that two single nucleotide polymorphisms (SNPs), rs2118181 and rs10519177 in the FBN-1 gene (encoding Fibrillin-1), were associated with thoracic aortic dissection (TAD), non-dissecting thoracic aortic aneurysm (TAA), and thoracic aortic aneurysm or dissection (TAAD); the largest effect was observed for the association of rs2118181 with TAD. We investigated whether rs2118181 and rs10519177 were associated with TAD, TAA, and TAAD in the Yale study. METHODS: The genotypes of rs2118181 and rs10519177 were determined for participants in the Yale study: 637 TAAD cases (140 TAD, 497 TAA) and 275 controls from the United States, Hungary, and Greece. The association of the genotypes with TAD, TAA and TAAD were assessed using logistic regression models adjusted for sex, age, study center and hypertension. RESULTS AND CONCLUSIONS: In the Yale study, rs2118181 was associated with TAD: compared with non-carriers, carriers of the risk allele had an unadjusted odds ratio for TAD of 1.80 (95% CI 1.15-2.80) and they had odds ratio for TAD of 1.87 (95% CI 1.09-3.20) after adjusting for sex, age, study center and hypertension. We did not find significant differences in aortic size, a potential confounder for TAD, between rs2118181 risk variant carriers and non-carriers: mean aortic size was 5.56 (95% CI: 5.37-5.73) for risk variant carriers (CC+CT) and was 5.48 (95% CI: 5.36-5.61) for noncarriers (TT) (p = 0.56). rs2118181 was not associated with TAA or TAAD. rs10519177 was not associated with TAD, TAA, or TAAD in the Yale study. Thus, the Yale study provided further support for the association of the FBN-1 rs2118181SNP with TAD

Challenges to immunization: the experiences of homeless youth

<p>Abstract</p> <p>Background</p> <p>Homelessness is a critical social issue, both a product of, and contributing to, poor mental and physical health. Over 150,000 young Canadians live on the streets. Homeless youth experience a high incidence of infectious diseases, many of which are vaccine preventable. Early departure from school and limited access to public health services makes them a particularly vulnerable high-risk group. This study explores challenges to obtaining essential vaccines experienced by homeless youth.</p> <p>Methods</p> <p>A qualitative research study to explore knowledge, attitudes, beliefs, and experiences surrounding immunization of hard-to-reach homeless youth was designed. Participants were recruited for focus groups from Phoenix House and Shelter, a non-profit, community-based organization assisting homeless youth in Halifax, Nova Scotia, Canada. An experienced facilitator guided the recorded discussions. Transcripts of audiotapes were analyzed using a constant comparative method until data revealed a set of exemplars and themes that best captured participants’ knowledge, attitudes, beliefs and experiences surrounding immunization and infectious diseases.</p> <p>Results</p> <p>Important themes emerged from our analysis. Considerable variability in knowledge about immunization and vaccine preventable diseases was found. The homeless youth in the study had limited awareness of meningitis in contrast to a greater knowledge about sexually transmitted infections and influenza, gained during the H1N1/09 public health campaign. They recognized their poverty as a risk for contracting infectious diseases, along with their inability to always employ known strategies to prevent infectious diseases, due to circumstances. They showed considerable insight into the detrimental effects of poor hygiene, sleeping locations and risk behaviour. Interviewed homeless youth regarded themselves as good compliers of health professional advice and offered valuable suggestions to improve immunization in their population.</p> <p>Conclusions</p> <p>To provide effective public health interventions, it is necessary to consider the knowledge, attitudes, beliefs, and experiences of hard to reach, high risk groups. Our study shows that homeless youth are interested and capable in discussing immunization. Active targeting of homeless youth for public health immunization programs is needed. Working collaboratively with non-profit organizations that assist homeless youth provides an opportunity to increase their knowledge of infectious risks and to improve immunization strategies in this vulnerable group.</p

Standard of Practice for the Endovascular Treatment of Thoracic Aortic Aneurysms and Type B Dissections

Thoracic endovascular aortic repair (TEVAR) represents a minimally invasive technique alternative to conventional open surgical reconstruction for the treatment of thoracic aortic pathologies. Rapid advances in endovascular technology and procedural breakthroughs have contributed to a dramatic transformation of the entire field of thoracic aortic surgery. TEVAR procedures can be challenging and, at times, extraordinarily difficult. They require seasoned endovascular experience and refined skills. Of all endovascular procedures, meticulous assessment of anatomy and preoperative procedure planning are absolutely paramount to produce optimal outcomes. These guidelines are intended for use in quality-improvement programs that assess the standard of care expected from all physicians who perform TEVAR procedures

Intramural haematoma of the thoracic aorta: who's to be alerted the cardiologist or the cardiac surgeon?

This review article is written so as to present the pathophysiology, the symptomatology and the ways of diagnosis and treatment of a rather rare aortic disease called Intra-Mural Haematoma (IMH). Intramural haematoma is a quite uncommon but potentially lethal aortic disease that can strike as a primary occurrence in hypertensive and atherosclerotic patients to whom there is spontaneous bleeding from vasa vasorum into the aortic wall (media) or less frequently, as the evolution of a penetrating atherosclerotic ulcer (PAU). IMH displays a typical of dissection progress, and could be considered as a precursor of classic aortic dissection. IMH enfeebles the aortic wall and may progress to either outward rupture of the aorta or inward disruption of the intima layer, which ultimately results in aortic dissection. Chest and back acute penetrating pain is the most commonly noticed symptom at patients with IMH. Apart from a transesophageal echocardiography (TEE), a tomographic imaging such as a chest computed tomography (CT), a magnetic resonance (MRI) and most lately a multy detector computed tomography (MDCT) can ensure a quick and accurate diagnosis of IMH. Similar to type A and B aortic dissection, surgery is indicated at patients with type-A IMH, as well as at patients with a persistent and/or recurrent pain. For any other patient (with type-B IMH without an incessant pain and/or without complications), medical treatment is suggested, as applied in the case of aortic dissection. The outcome of IMH in ascending aorta (type A) appears favourable after immediate (emergent or urgent) surgical intervention, but according to international bibliography patients with IMH of the descending aorta (type B) show similar mortality rates to those being subjected to conservative medical or surgical treatment. Endovascular surgery and stent-graft placement is currently indicated in type B IMH