Identification of candidate small-molecule therapeutics to cancer by gene-signature perturbation in connectivity mapping.

Connectivity mapping is a recently developed technique for discovering the underlying connections between different biological states based on gene-expression similarities. The sscMap method has been shown to provide enhanced sensitivity in mapping meaningful connections leading to testable biological hypotheses and in identifying drug candidates with particular pharmacological and/or toxicological properties. Challenges remain, however, as to how to prioritise the large number of discovered connections in an unbiased manner such that the success rate of any following-up investigation can be maximised. We introduce a new concept, gene-signature perturbation, which aims to test whether an identified connection is stable enough against systematic minor changes (perturbation) to the gene-signature. We applied the perturbation method to three independent datasets obtained from the GEO database: acute myeloid leukemia (AML), cervical cancer, and breast cancer treated with letrozole. We demonstrate that the perturbation approach helps to identify meaningful biological connections which suggest the most relevant candidate drugs. In the case of AML, we found that the prevalent compounds were retinoic acids and PPAR activators. For cervical cancer, our results suggested that potential drugs are likely to involve the EGFR pathway; and with the breast cancer dataset, we identified candidates that are involved in prostaglandin inhibition. Thus the gene-signature perturbation approach added real values to the whole connectivity mapping process, allowing for increased specificity in the identification of possible therapeutic candidates.

Can the spread of non-native oysters (Crassostrea gigas) at the early stages of population expansion be managed?

The Pacific oyster (Crassostrea gigas) was introduced into Strangford Lough, Northern Ireland in the 1970s. It was assumed that local environmental conditions would not facilitate successful reproduction. However, in the 1990s there were reports of C. gigas outside licensed aquaculture sites and this investigation set out to ascertain the current distribution, years of likely recruitment and population structure of the species. C. gigas were found distributed widely throughout the northern basin during surveys; the frequency distribution suggesting C. gigas is not recruiting every year. Establishment of feral populations of C. gigas elsewhere have linked to habitat change. A pilot cull was initiated to assess the success rate of early intervention. This paper demonstrates the potential benefits of responding rapidly to initial reports of non-native species in a way that may curtail establishment and expansion. The method advocated in simple and can be recommended to the appropriate regulatory authorities.

Development of primary human nasal epithelial cell cultures for the study of cystic fibrosis pathophysiology

Cultured primary epithelial cells are used to examine inflammation in cystic fibrosis (CF). We describe a new human model system using cultured nasal brushings. Nasal brushings were obtained from 16 F508del homozygous patients and 11 healthy controls. Cells were resuspended in airway epithelial growth medium and seeded onto collagen-coated flasks and membranes for use in patch-clamp, ion transport, and mediator release assays. Viable cultures were obtained with a 75% success rate from subjects with CF and 100% from control subjects. Amiloride-sensitive epithelial Na channel current of similar size was present in both cell types while forskolin-activated CF transmembrane conductance regulator current was lacking in CF cells. In Ussing chambers, cells from CF patients responded to UTP but not to forskolin. Spontaneous and cytomix-stimulated IL-8 release was similar (stimulated 29,448 ± 9,025 pg/ml; control 16,336 ± 3,308 pg/ml CF; means ± SE). Thus nasal epithelial cells from patients with CF can be grown from nasal brushings and used in electrophysiological and mediator release studies in CF research.

Simultaneous use of mitomycin-C with Baerveldt implantation

BACKGROUND AND OBJECTIVE: To evaluate the outcome of Baerveldt implantation with adjunctive mitomycin-C in cases of complicated glaucoma. PATIENTS AND METHODS: The authors reviewed the charts of all patients who had undergone Baerveldt implantation with mitomycin-C between January 1993 and March 1995. Success was defined before data collection as an intraocular pressure (IOP) between 5 and 21 mm Hg, with or without medications. The success rate was calculated using the Kaplan-Meier actuarial method. RESULTS: Twenty-nine patients were identified. The mean preoperative IOP was 33.6 mm Hg, with an average of 2.0 antiglaucoma medications. The probability of success at 6 and 12 months for patients who received mitomycin-C during Baerveldt implantation was 82.4% and 73.3%, respectively. Choroidal effusion with a flat anterior chamber (10.3%), corneal edema (6.8%), and conjunctival erosion (6.8%) were the most frequent complications. CONCLUSION: In this retrospective series of complicated glaucoma, the implantation of a Baerveldt drainage device with adjunctive mitomycin-C had a satisfactory outcome. The complications encountered and the clinical efficacy were comparable to those of previously reported series in which mitomycin-C was not used.

Severe visual loss after autologous blood injection for mitomycin-C- associated hypotonous maculopathy

It has been shown that mitomycin-C increases the success rate of trabeculectomy; however, a rise in the incidence of postoperative complications has also been reported. Consequently, the use of antimetabolite is usually reserved for patients who are at high risk of surgical failure or for patients with advanced glaucoma in whom low intraocular pressure is desired. This report describes a patient who suffered severe visual loss which was a direct result of hypotonous maculopathy after trabeculectomy with mitomycin-C and various other complications from the subsequent interventions.

Control of intraocular pressure after deep sclerectomy

Aim: To study the long-term outcome of deep sclerectomy in patients with open angle glaucoma. Methods: Prospective consecutive series of 43 eyes (38 patients) with medically uncontrolled open-angle glaucoma undergoing deep sclerectomy. All patients underwent clinical assessment before and after surgery at day 7 and at months 1, 3, 6, 12, 18, 24, 36. Surgical success was considered if the patient's intraocular pressure (IOP)>22 mmHg and the IOP was lowered by more than 20% without the use of any medication. Kaplan-Meier survival curves were used to evaluate the success rate. Results: The mean follow-up time was 28.1±8.2 months. Mean IOP decreased significantly from a preoperative value of 24.6±5.5 mmHg to a postoperative value of 18.5±4.6 mmHg at 36 months (P>0.001). Microperforation of TDM occurred in three cases (7.0%) and ciliary body prolapse in one case (2.3%) but did not prevent completion of the operation. Postoperatively, hyphaema was detected in one case and shallow anterior chamber in another case and both were treated conservatively. Bleb encapsulation with elevation of IOP occurred in two cases (4.7%) and was treated with 5-fluorouracil subconjunctival injection. Goniopuncture with neodymium : YAG laser was performed in two cases (4.7%). There were no other late complications with the exception of failure of the operation. On the life-table analysis the success rate at 12, 24, and 30 months were 61.4, 36.6, and 18.9%, respectively. Conclusion: Deep sclerectomy reduced the IOP temporarily while minimising the risk of postoperative complications commonly encountered with standard trabeculectomy. However, after long-term follow-up surgery failed to maintain a low IOP. © 2006 Nature Publishing Group. All rights reserved.

The syntax of concealment:Reliable methods for plain text information hiding

Many plain text information hiding techniques demand deep semantic processing, and so suffer in reliability. In contrast, syntactic processing is a more mature and reliable technology. Assuming a perfect parser, this paper evaluates a set of automated and reversible syntactic transforms that can hide information in plain text without changing the meaning or style of a document. A large representative collection of newspaper text is fed through a prototype system. In contrast to previous work, the output is subjected to human testing to verify that the text has not been significantly compromised by the information hiding procedure, yielding a success rate of 96% and bandwidth of 0.3 bits per sentence. © 2007 SPIE-IS&T.

Pseudomonas aeruginosa genotypes acquired by children with cystic fibrosis by age 5-years

Background

We describe Pseudomonas aeruginosa acquisitions in children with cystic fibrosis (CF) aged ≤5-years, eradication treatment efficacy, and genotypic relationships between upper and lower airway isolates and strains from non-CF sources.

Methods

 Of 168 CF children aged ≤5-years in a bronchoalveolar lavage (BAL)-directed therapy trial, 155 had detailed microbiological results. Overall, 201/271 (74%) P. aeruginosa isolates from BAL and oropharyngeal cultures were available for genotyping, including those collected before and after eradication therapy.

Results

Eighty-two (53%) subjects acquired P. aeruginosa, of which most were unique strains. Initial eradication success rate was 90%, but 36 (44%) reacquired P. aeruginosa, with genotypic substitutions more common in BAL (12/14) than oropharyngeal (3/11) cultures. Moreover, oropharyngeal cultures did not predict BAL genotypes reliably.

Conclusions

 CF children acquire environmental P. aeruginosa strains frequently. However, discordance between BAL and oropharyngeal strains raises questions over upper airway reservoirs and how to best determine eradication in non-expectorating children.

An evidence based approach for the provision of resin-bonded bridgework

Resin bonded bridgework (RBB) is a technique often overlooked by practitioners despite a large amount of evidence supporting the technique. In Cork University Dental School an evidence-based, standardised approach for the delivery of RBB by undergraduate students has been developed over the past 10 years. The aim of this study was to evaluate the success of this standardised approach on the delivery of RBB by students. 222 bridges were reviewed which had been delivered over a 6 year time period between 2002 and 2007. A success rate of 84.1% was achieved with a mean survival time of 41 months. This study illustrates that predictable and highly successful RBB can be delivered by inexperienced clinicians using an evidence-based, standardised approach.

Risk-aware Planning in BDI Agents

The ability of an autonomous agent to select rational actions is vital in enabling it to achieve its goals. To do so effectively in a high-stakes setting, the agent must be capable of considering the risk and potential reward of both immediate and future actions. In this paper we provide a novel method for calculating risk alongside utility in online planning algorithms. We integrate such a risk-aware planner with a BDI agent, allowing us to build agents that can set their risk aversion levels dynamically based on their changing beliefs about the environment. To guide the design of a risk-aware agent we propose a number of principles which such an agent should adhere to and show how our proposed framework satisfies these principles. Finally, we evaluate our approach and demonstrate that a dynamically risk-averse agent is capable of achieving a higher success rate than an agent that ignores risk, while obtaining a higher utility than an agent with a static risk attitude.

Novel tools for conservation genomics: comparing two high-throughput approaches for SNP discovery in the transcriptome of the European hake

The growing accessibility to genomic resources using next-generation sequencing (NGS) technologies has revolutionized the application of molecular genetic tools to ecology and evolutionary studies in non-model organisms. Here we present the case study of the European hake (Merluccius merluccius), one of the most important demersal resources of European fisheries. Two sequencing platforms, the Roche 454 FLX (454) and the Illumina Genome Analyzer (GAII), were used for Single Nucleotide Polymorphisms (SNPs) discovery in the hake muscle transcriptome. De novo transcriptome assembly into unique contigs, annotation, and in silico SNP detection were carried out in parallel for 454 and GAII sequence data. High-throughput genotyping using the Illumina GoldenGate assay was performed for validating 1,536 putative SNPs. Validation results were analysed to compare the performances of 454 and GAII methods and to evaluate the role of several variables (e.g. sequencing depth, intron-exon structure, sequence quality and annotation). Despite well-known differences in sequence length and throughput, the two approaches showed similar assay conversion rates (approximately 43%) and percentages of polymorphic loci (67.5% and 63.3% for GAII and 454, respectively). Both NGS platforms therefore demonstrated to be suitable for large scale identification of SNPs in transcribed regions of non-model species, although the lack of a reference genome profoundly affects the genotyping success rate. The overall efficiency, however, can be improved using strict quality and filtering criteria for SNP selection (sequence quality, intron-exon structure, target region score).

In-the-Bag Intraocular Lens Placement via Secondary Capsulorhexis with Radiofrequency Diathermy in Pediatric Aphakic Eyes

Pediatric ophthalmologists increasingly recognize that the ideal site for intraocular lens (IOL) implantation is in the bag for aphakic eyes, but it is always very difficult via conventional technique. We conducted a prospective case series study to investigate the success rate and clinical outcomes of capsular bag reestablishment and in-the-bag IOL implantation via secondary capsulorhexis with radiofrequency diathermy (RFD) in pediatric aphakic eyes, in which twenty-two consecutive aphakic pediatric patients (43 aphakic eyes) enrolled in the Childhood Cataract Program of the Chinese Ministry of Health were included. The included children underwent either our novel technique for secondary IOL implantation (with RFD) or the conventional technique (with a bent needle or forceps), depending on the type of preoperative proliferative capsular bag present. In total, secondary capsulorhexis with RFD was successfully applied in 32 eyes (32/43, 74.4%, age 5.6±2.3 years), of which capsular bag reestablishment and in-the-bag IOL implantation were both achieved in 30 eyes (30/43, 70.0%), but in the remaining 2 eyes (2/32, 6.2%) the IOLs were implanted in the sulcus with a capsular bag that was too small. Secondary capsulorhexis with conventional technique was applied in the other 11 eyes (11/43, 25.6%, age 6.9±2.3 years), of which capsular bag reestablishment and in-the-bag IOL implantation were both achieved only in 3 eyes(3/43, 7.0%), and the IOLs were implanted in the sulcus in the remaining 8 eyes. A doughnut-like proliferative capsular bag with an extensive Soemmering ring (32/43, 74.4%) was the main success factor for secondary capsulorhexis with RFD, and a sufficient capsular bag size (33/43, 76.7%) was an additional factor in successful in-the-bag IOL implantation. In conclusion, RFD secondary capsulorhexis technique has 70% success rate in the capsular bag reestablishment and in-the-bag IOL implantation in pediatric aphakic eyes, particularly effective in cases with a doughnut-like, extensively proliferative Soemmering ring. © 2013 Luo et al.

Outcomes of surgical bleb revision for complications of trabeculectomy.

OBJECTIVE: To describe the results of revision surgery for complications of trabeculectomy in a case series from an academic glaucoma service. DESIGN: Retrospective case series. PARTICIPANTS: A total of 177 eyes of 167 adult patients who underwent revision of trabeculectomy at the Wilmer Eye Institute between 1994 and 2007. METHODS: Three indications for surgery were identified: hypotony without leak, bleb leak, and bleb dysesthesia. Revision was deemed successful when all of the following were true: the primary indication was eliminated, further intraocular pressure (IOP)-lowering surgery was not required, no major complication occurred, and a new bleb-related problem did not develop. Patients with less than 3 months of follow-up were excluded unless failure occurred earlier. Surgical procedures included variations on excision of thin or leaking conjunctiva with advancement. MAIN OUTCOME MEASURES: Change in IOP, change in visual acuity, need for further IOP-lowering surgery, and complications after bleb revision. RESULTS: Subjects' mean age was 67+/-14 years, 54% were female, and mean follow-up was 2.8+/-2.7 years, with a mean interval from trabeculectomy to revision of 3.5+/-3.7 years. Overall success rate was 63% (112/177), which was slightly higher for leak repair (65%; 64/98) and hypotony (63%; 32/51) than for dysesthesia (57%; 16/28) indications. By Kaplan-Meier analysis, overall cumulative success rates at 1, 2, 5, and 10 years after bleb revision were 80%, 75%, 50%, and 41%, respectively. IOP and visual acuity improved significantly in both hypotony and leak groups (P values ranging from 0.004 to <0.0001). Additional IOP-lowering surgery was required in 9%. In multivariate regression analysis adjusting for age, gender, and number of prior surgeries, patients with glaucoma other than primary open-angle glaucoma were twice as likely to have failed bleb revision. CONCLUSIONS: Surgical bleb revision often provides successful resolution of bleb-related complications. Most patients maintain IOP control without need for further IOP-lowering surgery. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Landslide susceptibility evaluation and validation at a regional scale

Tese de doutoramento, Geografia (Geografia Física), Universidade de Lisboa, Instituto de Geografia e Ordenamento do Território, 2014

Percutaneous Treatment of Mitral Valve Regurgitation: Initial Experience with the MitraClip Device

INTRODUCTION: Mitral regurgitation (MR) is the most common valvular disease and has recently become the target of a number of percutaneous approaches. The MitraClip is virtually the only device for which there is considerable experience, with more than 20,000 procedures performed worldwide. OBJECTIVE: To describe our initial experience of the percutaneous treatment of MR with the MitraClip device. METHODS: We describe the first six MitraClip cases performed in this institution (mean age 58.5 ± 13.1 years), with functional MR grade 4+ and New York Heart Association (NYHA) heart failure class III or IV (n=3), with a mean follow-up of 290 ± 145 days. RESULTS: Procedural success (MR ≤ 2+) was 100%. Total procedure time was 115.8 ± 23.7 min, with no in-hospital adverse events and discharge between the fourth and eighth day, and consistent improvement in the six-minute walk test (329.8 ± 98.42 vs. 385.33 ± 106.95 m) and in NYHA class (three patients improved by two NYHA classes). During follow-up there were two deaths, in two of the four patients who had been initially considered for heart transplantation. CONCLUSION: In patients with functional MR the MitraClip procedure is safe, with both a high implantation and immediate in-hospital success rate. A longer follow-up suggests that the clinical benefit decreases or disappears completely in patients with more advanced heart disease, namely those denied transplantation or on the heart transplant waiting list.