Optimal Computation of Overabundant Words

The observed frequency of the longest proper prefix, the longest proper suffix, and the longest infix of a word w in a given sequence x can be used for classifying w as avoided or overabundant. The definitions used for the expectation and deviation of w in this statistical model were described and biologically justified by Brendel et al. (J Biomol Struct Dyn 1986). We have very recently introduced a time-optimal algorithm for computing all avoided words of a given sequence over an integer alphabet (Algorithms Mol Biol 2017). In this article, we extend this study by presenting an O(n)-time and O(n)-space algorithm for computing all overabundant words in a sequence x of length n over an integer alphabet. Our main result is based on a new non-trivial combinatorial property of the suffix tree T of x: the number of distinct factors of x whose longest infix is the label of an explicit node of T is no more than 3n-4. We further show that the presented algorithm is time-optimal by proving that O(n) is a tight upper bound for the number of overabundant words. Finally, we present experimental results, using both synthetic and real data, which justify the effectiveness and efficiency of our approach in practical terms

Epidemiology of interstitial lung diseases in Greece

SummaryIntroductionFew data are available on the epidemiology of interstitial lung diseases (ILDs), especially after the current classification of idiopathic interstitial pneumonias. The aim of this study is to provide data on the epidemiology of ILDs in Greece, under the ATS/ERS international consensus.MethodsDepartments of Pneumonology were contacted and asked to complete a questionnaire for every case of ILD that was alive on 2004 as well as for every new case from 1st January 2004 to 31st December 2004. Questions on the patients' demographic data, the exact diagnosis and the procedures used to establish the diagnosis were included. Centers covering about 60% of the Greek population have been analyzed.ResultsA total of 967 cases have been registered. The estimated prevalence of ILDs is 17.3 cases per 100,000 inhabitants. The estimated annual incidence of ILDs is 4.63 new cases per 100,000 inhabitants. The most frequent disease is sarcoidosis (34.1%), followed in decreasing order by idiopathic pulmonary fibrosis (19.5%), ILD associated with collagen vascular diseases (12.4%), cryptogenic organizing pneumonia (5.3%), histiocytosis (3.8%), and hypersensitivity pneumonitis (2.6%). Unclassified ILD or not otherwise specified accounted for the 8.5% of prevalent cases.ConclusionsThese data suggest that sarcoidosis and idiopathic pulmonary fibrosis are the most frequent ILDs in our population. In comparison with the few previous reports, interesting dissimilarities have been observed

Herbal substance, acteoside, alleviates intestinal mucositis in mice

This study investigated the role of acteoside in the amelioration of mucositis. C57BL/6 mice were gavaged daily with acteoside 600 μg for 5 d prior to induction of mucositis and throughout the experimental period. Mucositis was induced by methotrexate (MTX; 12.5 mg/kg; s.c.). Mice were culled on d 5 and d 11 after MTX. The duodenum, jejunum, and ileum were collected for myeloperoxidase (MPO) activity, metallothionein (MT) levels, and histology. Acteoside reduced histological severity scores by 75, 78, and 88% in the duodenum, jejunum, and ileum, respectively, compared to MTX-controls on d 5. Acteoside reduced crypt depth by 49, 51, and 33% and increased villus height by 19, 38, and 10% in the duodenum, jejunum, and ileum, respectively, compared to MTX-controls on d 5. Acteoside decreased MT by 50% compared to MTX-control mice on d 5. Acteoside decreased MPO by 60% and 30% in the duodenum and jejunum, respectively, compared to MTX-controls on d 5. Acteoside alleviated MTX-induced small intestinal mucositis possibly by preventing inflammation.Daniel Reinke, Stamatiki Kritas, Panagiotis Polychronopoulos, Alexios L. Skaltsounis, Nektarios Aligiannis, and Cuong D. Tra

Stroke genetics: prospects for personalized medicine.

Epidemiologic evidence supports a genetic predisposition to stroke. Recent advances, primarily using the genome-wide association study approach, are transforming what we know about the genetics of multifactorial stroke, and are identifying novel stroke genes. The current findings are consistent with different stroke subtypes having different genetic architecture. These discoveries may identify novel pathways involved in stroke pathogenesis, and suggest new treatment approaches. However, the already identified genetic variants explain only a small proportion of overall stroke risk, and therefore are not currently useful in predicting risk for the individual patient. Such risk prediction may become a reality as identification of a greater number of stroke risk variants that explain the majority of genetic risk proceeds, and perhaps when information on rare variants, identified by whole-genome sequencing, is also incorporated into risk algorithms. Pharmacogenomics may offer the potential for earlier implementation of 'personalized genetic' medicine. Genetic variants affecting clopidogrel and warfarin metabolism may identify non-responders and reduce side-effects, but these approaches have not yet been widely adopted in clinical practice

Add-on topiramate in the treatment of refractory partial-onset epilepsy: Clinical experience of outpatient epilepsy clinics from 11 general hospitals

SummaryAn open, prospective, observational study was performed to assess efficacy and adverse-event profile of topiramate as add-on therapy in epilepsy. Outpatient neurology clinics from 11 general hospitals in Greece participated in the study. In total, 211 patients with treatment resistant partial-onset seizures who met the inclusion criteria, were studied. After baseline evaluation, topiramate was given at a target dose of 200mg/day over a 1-month titration period. In the subsequent maintenance period, the topiramate dose could be varied according to the clinical results. Patients were followed for in total 6 months, with monthly visits and regular physical, neurological and laboratory examinations. Seizure frequencies decreased to 35–40% of baseline values following 3 months of treatment and remained relatively constant thereafter. The average monthly seizure frequency over the 6-month study period was 4.61, compared to 9.21 at baseline. The number of responders (patients with at least 50% reduction in seizure frequency) followed a similar pattern, i.e., increase during the first 3 months levelling off at a final 80–85% response rate. Of those completing the study, 30% had been seizure-free for at least 3 months and 12% for 5 months. Topiramate was well tolerated, no deviations in laboratory values were found. Adverse events appeared to occur less frequently, and antiepileptic effects were more pronounced in this prospective open-label study than in earlier reports from randomised controlled trials. The nature of the patient population and the application of individualised dose optimisation are proposed as contributing factors to explain the favourable results of this study

Unravelling the Genetics of Ischaemic Stroke

Hugh Markus discusses genetic factors in stroke risk, and emphasizes the importance of large sample studies and rigorous replication of results in genetic stroke research

The effect of stimulation technique on sympathetic skin responses in healthy subjects

The aim of this study was to collect normative data for sympathetic skin responses (SSR) elicited by electrical stimulus of the ipsilateral and contralateral peripheral nerves, and by magnetic stimulus of cervical cord. SSRs were measured at the mid-palm of both hands following electrical stimulation of the left median nerve at the wrist and magnetic stimulation at the neck in 40 healthy adult volunteers (mean age 52.2 ± 12.2 years, 19 males). The onset latency, peak latency, amplitude and area were estimated in “P” type responses (i.e., waveforms with a larger positive, compared to negative, component). SSR onset and peak latency were prolonged when the electrical stimulus was applied at the contralateral side (i.e., the SSR recorded in the right palm P < 0.001). The onset latency was similar on both sides during cervical magnetic stimulation. However, peak latency was faster on the left side (P < 0.03). Comparison of electrical and magnetic stimulation revealed that both the onset and peak latency were shorter with magnetic stimulation (P < 0.001). The latency of a SSR varies depending on what type of stimulation is used and where the stimulus is applied. Electrically generated SSRs have a longer delay and the delay is prolonged at the contralateral side. These factors should be taken into account when interpreting SSR data

Assessing the digenic model in rare disorders using population sequencing data

An important fraction of patients with rare disorders remains with no clear genetic diagnostic, even after whole-exome or whole-genome sequencing, posing a difficulty in giving adequate treatment and genetic counseling. The analysis of genomic data in rare disorders mostly considers the presence of single gene variants in coding regions that follow a concrete monogenic mode of inheritance. A digenic inheritance, with variants in two functionally-related genes in the same individual, is a plausible alternative that might explain the genetic basis of the disease in some cases. In this case, digenic disease combinations should be absent or underrepresented in healthy individuals. We develop a framework to evaluate the significance of digenic combinations and test its statistical power in different scenarios. We suggest that this approach will be relevant with the advent of new sequencing efforts including hundreds of thousands of samples

Identification of 4 novel human ocular coloboma genes ANK3, BMPR1B, PDGFRA, and CDH4 through evolutionary conserved vertebrate gene analysis

Purpose: Ocular coloboma arises from genetic or environmental perturbations that inhibit optic fissure (OF) fusion during early eye development. Despite high genetic heterogeneity, 70% to 85% of patients remain molecularly undiagnosed. In this study, we have identified new potential causative genes using cross-species comparative meta-analysis. Methods: Evolutionarily conserved differentially expressed genes were identified through in silico analysis, with in situ hybridization, gene knockdown, and rescue performed to confirm spatiotemporal gene expression and phenotype. Interrogation of the 100,000 Genomes Project for putative pathogenic variants was performed. Results: Nine conserved differentially expressed genes between zebrafish and mouse were identified. Expression of zebrafish ank3a, bmpr1ba/b, cdh4, and pdgfaa was localized to the OF, periocular mesenchyme cells, or ciliary marginal zone, regions traversed by the OF. Knockdown of ank3, bmpr1b, and pdgfaa revealed a coloboma and/or microphthalmia phenotype. Novel pathogenic variants in ANK3, BMPR1B, PDGFRA, and CDH4 were identified in 8 unrelated coloboma families. We showed BMPR1B rescued the knockdown phenotype but variant messenger RNAs failed, providing evidence of pathogenicity. Conclusion: We show the utility of cross-species meta-analysis to identify several novel coloboma disease-causing genes. There is a potential to increase the diagnostic yield for new and unsolved patients while adding to our understanding of the genetic basis of OF morphogenesis