Rare mutations in PROC, PROS1 or SERPINC1 as well as common variants in F5, F2, F11 and SERPINC1 have been identified as risk factors for deep vein thrombosis (DVT). To identify novel genetic risk ...factors for DVT, we have developed and applied next-generation DNA sequencing (NGS) of the coding area of hemostatic and proinflammatory genes. Using this strategy, we previously identified a single nucleotide variant (SNV) rs6050 in the FGA gene and novel, rare SNVs in the ADAMTS13 gene associated with DVT. To identify novel coding variants in the genetic predisposition to DVT, we applied NGS analysis of the coding area of 186 hemostatic and proinflammatory genes in 94 DVT cases and 98 controls and we identified 18 variants with putative role in DVT. A group of 585 Italian idiopathic DVT patients and 550 healthy controls was used to genotype all the 18 risk-associated variants identified by NGS. Replication study in the Italian population identified the rs2232710 variant in the protein Z-dependent protease inhibitor (ZPI) gene to be associated with an increased risk of DVT (OR 2.74; 95% CI 1.33-5.65; P = 0.0045; Bonferroni P = 0.081). However, the rs2232710 SNV showed no association with DVT in two Dutch replication cohorts the LETS study (454 patients and 451 controls) and the MEGA study (3799 patients and 4399 controls), indicating that the rs2232710 variant is not a risk factor for DVT.
Coagulation factor XI (FXI) has become increasingly interesting for its role in pathogenesis of thrombosis. While elevated plasma levels of FXI have been associated with venous thromboembolism and ...ischemic stroke, its deficiency is associated with mild bleeding. We aimed to determine novel genetic and post-transcriptional plasma FXI regulators.We performed a genome-wide association study (GWAS) for plasma FXI levels, using novel data imputed to the 1000 Genomes reference panel. Individual GWAS analyses, including a total of 16,169 European individuals from the ARIC, GHS, MARTHA and PROCARDIS studies, were meta-analysed and further replicated in 2,045 individuals from the F5L family, GAIT2 and MEGA studies. Additional association with activated partial thromboplastin time (aPTT) was tested for the top SNPs. In addition, a study on the effect of miRNA on FXI regulation was performed using in silico prediction tools and in vitro luciferase assays.Three loci showed robust, replicating association with circulating FXI levels: KNG1 (rs710446, P-value = 2.07 × 10-302), F11 (rs4253417, P-value = 2.86 × 10-193), and a novel association in GCKR (rs780094, P-value = 3.56 ×10-09), here for the first time implicated in FXI regulation. The two first SNPs (rs710446 and rs4253417) also associated with aPTT. Conditional and haplotype analyses demonstrated a complex association signal, with additional novel SNPs modulating plasma FXI levels in both the F11 and KNG1 loci. Finally, eight miRNAs were predicted to bind F11 mRNA. Over-expression of either miR-145 or miR-181 significantly reduced the luciferase activity in cells transfected with a plasmid containing FXI-3'UTR.These results should open the door to new therapeutic targets for thrombosis prevention.
•A large proportion of pwMS may experience a wide array of visual complaints.•Especially complaints regarding light were reported by more pwMS than controls.•PwMS with and without a history of ON ...show similar visual complaints.•Visual complaints may occur anytime along the disease course.•Regularly screening for visual complaints may help pwMS reach care.
Visual disturbances are common in multiple sclerosis (MS), but visual complaints may be underestimated. While these complaints decrease quality of life, they may not be discussed during clinic visits. People with MS (pwMS) may not be referred to appropriate care. We therefore investigated the prevalence, nature and associations of visual complaints of pwMS.
We performed a cohort study with a comparison group. PwMS (n = 493) and healthy controls (n = 661) filled out the Screening Visual Complaints questionnaire (SVCq). Primary outcomes were the percentage of pwMS and controls that reported the 19 complaints, and total scores of the SVCq. We also compared the scores on the SVCq between different groups of pwMS.
In general, the complaints were reported more often by pwMS than by controls. PwMS especially reported experiencing complaints ‘often/always’, while controls reported the complaints primarily ‘sometimes’. PwMS with and without a history of optic neuritis showed similar complaints. PwMS with a longer disease duration and those with SPMS reported more complaints. EDSS score and disease duration only showed a limited association with discomfort of visual complaints.
The prevalence of visual complaints among pwMS is high and any person with MS may experience a wide array of different visual complaints anywhere along the disease course, regardless of a history of optic neuritis. Using the SVCq may help detect pwMS’ visual complaints and may facilitate referrals to appropriate care.
Multiple sclerosis (MS) can manifest itself in many ways, all of which can affect the independent outdoor mobility of persons with MS (pwMS). In most studies, mobility of pwMS is defined by the ...ability to walk. However, mobility comprises more than walking alone. This systematic review provides an overview of the literature on several types of independent outdoor mobility of pwMS. We aimed to identify which specific factors may influence outdoor mobility and how the lives of pwMS may be affected by a reduced mobility.
A systematic literature search was performed, using three databases (PubMed, PsychInfo and Web of Science). Studies had to describe a group of pwMS sclerosis and had to concern some type of mobility other than walking.
The 57 studies that fulfilled the criteria included in total 10,394 pwMS and in addition, 95,300 pwMS in separate prevalence study. These studies showed that pwMS as a group have a decreased fitness to drive, make use of a wheelchair or mobility scooter more often and have difficulties making use of public transport. Mobility problems especially occur in patients with cognitive problems, secondary progressive MS or high disability scores.
The reduced mobility may prevent pwMS participating in society. However, few studies investigating interventions or rehabilitation options to improve mobility were found in the existing literature, highlighting an until now under recognised unmet need.
Deinterlacing-an overview De Haan, G.; Bellers, E.B.
Proceedings of the IEEE,
09/1998, Volume:
86, Issue:
9
Journal Article
Peer reviewed
The question "to interlace or not to interlace" divides the television and the personal computer communities. A proper answer requires a common understanding of what is possible nowadays in ...deinterlacing video signals. This paper outlines the most relevant proposals, ranging front simple linear methods to advanced motion-compensated algorithms, and provides a relative performance comparison for 12 of these methods. Next to objective performance indicators, screen photographs have been used to illustrate typical artifacts of individual deinterlacers. The overview provides no final answer in the interlace debate, as such requires unavailable capabilities in balancing technical and nontechnical issues.
TaqMan assays were developed for the detection of seven
Dickeya
species, namely
D. dianthicola, D. dadantii, D. paradisiaca, D. chrysanthemi, D. zeae, D. dieffenbachiae
and
D. solani
. Sequences of ...the gene coding for
dnaX
were used for the design of primers and probes. In studies with axenic cultures of bacteria, the assays were highly specific and only reacted with strains of the target species, and not with non-target bacteria, including those belonging to other
Dickeya
species and other genera. The detection thresholds for DNA extracted from pure cultures of target strains ranged from 10 to 100 fg. The TaqMan assays for
D. dianthicola
and
D. solani
were more extensively evaluated as part of a method validation procedure. The threshold level for target bacteria added to a potato peel extract diluted ten-times in a semi-selective broth, was strain dependent and ranged from 1,000 to 100,000 cfu/ml. The coefficients of variation for repeatability and reproducibility were low and results were largely independent of the type of substrate, i.e. potato tuber or carnation leaf extracts. However, during routine testing of seed potatoes, false-positive reactions were found with the assay for
D. solani
. The use of the TaqMan assays for inspection of plant propagation material, ecological studies and studies on the effect of control strategies in disease management strategies is discussed.
Aims To investigate the pharmacokinetic and pharmacodynamic profile of midazolam administered as a concentrated intranasal spray, compared with intravenous midazolam, in healthy adult subjects.
...Methods Subjects were administered single doses of 5 mg midazolam intranasally and intravenously in a cross‐over design with washout period of 1 week. The total plasma concentrations of midazolam and the metabolite 1‐hydroxymidazolam after both intranasal and intravenous administration were described with a single pharmacokinetic model. β‐band EEG activity was recorded and related to midazolam plasma concentrations using an exponential pharmacokinetic/pharmacodynamic model.
Results Administration of the intranasal spray led to some degree of temporary irritation in all six subjects, who nevertheless found intranasal administration acceptable and not painful. The mean (±s.d.) peak plasma concentration of midazolam of 71 (±25 ng ml−1) was reached after 14 (±5 min). Mean bioavailability following intranasal administration was 0.83±0.19. After intravenous and intranasal administration, the pharmacokinetic estimates of midazolam were: mean volume of distribution at steady state 1.11±0.25 l kg−1, mean systemic clearance 16.1±4.1 ml min−1 kg−1 and harmonic mean initial and terminal half lives 8.4±2.4 and 79±30 min, respectively. Formation of the 1‐hydroxymetabolite after intranasal administration did not exceed that after intravenous administration.
Conclusions In this study in healthy volunteers a concentrated midazolam nasal spray was easily administered and well tolerated. No serious complications of the mode of administration or the drug itself were reported. Rapid uptake and high bioavailability were demonstrated. The potential of midazolam given via a nasal spray in the acute treatment of status epilepticus and other seizure disruptions should be evaluated.
This paper describes a comparison study of test methods and supports the use of real‐time polymerase chain reaction (PCR) for the detection of Clavibacter michiganensis subsp. sepedonicus and ...Ralstonia solanacearum in potato tubers in routine testing. These 2 bacteria are quarantine organisms under European Union (EU) regulatory control and testing for (latent) infections of these bacteria in seed potatoes is mandatory. Real‐time PCR tests were performed on 276 routine potato tuber samples, including samples infected with either C. michiganensis subsp. sepedonicus or R. solanacearum, and the performance of these real‐time PCR tests was compared with that of immunofluorescence (IF). Real‐time PCR tests, using different primer sets and extraction and PCR protocols, proved to be sensitive and specific for the detection of C. michiganensis subsp. sepedonicus and R. solanacearum in potato tubers in routine testing, and performed at least as well as IF. Real‐time PCR is a good addition to the detection protocols as laid down in EU regulations (EU Council Directives 2006/56/EC and 2006/63/EC).
Performance de la PCR en temps réel et de l'IF, pour la détection de Clavibacter michiganensis subsp. sepedonicus et Ralstonia solanacearum dans les tubercules de pomme de terre en tests de routine
Cet article décrit une étude comparative de méthodes d'analyse et recommande l'utilisation de la PCR temps réel pour la détection de Clavibacter michiganensis subsp. sepedonicus et de Ralstonia solanacearum dans les tubercules de pomme de terre dans les tests de routine. Ces 2 bactéries sont des organismes de quarantaine soumis à lutte officielle dans l’UE et des tests pour la détection d'infections (latentes) de ces bactéries dans les pommes de terre de semence sont obligatoires. Des tests PCR temps réel ont été effectués sur 276 échantillons de routine de tubercules de pomme de terre comprenant des échantillons infectés, soit avec C. michiganensis subsp. sepedonicus soit avec R. solanacearum, et la performance de ces tests de PCR en temps réel a été comparée avec celle de l‘immunofluorescence (IF). Des tests PCR temps réel, utilisant différents jeux d'amorces et différentes méthodes d'extraction et de protocole de PCR se sont avérés être sensibles et spécifiques pour la détection de C. michiganensis subsp. sepedonicus et R. solanacearum dans les tubercules de pomme de terre dans les tests de routine, et se sont révélés au moins aussi performants que l’IF. La PCR temps réel est un bon ajout aux protocoles de détection telles que stipulées dans la réglementation européenne (Directives du Conseil de l’UE 2006/56 / CE et 2006/63 / CE).
Сопоставление рабочих показателей ПЦР в реальном времени и иммунофлуоресценции при выявлении Clavibacter michiganensis subsp. sepedonicus и Ralstonia solanacearum в клубнях картофеля в условиях рутинного тестирования
В статье приводится описание сравнительного исследования методов тестирования и отдается предпочтение использованию ПЦР в реальном времени для обнаружения Clavibacter michiganensis subsp. sepedonicus и Ralstonia solanacearum в клубнях картофеля при рутинном тестировании. Эти 2 бактерии являются карантинными вредными организмами в рамках системы фитосанитарного контроля ЕС и тестирование на наличие (латентного) заражения семенного картофеля этими бактериями является обязательным. Тестирование методом ПЦР в реальном времени проводилось на 276 рутинных образцах клубней картофеля, включая образцы, зараженные либо C. michiganensis subsp. sepedonicus либо R. solanacearum, и показатели этих тестов с помощью ПЦР в реальном времени сравнивались с показателями тестирования методом иммунофлюоресценции. Тестирование методом ПЦР в реальном времени с использованием различных комплектов праймеров и экстрактов, а также протоколов ПЦР, оказалось чувствительным и специфичным в обнаружении C. michiganensis subsp. sepedonicus и R. solanacearum в картофельных клубнях при рутинном тестировании и показывают результаты, во всяком случае, не хуже иммунофлюоресценции. ПЦР в реальном времени служит хорошим дополнением к протоколам выявления в соответствии с правилами ЕС (Директивы Совета ЕС 2006/56/EC и 2006/63/EC).
Abstract Generic substitution is encouraged as a cost containment strategy for the management of health care resources. However, in epilepsy, the consequences of loss of symptom control are ...important, and antiepileptic drugs have narrow therapeutic indices. For this reason, generic substitution may be problematic, and certain health authorities have excluded antiepileptic drugs from overall policy recommendations on generic prescribing. The absence of bioequivalence data among generic forms and the relatively broad criteria for bioequivalence with the branded drug allow differences in drug exposure to arise that may be clinically relevant and necessitate monitoring of plasma levels when switching formulations to avoid loss of seizure control or emergence of side effects. Management of these issues carries a significant cost, which should be weighed carefully against the cost savings acquired when purchasing the drug. Both physicians and patients have a right to be informed and approve before pharmacists make a generic substitution or switch between generics.
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