| 1. |
- Beyder, Arthur, et al.
(author)
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Loss-of-Function of the Voltage-Gated Sodium Channel Na(V)1.5 (Channelopathies) in Patients With Irritable Bowel Syndrome
- 2014
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In: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 146:7, s. 1659-1668
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Journal article (peer-reviewed)abstract
- BACKGROUND & AIMS: SCN5A encodes the a-subunit of the voltage-gated sodium channel Na(V)1.5. Many patients with cardiac arrhythmias caused by mutations in SCN5A also have symptoms of irritable bowel syndrome (IBS). We investigated whether patients with IBS have SCN5A variants that affect the function of Na(V)1.5. METHODS: We performed genotype analysis of SCN5A in 584 persons with IBS and 1380 without IBS (controls). Mutant forms of SCN5A were expressed in human embryonic kidney-293 cells, and functions were assessed by voltage clamp analysis. A genome-wide association study was analyzed for an association signal for the SCN5A gene, and replicated in 1745 patients in 4 independent cohorts of IBS patients and controls. RESULTS: Missense mutations were found in SCN5A in 13 of 584 patients (2.2%, probands). Diarrhea-predominant IBS was the most prevalent form of IBS in the overall study population (25%). However, a greater percentage of individuals with SCN5A mutations had constipation-predominant IBS (31%) than diarrhea-predominant IBS (10%; P < .05). Electrophysiologic analysis showed that 10 of 13 detected mutations disrupted Na(V)1.5 function (9 loss-of-function and 1 gain-of-function function). The p. A997T-Na(V)1.5 had the greatest effect in reducing Na(V)1.5 function. Incubation of cells that expressed this variant with mexiletine restored their sodium current and administration of mexiletine to 1 carrier of this mutation (who had constipation-predominant IBS) normalized their bowel habits. In the genome-wide association study and 4 replicated studies, the SCN5A locus was strongly associated with IBS. CONCLUSIONS: About 2% of patients with IBS carry mutations in SCN5A. Most of these are loss-of-function mutations that disrupt Na(V)1.5 channel function. These findings provide a new pathogenic mechanism for IBS and possible treatment options.
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| 2. |
- Beyder, Arthur, et al.
(author)
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Loss-of-function of the voltage-gated sodium channel NaV1.5 (channelopathies) in patients with irritable bowel syndrome.
- 2014
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In: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 146:7
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Journal article (peer-reviewed)abstract
- BACKGROUND & AIMS: SCN5A encodes the α-subunit of the voltage-gated sodium channel NaV1.5. Many patients with cardiac arrhythmias caused by mutations in SCN5A also have symptoms of irritable bowel syndrome (IBS). We investigated whether patients with IBS have SCN5A variants that affect the function of NaV1.5.METHODS: We performed genotype analysis of SCN5A in 584 persons with IBS and 1380 without IBS (controls). Mutant forms of SCN5A were expressed in human embryonic kidney-293 cells, and functions were assessed by voltage clamp analysis. A genome-wide association study was analyzed for an association signal for the SCN5A gene, and replicated in 1745 patients in 4 independent cohorts of IBS patients and controls.RESULTS: Missense mutations were found in SCN5A in 13 of 584 patients (2.2%, probands). Diarrhea-predominant IBS was the most prevalent form of IBS in the overall study population (25%). However, a greater percentage of individuals with SCN5A mutations had constipation-predominant IBS (31%) than diarrhea-predominant IBS (10%; P < .05). Electrophysiologic analysis showed that 10 of 13 detected mutations disrupted NaV1.5 function (9 loss-of-function and 1 gain-of-function function). The p. A997T-NaV1.5 had the greatest effect in reducing NaV1.5 function. Incubation of cells that expressed this variant with mexiletine restored their sodium current and administration of mexiletine to 1 carrier of this mutation (who had constipation-predominant IBS) normalized their bowel habits. In the genome-wide association study and 4 replicated studies, the SCN5A locus was strongly associated with IBS.CONCLUSIONS: About 2% of patients with IBS carry mutations in SCN5A. Most of these are loss-of-function mutations that disrupt NaV1.5 channel function. These findings provide a new pathogenic mechanism for IBS and possible treatment options.
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| 3. |
- Olivecrona, Gunilla, et al.
(author)
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Mutation of conserved cysteines in the Ly6 domain of GPIHBP1 in familial chylomicronemia
- 2010
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In: Journal of Lipid Research. - New York : Rockefeller U.P.. - 0022-2275 .- 1539-7262. ; 51:6, s. 1535-1545
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Journal article (peer-reviewed)abstract
- We investigated a family from northern Sweden in which three of four siblings have congenital chylomicronemia. Lipoprotein lipase (LPL) activity and mass in pre- and post-heparin plasma were low, and LPL release into plasma after heparin injection was delayed. LPL activity and mass in adipose tissue biopsies appeared normal. [35S]Methionine incorporation studies on adipose tissue showed that newly synthesized LPL was normal in size and normally glycosylated. Breast milk from the affected female subjects contained normal to elevated LPL mass and activity levels. The milk had a lower than normal milk lipid content, and the fatty acid composition was compatible with the milk lipids being derived from de novo lipogenesis, rather than from the plasma lipoproteins. Given the delayed release of LPL into the plasma after heparin, we suspected that the chylomicronemia might be caused by mutations in GPIHBP1. Indeed, all three affected siblings were compound heterozygotes for missense mutations involving highly conserved cysteines in the Ly6 domain of GPIHBP1 (C65S and C68G). The mutant GPIHBP1 proteins reached the surface of transfected CHO cells but were defective in their ability to bind LPL (as judged by both cell-based and cell-free LPL binding assays). Thus, the conserved cysteines in the Ly6 domain are crucial for GPIHBP1 function.
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| 4. |
- EL Hiar, Raida, et al.
(author)
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Enteroviral Central Nervous System Infections in Children of the Region of Monastir, Tunisia : Diagnosis, Laboratory Findings of Cerebrospinal Fluid and Clinical Manifestations
- 2012
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In: Indian Journal of Virology. - : Springer Science and Business Media LLC. - 0970-2822 .- 0974-0120. ; 23:3, s. 294-302
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Journal article (peer-reviewed)abstract
- Human enteroviruses (HEV) are one of the major causes of central nervous system (CNS) infections in pediatrics. A prospective study was conducted to assess the epidemiological, clinical, and laboratory characteristics of enterovirus (EV) infections of the CNS in children under 15-years-old, suspected of having viral CNS infections and admitted to the Pediatric Department of Monastir University Hospital, Tunisia. Enteroviral RNA was detected by 5' NCR nested RT-PCR assay in 33 % (20 out of 60) of cerebrospinal fluid specimens, whereas only six samples (10 %) were EV positive in cell culture. EV-positive patients were clustered according to their clinical manifestations, predominantly diagnosed as aseptic meningitis (65 %) and meningoencephalitis (20 %). Fever, headache, vomiting, and neck stiffness were the most pronounced symptoms. Pleocytosis with the predominance of lymphocytes was observed in 60 % of EV positive specimens. Although patients suffering from EV infections were encountered throughout the year, most occurred during spring and summer months. Using VP1-2A nested RT-PCR and sequence analysis, three of the 20 positive HEV were identified as Echovirus (E)-9. This is the first report of a cluster of aseptic meningitis cases caused by E-9 in Monastir.
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| 5. |
- Ezzat, Kariem, et al.
(author)
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PepFect 14, a novel cell-penetrating peptide for oligonucleotide delivery in solution and as solid formulation
- 2011
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In: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 39:12, s. 5284-5298
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Journal article (peer-reviewed)abstract
- Numerous human genetic diseases are caused by mutations that give rise to aberrant alternative splicing. Recently, several of these debilitating disorders have been shown to be amenable for splice-correcting oligonucleotides (SCOs) that modify splicing patterns and restore the phenotype in experimental models. However, translational approaches are required to transform SCOs into usable drug products. In this study, we present a new cell-penetrating peptide, PepFect14 (PF14), which efficiently delivers SCOs to different cell models including HeLa pLuc705 and mdx mouse myotubes; a cell culture model of Duchenne's muscular dystrophy (DMD). Non-covalent PF14-SCO nanocomplexes induce splice-correction at rates higher than the commercially available lipid-based vector Lipofectamine™ 2000 (LF2000) and remain active in the presence of serum. Furthermore, we demonstrate the feasibility of incorporating this delivery system into solid formulations that could be suitable for several therapeutic applications. Solid dispersion technique is utilized and the formed solid formulations are as active as the freshly prepared nanocomplexes in solution even when stored at an elevated temperatures for several weeks. In contrast, LF2000 drastically loses activity after being subjected to same procedure. This shows that using PF14 is a very promising translational approach for the delivery of SCOs in different pharmaceutical forms.
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| 6. |
- Gessler, Michael, et al.
(author)
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Didactics in VET - crisis, demands, concepts and open issues
- 2013
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In: Abstracts.
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Conference paper (other academic/artistic)abstract
- Four focus points (crisis, demands, concepts and open issues) are addressed from three different national perspectives (Sweden, Germany and Spain). Answers might be different, but challenges seem to be the same.(1) crisis: on the one hand we acknowledge a massive withdrawal of didactic discussion in the educational research: first the constructivism taught us that nobody can be taught (a nice antagonism), later the output orientation taught us that just the output counts and within the empirical turn of the educational sciences the topic didactics seems to be lost. (Chevallard, 2006, Moreno Herrera, 2012)(2) demands: On the other hand practitioners still expects that VET offers answers, methods and tools for their central questions: how can learners be empowered and learning be accelerated. Overall questions for the round table will therefore be: What implications have for didactics the fact that learning within this field happens in remarkably different context; namely, classroom and workshop? What is the value in developing a didactics for this specific complex learning context? Is the discourse on didactics a unique phenomenon for particular educational research traditions or is there a substance that is worth discussing? (Berglund & Lindberg, 2012; Ghaye, 2010)(3) concepts: One concept we want exemplary focus within this short proposal information: the didactic concept "task- and process-oriented learning". One concretization of this concept for the field of electrical trade is the so called "Competence toolbox“, which has been continuously developed for more than 10 years to give answers to the following practice-oriented research questions: How can work processes of skilled workers be analyzed and described? How can the results of work process analyses be transferred into work process oriented educational measures? What are the potentials of digital media and internet to support this work process orientation? How can these potentials be converted into task-oriented learning? (Howe & Knutzen, 2012).(4) open issues: see below "Conclusions, expected outcomes"Method:The overall approach of the above mentioned concept (as an example) is the so called Design-Based:Research: DBR characterized the methodical approach of converting the obtained results into work process oriented learning software. The learning software and the accordant task-oriented learning were tested in all learning venues, meaning companies, training centers and vocational schools. In detail following methods were used: (1) Expert workshops: In the first step expert workshops were held. These workshops were moderated by vocational scientists. Experienced master craftsman validated a list of spheres of activities through discussion. The agreed upon list of spheres of activities portrays the researched vocation. (2) Work process analysis: Related to every sphere of activity work process analysis had to be conducted in the second step. This approach is twofold from a methodological perspective. Initially the researcher led a qualitative interview with an experienced skilled worker or craftsman. (3) Online survey: The outcome of this kind of work process oriented learning was finally evaluated by an online survey of apprentices. After accomplishing a task the learners provided feedback relating to the learning software and task -oriented learning by filling in an online questionnaire.Expected outcomes:Expected outcomes of the round table is to fix (4) "open issues": In our view there is a great need to continue developing the basis of a didactic that will be encompassing and dynamic enough to deal with the complex and varied situation of guidance of the learning process in the VET field. In addition to the variety of context it is equally significant to consider the complexity derived from the various interacting components of the teaching and learning process. More is to be done in creating or continuing developing a didactics that encompasses the complexities of VET considering its different levels and different settings.
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| 7. |
- Giacalone, Davide, et al.
(author)
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Health and quality of life in an aging population : food and beyond
- 2014
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Conference paper (other academic/artistic)abstract
- In Europe, as in much of the Western world, the number of citizens aged 65 and over has grown at an unprecedented rate and is expected to account for over 30% of the total population by 2060. Coupled with a steady increase in life expectancy, this massive demographic change calls for a major effort to ensure quality of life in our older population. A thorough understanding of the elderly as food consumers, their nutritional needs, and their food perception and preferences is increasingly recognized as key areas for future research.Food perception change at a later age as a result of the psychophysiological changes that occur with aging, such as decreased appetite and chemosensory acuity. The latter generally decrease food intake and the pleasure that the elderly derive from their meals, making the identification of possible compensation strategies (e.g., flavor enhancement, textural changes, etc.) essential to food producers interested in developing products for this increasingly important segment. Promoting food satisfaction among the elderly is also paramount to ensuring adequate nutritional intake. This aspect has major public health implications, such as preventing malnutrition and sarcopenia, which are leading causes of decreased independence and lower quality of life. Additionally, the importance of social and psychological factors is increasingly recognized. Many conditions related to aging (e.g., tiredness, loneliness) may prevent elderly people from preparing and enjoying meals, calling for alternative vehicles – such as tailor-made distribution channels, social food preparation and eating situations – for promoting healthy eating.In this workshop, a range of international speakers with relevant professional experience will present their latest work. More generally, it is our intention with this workshop to raise awareness of how sensory and consumer research can contribute to promote well-being among the elderly, and ultimately to expand the number of healthy life years as we age.
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| 8. |
- Giacalone, Davide, et al.
(author)
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Health and quality of life in an aging population : food and beyond
- 2014
-
Conference paper (other academic/artistic)abstract
- In Europe, as in much of the Western world, the number of citizens aged 65 and over has grown at an unprecedented rate and is expected to account for over 30% of the total population by 2060. Coupled with a steady increase in life expectancy, this massive demographic change calls for a major effort to ensure quality of life in our older population. A thorough understanding of the elderly as food consumers, their nutritional needs, and their food perception and preferences is increasingly recognized as key areas for future research. Food perception change at a later age as a result of the psychophysiological changes that occur with aging, such as decreased appetite and chemosensory acuity. The latter generally decrease food intake and the pleasure that the elderly derive from their meals, making the identification of possible compensation strategies (e.g., flavor enhancement, textural changes, etc.) essential to food producers interested in developing products for this increasingly important segment. Promoting food satisfaction among the elderly is also paramount to ensuring adequate nutritional intake. This aspect has major public health implications, such as preventing malnutrition and sarcopenia, which are leading causes of decreased independence and lower quality of life. Additionally, the importance of social and psychological factors is increasingly recognized. Many conditions related to aging (e.g., tiredness, loneliness) may prevent elderly people from preparing and enjoying meals, calling for alternative vehicles – such as tailor-made distribution channels, social food preparation and eating situations – for promoting healthy eating. In this workshop, a range of international speakers with relevant professional experience will present their latest work. More generally, it is our intention with this workshop to raise awareness of how sensory and consumer research can contribute to promote well-being among the elderly, and ultimately to expand the number of healthy life years as we age.
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| 9. |
- Giagounidis, Aristoteles, et al.
(author)
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Outcomes in RBC transfusion-dependent patients with Low-/Intermediate-1-risk myelodysplastic syndromes with isolated deletion 5q treated with lenalidomide: a subset analysis from the MDS-004 study
- 2014
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In: European Journal of Haematology. - : Wiley. - 1600-0609 .- 0902-4441. ; 93:5, s. 429-438
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Journal article (peer-reviewed)abstract
- ObjectiveA subset analysis of the randomised, phase 3, MDS-004 study to evaluate outcomes in patients with International Prognostic Scoring System (IPSS)-defined Low-/Intermediate (Int)-1-risk myelodysplastic syndromes (MDS) with isolated del(5q). MethodsPatients received lenalidomide 10mg/d (days 1-21; n=47) or 5mg/d (days 1-28; n=43) on 28-d cycles or placebo (n=45). From the placebo and lenalidomide 5mg groups, 84% and 58% of patients, respectively, crossed over to lenalidomide 5 or 10mg at 16wk, respectively. ResultsRates of red blood cell-transfusion independence (RBC-TI) 182d were higher in the lenalidomide 10mg (57.4%; P<0.0001) and 5mg (37.2%; P=0.0001) groups vs. placebo (2.2%). Cytogenetic response rates (major+minor responses) were 56.8% (P<0.0001), 23.1% (P=0.0299) and 0%, respectively. Two-year cumulative risk of acute myeloid leukaemia progression was 12.6%, 17.4% and 16.7% in the lenalidomide 10mg, 5mg, and placebo groups, respectively. In a 6-month landmark analysis, overall survival was longer in lenalidomide-treated patients with RBC-TI 182d vs. non-responders (P=0.0072). The most common grade 3-4 adverse event was myelosuppression. ConclusionsThese data support the clinical benefits and acceptable safety profile of lenalidomide in transfusion-dependent patients with IPSS-defined Low-/Int-1-risk MDS with isolated del(5q).
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| 10. |
- Grövdal, Michael, et al.
(author)
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Maintenance treatment with azacytidine for patients with high-risk myelodysplastic syndromes (MDS) or acute myeloid leukaemia following MDS in complete remission after induction chemotherapy
- 2010
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In: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 150:3, s. 293-302
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Journal article (peer-reviewed)abstract
- This prospective Phase II study is the first to assess the feasibility and efficacy of maintenance 5-azacytidine for older patients with high-risk myelodysplastic syndrome (MDS), chronic myelomonocytic leukaemia and MDS-acute myeloid leukaemia syndromes in complete remission (CR) after induction chemotherapy. Sixty patients were enrolled and treated by standard induction chemotherapy. Patients that reached CR started maintenance therapy with subcutaneous azacytidine, 5/28 d until relapse. Promoter-methylation status of CDKN2B (P15 ink4b), CDH1 and HIC1 was examined pre-induction, in CR and 6, 12 and 24 months post CR. Twenty-four (40%) patients achieved CR after induction chemotherapy and 23 started maintenance treatment with azacytidine. Median CR duration was 13.5 months, >24 months in 17% of the patients, and 18-30.5 months in the four patients with trisomy 8. CR duration was not associated with CDKN2B methylation status or karyotype. Median overall survival was 20 months. Hypermethylation of CDH1 was significantly associated with low CR rate, early relapse, and short overall survival (P = 0.003). 5-azacytidine treatment, at a dose of 60 mg/m(2) was well tolerated. Grade III-IV thrombocytopenia and neutropenia occurred after 9.5 and 30% of the cycles, respectively, while haemoglobin levels increased during treatment. 5-azacytidine treatment is safe, feasible and may be of benefit in a subset of patients.
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