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Institution

Karolinska Institutet

EducationStockholm, Sweden
About: Karolinska Institutet is a education organization based out in Stockholm, Sweden. It is known for research contribution in the topics: Population & Poison control. The organization has 46212 authors who have published 121142 publications receiving 6008130 citations.


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Journal ArticleDOI
TL;DR: In this article, a 10-member subcommission of the Commission on Therapeutic Strategies of The International League Against Epilepsy (ILAE) evaluated available evidence found through a structured literature review including MEDLINE, Current Contents and the Cochrane Library for all applicable articles from 1940 until July 2005.
Abstract: Summary: Purpose: To assess which antiepileptic medications (AEDs) have the best evidence for long-term efficacy or effectiveness as initial monotherapy for patients with newly diagnosed or untreated epilepsy. Methods: A 10-member subcommission of the Commission on Therapeutic Strategies of The International League Against Epilepsy (ILAE), including adult and pediatric epileptologists, clinical pharmacologists, clinical trialists, and a statistician evaluated available evidence found through a structured literature review including MEDLINE, Current Contents and the Cochrane Library for all applicable articles from 1940 until July 2005. Articles dealing with different seizure types (for different age groups) and two epilepsy syndromes were assessed for quality of evidence (four classes) based on predefined criteria. Criteria for class I classification were a double-blind randomized controlled trial (RCT) design, ≥48-week treatment duration without forced exit criteria, information on ≥24-week seizure freedom data (efficacy) or ≥48-week retention data (effectiveness), demonstration of superiority or 80% power to detect a ≤20% relative difference in efficacy/effectiveness versus an adequate comparator, and appropriate statistical analysis. Class II studies met all class I criteria except for having either treatment duration of 24 to 47 weeks or, for noninferiority analysis, a power to only exclude a 21–30% relative difference. Class III studies included other randomized double-blind and open-label trials, and class IV included other forms of evidence (e.g., expert opinion, case reports). Quality of clinical trial evidence was used to determine the strength of the level of recommendation. Results: A total of 50 RCTs and seven meta-analyses contributed to the analysis. Only four RCTs had class I evidence, whereas two had class II evidence; the remainder were evaluated as class III evidence. Three seizure types had AEDs with level A or level B efficacy and effectiveness evidence as initial monotherapy: adults with partial-onset seizures (level A, carbamazepine and phenytoin; level B, valproic acid), children with partial-onset seizures (level A, oxcarbazepine; level B, None), and elderly adults with partial-onset seizures (level A, gabapentin and lamotrigine; level B, None). One adult seizure type [adults with generalized-onset tonic–clonic (GTC) seizures], two pediatric seizure types (GTC seizures and absence seizures), and two epilepsy syndromes (benign epilepsy with centrotemporal spikes and juvenile myoclonic epilepsy) had no AEDs with level A or level B efficacy and effectiveness evidence as initial monotherapy. Conclusions: This evidence-based guideline focused on AED efficacy or effectiveness as initial monotherapy for patients with newly diagnosed or untreated epilepsy. The absence of rigorous comprehensive adverse effects data makes it impossible to develop an evidence-based guideline aimed at identifying the overall optimal recommended initial-monotherapy AED. There is an especially alarming lack of well-designed, properly conducted RCTs for patients with generalized seizures/epilepsies and for children in general. The majority of relevant existing RCTs have significant methodologic problems that limit their applicability to this guideline's clinically relevant main question. Multicenter, multinational efforts are needed to design, conduct and analyze future clinically relevant RCTs that can answer the many outstanding questions identified in this guideline. The ultimate choice of an AED for any individual patient with newly diagnosed or untreated epilepsy should include consideration of the strength of the efficacy and effectiveness evidence for each AED along with other variables such as the AED safety and tolerability profile, pharmacokinetic properties, formulations, and expense. When selecting a patient's AED, physicians and patients should consider all relevant variables and not just efficacy and effectiveness.

704 citations

Journal ArticleDOI
Veryan Codd1, Christopher P. Nelson1, Eva Albrecht, Massimo Mangino2, Joris Deelen3, Jessica L. Buxton4, Jouke-Jan Hottenga5, Krista Fischer6, Tõnu Esko6, Ida Surakka7, Linda Broer, Dale R. Nyholt8, Irene Mateo Leach9, Perttu Salo, Sara Hägg10, Mary K. Matthews1, Jutta Palmen11, Giuseppe Danilo Norata, Paul F. O'Reilly4, Danish Saleheen12, Najaf Amin13, Anthony J. Balmforth14, Marian Beekman3, Rudolf A. de Boer9, Stefan Böhringer3, Peter S. Braund1, Paul Burton1, Anton J. M. de Craen3, Matthew Denniff1, Yanbin Dong15, Konstantinos Douroudis6, Elena Dubinina1, Johan G. Eriksson, Katia Garlaschelli, Dehuang Guo15, Anna-Liisa Hartikainen16, Anjali K. Henders8, Jeanine J. Houwing-Duistermaat3, Laura Kananen7, Lennart C. Karssen13, Johannes Kettunen7, Norman Klopp, Vasiliki Lagou17, Elisabeth M. van Leeuwen13, Pamela A. F. Madden18, Reedik Mägi6, Patrik K. E. Magnusson10, Satu Männistö19, Satu Männistö20, Mark I. McCarthy17, Mark I. McCarthy21, Mark I. McCarthy22, Sarah E. Medland8, Evelin Mihailov6, Grant W. Montgomery8, Ben A. Oostra13, Aarno Palotie, Annette Peters, Helen Pollard1, Anneli Pouta19, Anneli Pouta16, Inga Prokopenko17, Samuli Ripatti, Veikko Salomaa19, Veikko Salomaa20, H. Eka D. Suchiman3, Ana M. Valdes2, Niek Verweij9, Ana Viñuela2, Xiaoling Wang23, Xiaoling Wang24, H-Erich Wichmann25, Elisabeth Widen7, Gonneke Willemsen5, Margaret J. Wright8, Kai Xia26, Xiangjun Xiao27, Dirk J. van Veldhuisen9, Alberico L. Catapano28, Martin D. Tobin1, Alistair S. Hall14, Alexandra I. F. Blakemore4, Wiek H. van Gilst9, Haidong Zhu23, Haidong Zhu24, Jeanette Erdmann, Muredach P. Reilly29, Sekar Kathiresan30, Sekar Kathiresan31, Heribert Schunkert, Philippa J. Talmud11, Nancy L. Pedersen10, Markus Perola6, Markus Perola7, Markus Perola19, Willem H. Ouwehand, Jaakko Kaprio, Nicholas G. Martin8, Cornelia M. van Duijn, Iiris Hovatta19, Iiris Hovatta7, Christian Gieger11, Andres Metspalu6, Dorret I. Boomsma5, Marjo-Riitta Järvelin, P. Eline Slagboom3, John R Thompson1, Tim D. Spector2, Pim van der Harst1, Nilesh J. Samani1, Nilesh J. Samani32 
TL;DR: In this paper, a genome-wide meta-analysis of 37,684 individuals with replication of selected variants in an additional 10,739 individuals was carried out to identify seven loci, including five new loci associated with mean leukocyte telomere length (LTL) (P < 5 × 10−8).
Abstract: Interindividual variation in mean leukocyte telomere length (LTL) is associated with cancer and several age-associated diseases. We report here a genome-wide meta-analysis of 37,684 individuals with replication of selected variants in an additional 10,739 individuals. We identified seven loci, including five new loci, associated with mean LTL (P < 5 × 10(-8)). Five of the loci contain candidate genes (TERC, TERT, NAF1, OBFC1 and RTEL1) that are known to be involved in telomere biology. Lead SNPs at two loci (TERC and TERT) associate with several cancers and other diseases, including idiopathic pulmonary fibrosis. Moreover, a genetic risk score analysis combining lead variants at all 7 loci in 22,233 coronary artery disease cases and 64,762 controls showed an association of the alleles associated with shorter LTL with increased risk of coronary artery disease (21% (95% confidence interval, 5-35%) per standard deviation in LTL, P = 0.014). Our findings support a causal role of telomere-length variation in some age-related diseases.

703 citations

Journal ArticleDOI
TL;DR: It is proposed that HIV-1 can spread using nanotubular connections formed by short-term intercellular unions in which T cells specialize, and an extracellular matrix scaffold allows T-cell nanotubes to adopt variably shaped contours.
Abstract: Transmission of HIV-1 via intercellular connections has been estimated as 100-1000 times more efficient than a cell-free process, perhaps in part explaining persistent viral spread in the presence of neutralizing antibodies. Such effective intercellular transfer of HIV-1 could occur through virological synapses or target-cell filopodia connected to infected cells. Here we report that membrane nanotubes, formed when T cells make contact and subsequently part, provide a new route for HIV-1 transmission. Membrane nanotubes are known to connect various cell types, including neuronal and immune cells, and allow calcium-mediated signals to spread between connected myeloid cells. However, T-cell nanotubes are distinct from open-ended membranous tethers between other cell types, as a dynamic junction persists within T-cell nanotubes or at their contact with cell bodies. We also report that an extracellular matrix scaffold allows T-cell nanotubes to adopt variably shaped contours. HIV-1 transfers to uninfected T cells through nanotubes in a receptor-dependent manner. These data lead us to propose that HIV-1 can spread using nanotubular connections formed by short-term intercellular unions in which T cells specialize.

702 citations

Journal ArticleDOI
TL;DR: The epigenetic changes described most likely represent molecular mechanisms responsible for the rapid progression of premature aging in HGPS patients.
Abstract: The premature aging disease Hutchinson–Gilford Progeria Syndrome (HGPS) is caused by a mutant lamin A (LAΔ50). Nuclei in cells expressing LAΔ50 are abnormally shaped and display a loss of heterochromatin. To determine the mechanisms responsible for the loss of heterochromatin, epigenetic marks regulating either facultative or constitutive heterochromatin were examined. In cells from a female HGPS patient, histone H3 trimethylated on lysine 27 (H3K27me3), a mark for facultative heterochromatin, is lost on the inactive X chromosome (Xi). The methyltransferase responsible for this mark, EZH2, is also down-regulated. These alterations are detectable before the changes in nuclear shape that are considered to be the pathological hallmarks of HGPS cells. The results also show a down-regulation of the pericentric constitutive heterochromatin mark, histone H3 trimethylated on lysine 9, and an altered association of this mark with heterochromatin protein 1α (Hp1α) and the CREST antigen. This loss of constitutive heterochromatin is accompanied by an up-regulation of pericentric satellite III repeat transcripts. In contrast to these decreases in histone H3 methylation states, there is an increase in the trimethylation of histone H4K20, an epigenetic mark for constitutive heterochromatin. Expression of LAΔ50 in normal cells induces changes in histone methylation patterns similar to those seen in HGPS cells. The epigenetic changes described most likely represent molecular mechanisms responsible for the rapid progression of premature aging in HGPS patients.

702 citations

Journal ArticleDOI
TL;DR: Evidence was obtained that at least some cell bodies in the medullary raphe nuclei and adjacent areas contained all three compounds, 5-hydroxytryptamine, thyrotropin releasing hormone (TRH) and substance P immunoreactive neurons in normal and colchicine-treated rats.

700 citations


Authors

Showing all 46522 results

NameH-indexPapersCitations
Meir J. Stampfer2771414283776
Albert Hofman2672530321405
Guido Kroemer2361404246571
Eric B. Rimm196988147119
Scott M. Grundy187841231821
Jing Wang1844046202769
Tadamitsu Kishimoto1811067130860
John Hardy1771178171694
Marc G. Caron17367499802
Ramachandran S. Vasan1721100138108
Adrian L. Harris1701084120365
Douglas F. Easton165844113809
Zulfiqar A Bhutta1651231169329
Judah Folkman165499148611
Ralph A. DeFronzo160759132993
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Performance
Metrics
No. of papers from the Institution in previous years
YearPapers
2023101
2022500
20217,763
20206,922
20196,057
20185,548