Author
Yoshiki Sekijima
Other affiliations: Institute of Medical Science, Boston University, Scripps Research Institute
Bio: Yoshiki Sekijima is an academic researcher from Shinshu University. The author has contributed to research in topics: Transthyretin & Amyloidosis. The author has an hindex of 36, co-authored 216 publications receiving 6686 citations. Previous affiliations of Yoshiki Sekijima include Institute of Medical Science & Boston University.
Papers published on a yearly basis
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National Taiwan University1, Kumamoto University2, Heidelberg University3, University of Münster4, Boston University5, University of Messina6, University of British Columbia7, University of Barcelona8, Columbia University9, Sungkyunkwan University10, Konkuk University11, Istanbul University12, Shinshu University13, University College London14, Harvard University15, Johns Hopkins University16, Mayo Clinic17, Alnylam Pharmaceuticals18, Umeå University19
TL;DR: Patisiran improved multiple clinical manifestations of hereditary transthyretin amyloidosis with polyneuropathy and showed an effect on gait speed and modified BMI.
Abstract: BACKGROUND: Patisiran, an investigational RNA interference therapeutic agent, specifically inhibits hepatic synthesis of transthyretin.METHODS: In this phase 3 trial, we randomly assigned patients ...
1,671 citations
TL;DR: Among patients with familial amyloid polyneuropathy, the use of diflunisal compared with placebo for 2 years reduced the rate of progression of neurological impairment and preserved quality of life.
Abstract: RESULTS By multiple imputation, the NIS+7 score increased by 25.0 (95% CI, 18.4-31.6) points in the placebo group and by 8.7 (95% CI, 3.3-14.1) points in the diflunisal group, a difference of 16.3 points (95% CI, 8.1-24.5 points; P < .001). Mean SF-36 physical scores decreased by 4.9 (95% CI, −7.6 to −2.2) points in the placebo group and increased by 1.5 (95% CI, −0.8 to 3.7) points in the diflunisal group (P < .001). Mean SF-36 mental scores declined by 1.1 (95% CI, −4.3 to 2.0) points in the placebo group while increasing by 3.7 (95% CI, 1.0-6.4) points in the diflunisal group (P = .02). By responder analysis, 29.7% of the diflunisal group and 9.4% of the placebo group exhibited neurological stability at 2 years (<2-point increase in NIS+7 score; P = .007). CONCLUSIONS AND RELEVANCE Among patients with familial amyloid polyneuropathy, the use of diflunisal compared with placebo for 2 years reduced the rate of progression of neurological impairment and preserved quality of life. Although longer-term follow-up studies are needed, these findings suggest benefit of this treatment for familial amyloid polyneuropathy.
539 citations
TL;DR: It is demonstrated that mammalian cells secrete numerous transthyretin disease-associated variants with wild-type efficiency in spite of compromised folding energetics and proposed that ERAF (influenced by the energetICS of the protein fold, chaperone enzyme distributions, and metabolite chaperones) in competition with ERAD defines the unique secretory aptitude of each tissue.
424 citations
TL;DR: A new gene encoding a member of the histidine triad (HIT) superfamily as the 'causative' gene is identified and called aprataxin; the gene symbol is APTX and it is the first to be linked to a distinct phenotype.
Abstract: Friedreich ataxia (FRDA), the most common autosomal recessive neurodegenerative disease among Europeans and people of European descent, is characterized by an early onset (usually before the age of 25), progressive ataxia, sensory loss, absence of tendon reflexes and pyramidal weakness of the legs1,2,3,4. We have recently identified a unique group of patients whose clinical presentations are characterized by autosomal recessive inheritance, early age of onset, FRDA-like clinical presentations and hypoalbuminemia. Linkage to the FRDA locus, however, was excluded. Given the similarities of the clinical presentations to those of the recently described ataxia with oculomotor apraxia (AOA) linked to chromosome 9p13, we confirmed that the disorder of our patients is also linked to the same locus5. We narrowed the candidate region and have identified a new gene encoding a member of the histidine triad (HIT) superfamily as the 'causative' gene. We have called its product aprataxin; the gene symbol is APTX. Although many HIT proteins have been identified, aprataxin is the first to be linked to a distinct phenotype.
364 citations
TL;DR: The nomenclature committee of the International Society of Amyloidosis (ISA) meets every second year to discuss and formulate recommendations as discussed by the authors, and the conclusions from the discussion at the XVI International Symposium on Amyloids in Kumamoto, Japan, 25-29 March 2018 and afterwards are summarized in this Nomenclatures Article.
Abstract: The nomenclature committee of the International Society of Amyloidosis (ISA) meets every second year to discuss and formulate recommendations. The conclusions from the discussion at the XVI International Symposium on Amyloidosis in Kumamoto, Japan, 25-29 March 2018 and afterwards are summarized in this Nomenclature Article. From having recommended the use of the designation "amyloid fibril" for in vivo material only, ISA's nomenclature committee now accepts its use more broadly following the international scientific literature. However, it is important always to stress the origin of the β-fibrils in order to avoid misunderstanding. Given the more broad use of the word "amyloid" several classes of amyloid fibrils may be distinguished. For the medical in vivo situation, and to be included in the amyloid nomenclature list, "amyloid" still means mainly extracellular tissue deposits of protein fibrils, recognized by specific properties, such as green-yellow birefringence after staining with Congo red. It should also be underlined that in vivo amyloid fibrils, in addition to the main protein contain associated compounds, particularly serum amyloid P-component (SAP) and proteoglycans, mainly heparan sulfate proteoglycan. With this definition there are presently 36 human amyloid proteins of which 14 appear only associated with systemic amyloidosis and 19 as localized forms. Three proteins can occur both as localized and systemic amyloidosis. Strictly intracellular aggregates are not included in this list.
363 citations
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TL;DR: Evidence that the presenilin proteins, mutations in which cause the most aggressive form of inherited AD, lead to altered intramembranous cleavage of the beta-amyloid precursor protein by the protease called gamma-secretase has spurred progress toward novel therapeutics and provided discrete biochemical targets for drug screening and development.
Abstract: Rapid progress in deciphering the biological mechanism of Alzheimer's disease (AD) has arisen from the application of molecular and cell biology to this complex disorder of the limbic and association cortices. In turn, new insights into fundamental aspects of protein biology have resulted from research on the disease. This beneficial interplay between basic and applied cell biology is well illustrated by advances in understanding the genotype-to-phenotype relationships of familial Alzheimer's disease. All four genes definitively linked to inherited forms of the disease to date have been shown to increase the production and/or deposition of amyloid β-protein in the brain. In particular, evidence that the presenilin proteins, mutations in which cause the most aggressive form of inherited AD, lead to altered intramembranous cleavage of the β-amyloid precursor protein by the protease called γ-secretase has spurred progress toward novel therapeutics. The finding that presenilin itself may be the long-sought γ-...
5,890 citations
TL;DR: Together, at least three mechanistically distinct arms of the UPR regulate the expression of numerous genes that function within the secretory pathway but also affect broad aspects of cell fate and the metabolism of proteins, amino acids and lipids.
Abstract: The endoplasmic reticulum (ER) responds to the accumulation of unfolded proteins in its lumen (ER stress) by activating intracellular signal transduction pathways - cumulatively called the unfolded protein response (UPR). Together, at least three mechanistically distinct arms of the UPR regulate the expression of numerous genes that function within the secretory pathway but also affect broad aspects of cell fate and the metabolism of proteins, amino acids and lipids. The arms of the UPR are integrated to provide a response that remodels the secretory apparatus and aligns cellular physiology to the demands imposed by ER stress.
5,701 citations
TL;DR: It is concluded that multiple Imputation for Nonresponse in Surveys should be considered as a legitimate method for answering the question of why people do not respond to survey questions.
Abstract: 25. Multiple Imputation for Nonresponse in Surveys. By D. B. Rubin. ISBN 0 471 08705 X. Wiley, Chichester, 1987. 258 pp. £30.25.
3,216 citations
TL;DR: In this paper, a longitudinal study of 128 patients with Alzheimer's disease was conducted, where the authors used the participant's age at baseline assessment and the parent's age to calculate the estimated years from expected symptom onset (age of the participant minus parent's ages at symptom onset).
Abstract: A B S T R AC T BACKGROUND The order and magnitude of pathologic processes in Alzheimer’s disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer’s disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease. METHODS In this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participant’s age at baseline assessment and the parent’s age at the onset of symptoms of Alzheimer’s disease to calculate the estimated years from expected symptom onset (age of the participant minus parent’s age at symptom onset). We conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiological changes. RESULTS Concentrations of amyloid-beta (Aβ)42 in the CSF appeared to decline 25 years before expected symptom onset. Aβ deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini–Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset. CONCLUSIONS We found that autosomal dominant Alzheimer’s disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer’s disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Our results require confirmation with the use of longitudinal data and may not apply to patients with sporadic Alzheimer’s disease. (Funded by the National Institute on Aging and others; DIAN ClinicalTrials.gov number, NCT00869817.)
2,907 citations
Journal Article•
TL;DR: High-dose of intravenous immunoglobulin (0.4 g/kg daily for 5 days) and PE are equally effective in intermediate and severe forms and the choice between the two treatments depends on their respective contra-indications and local availability.
Abstract: L'incidence annuelle du syndrome de Guillain-Barre est de 1,5/100000 habitants La mortalite actuelle est estimee a environ 5 % d'apres des essais therapeutiques recents, bien conduits Dix pour cent des malades gardent des sequelles motrices tres invalidantes un an apres le debut des premiers signes neurologiques La prise en charge de ces malades necessite des equipes entrainees, multidisciplinaires, pouvant pratiquer l'ensemble des therapeutiques specifiques La corticotherapie per os'ou par voie intraveineuse est inefficace Les echanges plasmatiques sont le premier traitement dont l'efficacite a ete demontree par rapport a un groupe controle Les indications sont maintenant mieux connues Les formes benignes (marche possible) beneficient de 2 echanges plasmatiques; 2 echanges supplementaires sont realises en cas d'aggravation Dans les formes intermediaires (marche impossible) et les formes severes (recours a la ventilation mecanique), 4 echanges plasmatiques sont conseilles Il n'est pas utile d'augmenter leur nombre dans les formes severes ou en cas d'absence d'amelioration De fortes doses d'immunoglobulines donnees par voie intraveineuse (lq IV) [0,4 g/kg/j pendant 5 jours] sont aussi efficaces que les echanges plasmatiques dans les formes intermediaires et severes Dans ces formes, le choix entre Ig IV et echanges plasmatiques depend des contre-indications respectives de ces traitements et de leur faisabilite Les travaux en cours ont comme objectif de mieux preciser les indications respectives des echanges plasmatiques et des lq IV dans des formes de gravite differente, leur morbidite comparee, la dose optimale des lq IV
1,842 citations