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Article ; Online: New reference limits for cardiac troponin T and N-terminal b-type natriuretic propeptide in elders.

Heikkilä, Elisa / Katajamäki, Taina / Salminen, Marika / Irjala, Kerttu / Viljanen, Anna / Koivula, Marja-Kaisa / Pulkki, Kari / Isoaho, Raimo / Kivelä, Sirkka-Liisa / Viitanen, Matti / Löppönen, Minna / Vahlberg, Tero / Viikari, Laura

Clinica chimica acta; international journal of clinical chemistry

2024 Volume 556, Page(s) 117844

Abstract: Background and aims: Our aim was to define reference limits for cardiac troponin T (cTnT) and N ...

Abstract	Background and aims: Our aim was to define reference limits for cardiac troponin T (cTnT) and N-terminal pro B-type natriuretic peptide (proBNP) that would better reflect their concentrations in older people. In addition, the incidence of acute myocardial infarctions (AMIs) was studied using these reference limits in an older population with and without previous heart diseases. Materials and methods: A population-based study with a ten-year follow-up. The reference population was formed by 763 individuals aged over 64 years, with no diagnoses of heart or kidney diseases. Results: There was a significant increase in cTnT and proBNP concentrations with age. The 99 % reference limits for cTnT were 25 ng/L, 28 ng/l, 38 ng/l, and 71 ng/l for men in five-year-intervals starting from 64 to 69 years to 80 years and older, and 18 ng/L, 22 ng/l, 26 ng/l, and 52 ng/L for women, respectively. The 97.5 % reference limits for proBNP were 272 ng/L, 287 ng/l, 373 ng/l and 686 ng/L for men, and 341 ng/L, 377 ng/l, 471 ng/l, and 794 ng/L for women, respectively. Elevated proBNP was statistically significantly associated with future AMIs in subjects with and without a previous heart disease. Conclusions: Age-specific reference limits for cTnT and proBNP are needed to better evaluate cardiac symptoms.
MeSH term(s)	Male ; Humans ; Female ; Aged ; Troponin T ; Biomarkers ; Myocardial Infarction/diagnosis ; Heart ; Heart Diseases ; Peptide Fragments ; Natriuretic Peptide, Brain
Chemical Substances	Troponin T ; Biomarkers ; Peptide Fragments ; Natriuretic Peptide, Brain (114471-18-0)
Language	English
Publishing date	2024-02-23
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	80228-1
ISSN	1873-3492 ; 0009-8981
ISSN (online)	1873-3492
ISSN	0009-8981
DOI	10.1016/j.cca.2024.117844
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Article ; Online: Epithelial recurrent erosion dystrophy (ERED) from the splice site altering COL17A1 variant c.3156C>T in families of Finnish-Swedish ancestry.

Turunen, Joni A / Tuisku, Ilpo S / Repo, Pauliina / Mörtenhumer, Sanna / Kawan, Sabita / Järvinen, Reetta-Stiina / Korsbäck, Anna / Immonen, Annamari T / Kivelä, Tero T

Acta ophthalmologica

2023 Volume 102, Issue 3, Page(s) 296–305

Abstract: ... caused by the pathogenic variant c.3156C>T in collagen type XVII alpha 1 chain gene (COL17A1).: Methods ... immunohistochemistry.: Results: The common splice-site altering synonymous variant c.3156C > T, p.(Gly1052 ... reports of the c.3156C > T variant, although the severity has varied between reports. The phenotype may be ...

Abstract	Purpose: To describe four Finnish families with epithelial recurrent erosion dystrophy (ERED) caused by the pathogenic variant c.3156C>T in collagen type XVII alpha 1 chain gene (COL17A1). Methods: Eleven affected and two unaffected individuals underwent clinical ophthalmological examination, anterior segment photography, and corneal topography. Two of them underwent phototherapeutic keratectomy (PTK). Genetic analysis included both next-generation and Sanger sequencing. Specimens from the manual keratectomy of one patient were available for ophthalmic pathologic examination, including immunohistochemistry. Results: The common splice-site altering synonymous variant c.3156C > T, p.(Gly1052=) in COL17A1 was confirmed in 15 individuals with ERED from the four families. Subepithelial corneal scarring grades varied and increased with age, leading to decreased best-corrected visual acuity. PTK improved vision in 58- and 67-year-old individuals without reactivating the disease. The keratectomy specimens showed an uneven epithelium and a spectrum of basement membrane abnormalities, including breaks, fragmentation, multiplication and entrapment within the subepithelial scar, reflecting recurrent erosions. The stromal cells consisted of varying proportions of bland and activated fibroblasts and myofibroblasts, reflecting different ages of scars. The family with the largest number of known affected generations originated from Southern Sweden. Conclusion: The phenotype in the Finnish ERED families is consistent with earlier reports of the c.3156C > T variant, although the severity has varied between reports. The phenotype may be modulated by other genes. This study suggests a likely founder effect of the variant in both Finnish and Swedish populations due to their shared population histories. If vision is compromised, PTK can be considered especially in older patients.
MeSH term(s)	Aged ; Humans ; Middle Aged ; Corneal Dystrophies, Hereditary/diagnosis ; Corneal Dystrophies, Hereditary/genetics ; Corneal Dystrophies, Hereditary/surgery ; Epithelium, Corneal/pathology ; Finland/epidemiology ; Photorefractive Keratectomy ; Sweden
Language	English
Publishing date	2023-06-08
Publishing country	England
Document type	Journal Article
ZDB-ID	2408333-1
ISSN	1755-3768 ; 1755-375X
ISSN (online)	1755-3768
ISSN	1755-375X
DOI	10.1111/aos.15716
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Article ; Online: Keratitis fugax hereditaria: hiding in plain sight in Sweden?

Kivelä, Tero T

Acta ophthalmologica

2022 Volume 100, Issue 6, Page(s) 603–604

MeSH term(s)	Humans ; Keratitis/congenital ; Keratitis/diagnosis ; Sweden/epidemiology
Language	English
Publishing date	2022-08-10
Publishing country	England
Document type	Editorial
ZDB-ID	2408333-1
ISSN	1755-3768 ; 1755-375X
ISSN (online)	1755-3768
ISSN	1755-375X
DOI	10.1111/aos.15064
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Article ; Online: Beware of Polymegathism.

Kivelä, Tero T

Cornea

2021 Volume 40, Issue 7, Page(s) e15

MeSH term(s)	Cell Size ; Endothelium, Corneal/pathology ; Eye Diseases, Hereditary/pathology ; Genetic Diseases, X-Linked/pathology ; Humans ; Ophthalmology ; Societies, Medical ; Terminology as Topic
Language	English
Publishing date	2021-03-25
Publishing country	United States
Document type	Letter
ZDB-ID	604826-2
ISSN	1536-4798 ; 0277-3740
ISSN (online)	1536-4798
ISSN	0277-3740
DOI	10.1097/ICO.0000000000002732
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Article ; Online: Clinical and Histopathologic Characteristics and Template of the TGFBI p.(His626Arg) Missense Variant Lattice Corneal Dystrophy.

Jaakkola, Aino M / Kivelä, Tero T

Cornea

2023 Volume 42, Issue 9, Page(s) 1124–1132

Abstract: Purpose: The aim of this study was to define, following the IC3D template format, the clinical and histopathologic phenotype of the p.(His626Arg) missense variant lattice corneal dystrophy (LCDV-H626R), the most common variant lattice dystrophy, and to ... ...

Abstract	Purpose: The aim of this study was to define, following the IC3D template format, the clinical and histopathologic phenotype of the p.(His626Arg) missense variant lattice corneal dystrophy (LCDV-H626R), the most common variant lattice dystrophy, and to record long-term outcome of corneal transplantation in this dystrophy. Methods: A database search and a meta-analysis of published data on LCDV-H626R were conducted. A patient diagnosed with LCDV-H626R who underwent bilateral lamellar keratoplasty followed by rekeratoplasty of 1 eye is described, including histopathologic examination of the 3 keratoplasty specimens. Results: One hundred forty-five patients from at least 61 families and 11 countries diagnosed with LCDV-H626R were found. This dystrophy is characterized by recurrent erosions, asymmetric progression, and thick lattice lines that extend to corneal periphery. The median age is 37 (range, 25-59) years at the onset of symptoms, 45 (range, 26-62) years at the time of diagnosis, and 50 (range, 41-78) years at the time of the first keratoplasty, suggesting a median interval from the first symptoms to diagnosis and to keratoplasty of 7 and 12 years, respectively. Clinically unaffected carriers have been of age 6 to 45 years. Central anterior stromal haze and centrally thick, peripherally thinner branching lattice lines in the anterior to midstroma of the cornea were noted preoperatively. Histopathology of the host anterior corneal lamella showed a subepithelial fibrous pannus, a destroyed Bowman layer, and amyloid deposits extending to the deep stroma. In the rekeratoplasty specimen, amyloid localized to scarring along the Bowman membrane and to the margins of the graft. Conclusions: The IC3D-type template for LCDV-H626R should help diagnose and manage variant carriers. The histopathologic spectrum of findings is broader and more nuanced than what has been reported.
MeSH term(s)	Humans ; Amyloid Neuropathies, Familial ; Cornea/pathology ; Corneal Dystrophies, Hereditary/diagnosis ; Corneal Dystrophies, Hereditary/genetics ; Corneal Dystrophies, Hereditary/surgery ; Corneal Transplantation ; Extracellular Matrix Proteins/genetics ; Mutation, Missense ; Transforming Growth Factor beta/genetics
Chemical Substances	Extracellular Matrix Proteins ; Transforming Growth Factor beta ; betaIG-H3 protein (148710-76-3)
Language	English
Publishing date	2023-02-10
Publishing country	United States
Document type	Meta-Analysis ; Journal Article
ZDB-ID	604826-2
ISSN	1536-4798 ; 0277-3740
ISSN (online)	1536-4798
ISSN	0277-3740
DOI	10.1097/ICO.0000000000003247
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Article ; Online: Functional assay for assessment of pathogenicity of BAP1 variants.

Repo, Pauliina E / Backlund, Michael P / Kivelä, Tero T / Turunen, Joni A

Human molecular genetics

2024 Volume 33, Issue 5, Page(s) 426–434

Abstract: ... confluence later, and CI was 78% reduced (p < 0.0001). BAP1-TPDS-associated null variants c.67+1G>T and c ... both by at least 50% (all p ≤ 0.032), whereas cells edited with likely benign one c.1526C>T grew similarly to WT ...

Abstract	Background: Pathogenic germline variants in BRCA1-Associated Protein 1 (BAP1) cause BAP1 tumor predisposition syndrome (BAP1-TPDS). Carriers run especially a risk of uveal (UM) and cutaneous melanoma, malignant mesothelioma, and clear cell renal carcinoma. Approximately half of increasingly reported BAP1 variants lack accurate classification. Correct interpretation of pathogenicity can improve prognosis of the patients through tumor screening with better understanding of BAP1-TPDS. Methods: We edited five rare BAP1 variants with differing functional characteristics identified from patients with UM in HAP1 cells using CRISPR-Cas9 and assayed their effect on cell adhesion/spreading (at 4 h) and proliferation (at 48 h), measured as cell index (CI), using xCELLigence real-time analysis system. Results: In BAP1 knockout HAP1 cultures, cell number was half of wild type (WT) cultures at 48 h (p = 0.00021), reaching confluence later, and CI was 78% reduced (p < 0.0001). BAP1-TPDS-associated null variants c.67+1G>T and c.1780_1781insT, and a likely pathogenic missense variant c.281A>G reduced adhesion (all p ≤ 0.015) and proliferation by 74%-83% (all p ≤ 0.032). Another likely pathogenic missense variant c.680G>A reduced both by at least 50% (all p ≤ 0.032), whereas cells edited with likely benign one c.1526C>T grew similarly to WT. Conclusions: BAP1 is essential for optimal fitness of HAP1 cells. Pathogenic and likely pathogenic BAP1 variants reduced cell fitness, reflected in adhesion/spreading and proliferation properties. Further, moderate effects were quantifiable. Variant modelling in HAP1 with CRISPR-Cas9 enabled functional analysis of coding and non-coding region variants in an endogenous expression system.
MeSH term(s)	Humans ; Melanoma/pathology ; Skin Neoplasms ; Virulence ; Genetic Predisposition to Disease ; Uveal Neoplasms ; Germ-Line Mutation/genetics ; Ubiquitin Thiolesterase/genetics ; Ubiquitin Thiolesterase/metabolism ; Kidney Neoplasms ; Tumor Suppressor Proteins/genetics
Chemical Substances	Ubiquitin Thiolesterase (EC 3.4.19.12) ; BAP1 protein, human ; Tumor Suppressor Proteins
Language	English
Publishing date	2024-01-08
Publishing country	England
Document type	Journal Article
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddad193
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Article ; Online: Histopathology of Exfoliation Syndrome.

Kivelä, Tero T

Journal of glaucoma

2018 Volume 27 Suppl 1, Page(s) S38–S43

Abstract: Exfoliation syndrome (XFS) is characterized by light and electron microscopy by age-dependent gradual accumulation of whitish material of largely unknown composition and origin along both the anterior and posterior chambers and widely within the iris ... ...

Abstract	Exfoliation syndrome (XFS) is characterized by light and electron microscopy by age-dependent gradual accumulation of whitish material of largely unknown composition and origin along both the anterior and posterior chambers and widely within the iris stroma. These deposits can be fairly specifically labeled with selected antibodies and lectins. Immunohistochemistry shows that intraocular exfoliation deposits share antigens with the microfibrillar elastic fiber system and several basement membrane components, including carbohydrate epitopes on glycosaminoglycans, proteoglycans, and cell adhesion molecules. The earliest histopathologic manifestation of XFS seems to be the deposition of characteristic fibers in various extraocular and anterior segment tissues, as observed by electron microscopy, and perivascular deposition of material within the iris stroma, which is antigenically typical of that found in classic intraocular exfoliation deposits. These findings precede the clinical diagnosis of XFS and likewise can be detected in the seemingly uninvolved fellow eyes of patients with clinically unilateral XFS. Indeed, histopathologic examination of capsulotomy, iridectomy, and trabeculectomy specimens can lead to a clinically unexpected diagnosis of XFS. Exfoliation fibers are additionally found widely distributed in extraocular connective tissues and visceral organs, but the matrix of these fibers seems to differ from that of intraocular deposits. In addition to this histopathologic discrepancy, both the frequent occurrence of clinically unilateral, histopathologically highly asymmetric exfoliation deposits, and the relationship between the early iris vasculopathy that not infrequently may be observed histopathologically for years before classic widespread exfoliation deposits appear along the anterior and posterior chambers remain to be resolved.
MeSH term(s)	Anterior Eye Segment/pathology ; Elastic Tissue/pathology ; Exfoliation Syndrome/pathology ; Glaucoma, Open-Angle/pathology ; Humans ; Intraocular Pressure ; Trabeculectomy
Language	English
Publishing date	2018-03-10
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	913494-3
ISSN	1536-481X ; 1057-0829
ISSN (online)	1536-481X
ISSN	1057-0829
DOI	10.1097/IJG.0000000000000947
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Article ; Online: Letter to the editor: Keratitis fugax hereditaria is an eye-specific cryopyrin-associated periodic syndrome.

Turunen, Joni A / Immonen, Annamari T / Kivelä, Tero T

Autoimmunity reviews

2022 Volume 21, Issue 7, Page(s) 103054

MeSH term(s)	Cryopyrin-Associated Periodic Syndromes/complications ; Cryopyrin-Associated Periodic Syndromes/diagnosis ; Cryopyrin-Associated Periodic Syndromes/genetics ; Humans ; Keratitis/congenital ; Keratitis/diagnosis ; Keratitis/genetics ; NLR Family, Pyrin Domain-Containing 3 Protein
Chemical Substances	NLR Family, Pyrin Domain-Containing 3 Protein
Language	English
Publishing date	2022-01-26
Publishing country	Netherlands
Document type	Letter ; Comment
ZDB-ID	2144145-5
ISSN	1873-0183 ; 1568-9972
ISSN (online)	1873-0183
ISSN	1568-9972
DOI	10.1016/j.autrev.2022.103054
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Article ; Online: Sleep medicines are often prescribed for older adults (≥75 years) without appropriate dosing instructions: A nationwide retrospective register study in Finland.

Eronen, Sini-Tuulia / Kurko, Terhi / Kivelä, Sirkka-Liisa / Paunio, Tiina / Airaksinen, Marja / Rantamäki, Tomi

Acta psychiatrica Scandinavica

2024 Volume 149, Issue 4, Page(s) 350–360

Abstract: Background: Sleep medicines should be prescribed cautiously, accompanied by instructions that ensure appropriate use and reduce risks. This is especially important for older adults, for whom many of these medicines are classified as potentially ... ...

Abstract	Background: Sleep medicines should be prescribed cautiously, accompanied by instructions that ensure appropriate use and reduce risks. This is especially important for older adults, for whom many of these medicines are classified as potentially inappropriate medicines. Methods: We investigated the use and appropriateness of dosing instructions for sleep medicines (described in the Finnish National Current Care Guideline for Insomnia) prescribed for older adults (≥75 years) and dispensed with instruction label in pharmacies. The retrospective reimbursement register data for year 2020 by the Social Insurance Institution of Finland was used as the data source (1,080,843 purchases by 143,886 individuals of which 565,228 purchases were pharmacy dispenses). The appropriateness of the pharmacy dosing instructions containing keyword(s) referring to insomnia treatment was examined according to the prescribed dose, time of intake, frequency of use, and warnings/remarks. A random sample of 1000 instructions was used to manually analyze the phrasing and appropriateness. Outcomes: We focused our analysis on 58.1% (328,285 purchases by 87,396 individuals) of the pharmacy dispenses, which contained dosing instructions referring insomnia treatment. Of these, zopiclone and mirtazapine were the most prescribed drugs (134,631 and 112,463 purchases, respectively). Dose and time of intake were specified in most of the instructions (98.4% and 83.4%, respectively), whereas frequency of use was specified in 57.3%. A small percentage of the instructions included warnings/remarks (2.8%). Overall, only 2.1% of the instructions contained information about a single dose, time of intake, temporary use, and warnings/remarks and were thus defined as sufficient. Notably, 47.7% (n = 515,615) of all the purchases in our dataset were dispensed via automated multi-dose dispensing systems, which is aimed for long-term treatment. Interpretation: It is common to prescribe sleep medicines for older adults without appropriate dosing instructions, particularly excluding warnings against long-term, regular use. Actions to change the current prescribing practices are warranted.
MeSH term(s)	Humans ; Aged ; Finland ; Retrospective Studies ; Sleep Initiation and Maintenance Disorders/drug therapy ; Drug Prescriptions ; Sleep
Language	English
Publishing date	2024-01-24
Publishing country	United States
Document type	Journal Article
ZDB-ID	103-x
ISSN	1600-0447 ; 0001-690X
ISSN (online)	1600-0447
ISSN	0001-690X
DOI	10.1111/acps.13661
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Article ; Online: The first description of the complete natural history of uveal melanoma by two Scottish surgeons, Allan Burns and James Wardrop.

Kivelä, Tero T

Acta ophthalmologica

2017

Abstract: James Wardrop (1782-1869), a young Scottish surgeon and an early ophthalmologist in Edinburgh, is credited for describing in 1809 retinoblastoma as an entity in his treatise 'Observations on Fungus Haematodes or Soft Cancer'. His treatise also reveals ... ...

Abstract	James Wardrop (1782-1869), a young Scottish surgeon and an early ophthalmologist in Edinburgh, is credited for describing in 1809 retinoblastoma as an entity in his treatise 'Observations on Fungus Haematodes or Soft Cancer'. His treatise also reveals that Allan Burns (1781-1813), another young Scottish surgeon and anatomist, had invited Wardrop to assist in enucleating an eye from a 41-year-old Glasgow woman who, in retrospect, had a uveal melanoma. Her eye had become blind 4 months after symptoms of exudative retinal detachment had appeared, and it had become painful after a further 2-4 months. The tumour eventually perforated the sclera, and she died within a year thereafter of hepatic metastases. Burns and Wardrop went on to publish detailed parallel accounts of the symptoms, signs, ophthalmic pathology and post-mortem findings regarding the primary, recurrent and metastatic tumour. Burns may have performed the post-mortem after exhuming the body, a common occurrence in early 19th Century Scotland, a thriving hub for teaching morbid anatomy to young surgeons at the time.
Language	English
Publishing date	2017-08-21
Publishing country	England
Document type	Journal Article
ZDB-ID	2408333-1
ISSN	1755-3768 ; 1755-375X
ISSN (online)	1755-3768
ISSN	1755-375X
DOI	10.1111/aos.13535
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