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Introduction: Keloids form as a pathological response to skin wound healing, and their etiopathology is poorly understood. Myofibroblasts, which are cells transformed from normal fibroblasts, are believed to contribute to pathological scar formation in wounds., Methods: We carried out a double-blinded randomized controlled trial (RCT) comparing the efficacy of intralesional 5-fluorouracil (5-FU) and triamcinolone (TAC) injections in treating keloids. A total of 43 patients with 50 keloids were treated with either intralesional TAC or 5-FU injections, and their clinical response was evaluated. Biopsies were collected before, during, and after injection therapy from the active border of a keloid. To understand the role of myofibroblasts in keloids, we conducted an immunohistochemical analysis to identify myofibroblasts [α-smooth muscle actin (αSMA)] from the biopsies. We first defined the three histologically distinct regions-superficial, middle, and deep dermis-in each keloid., Results: We then demonstrated that myofibroblasts almost exclusively exist in the middle dermis of the keloids as 80% of the cells in the middle dermis were αSMA positive. However, both the percentage of myofibroblasts as well as the area covered by them was substantially lower in the superficial and deep dermis than in the middle dermis of the keloids. Myofibroblasts do not predict the clinical response to intralesional injection therapies. There is no difference in the myofibroblast numbers in keloids or in the induced change in myofibroblasts between the responders and non-responders after treatment., Discussion: This study demonstrates that myofibroblasts reside almost exclusively in the middle dermis layer of the keloids, but their numbers do not predict the clinical response to intralesional injection therapies in the RCT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Komulainen, Daymond, Hietanen, Kaartinen and Järvinen.)

We studied a patient with mitochondrial DNA depletion in skeletal muscle and a multiorgan phenotype, including fatal encephalomyopathy, retinopathy, optic atrophy, and sensorineural hearing loss. Instead of pathogenic variants in the mitochondrial maintenance genes, we identified previously unpublished variant in DHX16 gene, a de novo heterozygous c.1360C>T (p. Arg454Trp). Variants in DHX16 encoding for DEAH-box RNA helicase have previously been reported only in five patients with a phenotype called as neuromuscular oculoauditory syndrome including developmental delay, neuromuscular symptoms, and ocular or auditory defects with or without seizures. We performed functional studies on patient-derived fibroblasts and skeletal muscle revealing, that the DHX16 expression was decreased. Clinical features together with functional data suggest, that our patient's disease is associated with a novel pathogenic DHX16 variant, and mtDNA depletion could be a secondary manifestation of the disease., (© 2023 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

Introduction: Transient global amnesia (TGA) is a spontaneously resolving, anterograde amnesia that lasts mostly <24 h and often occurs with retrograde amnesia. The etiology of TGA remains unclear, although in recent decades, many risk factors and preceding events have been identified. There are few up-to-date reports on the TGA incidence in Northern Europe. In this study, we report the incidence and risk factors associated with TGA in Finland., Materials and Methods: The study included all patients with suspected TGA that were referred to Kuopio University Hospital (KUH) in 2017. The hospital catchment area included 246,653 individuals. Risk factors and demographic data were collected from medical records. The TGA incidence rates were calculated as the number of patients with TGA divided by the number of individuals at risk in different age groups., Results: In 2017, 56 patients were treated for TGA at KUH. Of these, 46 had a first-ever TGA. The most common event preceding TGA was physical effort (n = 28, 50%), followed by emotional stress (n = 11, 19.6%) and water contact or a temperature change (n = 11, 19.6%). The most common comorbidities were hypercholesterolemia (n = 22, 39.3%), hypertensive disease (n = 21, 37.5%), hypothyroidism (n = 11, 19.6%), coronary artery disease (n = 8, 14.3%), and migraine (n = 7, 12.5%). TGA occurred most often in December (n = 9, 16.0%), March (n = 8, 14.3%), or October (n = 8, 14.3%), and least often in November and May (n = 2, 3.6% in both months). The crude incidence of a first TGA in Eastern Finland was 18.6/100,000 inhabitants, and when standardized to the European population in 2010, it was 14.3/100,000 inhabitants. Therefore, the TGA incidence was higher than previously reported in European countries., Discussion: The most common precipitating factors for TGA were physical effort, emotional stress, and water contact/temperature change. The incidence of TGA was high in the Eastern Finnish population., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Objectives: The incidence of stroke has been declining in Finland, as well as in Europe. However, it is unclear whether the incidence of transient ischemic attack (TIA) is also decreasing. In fact, the TIA incidence in the Finnish population has never been reported. Therefore, here we investigated the incidence of TIA in the Eastern Finnish population in 2017., Materials and Methods: All patients with suspected TIA, from a defined catchment area, were referred to a neurological emergency unit at Kuopio University Hospital (KUH) in the Northern Savonia region of Eastern Finland, which had a population of 246,653 in 2017. The original study population comprised TIA patients diagnosed based on the WHO TIA criteria in 2017. Incidence rates were calculated by dividing the number of TIA cases by the number of people in different age groups., Results: Among 432 patients with a suspected TIA referred to the neurological emergency unit at Kuopio University Hospital in 2017, 293 were living in Northern Savonia and were ultimately diagnosed with TIA after neurological examinations. The number of first-ever TIAs was 211. The crude incidence of all TIA was 122/100,000 inhabitants, and of first-ever TIA was 86/100,000. The age-standardized incidence (European population 2010) of the first-ever TIA was calculated to be 64/100,000. The mean age of first-ever TIA patients was 70 years: 72 years for women versus 68 years for men., Conclusions: We found a high incidence of TIA in Eastern Finland., (© 2022 The Authors. Acta Neurologica Scandinavica published by John Wiley & Sons Ltd.)

Endometriosis is a common inflammatory estrogen-dependent gynecological disorder, associated with pelvic pain and reduced fertility in women. Several aspects of this disorder and its cellular and molecular etiology remain unresolved. We have analyzed the global gene expression patterns in the endometrium, peritoneum and in endometriosis lesions of endometriosis patients and in the endometrium and peritoneum of healthy women. In this report, we present the EndometDB, an interactive web-based user interface for browsing the gene expression database of collected samples without the need for computational skills. The EndometDB incorporates the expression data from 115 patients and 53 controls, with over 24000 genes and clinical features, such as their age, disease stages, hormonal medication, menstrual cycle phase, and the different endometriosis lesion types. Using the web-tool, the end-user can easily generate various plot outputs and projections, including boxplots, and heatmaps and the generated outputs can be downloaded in pdf-format.Availability and implementationThe web-based user interface is implemented using HTML5, JavaScript, CSS, Plotly and R. It is freely available from https://endometdb.utu.fi/ .

Defects in the respiratory chain or mitochondrial ATP synthase (complex V) result in mitochondrial dysfunction that is an important cause of inherited neurological disease. Two of the subunits of complex V are encoded by MT-ATP6 and MT-ATP8 in the mitochondrial genome. Pathogenic mutations in MT-ATP6 are associated with the Leigh syndrome, the syndrome of neuropathy, ataxia, and retinitis pigmentosa (NARP), as well as with non-classical phenotypes, while MT-ATP8 is less frequently mutated in patients with mitochondrial disease. We investigated two adult siblings presenting with features of cerebellar ataxia, peripheral neuropathy, diabetes mellitus, sensorineural hearing impairment, and hypergonadotropic hypogonadism. As the phenotype was suggestive of mitochondrial disease, mitochondrial DNA was sequenced and a novel heteroplasmic mutation m.8561C>G in the overlapping region of the MT-ATP6 and MT-ATP8 was found. The mutation changed amino acids in both subunits. Mutation heteroplasmy correlated with the disease phenotype in five family members. An additional assembly intermediate of complex V and increased amount of subcomplex F 1 were observed in myoblasts of the two patients, but the total amount of complex V was unaffected. Furthermore, intracellular ATP concentration was lower in patient myoblasts indicating defective energy production. We suggest that the m.8561C>G mutation in MT-ATP6/8 is pathogenic, leads biochemically to impaired assembly and decreased ATP production of complex V, and results clinically in a phenotype with the core features of cerebellar ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism.

Sodium valproate (VPA) is a potentially hepatotoxic antiepileptic drug. Risk of VPA-induced hepatotoxicity is increased in patients with mitochondrial diseases and especially in patients with POLG1 gene mutations. We used a HepG2 cell in vitro model to investigate the effect of VPA on mitochondrial activity. Cells were incubated in glucose medium and mitochondrial respiration-inducing medium supplemented with galactose and pyruvate. VPA treatments were carried out at concentrations of 0-2.0mM for 24-72 h. In both media, VPA caused decrease in oxygen consumption rates and mitochondrial membrane potential. VPA exposure led to depleted ATP levels in HepG2 cells incubated in galactose medium suggesting dysfunction in mitochondrial ATP production. In addition, VPA exposure for 72 h increased levels of mitochondrial reactive oxygen species (ROS), but adversely decreased protein levels of mitochondrial superoxide dismutase SOD2, suggesting oxidative stress caused by impaired elimination of mitochondrial ROS and a novel pathomechanism related to VPA toxicity. Increased cell death and decrease in cell number was detected under both metabolic conditions. However, immunoblotting did not show any changes in the protein levels of the catalytic subunit A of mitochondrial DNA polymerase γ, the mitochondrial respiratory chain complexes I, II and IV, ATP synthase, E3 subunit dihydrolipoyl dehydrogenase of pyruvate dehydrogenase, 2-oxoglutarate dehydrogenase and glutathione peroxidase. Our results show that VPA inhibits mitochondrial respiration and leads to mitochondrial dysfunction, oxidative stress and increased cell death, thus suggesting an essential role of mitochondria in VPA-induced hepatotoxicity., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: To study the clinical manifestations and occurrence of mtDNA depletion and deletions in paediatric patients with neuromuscular diseases and to identify novel clinical phenotypes associated with mtDNA depletion or deletions., Methods: Muscle DNA samples from patients presenting with undefined encephalomyopathies or myopathies were analysed for mtDNA content by quantitative real-time PCR and for deletions by long-range PCR. Direct sequencing of mtDNA maintenance genes and whole-exome sequencing were used to study the genetic aetiologies of the diseases. Clinical and laboratory findings were collected., Results: Muscle samples were obtained from 104 paediatric patients with neuromuscular diseases. mtDNA depletion was found in three patients with severe early-onset encephalomyopathy or myopathy. Two of these patients presented with novel types of mitochondrial DNA depletion syndromes associated with increased serum creatine kinase (CK) and multiorgan disease without mutations in any of the known mtDNA maintenance genes; one patient had pathologic endoplasmic reticulum (ER) membranes in muscle. The third patient with mtDNA depletion was diagnosed with merosine-deficient muscular dystrophy caused by a homozygous mutation in the LAMA2 gene. Two patients with an early-onset Kearns-Sayre/Pearson-like phenotype harboured a large-scale mtDNA deletion, minor multiple deletions and high mtDNA content., Conclusions: Novel encephalomyopathic mtDNA depletion syndrome with structural alterations in muscle ER was identified. mtDNA depletion may also refer to secondary mitochondrial changes related to muscular dystrophy. We suggest that a large-scale mtDNA deletion, minor multiple deletions and high mtDNA content associated with Kearns-Sayre/Pearson syndromes may be secondary changes caused by mutations in an unknown nuclear gene.

Patients with mutations in the POLG1 gene encoding mitochondrial DNA polymerase gamma have an increased risk of valproate-induced liver failure. POLG1 mutations are common, and these patients often suffer from intractable seizures. The role of liver transplantation in the treatment of patients with mitochondrial diseases has been controversial. We studied valproate-induced liver failure associated with POLG1 mutations and the prognosis for these patients after liver transplantation. POLG1 was analyzed in blood DNA, mitochondrial DNA (mtDNA) was quantified in liver samples, and clinical data were collected. Five patients with valproate-induced liver failure associated with POLG1 mutations were retrospectively identified. Three patients were previously suspected to have Wilson's disease. Four patients with homozygous p.W748S and p.E1143G mutations had mtDNA depletion in the liver. One of these patients died before anticipated transplantation; the other 3 patients with liver transplantation have survived 4 to 19 years. Two patients have presented with occasional epileptic seizures, and 1 patient has been seizure-free for 11 years. One patient with a heterozygous p.Q1236H mutation (but without mtDNA depletion in the liver) died suddenly 2 years after liver transplantation. In conclusion, the POLG1 mutation status and the age at presentation of valproate-induced liver failure can affect the prognosis after liver transplantation. A heterozygous POLG1 p.Q1236H mutation was related to valproate-induced liver failure without mtDNA depletion, whereas patients homozygous for POLG1 p.W748S and p.E1143G mutations had mtDNA depletion. An analysis of the POLG1 gene should be performed for all patients with suspected mitochondrial disease before the introduction of valproate therapy, and treatment with valproic acid should be avoided in these patients., (© 2014 American Association for the Study of Liver Diseases.)

Background: Our objective was to examine whether gestational diabetes mellitus (GDM) or newborns' high birthweight can be prevented by lifestyle counseling in pregnant women at high risk of GDM., Method and Findings: We conducted a cluster-randomized trial, the NELLI study, in 14 municipalities in Finland, where 2,271 women were screened by oral glucose tolerance test (OGTT) at 8-12 wk gestation. Euglycemic (n = 399) women with at least one GDM risk factor (body mass index [BMI] ≥ 25 kg/m(2), glucose intolerance or newborn's macrosomia (≥ 4,500 g) in any earlier pregnancy, family history of diabetes, age ≥ 40 y) were included. The intervention included individual intensified counseling on physical activity and diet and weight gain at five antenatal visits. Primary outcomes were incidence of GDM as assessed by OGTT (maternal outcome) and newborns' birthweight adjusted for gestational age (neonatal outcome). Secondary outcomes were maternal weight gain and the need for insulin treatment during pregnancy. Adherence to the intervention was evaluated on the basis of changes in physical activity (weekly metabolic equivalent task (MET) minutes) and diet (intake of total fat, saturated and polyunsaturated fatty acids, saccharose, and fiber). Multilevel analyses took into account cluster, maternity clinic, and nurse level influences in addition to age, education, parity, and prepregnancy BMI. 15.8% (34/216) of women in the intervention group and 12.4% (22/179) in the usual care group developed GDM (absolute effect size 1.36, 95% confidence interval [CI] 0.71-2.62, p = 0.36). Neonatal birthweight was lower in the intervention than in the usual care group (absolute effect size -133 g, 95% CI -231 to -35, p = 0.008) as was proportion of large-for-gestational-age (LGA) newborns (26/216, 12.1% versus 34/179, 19.7%, p = 0.042). Women in the intervention group increased their intake of dietary fiber (adjusted coefficient 1.83, 95% CI 0.30-3.25, p = 0.023) and polyunsaturated fatty acids (adjusted coefficient 0.37, 95% CI 0.16-0.57, p < 0.001), decreased their intake of saturated fatty acids (adjusted coefficient -0.63, 95% CI -1.12 to -0.15, p = 0.01) and intake of saccharose (adjusted coefficient -0.83, 95% CI -1.55 to -0.11, p  =  0.023), and had a tendency to a smaller decrease in MET minutes/week for at least moderate intensity activity (adjusted coefficient 91, 95% CI -37 to 219, p = 0.17) than women in the usual care group. In subgroup analysis, adherent women in the intervention group (n = 55/229) had decreased risk of GDM (27.3% versus 33.0%, p = 0.43) and LGA newborns (7.3% versus 19.5%, p = 0.03) compared to women in the usual care group., Conclusions: The intervention was effective in controlling birthweight of the newborns, but failed to have an effect on maternal GDM., Trial Registration: Current Controlled Trials ISRCTN33885819. Please see later in the article for the Editors' Summary.

Objectives: To examine whether a diagnosis for major depression, chronic depression or specific symptoms of depression is associated with the risk of quitting a weight loss program., Study Design: The study involved 82 overweight adults participating in the Lifestyle Intervention Treatment Evaluation (LITE) follow-up study at Oulu University Hospital in northern Finland., Methods: Psychiatric diagnostic assessments were based on the Structured Clinical Interview for DSMIV disorders (SCID-I) conducted by a clinical psychiatrist. Anhedonia (lack of pleasure) was assessed as one of the core symptoms of major depression and chronic depression (dysthymia). Anhedonia was defined to be present if the participants reported having suffered a major loss of interest during the previous month., Results: Twenty participants (24.4%) quit during the 6-month intervention period. Anhedonia put individuals at risk of quitting the weight loss program (bivariate analysis OR 3.1, 95% CI 0.8-11.6, p=0.091, multivariate analysis OR 6.5, 95% CI 1.1-38.2, p=0.038). However, a diagnosis for major depression or chronic depression did not predict quitting., Conclusions: Individual assessments of obesity and overweight should also include an assessment for subthreshold depression, mainly anhedonia.

Background: The c.2447G>A (p.R722H) mutation in the gene POLG1 of the catalytic subunit of human mitochondrial polymerase gamma has been previously found in a few occasions but its pathogenicity has remained uncertain. We set out to ascertain its contribution to neuromuscular disease., Methods: Probands from two families with probable mitochondrial disease were examined clinically, muscle and buccal epithelial DNA were analyzed for mtDNA deletions, and the POLG1, POLG2, ANT1 and Twinkle genes were sequenced., Results: An adult proband presented with progressive external ophthalmoplegia, sensorineural hearing impairment, diabetes mellitus, dysphagia, a limb myopathy and dementia. Brain MRI showed central and cortical atrophy, and 18F-deoxyglucose PET revealed reduced glucose uptake. Histochemical analysis of muscle disclosed ragged red fibers and cytochrome c oxidase-negative fibers. Electron microscopy showed subsarcolemmal aggregates of morphologically normal mitochondria. Multiple mtDNA deletions were found in the muscle, and sequencing of the POLG1 gene revealed a homozygous c.2447G>A (p.R722H) mutation. His two siblings were also homozygous with respect to the p.R722H mutation and presented with dementia and sensorineural hearing impairment. In another family the p.R722H mutation was found as compound heterozygosity with the common p.W748S mutation in two siblings with mental retardation, ptosis, epilepsy and psychiatric symptoms. The estimated carrier frequency of the p.R722H mutation was 1:135 in the Finnish population. No mutations in POLG2, ANT1 and Twinkle genes were found. Analysis of the POLG1 sequence by homology modeling supported the notion that the p.R722H mutation is pathogenic., Conclusions: The recessive c.2447G>A (p.R722H) mutation in the linker region of the POLG1 gene is pathogenic for multiple mtDNA deletions in muscle and is associated with a late-onset neurological phenotype as a homozygous state. The onset of the disease can be earlier in compound heterozygotes.

The clinical features of severe myoclonic epilepsy of infancy (SMEI) resemble those of mitochondrial diseases, although most patients have the sodium channel (SCN1A) mutation. We describe a patient with SMEI and enlarged muscle mitochondria associated with mutations in mitochondrial polymerase gamma 1 (POLG1) and SCN1A. Due to increased risk of valproate-induced liver failure in patients with POLG1 mutations, we recommend POLG1 gene analysis for SMEI patients before valproate administration.