Browsing by Subject "PATHOLOGY"

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  • Pikkarainen, Sampsa; Martelius, Timi; Ristimäki, Ari; Siitonen, Sanna; Seppänen, Mikko R. J.; Färkkilä, Martti (2019)
    OBJECTIVES: Common variable immunodeficiency (CVID) is associated with a spectrum of autoimmune complications. We studied the prevalence of gastrointestinal (GI) manifestations and infections in patients with CVID. METHODS: Complete clinical data of 132 Finnish patients with CVID (106 probable and 26 possible CVID) followed up between 2007 and 2016 were collected to a structured database. Data on endoscopies, histology, and laboratory studies were retrieved from patient files. RESULTS: Most common referral indications were diarrhea and/or weight loss (47%-67%). Patients with probable CVID had higher fecal calprotectin and a1-antitrypsin and lower blood vitamin B12 than patients with possible CVID. Gastroscopy and colonoscopy were done to 71 (67%) and 63 (59%) patients with probable CVID, respectively. Endoscopies showed that 15% of them had chronic active gastritis and 17% atrophic gastritis and 3% had gastric adenocarcinoma. A celiac sprue-like condition was found in 7 patients (10%), of whom 3 responded to a gluten-free diet. Colonoscopies demonstrated unspecific colitis (14%), ulcerative colitis (8%), microscopic colitis (10%), and Crohn's disease (2%). Colonic polyps were noted in30% of patients, and3% had lower GI malignancies. Thirty-five patients with CVID had bacterial or parasitic gastroenteritis; chronic norovirus was detected in 4 patients with probable CVID. Patients with GI inflammation had higher levels of fecal calprotectin and blood CD81 T lymphocytes but lower counts of CD191CD271 memory B cells and/or CD191 B cells. Immunophenotype with low B-cell counts was associated with higher fecal calprotectin levels. DISCUSSION: Patients with CVID had a high prevalence of GI manifestations and infections of the GI tract. GI inflammation was associated with a distinct immunophenotype and elevated fecal calprotectin.
  • Kuuluvainen, Liina; Pöyhönen, Minna; Pasanen, Petra; Siitonen, Maija; Rummukainen, Jaana; Tienari, Pentti J.; Paetau, Anders; Myllykangas, Liisa (2017)
    Mutations in the progranulin (GRN) gene represent about 5-10% of frontotemporal lobar degeneration (FTLD). We describe a proband with a novel GRN mutation c.687T>A, p.(Tyr229*), presenting with dyspraxia, dysgraphia, and dysphasia at the age of 60 and a very severe FTLD neuropathological phenotype with TDP43 inclusions. The nephew of the proband had signs of dementia and personality changes at the age of 60 and showed similar but milder FTLD pathology. Three other family members had had early-onset dementia. Gene expression studies showed decreased GRN gene expression in mutation carriers' blood samples. In conclusion, we describe a novel GRN, p.(Tyr229*) mutation, resulting in haploinsufficiency of GRN and a severe neuropathologic FTLD phenotype.
  • Parekh, Utsav; Chariot, Patrick; Dang, Catherine; Stray-Pedersen, Arne; Druid, Henrik; Sajantila, Antti (2020)
    The COVID-19 pandemic has forced forensic practitioners to consider how we perform our normal duties, especially when those duties involve humans. The potential for contracting the virus from working in close contact with living sufferers is high, and we have yet to fully determine the risk of infection from the deceased. In an attempt to support the community, the Journal of Forensic & Legal Medicine has drawn together three articles which underline the importance of continued forensic medical practice during the pandemic and highlight some factors to consider in a Roadmap towards safe practice. Our Roadmap has intentionally taken an international perspective and supports other work we have published in the Journal on our collective response to the COVID-19 crisis.
  • Oikari, Lotta E.; Pandit, Rucha; Stewart, Romal; Cuní-López, Carla; Quek, Hazel; Sutharsan, Ratneswary; Rantanen, Laura M.; Oksanen, Minna; Lehtonen, Sarka; de Boer, Carmela Maria; Polo, Jose M.; Götz, Jürgen; Koistinaho, Jari; White, Anthony R. (2020)
    The blood-brain barrier (BBB) presents a barrier for circulating factors, but simultaneously challenges drug delivery. How the BBB is altered in Alzheimer disease (AD) is not fully understood. To facilitate this analysis, we derived brain endothelial cells (iBECs) from human induced pluripotent stem cells (hiPSCs) of several patients carrying the familial AD PSEN1 mutation. We demonstrate that, compared with isogenic PSEN1 corrected and control iBECs, AD-iBECs exhibit altered tight and adherens junction protein expression as well as efflux properties. Furthermore, by applying focused ultrasound (FUS) that transiently opens the BBB and achieves multiple therapeutic effects in AD mouse models, we found an altered permeability to 3-5 kDa dextran as a model cargo and the amyloid-beta (A beta) peptide in AD-iBECs compared with control iBECs. This presents human-derived in vitro models of the BBB as a valuable tool to understand its role and properties in a disease context, with possible implications for drug delivery.
  • FIDELITY Finnish Degenerative Meni; Sihvonen, Raine; Paavola, Mika; Malmivaara, Antti; Itälä, Ari; Joukainen, Antti; Kalske, Juha; Nurmi, Heikki; Kumm, Jaanika; Sillanpää, Niko; Kiekara, Tommi; Turkiewicz, Aleksandra; Toivonen, Pirjo; Englund, Martin; Taimela, Simo; Järvinen, Teppo L. N. (2020)
    Objectives To assess the long-term effects of arthroscopic partial meniscectomy (APM) on the development of radiographic knee osteoarthritis, and on knee symptoms and function, at 5 years follow-up. Design Multicentre, randomised, participant- and outcome assessor-blinded, placebo-surgery controlled trial. Setting Orthopaedic departments in five public hospitals in Finland. Participants 146 adults, mean age 52 years (range 35-65 years), with knee symptoms consistent with degenerative medial meniscus tear verified by MRI scan and arthroscopically, and no clinical signs of knee osteoarthritis were randomised. Interventions APM or placebo surgery (diagnostic knee arthroscopy). Main outcome measures We used two indices of radiographic knee osteoarthritis (increase in Kellgren and Lawrence grade >= 1, and increase in Osteoarthritis Research Society International (OARSI) atlas radiographic joint space narrowing and osteophyte sum score, respectively), and three validated patient-relevant measures of knee symptoms and function ( Western Ontario Meniscal Evaluation Tool (WOMET), Lysholm, and knee pain after exercise using a numerical rating scale). Results There was a consistent, slightly greater risk for progression of radiographic knee osteoarthritis in the APM group as compared with the placebo surgery group (adjusted absolute risk difference in increase in Kellgren-Lawrence grade >= 1 of 13%, 95% CI -2% to 28%; adjusted absolute mean difference in OARSI sum score 0.7, 95% CI 0.1 to 1.3). There were no relevant between-group differences in the three patient-reported outcomes: adjusted absolute mean differences (APM vs placebo surgery), -1.7 (95% CI -7.7 to 4.3) in WOMET, -2.1 (95% CI -6.8 to 2.6) in Lysholm knee score, and -0.04 (95% CI -0.81 to 0.72) in knee pain after exercise, respectively. The corresponding adjusted absolute risk difference in the presence of mechanical symptoms was 18% (95% CI 5% to 31%); there were more symptoms reported in the APM group. All other secondary outcomes comparisons were similar. Conclusions APM was associated with a slightly increased risk of developing radiographic knee osteoarthritis and no concomitant benefit in patient-relevant outcomes, at 5 years after surgery.
  • Zhang, Sidi; Samocha, Kaitlin E.; Rivas, Manuel A.; Karczewski, Konrad J.; Daly, Emma; Schmandt, Ben; Neale, Benjamin M.; MacArthur, Daniel G.; Daly, Mark J. (2018)
    Variation in RNA splicing (i.e., alternative splicing) plays an important role in many diseases. Variants near 5' and 3' splice sites often affect splicing, but the effects of these variants on splicing and disease have not been fully characterized beyond the two "essential" splice nucleotides flanking each exon. Here we provide quantitative measurements of tolerance to mutational disruptions by position and reference allele-alternative allele combinations. We show that certain reference alleles are particularly sensitive to mutations, regardless of the alternative alleles into which they are mutated. Using public RNA-seq data, we demonstrate that individuals carrying such variants have significantly lower levels of the correctly spliced transcript, compared to individuals without them, and confirm that these specific substitutions are highly enriched for known Mendelian mutations. Our results propose a more refined definition of the "splice region" and offer a new way to prioritize and provide functional interpretation of variants identified in diagnostic sequencing and association studies.
  • Kilpeläinen, Tommi; Julku, Ulrika; Svarcbahs, Reinis; Myöhänen, Timo (2019)
    Alpha-synuclein (aSyn) is the main component of Lewy bodies, the histopathological marker in Parkinson's disease (PD), and point mutations and multiplications of the aSyn coding SNCA gene correlate with early onset PD. Therefore, various transgenic mouse models overexpressing native or point-mutated aSyn have been developed. Although these models show highly increased aSyn expression they rarely capture dopaminergic cell loss and show a behavioural phenotype only at old age, whereas SNCA mutations are risk factors for PD with earlier onset. The aim of our study was to re-characterize a transgenic mouse strain carrying both A30P and A53T mutated human aSyn. Our study revealed decreased locomotor activity for homozygous transgenic mice starting from 3 months of age which was different from previous studies with this mouse strain that had behavioural deficits starting only after 7-9 months. Additionally, we found a decreased amphetamine response in locomotor activity and decreased extracellular dopaminergic markers in the striatum and substantia nigra with significantly elevated levels of aSyn oligomers. In conclusion, homozygous transgenic A30P*A53T aSyn mice capture several phenotypes of PD with early onset and could be a useful tool for aSyn studies.
  • Aguilar, Cristian; Carbajal, Tomas; Beltran, Brady E.; Segura, Pedro; Muhammad, Sajjad; Choque-Velasquez, Joham (2021)
    Systemic embolization has been reported in up to 40% of patients with left atrial myxoma, half of them with cerebral involvement. However, development of intracerebral embolization associated with parenchymal seeding of the myxoma emboli is an extremely rare complication, with only 36 histologically diagnosed cases reported in the published literature. We describe a 69-year-old woman who arrived at the emergency service with hemiparesis associated with drug-resistant epilepsy and a medical history of resection of a left atrial myxoma 10 months previously. Cranial computed tomography revealed multiple large lesions of heterogeneous density and cystic components in the occipital lobes and posterior fossa parenchyma. Histopathological analyses after stereotactic biopsy of the occipital lesion revealed infiltrative myxoma cells with benign histological findings and uniform expression of calretinin similar to that of the primary cardiac myxoma. Additional immunohistochemical studies confirmed brain parenchymal seeding of the myxoma cells with strong expression of interleukin-6 (IL-6) and focal expression of matrix metalloproteinases-2 (MMP-2). Here, we discuss the clinicopathological features of intracerebral embolization of left atrial myxomas associated with progressive parenchymal seeding of the tumor emboli and the potential pathogenic role of IL-6 and MMPs.
  • Karukivi, Max; Vahlberg, Tero; Horjamo, Kalle; Nevalainen, Minna; Korkeila, Jyrki (2017)
    Background: Current categorical classification of personality disorders has been criticized for overlooking the dimensional nature of personality and that it may miss some sub-threshold personality disturbances of clinical significance. We aimed to evaluate the clinical importance of these conditions. For this, we used a simple four-level dimensional categorization based on the severity of personality disturbance. Methods: The sample consisted of 352 patients admitted to mental health services. All underwent diagnostic assessments (SCID-I and SCID-II) and filled in questionnaires concerning their social situation and childhood adversities, and other validated tools, including the Beck Depression Inventory (BDI), Alcohol Use Disorders Identification Test (AUDIT), health-related quality of life (15D), and the five-item Mental Health Index (MHI-5). The patients were categorized into four groups according to the level of personality disturbance: 0 = No personality disturbance, 1 = Personality difficulty (one criterion less than threshold for one or more personality disorders), 2 = Simple personality disorder (one personality disorder), and 3 = Complex/Severe personality disorder (two or more personality disorders or any borderline and antisocial personality disorder). Results: The proportions of the groups were as follows: no personality disturbance 38.4% (n = 135), personality difficulty 14.5% (n = 51), simple personality disorder 19.9% (n = 70), and complex/severe personality disorder 24.4% (n = 86). Patients with no personality disturbance were significantly differentiated (p <0.05) from the other groups regarding the BDI, 15D, and MHI-5 scores as well as the number of Axis I diagnoses. Patients with complex/severe personality disorders stood out as being worst off. Social dysfunction was related to the severity of the personality disturbance. Patients with a personality difficulty or a simple personality disorder had prominent symptoms and difficulties, but the differences between these groups were mostly non-significant. Conclusions: An elevated severity level of personality disturbance is associated with an increase in psychiatric morbidity and social dysfunction. Diagnostically sub-threshold personality difficulties are of clinical significance and the degree of impairment corresponds to actual personality disorders. Since these two groups did not significantly differ from each other, our findings also highlight the complexity related to the use of diagnostic thresholds for separate personality disorders.
  • Mustonen, Tuuli; Schmidt, Eeva-Kaisa; Valori, Miko; Tienari, Pentti J.; Atula, Sari; Kiuru-Enari, Sari (2018)
    Finnish gelsolin amyloidosis (AGel amyloidosis) is an autosomal dominantly inherited systemic disorder with ophthalmologic, neurologic and dermatologic symptoms. Only the gelsolin (GSN) c.640G>A variant has been found in the Finnish patients thus far. The purpose of this study was to examine whether the Finnish patients have a common ancestor or whether multiple mutation events have occurred at c.640G, which is a known mutational hot spot. A total of 79 Finnish AGel amyloidosis families including 707 patients were first discovered by means of patient interviews, genealogic studies and civil and parish registers. From each family 1-2 index patients were chosen. Blood samples were available from 71 index patients representing 64 families. After quality control, SNP array genotype data were available from 68 patients from 62 nuclear families. All the index patients had the same c.640G>A variant (rs121909715). Genotyping was performed using the Illumina CoreExome SNP array. The homozygosity haplotype method was used to analyse shared haplotypes. Haplotype analysis identified a shared haplotype, common to all studied patients. This shared haplotype included 17 markers and was 361 kb in length (GRCh37 coordinates 9:124003326–124364349) and this level of haplotype sharing was found to occur highly unlikely by chance. This GSN haplotype ranked as the largest shared haplotype in the 68 patients in a genome-wide analysis of haplotype block lengths. These results provide strong evidence that although there is a known mutational hot spot at GSN c.640G, all of the studied 62 Finnish AGel amyloidosis families are genetically linked to a common ancestor.
  • Lopes, Nair; Bergsland, Christian Holst; Bjornslett, Merete; Pellinen, Teijo; Svindland, Aud; Nesbakken, Arild; Almeida, Raquel; Lothe, Ragnhild A.; David, Leonor; Bruun, Jarle (2020)
    Flourescence-based multiplex immunohistochemistry (mIHC) combined with multispectral imaging and digital image analysis (DIA) is a quantitative high-resolution method for determination of protein expression in tissue. We applied this method for five biomarkers (CDX2, SOX2, SOX9, E-cadherin, and beta-catenin) using tissue microarrays of a Norwegian unselected series of primary colorectal cancer. The data were compared with previously obtained chromogenic IHC data of the same tissue cores, visually assessed by the Allred method. We found comparable results between the methods, although confirmed that DIA offered improved resolution to differentiate cases with high and low protein expression. However, we experienced inherent challenges with digital image analysis of membrane staining, which was better assessed visually. DIA and mIHC enabled quantitative analysis of biomarker coexpression on the same tissue section at the single-cell level, revealing a strong negative correlation between the differentiation markers CDX2 and SOX2. Both methods confirmed known prognostic associations for CDX2, but DIA improved data visualization and detection of clinicopathological and biological associations. In summary, mIHC combined with DIA is an efficient and reliable method to evaluate protein expression in tissue, here shown to recapitulate and improve detection of known clinicopathological and survival associations for the emerging biomarker CDX2, and is therefore a candidate approach to standardize CDX2 detection in pathology laboratories.
  • Zheng, Guoqiao; Yu, Hongyao; Hemminki, Akseli; Forsti, Asta; Sundquist, Kristina; Hemminki, Kari (2017)
    Male breast cancer is associated with female breast cancer in families but whether male breast cancer clusters with other discordant cancers has not been studied. As concordant male breast cancers are utterly rare, discordant associations of male breast cancer with other cancers may reveal genetic and possible environmental risk factors contributing to male breast cancer susceptibility. We calculated relative risks (RRs) for male breast cancer in families with discordant cancers, and conversely, for discordant cancers in families of male breast cancer patients, based on 15.7 million individuals in the Swedish Family-Cancer Database. Among 1428 male breast cancer patients, 16.2% had a female relative diagnosed with breast cancer. Ovarian and female anal cancers showed the strongest associations with male breast cancer (p value <0.0005). The other significant associations included colorectal, small intestinal, and thyroid cancers, cancer of unknown primary and non-Hodgkin lymphoma but these were each based on a single positive association with male breast cancer. The RRs for male breast cancer were increased in families in which multiple patients were diagnosed with diverse cancers, reaching an RR of 2.58 when three or more family members were affected. The results suggest that male breast cancer shares susceptibility with a number of other cancers but confirmation is needed in other datasets.
  • Helin, Henrik O.; Tuominen, Vilppu J.; Ylinen, Onni; Helin, Heikki; Isola, Jorma (2016)
    Evaluation of human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) is subject to interobserver variation and lack of reproducibility. Digital image analysis (DIA) has been shown to improve the consistency and accuracy of the evaluation and its use is encouraged in current testing guidelines. We studied whether digital image analysis using a free software application (ImmunoMembrane) can assist in interpreting HER2 IHC in equivocal 2+ cases. We also compared digital photomicrographs with whole-slide images (WSI) as material for ImmunoMembrane DIA. We stained 750 surgical resection specimens of invasive breast cancers immunohistochemically for HER2 and analysed staining with ImmunoMembrane. The ImmunoMembrane DIA scores were compared with the originally responsible pathologists' visual scores, a researcher's visual scores and in situ hybridisation (ISH) results. The originally responsible pathologists reported 9.1 % positive 3+ IHC scores, for the researcher this was 8.4 % and for ImmunoMembrane 9.5 %. Equivocal 2+ scores were 34 % for the pathologists, 43.7 % for the researcher and 10.1 % for ImmunoMembrane. Negative 0/1+ scores were 57.6 % for the pathologists, 46.8 % for the researcher and 80.8 % for ImmunoMembrane. There were six false positive cases, which were classified as 3+ by ImmunoMembrane and negative by ISH. Six cases were false negative defined as 0/1+ by IHC and positive by ISH. ImmunoMembrane DIA using digital photomicrographs and WSI showed almost perfect agreement. In conclusion, digital image analysis by ImmunoMembrane can help to resolve a majority of equivocal 2+ cases in HER2 IHC, which reduces the need for ISH testing.
  • Whiting-Fawcett, Flora; Field, Kenneth; Puechmaille, Sébastien J.; Blomberg, Anna; Lilley, Thomas M. (2021)
    Hibernation, a period where bats have suppressed immunity and low body temperatures, provides the psychrophilic fungus Pseudogymnoascus destructans the opportunity to colonise bat skin, leading to severe disease in susceptible species. Innate immunity, which requires less energy and may remain more active during torpor, can control infections with local inflammation in some bat species that are resistant to infection. If infection is not controlled before emergence from hibernation, ineffective adaptive immune mechanisms are activated, including incomplete Th1, ineffective Th2, and variable Th17 responses. The Th17 and neutrophil responses, normally beneficial antifungal mechanisms, appear to be sources of immunopathology for susceptible bat species, because they are hyperactivated after return to homeothermy. Non-susceptible species show both well-balanced and suppressed immune responses both during and after hibernation.
  • Vesala, Tommi; Ekholm, Marja; Ventä, Irja (2021)
    Objective:The purpose of this study was to determine, if a dental panoramic tomograph (DPT) is appropriate for every young adult due to third molars. Materials and methods:The study sample consisted of 217 university students (20% men and 80% women; mean age 20.7 years; SD +/- 0.6 years) and included a questionnaire about symptoms caused by third molars, clinical oral examination of third molars, and a DPT. Subjects were divided into the following groups: subjects with a clinical indication for a DPT and subjects without such indication. The DPTs were then examined for findings regarding third molars. Results:Clinical indication for a DPT was observed in 64% of the subjects. Radiography revealed an additional 1.4% of the subjects with >= 1 radiographic signs of disease in relation to their third molars. Also, an additional 27% of the subjects had >= 1 other radiographic findings in relation to third molars that may have affected the clinical decision making. Conclusions:In our study population, clinically undetectable pathology cannot be considered as an indication for a DPT. However, if prevailing clinical practice supports preventive removals and detecting or monitoring of unerupted third molars, a referral to DPT can be considered as good clinical practice.
  • Brackhan, Mirjam; Calza, Giulio; Lundgren, Anna Kristiina; Bascunana, Pablo; Bruning, Thomas; Soliymani, Rabah; Kumar, Rakesh; Abelein, Axel; Baumann, Marc; Lalowski, Maciej; Pahnke, Jens (2022)
    Findings of early cerebral amyloid-β deposition in mice after peripheral injection of amyloid-β-containing brain extracts, and in humans following cadaveric human growth hormone treatment raised concerns that amyloid-β aggregates and possibly Alzheimer’s disease may be transmissible between individuals. Yet, proof that Aβ actually reaches the brain from the peripheral injection site is lacking. Here, we use a proteomic approach combining stable isotope labeling of mammals and targeted mass spectrometry. Specifically, we generate 13C-isotope-labeled brain extracts from mice expressing human amyloid-β and track 13C-lysine-labeled amyloid-β after intraperitoneal administration into young amyloid precursor protein-transgenic mice. We detect injected amyloid-β in the liver and lymphoid tissues for up to 100 days. In contrast, injected 13C-lysine-labeled amyloid-β is not detectable in the brain whereas the mice incorporate 13C-lysine from the donor brain extracts into endogenous amyloid-β. Using a highly sensitive and specific proteomic approach, we demonstrate that amyloid-β does not reach the brain from the periphery. Our study argues against potential transmissibility of Alzheimer’s disease while opening new avenues to uncover mechanisms of pathophysiological protein deposition.
  • Thunnissen, Erik; Weynand, Birgit; Udovicic-Gagula, Dalma; Brcic, Luka; Szolkowska, Malgorzata; Hofman, Paul; Smojver-Jezek, Silvana; Anttila, Sisko; Calabrese, Fiorella; Kern, Izidor; Skov, Birgit; Perner, Sven; Dale, Vibeke G.; Eri, Zivka; Haragan, Alex; Leonte, Diana; Carvallo, Lina; Prince, Spasenja Savic; Nicholson, Siobhan; Sansano, Irene; Ryska, Ales (2020)
    A questionnaire on biomarker testing previously used in central European countries was extended and distributed in Western and Central European countries to the pathologists participating at the Pulmonary Pathology Society meeting 26-28 June 2019 in Dubrovnik, Croatia. Each country was represented by one responder. For recent biomarkers the availability and reimbursement of diagnoses of molecular alterations in non-small cell lung carcinoma varies widely between different, also western European, countries. Reimbursement of such assessments varies widely between unavailability and payments by the health care system or even pharmaceutical companies. The support for testing from alternative sources, such as the pharmaceutical industry, is no doubt partly compensating for the lack of public health system support, but it is not a viable or long-term solution. Ideally, a structured access to testing and reimbursement should be the aim in order to provide patients with appropriate therapeutic options. As biomarker enabled therapies deliver a 50% better probability of outcome success, improved and unbiased reimbursement remains a major challenge for the future.
  • Oinas, Minna; Polvikoski, Tuomo; Sulkava, Raimo; Myllykangas, Liisa; Juva, Kati; Notkola, Irma-Leena; Rastas, Sari; Niinisto, Leena; Kalimo, Hannu; Paetau, Anders (2009)