Limbic-predominant age-related TDP-43 encephalopathy in the oldest old: a population-based study.

Population-based cohort studies are essential for understanding the pathological basis of dementia in older populations. Previous studies have shown that limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) increases with age, but there have been only a few studies, which have investigated this entity in a population-based setting. Here we studied the frequency of LATE-NC and its associations with other brain pathologies and cognition in a population aged ≥ 85 years. The population-based Vantaa 85+ study cohort includes all 601 individuals aged ≥ 85 years who were living in Vantaa, Finland in 1991. A neuropathological examination was performed on 304 subjects (50.5%) and LATE-NC staging was possible in 295 of those. Dementia status and Mini-Mental State Examination (MMSE) scores were defined in the baseline study and 3 follow-ups (1994-99). The LATE-NC stages were determined based on TDP-43 immunohistochemistry, according to recently updated recommendations. Arteriolosclerosis was digitally assessed by calculating the average sclerotic index of five random small arterioles in amygdala and hippocampal regions, and frontal white matter. The association of LATE-NC with arteriolosclerosis and previously determined neuropathological variables including Alzheimer's disease neuropathological change (ADNC), Lewy-related pathology (LRP), hippocampal sclerosis (HS), and cerebral amyloid angiopathy (CAA), and cognitive variables were analysed by Fisher's exact test, linear and logistic regression (univariate and multivariate) models. LATE-NC was found in 189 of 295 subjects (64.1%). Stage 2 was the most common (28.5%) and stage 3 the second most common (12.9%), whereas stages 1a, 1b and 1c were less common (9.5%, 5.1% and 8.1%, respectively). Stages 1a (P < 0.01), 2 (P < 0.001) and 3 (P < 0.001) were significantly associated with dementia and lower MMSE scores. LATE-NC was associated with ADNC (P < 0.001), HS (P < 0.001), diffuse neocortical LRP (P < 0.002), and arteriolosclerosis in amygdala (P < 0.02). In most cases LATE-NC occurred in combination alongside other neuropathological changes. There were only six subjects with dementia who had LATE-NC without high levels of ADNC or LRP (2% of the cohort, 3% of the cases with dementia), and five of these had HS. In all multivariate models, LATE-NC was among the strongest independent predictors of dementia. When LATE-NC and ADNC were assessed in a multivariate model without other dementia-associated pathologies, the attributable risk was higher for LATE-NC than ADNC (24.2% vs. 18.6%). This population-based study provides evidence that LATE-NC is very common and one of the most significant determinants of dementia in the general late-life aged population.

Machine-learning-driven biomarker discovery for the discrimination between allergic and irritant contact dermatitis.

Contact dermatitis tremendously impacts the quality of life of suffering patients. Currently, diagnostic regimes rely on allergy testing, exposure specification, and follow-up visits; however, distinguishing the clinical phenotype of irritant and allergic contact dermatitis remains challenging. Employing integrative transcriptomic analysis and machine-learning approaches, we aimed to decipher disease-related signature genes to find suitable sets of biomarkers. A total of 89 positive patch-test reaction biopsies against four contact allergens and two irritants were analyzed via microarray. Coexpression network analysis and Random Forest classification were used to discover potential biomarkers and selected biomarker models were validated in an independent patient group. Differential gene-expression analysis identified major gene-expression changes depending on the stimulus. Random Forest classification identified CD47, BATF, FASLG, RGS16, SYNPO, SELE, PTPN7, WARS, PRC1, EXO1, RRM2, PBK, RAD54L, KIFC1, SPC25, PKMYT, HISTH1A, TPX2, DLGAP5, TPX2, CH25H, and IL37 as potential biomarkers to distinguish allergic and irritant contact dermatitis in human skin. Validation experiments and prediction performances on external testing datasets demonstrated potential applicability of the identified biomarker models in the clinic. Capitalizing on this knowledge, novel diagnostic tools can be developed to guide clinical diagnosis of contact allergies.

Primary age-related tauopathy in a Finnish population-based study of the oldest old (Vantaa 85+).

AIMS: Few studies have investigated primary age-related tauopathy (PART) in a population-based setting. Here, we assessed its prevalence, genetic background, comorbidities and features of cognitive decline in an unselected elderly population. METHODS: The population-based Vantaa 85+ study includes all 601 inhabitants of Vantaa aged ≥ 85 years in 1991. Neuropathological assessment was possible in 301. Dementia (DSM IIIR criteria) and Mini-Mental State Examination (MMSE) scores were assessed at the baseline of the study and follow-ups. PART subjects were identified according to the criteria by Crary et al and were compared with subjects with mild and severe Alzheimer's disease (AD) neuropathological changes. The effects of other neuropathologies were taken into account using multivariate and sensitivity assays. Genetic analyses included APOE genotypes and 29 polymorphisms of the MAPT 3' untranslated region (3'UTR region). RESULTS: The frequency of PART was 20% (n = 61/301, definite PART 5%). When PART subjects were compared with those with severe AD pathology, dementia was less common, its age at onset was higher and duration shorter. No such differences were seen when compared with those with milder AD pathology. However, both AD groups showed a steeper decline in MMSE scores in follow-ups compared with PART. APOE ε4 frequency was lower, and APOE ε2 frequency higher in the PART group compared with each AD group. The detected nominally significant associations between PART and two MAPT 3'UTR polymorphisms and haplotypes did not survive Bonferroni correction. CONCLUSIONS: PART is common among very elderly. PART subjects differ from individuals with AD-type changes in the pattern of cognitive decline, associated genetic and neuropathological features.

Frequency of LATE neuropathologic change across the spectrum of Alzheimer's disease neuropathology: combined data from 13 community-based or population-based autopsy cohorts.

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) and Alzheimer's disease neuropathologic change (ADNC) are each associated with substantial cognitive impairment in aging populations. However, the prevalence of LATE-NC across the full range of ADNC remains uncertain. To address this knowledge gap, neuropathologic, genetic, and clinical data were compiled from 13 high-quality community- and population-based longitudinal studies. Participants were recruited from United States (8 cohorts, including one focusing on Japanese-American men), United Kingdom (2 cohorts), Brazil, Austria, and Finland. The total number of participants included was 6196, and the average age of death was 88.1 years. Not all data were available on each individual and there were differences between the cohorts in study designs and the amount of missing data. Among those with known cognitive status before death (n = 5665), 43.0% were cognitively normal, 14.9% had MCI, and 42.4% had dementia-broadly consistent with epidemiologic data in this age group. Approximately 99% of participants (n = 6125) had available CERAD neuritic amyloid plaque score data. In this subsample, 39.4% had autopsy-confirmed LATE-NC of any stage. Among brains with "frequent" neuritic amyloid plaques, 54.9% had comorbid LATE-NC, whereas in brains with no detected neuritic amyloid plaques, 27.0% had LATE-NC. Data on LATE-NC stages were available for 3803 participants, of which 25% had LATE-NC stage > 1 (associated with cognitive impairment). In the subset of individuals with Thal Aß phase = 0 (lacking detectable Aß plaques), the brains with LATE-NC had relatively more severe primary age-related tauopathy (PART). A total of 3267 participants had available clinical data relevant to frontotemporal dementia (FTD), and none were given the clinical diagnosis of definite FTD nor the pathological diagnosis of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). In the 10 cohorts with detailed neurocognitive assessments proximal to death, cognition tended to be worse with LATE-NC across the full spectrum of ADNC severity. This study provided a credible estimate of the current prevalence of LATE-NC in advanced age. LATE-NC was seen in almost 40% of participants and often, but not always, coexisted with Alzheimer's disease neuropathology.

Lewy-related pathology exhibits two anatomically and genetically distinct progression patterns: a population-based study of Finns aged 85.

According to a generally accepted concept Lewy-related pathology (LRP) follows hierarchical caudo-rostral progression. LRP is also frequently present concomitantly with Alzheimer's disease (AD), and it has been hypothesized that AD-associated LRP forms a distinct type of α-synucleinopathy, where LRP originates in the amygdala. The frequency of distinct forms of LRP progression types has not been studied in a population-based setting. We investigated the distribution and progression of LRP and its relation to AD pathology and apolipoprotein (APOE) ε4 in a population-based sample of Finns aged over 85 years (N = 304). Samples from spinal cord to neocortical areas representing 11 anatomical sites without any hierarchical selection were analyzed immunohistochemically (α-synuclein antibody clone 5G4). LRP was present in 124 individuals (41%) and according to DLB Consortium guidelines 19 of them were categorized as brainstem, 10 amygdala-predominant, 41 limbic, and 43 diffuse neocortical type, whereas 11 could not be classified. To determine the LRP progression patterns, a systematic anatomical scoring was carried out by taking into account the densities of the semiquantitative LRP scores in each anatomic site. With this scoring 123 (99%) subjects could be classified into two progression pattern types: 67% showed caudo-rostral and 32% amygdala-based progression. The unsupervised statistical K-means cluster analysis was used as a supplementary test and supported the presence of two progression patterns and had a 90% overall concordance with the systematic anatomical scoring method. Severe Braak NFT stage, high CERAD score and APOE ε4 were significantly (all p < 0.00001) associated with amygdala-based, but not with caudo-rostral progression type (all p > 0.2). This population-based study demonstrates two distinct common LRP progression patterns in the very elderly population. The amygdala-based pattern was associated with APOE ε4 and AD pathology. The results confirm the previous progression hypotheses but also widen the concept of the AD-associated LRP.

ALK and EGFR expression by immunohistochemistry are associated with Merkel cell polyomavirus status in Merkel cell carcinoma.

AIMS: Merkel cell carcinoma, a rare cutaneous neuroendocrine tumour of the skin, can be categorised into two groups according to Merkel cell polyomavirus (MCV) presence. MCV-negative tumours are more aggressive and frequently associated with gene mutations. Some of the genes are potential therapeutic targets. We have previously reported EGFR mutations in six of 27 MCC tumours and overexpression of ALK and EZH2 at mRNA level in MCC tumours. In this study, we sought to determine expression of ALK, EGFR and EZH2 in MCC samples and assess their correlation to MCV status and clinical parameters. METHODS AND RESULTS: Tissue microarrays were utilised and stained with primary antibodies. Staining data were statistically compared to patient sex, tumour location and development of metastasis and MCC-specific death; 112 tumours and their corresponding patient data were included. We found strong expression of ALK in 51% and strong expression of EZH2 in 76% of the tumours. There was evident correlation of ALK expression with MCV-positivity. Expression of EGFR was infrequent, presenting only in seven MCV-negative tumours. None of the proteins associated with development of metastasis or MCC specific death. CONCLUSIONS: ALK and EZH2 expression are frequent in MCC and ALK expression correlates to MCV positivity. EGFR positive tumours might respond to EGFR inhibiting treatment.

Fatal Tick-Borne Encephalitis Virus Infections Caused by Siberian and European Subtypes, Finland, 2015.

In most locations except for Russia, tick-borne encephalitis is mainly caused by the European virus subtype. In 2015, fatal infections caused by European and Siberian tick-borne encephalitis virus subtypes in the same Ixodes ricinus tick focus in Finland raised concern over further spread of the Siberian subtype among widespread tick species.

Aberrant expression of ALK and EZH2 in Merkel cell carcinoma.

BACKGROUND: Distinct characteristic features categorize Merkel cell carcinoma (MCC) into two subgroups according to the Merkel cell polyomavirus infection. Many mutational studies on MCC have been carried out in recent years without identifying a prominent driver mutation. However, there is paucity reporting the expression of cancer genes at the RNA level in MCC tumors. In this study, we studied the RNA expression profiles of 26 MCC tumors, with a goal to identify prospective molecular targets that could improve the treatment strategies of MCC. METHODS: RNA expression of 50 cancer-related genes in 26 MCC tumors was analyzed by targeted amplicon based next-generation sequencing using the Ion Torrent technology and the expression compared with that of normal, non-cancerous skin samples. Sequencing data were processed using Torrent Suite™ Software. Expression profiles of MCV-negative and MCV-positive tumors were compared. Fluorescence in situ hybridization was performed to study ALK rearrangements and immunohistochemistry to study ALK expression in tumor tissue. RESULTS: ALK, CDKN2A, EZH2 and ERBB4 were overexpressed, and EGFR, ERBB2, PDGFRA and FGFR1 were underexpressed in MCC tumors compared to normal skin. In the MCV-negative tumors, MET, NOTCH1, FGFR3, and SMO were overexpressed and JAK3 and NPM1 were under-expressed compared to the MCV-positive tumors. CONCLUSIONS: High expression of ALK, CDKN2A and EZH2 was recorded in MCC tumors. No ALK fusion was seen by FISH analysis. Overexpression of EZH2 suggests its potential as a drug target in MCC.

ALK fusion and its association with other driver gene mutations in Finnish non-small cell lung cancer patients.

Screening of anaplastic lymphoma tyrosine kinase (ALK) gene fusions in non-small cell lung cancer (NSCLC) patients enables the identification of the patients likely to benefit from ALK-targeted therapy. Our aim was to assess the prevalence of ALK fusion in Finnish NSCLC patients, which has not been reported earlier, and to study the presence of ALK fusion in relation to clinicopathological characteristics and other driver gene mutations. A total of 469 formalin-fixed paraffin-embedded tumor tissue specimens from Finnish NSCLC patients were screened for ALK fusion by immunohistochemistry (IHC). For confirmation of IHC results, fluorescence in situ hybridization (FISH) was conducted for 171 specimens. Next-generation sequencing was performed for all ALK-positive specimens to characterize the association of ALK fusion with mutations in targeted regions of 22 driver genes. Of the 469 tumors screened, 11 (2.3%) harbored an ALK fusion, including nine adenocarcinomas and two large cell carcinomas. The IHC results for all 11 ALK-positive and 160 random ALK-negative specimens were confirmed by FISH. ALK fusion was significantly associated with never/ex-light smoking history (P<0.001) and younger age (P=0.004). Seven ALK-positive tumors showed additional mutations; three in MET, one in MET and CTNNB1, two in TP53, and one in PIK3CA. Our results show that ALK fusion is an infrequent alteration in Finnish NSCLC patients. Although the majority of ALK-positive cases were adenocarcinomas, the fusion was also seen in large cell carcinomas. Further studies are needed to elucidate the clinical significance of the coexistence of ALK fusion with MET, TP53, CTNNB1, and PIK3CA mutations.

Diagnostic performance of Idylla MSI test in colorectal cancer biopsies.

Universal testing for microsatellite instability (MSI) is recommended in colorectal cancer (CRC) to screen for Lynch syndrome and to guide optimal treatment and follow-up of the patients. Especially in neoadjuvant setting, where immuno-oncological treatments have recently shown excellent responses, identification of MSI status at biopsy is a prerequisite. Idylla MSI test offers a rapid and automated test to assess MSI-status from formalin-fixed paraffin-embedded tumor tissue sections. In this study, we compared the performance of the Idylla MSI test to mismatch repair (MMR) protein immunohistochemistry (IHC) using 117 CRC biopsies with previously known deficient MMR status. The concordance between Idylla and IHC was 99.0% (95/96) for biopsies with the recommended ≥ 20% tumor cell content. Further, 85.7% (18/21) of suboptimal CRC biopsy specimens (tumor cell content 5-15%) were diagnosed as MSI. Overall, we identified four discrepant cases of which three had tumor cell content less than 20%, explaining the discordant result. Our study shows that the Idylla MSI test offers a competent tool for MSI screening in CRC biopsy specimens.

N-Glycomic Profiling of Microsatellite Unstable Colorectal Cancer.

Aberrant glycosylation affects cancer progression and immune evasion. Approximately 15% of colorectal cancers (CRCs) demonstrate microsatellite instability (MSI) and display major differences in outcomes and therapeutic responses, as compared to corresponding microsatellite stable (MSS) tumors. We compared the N-glycan profiles of stage II and IV MSI CRC tumors, further subdivided into BRAFV600E wild-type and mutated subgroups (n = 10 in each subgroup), with each other and with those of paired non-neoplastic mucosal samples using mass spectrometry. Further, the N-glycans of BRAFV600E wild-type stage II MSI tumors were compared to corresponding MSS tumors (n = 9). Multiple differences in N-glycan profiles were identified between the MSI CRCs and control tissues, as well as between the stage II MSI and MSS samples. The MSI CRC tumors showed a lower relative abundance of high-mannose N-glycans than did the control tissues or the MSS CRCs. Among MSI CRC subgroups, acidic N-glycans showed tumor stage and BRAF mutation status-dependent variation. Specifically, the large, sulfated/phosphorylated, and putative terminal N-acetylhexosamine-containing acidic N-glycans differed between the MSI CRC subgroups, showing opposite changes in stages II and IV, when comparing BRAF mutated and wild-type tumors. Our results show that molecular subgroups of CRC exhibit characteristic glycan profiles that may explain certain carcinogenic properties of MSI tumors.

Gene fusions and oncogenic mutations in MLH1 deficient and BRAFV600E wild-type colorectal cancers.

Gene fusions can act as oncogenic drivers and offer targets for cancer therapy. Since fusions are rare in colorectal cancer (CRC), their universal screening seems impractical. Our aim was to investigate gene fusions in 62 CRC cases with deficient MLH1 (dMLH1) and BRAFV600E wild-type (wt) status from a consecutive real-life series of 2079 CRCs. First, gene fusions were analysed using a novel FusionPlex Lung v2 RNA-based next-generation sequencing (NGS) panel, and these results were compared to a novel Idylla GeneFusion assay and pan-TRK immunohistochemistry (IHC). NGS detected seven (7/62, 11%) NTRK1 fusions (TPM3::NTRK1, PLEKHA6::NTRK1 and LMNA::NTRK1, each in two cases, and IRF2BP2::NTRK1 in one case). In addition, two ALK, four RET and seven BRAF fusions were identified. Idylla detected seven NTRK1 expression imbalances, in line with the NGS results (overall agreement 100%). Furthermore, Idylla detected the two NGS-identified ALK rearrangements as one specific ALK fusion and one ALK expression imbalance, whilst only two of the four RET fusions were discovered. However, Idylla detected several expression imbalances of ALK (n = 7) and RET (n = 1) that were found to be fusion negative with the NGS. Pan-TRK IHC showed clearly detectable, fusion partner-dependent staining patterns in the seven NTRK1 fusion cases. Overall agreement for pan-TRK antibody clone EPR17341 was 98% and for A7H6R 100% when compared to the NGS. Of the 62 CRCs, 43 were MLH1 promoter hypermethylated (MLH1ph) and 39 were RASwt. All fusion cases were both MLH1ph and RASwt. Our results show that kinase fusions (20/30, 67%) and most importantly targetable NTRK1 fusions (7/30, 23%) are frequent in CRCs with dMLH1/BRAFV600Ewt/MLH1ph/RASwt. NGS was the most comprehensive method in finding the fusions, of which a subset can be screened by Idylla or IHC, provided that the result is confirmed by NGS.

Distribution of Lewy-related pathology in the brain, spinal cord, and periphery: the population-based Vantaa 85 + study.

Evolving evidence has supported the existence of two anatomically distinct Lewy-related pathology (LRP) types. Investigation of spinal cord and peripheral LRP can elucidate mechanisms of Lewy body disorders and origins of synuclein accumulation. Still, very few unselected studies have focused on LRP in these regions. Here we analysed LRP in spinal cord, dorsal root ganglion, and adrenal gland in the population-based Vantaa 85 + study, including every ≥ 85 years old citizen living in the city of Vantaa in 1991 (n = 601). Samples from spinal cord (C6-7, TH3-4, L3-4, S1-2) were available from 303, lumbar dorsal root ganglion from 219, and adrenal gland from 164 subjects. Semiquantitative scores of LRP were determined from immunohistochemically stained sections (anti-alpha-synuclein antibody 5G4). LRP in the ventral and dorsal horns of spinal cord, thoracic intermediolateral column, dorsal root ganglion and adrenal gland were compared with brain LRP, previously determined according to DLB Consortium criteria and by caudo-rostral versus amygdala-based LRP classification. Spinal LRP was found in 28% of the total population and in 61% of those who had LRP in the brain. Spinal cord LRP was found only in those subjects with LRP in the brain, and the quantity of spinal cord LRP was associated with the severity of brain LRP (p < 0.001). Unsupervised K-means analysis identified two cluster types of spinal and brain LRP corresponding to caudo-rostral and amygdala-based LRP types. The caudo-rostral LRP type exhibited more frequent and severe pathology in spinal cord, dorsal root ganglion and adrenal gland than the amygdala-based LRP type. Analysis of specific spinal cord regions showed that thoracic intermediolateral column and sacral dorsal horn were the most frequently affected regions in both LRP types. This population-based study on brain, spinal and peripheral LRP provides support to the concept of at least two distinct LRP types.

Detection of microsatellite instability with Idylla MSI assay in colorectal and endometrial cancer.

Universal testing of microsatellite instability (MSI) is recommended for colorectal cancer (CRC) and endometrial cancer (EC) to screen for Lynch syndrome and to aid in assessing prognosis and optimal treatment. We compared the performance of Idylla MSI test to immunohistochemistry (IHC) of mismatch repair (MMR) proteins in consecutive series of 100 CRC and 108 EC samples, as well as in retrospective series of 28 CRC and 33 EC specimens with known deficient MMR protein expression. The concordance between the Idylla test and IHC was 100% in all CRC samples (n=128) but lower in EC samples (87.2%; n=141). In the EC samples, sensitivity of Idylla test was 72.7% and specificity 100%. EC MSI/dMMR agreement was 85.4% for MLH1, 87.5% for MSH2, and only 35.3% for MSH6. When we analyzed 14 EC samples that were discrepant, i.e., dMMR using IHC and microsatellite stable using Idylla, with microsatellite markers BAT25 and BAT26, we found four cases to be replication error (RER) positive. All RER positive cases were deficient for MSH6 protein expression. We also re-analyzed EC samples with variable tumor cellularity to determine the limit of detection of the Idylla test and found that a 30% or higher tumor cellularity is required. We conclude that Idylla MSI test offers a sensitive and specific method for CRC diagnostics but is less sensitive in EC samples especially in the case of MSH6 deficiency.

GNEN-1: a spontaneously immortalized cell line from gastric neuroendocrine neoplasia.

Mixed neuroendocrine-non-neuroendocrine neoplasms (MINEN) are rare tumors that consist of at least 30% of both neuroendocrine and non-neuroendocrine components. The data concerning the pathogenesis of MINEN suggest a monoclonal origin. We describe a spontaneously immortalized cell line derived from gastric MINEN called GNEN-1. Primary tumor consisted of components of high-grade neuroendocrine carcinoma and adenocarcinoma. The GNEN-1 cell line was initiated from metastatic tumor cells of peritoneal fluid and expresses a purely neuroendocrine phenotype. The GNEN-1 cell line grows as monolayers and has retained the neuroendocrine phenotype with positivity for chromogranin A in immunohistochemistry. Electron microscopy showed cytoplasmic dense core granules and axon hillocks. The karyotype revealed alterations typical of both adenocarcinoma and neuroendocrine carcinoma such as trisomy 7 and 8. GNEN-1 cells were also positive for stanniocalcin-1, a marker of poor prognosis in gastric carcinomas. Expression of several markers related to neuroendocrine tumors was found. There have been only a few studies on the pathogenesis of MINEN and management of the disease due to the rarity of this tumor type. Here we describe for the first time an immortalized cell line derived from mixed gastric NEN. The GNEN-1 line offers a tool for future research on gastric NEN.

APOE ε4 associates with increased risk of severe COVID-19, cerebral microhaemorrhages and post-COVID mental fatigue: a Finnish biobank, autopsy and clinical study.

Apolipoprotein E ε4 allele (APOE4) has been shown to associate with increased susceptibility to SARS-CoV-2 infection and COVID-19 mortality in some previous genetic studies, but information on the role of APOE4 on the underlying pathology and parallel clinical manifestations is scarce. Here we studied the genetic association between APOE and COVID-19 in Finnish biobank, autopsy and prospective clinical cohort datasets. In line with previous work, our data on 2611 cases showed that APOE4 carriership associates with severe COVID-19 in intensive care patients compared with non-infected population controls after matching for age, sex and cardiovascular disease status. Histopathological examination of brain autopsy material of 21 COVID-19 cases provided evidence that perivascular microhaemorrhages are more prevalent in APOE4 carriers. Finally, our analysis of post-COVID fatigue in a prospective clinical cohort of 156 subjects revealed that APOE4 carriership independently associates with higher mental fatigue compared to non-carriers at six months after initial illness. In conclusion, the present data on Finns suggests that APOE4 is a risk factor for severe COVID-19 and post-COVID mental fatigue and provides the first indication that some of this effect could be mediated via increased cerebrovascular damage. Further studies in larger cohorts and animal models are warranted.

Esophageal morbidity and function in adults with repaired esophageal atresia with tracheoesophageal fistula: a population-based long-term follow-up.

OBJECTIVE: We assessed esophageal morbidity and relationships between surgical complications, symptoms, endoscopic findings, immunohistochemistry, and esophageal motility in adults with repaired esophageal atresia (EA). SUMMARY OF BACKGROUND DATA: There exist no previous population-based long-term follow-up studies on EA. METHODS: Participants were interviewed, and they underwent esophageal endoscopy and manometry. Matched control subjects (n = 287) served as controls. RESULTS: A total of 101 (42%) individuals representative of the entire study population participated at a mean age of 36 years (range, 21-57). Symptomatic gastroesophageal reflux had occurred in 34% and dysphagia in 85% of the patients and in 8% and 2% of the controls (P < 0.001 for both). Endoscopic findings included hiatal hernia (28%), Barrett's esophagus (11%), esophagitis (8%), and anastomotic stricture (8%). Immunohistochemistry revealed esophagitis in 25%, and CDX2-positive columnar epithelial metaplasia in 21%, with additional goblet cells and MUC2 positivity in 6%. Gastroesophageal reflux and dysphagia were equally common in individuals with normal histology, esophagitis, or epithelial metaplasia. Manometry demonstrated nonpropagating peristalsis in 80% of the patients, and low distal wave amplitudes of the esophagus in all the changes being significantly worse in those with epithelial metaplasia (P < or = 0.022 metaplasia vs. esophagitis/normal). Anastomotic complications (odds ratio [OR]: 8.6-24, 95% confidence interval [CI]: 1.7-260, P = 0.011-0.008), age (OR: 20, 95% CI: 1.3-310, P = 0.034), low distal esophageal body pressure (OR: 2.6, 95% CI: 0.7-10, P = 0.002), and defective esophageal peristalsis (OR: 2.2, 95% CI: 0.4-11, P = 0.014) predicted development of epithelial metaplasia. CONCLUSIONS: Significant esophageal morbidity associated with EA extends into adulthood. Surgical complications, increasing age, and impaired esophageal motility predict development of epithelial metaplasia after repair of EA.

Putative risk alleles for LATE-NC with hippocampal sclerosis in population-representative autopsy cohorts.

Limbic-predominant age-related TAR-DNA-binding protein-43 (TDP-43) encephalopathy with hippocampal sclerosis pathology (LATE-NC + HS) is a neurodegenerative disorder characterized by severe hippocampal CA1 neuron loss and TDP-43-pathology, leading to cognitive dysfunction and dementia. Polymorphisms in GRN, TMEM106B and ABCC9 are proposed as LATE-NC + HS risk factors in brain bank collections. To replicate these results in independent population-representative cohorts, hippocampal sections from brains donated to three such studies (Cambridge City over 75-Cohort [CC75C], Cognitive Function and Ageing Study [CFAS], and Vantaa 85+ Study) were stained with hematoxylin-eosin (n = 744) and anti-pTDP-43 (n = 713), and evaluated for LATE-NC + HS and TDP-43 pathology. Single nucleotide polymorphism genotypes in GRN rs5848, TMEM106B rs1990622 and ABCC9 rs704178 were determined. LATE-NC + HS (n = 58) was significantly associated with the GRN rs5848 genotype (χ2 (2) = 20.61, P < 0.001) and T-allele (χ2 (1) = 21.04, P < 0.001), and TMEM106B rs1990622 genotype (Fisher's exact test, P < 0.001) and A-allele (χ2 (1) = 25.75, P < 0.001). No differences in ABCC9 rs704178 genotype or allele frequency were found between LATE-NC + HS and non-LATE-NC + HS neuropathology cases. Dentate gyrus TDP-43 pathology associated with GRN and TMEM106B variations, but the association with TMEM106B nullified when LATE-NC + HS cases were excluded. Our results indicate that GRN and TMEM106B are associated with severe loss of CA1 neurons in the aging brain, while ABCC9 was not confirmed as a genetic risk factor for LATE-NC + HS. The association between TMEM106B and LATE-NC + HS may be independent of dentate TDP-43 pathology.

Oral lichen planus and chronic junctional stomatitis: differences in lymphocyte subpopulations.

OBJECTIVE: Oral lichen planus (OLP) is an oral counterpart or oral manifestation of the common skin disease lichen planus. Chronic junctional stomatitis (CJS) is a relatively unknown condition characterized by a stromal lymphocyte infiltrate, which is also a diagnostic feature of OLP. The differential diagnosis of OLP and CJS is unclear and they have been suggested to represent variants of the same disease. MATERIAL AND METHODS: To investigate possible differences in lymphocyte (sub)populations between these two conditions, we immunostained 10 OLP and 10 CJS specimens for CD1-a, and the lymphocyte markers, CD3, CD4, CD5, CD8, and CD20. We scored the staining results by a four-step grading system and used the Fisher exact test to analyze them statistically. RESULTS: The proportional amount of (CD20 positive) B lymphocytes was higher in CJS than in OLP and the predominance of CD4 positive T lymphocytes over CD8 positive T lymphocytes was stronger in OLP than in CJS. The differences were statistically significant. CONCLUSION: The results reflect differences in the lymphatic infiltrate between OLP and CJS. Their significance needs further investigation.