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Background: Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative diseases. Their treatment options are rather limited, and no neuroprotective or disease-modifying treatments are available. Anti-diabetic drugs, such as glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) agonists, have been suggested as a potential therapeutic option. Aims: Assess GLP1R and GIPR genetic variability in relation to AD- and PD-related phenotypes. Methods: AD, PD patients and healthy control subjects were included in the study. Cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease were measured in AD patients, while cognitive impairment was evaluated in PD. All participants were genotyped for three SNPs: GLP1R rs10305420, GLP1R rs6923761 and GIPR rs1800437. Results: GLP1R rs10305420 genotypes were associated with increased odds for AD and PD development. GLP1R rs10305420 and GLP1R rs6923761 genotypes were significantly associated with Aβ42/40 ratio (p = 0.041 and p = 0.050), while GLP1R rs6923761 was also associated with p-tau levels (p = 0.022). Finally, GIPR rs1800437 heterozygotes as well as carriers of at least one GIPR rs1800437 C allele presented with increased odds for the development of dementia in PD (OR = 1.92; 95 % CI = 1.05–3.51; p = 0.034 and OR = 1.95; 95 % CI = 1.08–3.52; p = 0.027, respectively). Conclusion: GLP1R and GIPR genetic variability may affect the occurrence of AD and PD and is also associated with AD CSF biomarkers for Alzheimer's disease and dementia in PD. The data on GLP1R and GIPR genetic variability may support the function of incretin receptors in neurodegeneration.

Abstract Blood phosphorylated tau (p-tau) biomarkers, including p-tau217, show high associations with Alzheimer’s disease (AD) neuropathologic change and clinical stage. Certain plasma p-tau217 assays recognize tau forms phosphorylated additionally at threonine-212, but the contribution of p-tau212 alone to AD is unknown. We developed a blood-based immunoassay that is specific to p-tau212 without cross-reactivity to p-tau217. Here, we examined the diagnostic utility of plasma p-tau212. In five cohorts (n = 388 participants), plasma p-tau212 showed high performances for AD diagnosis and for the detection of both amyloid and tau pathology, including at autopsy as well as in memory clinic populations. The diagnostic accuracy and fold changes of plasma p-tau212 were similar to those for p-tau217 but higher than p-tau181 and p-tau231. Immunofluorescent staining of brain tissue slices showed prominent p-tau212 reactivity in neurofibrillary tangles that co-localized with p-tau217 and p-tau202/205. These findings support plasma p-tau212 as a peripherally accessible biomarker of AD pathophysiology.

Abstract Background To evaluate long-term outcomes and prognostic factors in patients with juvenile idiopathic arthritis (JIA), presenting as oligoarthritis, who received IAC as the first treatment for their disease. Methods We conducted retrospective study at the University Children’s Hospital Ljubljana, Slovenia, from January 2015 to May 2023 in children with JIA, clinically presenting as oligoarthritis receiving intra-articular corticosteroid injection (IAC) as the initial treatment. Patient and treatment data were collected, and the outcomes were categorized into three groups based on the later need for therapy: no therapy needed, only additional IAC needed and systemic therapy needed. The last group was further divided based on the requirement of bDMARD. Log-rank (Mantel-Cox) survival analyses compared different outcome groups. Results We included 109 patients with JIA, presenting as oligoarthritis (63% female), who were first treated with IAC. The mean age at IAC was 8.0 years, with a 4.3-year follow-up. Notably, 38.5% of patients did not require additional therapy post-IAC, whereas 15.5% required only additional IAC. Systemic therapy, mainly methotrexate (MTX), was necessary for 45.9% of patients, initiated in average 7.8 months post-IAC. Biologic therapy was initiated in 22% in average 2.2 years post-IAC. Number of injected joints correlated with the need for biologics. At the last follow-up, 88.9% had inactive disease. ANA positivity (P = 0.049, chi square 3.89) and HLA B27 antigen presence (P = 0.050, chi square 3.85) were associated with the need for systemic therapy. A subgroup of children older than 8 years, ANA and HLA B27 negative required significantly less systemic (25.8%) and biologic therapy (9.6%) compared to other patients (p = 0.050, chi square 3.77). Conclusion Almost 40% of children with oligoarticular JIA requiring IAC did not progress to chronic disease. Younger age, ANA positivity, and HLA B27 presence were predictive factors for systemic therapy, while the number of injected joints predicted the future need for biologic therapy.

BackgroundKappa free light chains (κ-FLC) in the cerebrospinal fluid (CSF) are an emerging biomarker in multiple sclerosis (MS).ObjectiveTo investigate whether κ-FLC index has similar diagnostic value in patients with primary progressive multiple sclerosis (PPMS) compared to oligoclonal bands (OCB).MethodsPatients with PPMS were recruited through 11 MS centres across 7 countries. κ-FLC were measured by immunonephelometry/-turbidimetry. OCB were determined by isoelectric focusing and immunofixation.ResultsA total of 174 patients (mean age of 52±11 years, 51% males) were included. κ-FLC index using a cut-off of 6.1 was positive in 161 (93%) and OCB in 153 (88%) patients.Conclusionκ-FLC index shows similar diagnostic sensitivity than OCB in PPMS.

Abstract Ear images have been shown to be a reliable modality for biometric recognition with desirable characteristics, such as high universality, distinctiveness, measurability and permanence. While a considerable amount of research has been directed towards ear recognition techniques, the problem of ear alignment is still under‐explored in the open literature. Nonetheless, accurate alignment of ear images, especially in unconstrained acquisition scenarios, where the ear appearance is expected to vary widely due to pose and view point variations, is critical for the performance of all downstream tasks, including ear recognition. Here, the authors address this problem and present a framework for ear alignment that relies on a two‐step procedure: (i) automatic landmark detection and (ii) fiducial point alignment. For the first (landmark detection) step, the authors implement and train a Two‐Stack Hourglass model (2‐SHGNet) capable of accurately predicting 55 landmarks on diverse ear images captured in uncontrolled conditions. For the second (alignment) step, the authors use the Random Sample Consensus (RANSAC) algorithm to align the estimated landmark/fiducial points with a pre‐defined ear shape (i.e. a collection of average ear landmark positions). The authors evaluate the proposed framework in comprehensive experiments on the AWEx and ITWE datasets and show that the 2‐SHGNet model leads to more accurate landmark predictions than competing state‐of‐the‐art models from the literature. Furthermore, the authors also demonstrate that the alignment step significantly improves recognition accuracy with ear images from unconstrained environments compared to unaligned imagery.

Abstract Metabolic brain biomarkers have been incorporated in various diagnostic guidelines of neurodegenerative diseases, recently. To improve their diagnostic accuracy a biologically and clinically homogeneous sample is needed for their identification. Alzheimer’s disease-related pattern (ADRP) has been identified previously in cohorts of clinically diagnosed patients with dementia due to Alzheimer’s disease (AD), meaning that its diagnostic accuracy might have been reduced due to common clinical misdiagnosis. In our study, we aimed to identify ADRP in a cohort of AD patients with CSF confirmed diagnosis, validate it in large out-of-sample cohorts and explore its relationship with patients’ clinical status. For identification we analyzed 2-[18F]FDG PET brain scans of 20 AD patients and 20 normal controls (NCs). For validation, 2-[18F]FDG PET scans from 261 individuals with AD, behavioral variant of frontotemporal dementia, mild cognitive impairment and NC were analyzed. We identified an ADRP that is characterized by relatively reduced metabolic activity in temporoparietal cortices, posterior cingulate and precuneus which co-varied with relatively increased metabolic activity in the cerebellum. ADRP expression significantly differentiated AD from NC (AUC = 0.95) and other dementia types (AUC = 0.76–0.85) and its expression correlated with clinical measures of global cognition and neuropsychological indices in all cohorts.

IntroductionAlthough children seem to be less susceptible to COVID-19, some of them develop a rare but serious hyperinflammatory condition called multisystem inflammatory syndrome in children (MIS-C). While several studies describe the clinical conditions of acute MIS-C, the status of convalescent patients in the months after acute MIS-C is still unclear, especially the question of persistence of changes in the specific subpopulations of immune cells in the convalescent phase of the disease.MethodsWe therefore analyzed peripheral blood of 14 children with MIS-C at the onset of the disease (acute phase) and 2 to 6 months after disease onset (post-acute convalescent phase) for lymphocyte subsets and antigen-presenting cell (APC) phenotype. The results were compared with six healthy age-matched controls.ResultsAll major lymphocyte populations (B cells, CD4 + and CD8+ T cells, and NK cells) were decreased in the acute phase and normalized in the convalescent phase. T cell activation was increased in the acute phase, followed by an increased proportion of γ/δ-double-negative T cells (γ/δ DN Ts) in the convalescent phase. B cell differentiation was impaired in the acute phase with a decreased proportion of CD21 expressing, activated/memory, and class-switched memory B cells, which normalized in the convalescent phase. The proportion of plasmacytoid dendritic cells, conventional type 2 dendritic cells, and classical monocytes were decreased, while the proportion of conventional type 1 dendritic cells was increased in the acute phase. Importantly the population of plasmacytoid dendritic cells remained decreased in the convalescent phase, while other APC populations normalized. Immunometabolic analysis of peripheral blood mononuclear cells (PBMCs) in the convalescent MIS-C showed comparable mitochondrial respiration and glycolysis rates to healthy controls.ConclusionsWhile both immunophenotyping and immunometabolic analyzes showed that immune cells in the convalescent MIS-C phase normalized in many parameters, we found lower percentage of plasmablasts, lower expression of T cell co-receptors (CD3, CD4, and CD8), an increased percentage of γ/δ DN Ts and increased metabolic activity of CD3/CD28-stimulated T cells. Overall, the results suggest that inflammation persists for months after the onset of MIS-C, with significant alterations in some immune system parameters, which may also impair immune defense against viral infections.

The study investigates the task of authorship attribution on short texts in Slovenian using the BERT language model. Authorship attribution is the task of attributing a written text to its author, frequently using stylometry or computational techniques. We create five custom datasets for different numbers of included text authors and fine-tune two BERT models, SloBERTa and BERT Multilingual (mBERT), to evaluate their performance in closed-class and open-class problems with varying numbers of authors. Our models achieved an F1 score of approximately 0.95 when using the dataset with the comments of the top five users by the number of written comments. Training on datasets that include comments written by an increasing number of people results in models with a gradually decreasing F1 score. Including out-of-class comments in the evaluation decreases the F1 score by approximately 0.05. The study demonstrates the feasibility of using BERT models for authorship attribution in short texts in the Slovenian language.

INTRODUCTION: The established cerebrospinal fluid (CSF) phosphorylated tau181 (p‐tau181) may not reliably reflect concomitant Alzheimer's disease (AD) and primary age‐related tauopathy (PART) found in Creutzfeldt–Jakob disease (CJD) at autopsy. METHODS: We investigated CSF N‐terminal p‐tau181, p‐tau217, and p‐tau231 with in‐house Simoa assays in definite CJD (n = 29), AD dementia (n = 75), mild cognitive impairment (MCI) due to AD (n = 65), and subjective cognitive decline (SCD, n = 28). Post‐mortem examination performed in patients with CJD 1.3 (0.3–14.3) months after CSF collection revealed no co‐pathology in 10, concomitant AD in 8, PART in 8, and other co‐pathologies in 3 patients. RESULTS: N‐terminal p‐tau was increased in CJD versus SCD (p < 0.0001) and correlated with total tau (t‐tau) in the presence of AD and PART co‐pathology (rho = 0.758–0.952, p ≤ 001). Concentrations in CJD+AD were indistinguishable from AD dementia, with the largest fold‐change in p‐tau217 (11.6), followed by p‐tau231 and p‐tau181 (3.2–4.5). DISCUSSION: Variable fold‐changes and correlation with t‐tau suggest that p‐tau closely associates with neurodegeneration and concomitant AD in CJD. Highlights: N‐terminal phosphorylated tau (p‐tau) biomarkers are increased in Creutzfeldt–Jakob disease (CJD) with and without concomitant AD.P‐tau217, p‐tau231, and p‐tau181 correlate with total tau (t‐tau) and increase in the presence of amyloid beta (Aβ) co‐pathology.N‐terminal p‐tau181 and p‐tau231 in Aβ‐negative CJD show variation among PRNP genotypes.Compared to mid‐region–targeting p‐tau181, cerebrospinal fluid (CSF) N‐terminal p‐tau has greater potential to reflect post‐mortem neuropathology in the CJD brain. [ABSTRACT FROM AUTHOR]

Marjolinov ulkus (MU) je redka, vendar izjemno agresivna oblika ulcerativnega ploščatoceličnega karcinoma, ki nastane iz kronične rane, najpogosteje po opeklinski poškodbi. Naš cilj je opozoriti na nevarnost maligne preobrazbe nestabilne brazgotine kot kronične rane (nastanek Marjolinovega ulkusa) ter možnosti njenega zdravljenja pri nas ter drugod po svetu. V Univerzitetnem kliničnem centru Ljubljana na Kliničnem oddelku za plastično, rekonstrukcijsko, estetsko kirurgijo in opekline smo v obdobju zadnjih 13 let obravnavali 5 bolnikov, operiranih zaradi nestabilne brazgotine, ki se je izkazovala kot kronična rana. Za potrebe članka smo opravili pregled angleške literature na temo ulceracije nestabilne opeklinske brazgotine. Marjolinov ulkus je epiteliomska sprememba, ki jo je možno preprečiti. Vsaka večja rana, ki se prepusti sekundarnemu celjenju, ima potencial za razvoj v kronično rano, ki lahko ulcerira in vodi v maligno spremembo. Še posebej moramo biti pozorni pri opeklinskih ranah ter brazgotinah. Če se pojavi kronična rana, je potrebna biopsija in kasnejše zdravljenje. Uspešnost zdravljenja je bila največja, kadar se je rana obravnavala, še preden se je preobrazila.

It is interesting phenomenon that chiral order can emerge in intrinsically achiral liquid crystals. Here Čopar et al. demonstrate achiral-to-chiral transition of the nematic liquid crystals flow in microfluidic channels and their behaviour, stability, and dependence on geometric and material parameters.

Oxidative stress and neuroinflammation are important processes involved in Alzheimer’s disease (AD) and mild cognitive impairment (MCI). Numerous risk factors, including genetic background, can affect the complex interplay between those mechanisms in the aging brain and can also affect typical AD hallmarks: amyloid plaques and neurofibrillary tangles. Our aim was to evaluate the association of polymorphisms in oxidative stress- and inflammation-related genes with cerebrospinal fluid (CSF) biomarker levels and cognitive test results. The study included 54 AD patients, 14 MCI patients with pathological CSF biomarker levels, 20 MCI patients with normal CSF biomarker levels and 62 controls. Carriers of two polymorphic IL1B rs16944 alleles had higher CSF Aβ1–42 levels (p = 0.025), while carriers of at least one polymorphic NFE2L2 rs35652124 allele had lower CSF Aβ1–42 levels (p = 0.040). Association with IL1B rs16944 remained significant in the AD group (p = 0.029). Additionally, MIR146A rs2910164 was associated with Aβ42/40 ratio (p = 0.043) in AD. Significant associations with cognitive test scores were observed for CAT rs1001179 (p = 0.022), GSTP1 rs1138272 (p = 0.005), KEAP1 rs1048290 and rs9676881 (both p = 0.019), as well as NFE2L2 rs35652124 (p = 0.030). In the AD group, IL1B rs1071676 (p = 0.004), KEAP1 rs1048290 and rs9676881 (both p = 0.035) remained associated with cognitive scores. Polymorphisms in antioxidative and inflammation genes might be associated with CSF biomarkers and cognitive test scores and could serve as additional biomarkers contributing to early diagnosis of dementia.

Necrotizing stomatitis is a rare, acute-onset disease that is usually associated with severely malnourished children or diminished systemic resistance. We describe a 1-year-old girl who developed necrotizing stomatitis, vasculitic rash, skin desquamation on the fingers and toes, and persistent hypertension after serologically confirmed SARS-CoV-2 infection. Her laboratory investigations revealed positive IgG anticardiolipin and IgG anti-β2 glycoprotein antibodies, and biopsy of the mucosa of the lower jaw showed necrosis and endothelial damage with mural thrombi. Swollen endothelial cells of small veins in the upper dermis were confirmed also by electron microscopy. As illustrated by our case, necrotizing stomatitis may develop as a rare complication associated with SARS-CoV-2 infection and can be considered as a part of the clinical spectrum of COVID-19 vasculopathy. The pathogenic mechanism could involve a consequence of inflammatory events with vasculopathy, hypercoagulability, and damage of endothelial cells as a response to SARS-CoV-2 infection.

Izhodišče: Primerjati kirurško obravnavo bolnikov z malformacijo Chiari I (CM-I) pri nas in po svetu ter ugotoviti primerljivost uspeha pri uporabi različnih kirurških tehnik. Metode: Opravili smo retrospektivno analizo 10 bolnikov, ki so bili operirani zaradi CM-I v UKC Maribor, Kirurška klinika, Oddelek za nevrokirurgijo v obdobju od januarja 2010 do maja 2016. Podatke o bolnikih smo zbrali v tabele in opravili deskriptivno statistično analizo vzorca. Pregledali smo literaturo v angleščini v podatkovnih bazah PubMed in Ovid na temo kirurškega zdravljenja CM-I. Rezultate raziskav smo primerjali s svojimi ugotovitvami. Rezultati: V obdobju od januarja 2010 do maja 2016 smo operirali 10 bolnikov: 8 žensk in 2 moška v starosti 11–57 let. Simptomi pred operacijo so trajali od 1 meseca do 29 let. Glavoboli so bili prisotni pri 8 bolnikih, bolečina v vratu je bila prisotna pri 4 bolnikih, vrtoglavica pri 2 bolnikih, mravljinčenje v rokah pa pri enem bolniku. Znaki pred operacijo pa so trajali od 1 leta do 29 let. Pri 2 bolnikih je bila prisotna spastična tetrapareza, pri 2 bolnikih motnja senzibilitete in pri 1 bolniku tremor rok. Pridruženo hidromielijo je imelo 5 bolnikov. Skoliozo sta imeli 2 bolnici. Pri vseh 10 bolnikih smo se odločili za kirurško obravnavo. V skupini 10 bolnikov, ki smo jih obravnavali, ni nihče umrl. Pri 2 bolnikih smo zaznali tekočinsko kolekcijo likvorja v podkožju, pri 1 bolniku tudi povišano telesno temperaturo in oteklino, izcedek iz rane pa pri 2 bolnikih. Bolnike smo sledili od 6 mesecev do 6 let. Vsi bolniki so navajali izboljšanje simptomov po operaciji. Zaključek: Rezultati naše raziskave so primerljivi z rezultati podobnih raziskav v literaturi. Ob tem pa moramo opomniti, da je bilo število bolnikov, vključenih v našo študijo, sorazmerno majhno. Razvidno je, da nikjer ni natančno določeno, kdaj se je treba odločiti za določen tip operacije, prav tako je v literaturi prisotna velika raznolikost v izidih po operaciji. Kirurško obravnavo je treba za vsakega bolnika individualizirati.

Numerous proteins target lipid droplets (LDs) through amphipathic helices (AHs). It is generally assumed that AHs insert bulky hydrophobic residues in packing defects at the LD surface. However, this model does not explain the targeting of perilipins, the most abundant and specific amphipathic proteins of LDs, which are weakly hydrophobic. A striking example is Plin4, whose gigantic and repetitive AH lacks bulky hydrophobic residues. Using a range of complementary approaches, we show that Plin4 forms a remarkably immobile and stable protein layer at the surface of cellular or in vitro generated oil droplets, and decreases LD size. Plin4 AH stability on LDs is exquisitely sensitive to the nature and distribution of its polar residues. These results suggest that Plin4 forms stable arrangements of adjacent AHs via polar/electrostatic interactions, reminiscent of the organization of apolipoproteins in lipoprotein particles, thus pointing to a general mechanism of AH stabilization via lateral interactions.