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The tumor architecture of high-grade gliomas is shaped by tumor cell necrosis, invasive growth and the leakage of a fibrin-rich edema from poorly organized tumor blood vessels. Here, we demonstrate a marked upregulation of clot formation in the interstitial spaces of tumor tissues from patients with glioblastoma while tumor-free brain is essentially devoid of fibrin. The accumulation of fibrin in tumor interstitial spaces is functionally relevant as we demonstrate increased infiltration and growth of primary glioblastoma cells after embedding in a 3-dimensional matrix made of fibrin ex vivo. Additionally, we detected accelerated tumor growth after implanting glioblastoma cells together with clotted plasma in brains of immune deficient mice while glioblastoma development in clotting-deficient hemophilia mice was delayed. Glioblastoma growth correlated with the outgrowth of invadopodia and their adhesive interactions with the 3-dimensional clot matrix, which was mediated by integrins β1 and β3 and their common downstream target focal adhesion kinase (FAK). Knocking down FAK with CRISPR Cas9 caused an upregulation of p21/p27 cell cycle inhibitors, strong growth inhibition in cultured glioblastoma cells and sustained anti-tumorigenic effects in orthotopic glioblastoma xenografts in vivo. These results go hand in hand with genomic data from The Cancer Genome Atlas that indicate increased clotting activity and reduced patient survival in glioma subgroups with high integrin β1 and β3 expression. We therefore conclude that clotting in glioma interstitial spaces provides tumor cells with a potent proliferative stimulus that can be reversed by targeting the adhesive machinery of glioblastoma cells via inhibition of FAK.

Uveal melanoma (UM), recognized as the most prevalent primary intraocular malignancy in adults, is primarily driven by mutations in the GNAQ and GNA11 genes. These genetic alterations are also implicated in other conditions, which exhibit distinct morphological characteristics. In this article, we investigate the role of GNAQ and GNA11 mutations across varied disorders (e.g., UM, skin blue nevi, and hemangiomas), emphasizing the shared pathogenic mechanisms that connect them despite their differing clinical manifestations. By investigating the molecular pathways affected by these mutations, we provide insights into the potential for targeted therapies that could address not only UM but also other disorders associated with GNAQ / GNA11 mutations. Moreover, we discuss the role of SOX10-positive perivascular cells that may be implicated in the complex pathophysiology of GNAQ/GNA11-related entities. Understanding the common molecular foundation of these conditions opens new ways for research and treatment opportunities, potentially leading to more effective, personalized therapeutic strategies.

Background: Traditional small-molecule chemotherapeutics usually do not distinguish tumors from healthy tissues. However, nanotechnology creates nanocarriers that selectively deliver drugs to their site of action. This work is the next step in the development of the quantum dot-β-cyclodextrin-folic acid (QD-β-CD-FA) platform for targeted and selected delivery of C-2028 unsymmetrical bisacridine in cancer therapy., Methods: Herein, we report an initial biological evaluation (using flow cytometry and light microscopy) as well as cell migration analysis of QD-β-CD(C-2028)-FA nanoconjugate and its components in the selected human lung and prostate cancer cells, as well as against their respective normal cells., Results: C-2028 compound induced apoptosis, which was much stronger in cancer cells compared to normal cells. Conjugation of C-2028 with QD green increased cellular senescence, while the introduction of FA to the conjugate significantly decreased this process. C-2028 nanoencapsulation also reduced cell migration. Importantly, QD green and QD green -β-CD-FA themselves did not induce any toxic responses in studied cells., Conclusions: In conclusion, the results demonstrate the high potential of a novel folic acid-targeted receptor quantum dot-β-cyclodextrin carrier (QD green -β-CD-FA) for drug delivery in cancer treatment. Nanoplatforms increased the amount of delivered compounds and demonstrated high suitability., (© 2024. The Author(s).)

Neuromuscular disorders (NMDs) include a wide range of diseases affecting the peripheral nervous system. The genetic diagnoses are increasingly obtained with using the next generation sequencing (NGS). We applied the custom-design targeted NGS panel including 89 genes, together with genotyping and multiplex ligation-dependent probe amplification (MLPA) to identify a genetic spectrum of NMDs in 52 Polish patients. As a result, the genetic diagnosis was determined by NGS panel in 29 patients so its diagnostic utility is estimated at 55.8%. The most pathogenic variants were found in CLCN1, followed by CAPN3, SCN4A, and SGCA genes. Genotyping of myotonic dystrophy type 1 and 2 (DM1 and DM2) as a secondary approach has been performed. The co-occurrence of CAPN3 and CNBP mutations in one patient as well as DYSF and CNBP mutations in another suggests possibly more complex inheritance as well as expression of a phenotype. In 7 individuals with single nucleotide variant found in NGS testing, the MLPA of the CAPN3 gene was performed detecting the deletion encompassing exons 2-8 in the CAPN3 gene in one patient, confirming recessive limb-girdle muscular dystrophy type 1 (LGMDR1). Thirty patients obtained a genetic diagnosis (57.7%) after using NGS testing, genotyping and MLPA analysis. The study allowed for the identification of 27 known and 4 novel pathogenic/likely pathogenic variants and variants of uncertain significance (VUS) associated with NMDs.In conclusion, the diagnostic approach with diverse molecular techniques enables to broaden the mutational spectrum and maximizes the diagnostic yield. Furthermore, the co-occurrence of DM2 and LGMD has been detected in 2 individuals., (© 2024. The Author(s).)

The objective of this paper was to determine the impact of EEG-biofeedback training on the motivation and efficiency of powerlifters during the bench press exercise in relation to the external load and the level of training. The study included 18 trained powerlifters who were divided into the intermediate (IG) and the advanced (AG) groups. EEG-biofeedback training was conducted every three days, lasting 27 minutes each time (5 × 3-minute intervals with recovery periods - lying on a bench - between them 4 × 3 minutes), and ended with a final EEG measurement in the second cycle of research. The repeated measures ANOVA showed intra-group differences due to external loading for the FAI (Frontal Alpha Asymmetry) obtained in the EEG both before and after biofeedback training. In AG group analysis revealed significant differences between 65%1RM and 35%1RM. In the IG group between 35%1RM and 50, 65 and 80%1RM. One of the major variables influencing the efficiency of strength training, including bench press workouts, is the level of training. The more successfully an athlete uses motivation when exercising, the better their training, which translates into greater results and a lower chance of injury., Competing Interests: The authors decleared no conflict of interest., (Copyright © Institute of Sport – National Research Instutite.)

Anti-thymocyte globulin (ATG) and post-transplantation cyclophosphamide (PTCy) are two frequently utilised strategies in graft-versus-host disease (GvHD) prophylaxis following allogeneic hematopoietic cell transplantation (allo-HCT), currently approved for different recipient-donor settings. In addition, being efficacious in preventing GvHD owing to their T-cell depleting capacity, the employment of these two agents increases the risk of infections, including CMV reactivation, which stands as one of the most common and serious infections following allo-HCT. We performed a systematic literature review of articles published until 1 September 2023, through PubMed, MEDLINE, and Scopus, with the main endpoint being CMV reactivation after PTCy or ATG allo-HCT. The majority of the studies included in the analysis provide supporting evidence for a reduced risk of CMV reactivations following the use of PTCy compared to ATG, although not all findings reached statistical significance. Additionally, it appears that utilising a haploidentical donor leads to a higher incidence of CMV infections and clinically significant CMV infections (CS-CMVis) compared to other donor settings in PTCy allo-HCT. This study aims to compare the risk of CMV infections following allo-HCT in patients who have received either ATG or PTCy as GvHD prophylaxis and discuss other factors that could influence the infectious outcomes of patients who have undergone allo-HCT.

Background: Acquired haemophilia A is caused by neutralising autoantibodies against coagulation factor VIII, leading to severe bleeding. Standard treatment involves immunosuppressive therapy, which is associated with adverse events and mortality in the frail population of patients with acquired haemophilia A. This study investigated whether emicizumab, a factor VIIIa mimetic antibody, protects patients with acquired haemophilia A from bleeding and allows deferral of immunosuppression during the first 12 weeks after diagnosis., Methods: We report final results of an open-label, single-arm, phase 2 clinical trial. Adult patients with acquired haemophilia A from 16 haemophilia treatment centres in Germany and Austria were eligible if they had not previously received immunosuppression. Patients received emicizumab subcutaneously (6 and 3 mg/kg on days 1 and 2, 1·5 mg/kg weekly until week 12), but no immunosuppression. Follow-up was until week 24. The primary endpoint was the number of clinically relevant bleeds per patient-week until week 12. Emicizumab was considered effective if the mean bleeding rate was significantly below 0·15 bleeds per patient-week, the rate observed in a previous study of patients with acquired haemophilia A treated with bypassing agents and immunosuppression but no emicizumab. The study is registered with clinicaltrials.gov, NCT04188639 and is complete., Findings: Of 49 patients screened from March 25, 2021, to June 10, 2022, 47 were enrolled (23 women, 24 men). Median age was 76 years (IQR 66-80), 46 (98%) of 47 patients were White, median factor VIII activity was 1·4 IU/dL (0·3-5·6), and median inhibitor concentration was 11·4 Bethesda units per mL (3·9-42·7). Mean breakthrough bleeding rate was 0·04 bleeds per patient-week (upper 97·5% CI 0·06). 33 (70%) of 47 patients had no bleeding events, seven patients (15%) had one bleed, six patients (13%) had two bleeds, and one patient (2%) had three bleeds. Adverse events of grade 3 or worse included COVID-19 (n=2), acute kidney injury (n=2), and stroke (n=1). Four of 47 patients died, including two deaths related to bleeding, one from COVID-19, and one from cardiac arrest (none were judged as related to emicizumab)., Interpretation: This study suggests that emicizumab prophylaxis prevents bleeding in patients with acquired haemophilia A and that immunosuppressive therapy can be deferred while patients are receiving this treatment. The low number of thromboembolic events, severe infections, and fatalities observed in this study are promising., Funding: This study was supported by funding from Hoffman-La Roche., Competing Interests: Declaration of interests AT reports institutional grants for research and studies from Bayer, Biotest, Chugai, Novo Nordisk, Octapharma, Pfizer, Roche, SOBI, and Takeda, and honoraria for lectures or consultancy from Bayer, Biomarin, Biotest, Chugai, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, SOBI, and Takeda. CH reports honoraria for lectures or consultancy from Bayer, SOBI, Roche, Pfizer, and Takeda. PK reports institutional grants for research and studies from Ablynx–Sanofi, Novo Nordisk, Roche, and Takeda, and honoraria for lectures or consultancy from Ablynx–Sanofi, Alexion, Biotest, CSL Behring, Novo Nordisk, Roche, Takeda, and Technoclone. RG reports institutional grants for research and studies from Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, Abbvie, Gilead, and Daiichi Sankyo, and honoraria for lectures or consultancy from Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, Abbvie, Gilead, Daiichi Sankyo, and Sanofi. JO reports institutional grants for research and studies from Bayer, Biotest, CSL Behring, Octapharma, Pfizer, SOBI, and Takeda, and honoraria for lectures or consultancy from Bayer, Biogen Idec, Biomarin, Biotest, CSL Behring, Chugai, Freeline, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Sparks, SOBI, and Takeda. UJS reports institutional grants for research and studies from Octapharma, and honoraria for lectures or consultancy from Bayer, SOBI, CSL Behring, and Pfizer. WM reports institutional grants for research and studies from Bayer, Biotest, CSL Behring, LFB, Novo Nordisk, Octapharma, Pfizer, and Takeda–Shire, and honoraria for lectures or consultancy from Bayer, Biomarin, Biotest, CSL Behring, Chugai, Freeline, LFB, Novo Nordisk, Octapharma, Pfizer, Regeneron, Roche, Sanofi, Takeda–Shire, and uniQure. CP reports institutional grants for research and studies from Chugai–Roche, Takeda, Zacros, and LeoPharma, and honoraria for lectures or consultancy from Bayer, Biomarin, Chugai–Roche, CSL Behring, Novo Nordisk, Pfizer, BMS, SOBI, and Takeda. KT-G reports honoraria for lectures or consultancy from Grifols, SOBI, Takeda, and Roche. KH reports institutional grants for research and studies from Bayer, CSL Behring, Novo Nordisk, Pfizer, and SOBI, and honoraria for lectures or consultancy from Bayer, Biotest, Chugai, CSL Behring, LFB, Novo Nordisk, Pfizer, Roche, SOBI, and Takeda. JP reports institutional grants for research and studies from Bayer, CSL Behring, and Pfizer, and honoraria for lectures or consultancy from Takeda, Bayer, and CSL Behring. PM reports institutional grants for research and studies from Baxter Innovations, Bayer, LFB, SOBI, Octapharma, Pfizer, and Roche, and honoraria for lectures or consultancy from Alexion, AstraZeneca, Biotest, CSL Behring, Shire, Octapharma, Pfizer, Roche, and Takeda. CD reports honoraria for lectures or consultancy from Novo Nordisk, Roche, and Takeda. SW reports institutional grants for research and studies from Biotest and Octapharma, and honoraria for lectures or consultancy from Biotest and Stago. RK reports institutional grants for research and studies from Bayer, CSL Behring, Novo Nordisk, Octapharma, and SOBI, and honoraria for lectures or consultancy from Bayer, Biotest, Biomarin, CSL Behring, Grifols, LFB, Novo Nordisk, Octapharma, Pfizer, Roche–Chugai, Sanofi, SOBI, and Takeda. CS, CW, DS, MM, and FJP have nothing to disclose., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The aim of the study was to expand the current knowledge on the effects of EEG biofeedback training on the reaction time of judo athletes, as well as to develop an optimal EEG training protocol in terms of the number of sessions and their duration that would significantly improve the reaction time of athletes. The study included 24 male athletes from the national team of the Polish Judo Association. The selected group was randomly divided into two subgroups: experimental and control. The study was conducted in four cycles varying in terms of frequency and duration of neurofeedback (NFB) sessions, both in the control and experimental groups. In the experimental group, each training cycle consisted of 15 sessions, followed by a four-week break. The effects of NFB training on the visual reaction time of judo athletes were evaluated using computerized simple and complex reaction time tests along with selected trials of the Vienna Test System (VTS). Following NFB training according to the theta/beta1 protocol, while maintaining appropriate duration and frequency of individual training sessions, statistically significant improvements in reaction times to visual stimuli of athletes, both in simple and complex tasks, were observed in the experimental group. No such changes were found in the control group. The greatest improvement in reaction times was observed in complex tasks, indicating the high effectiveness of EEG biofeedback training in enhancing this ability., Competing Interests: The authors declare no conflict of interest., (Copyright: © Academy of Physical Education in Katowice.)

To identify recurrent inflammation in hemophilia, we assessed the acute-phase response in the blood of patients with hemophilia A and B. Compared to age- and weight-matched controls, blood levels of interleukin-6 (IL-6), C-reactive protein (CRP), and LPS-binding protein (LBP) were significantly elevated in the entire cohort of hemophilia patients but exhibited a particularly pronounced increase in obese hemophilia patients with a body mass index (BMI) ≥30. Subgroup analysis of the remaining nonobese hemophilia patients (BMI: 18-29.9) revealed a significant spike of IL-6, CRP, and LBP in connection with a de-novo increase of soluble IL-6 receptor α (sIL-6Rα) in patients with bleeding events within the last month. Hemophilia patients who did not experience recent bleeding had IL-6, CRP, and sIL-6Rα blood levels similar to healthy controls. We did not find increased IL-6 or acute-phase reactants in hemophilia patients with arthropathy or infectious disease. The role of IL-6 as a marker of bleeding in hemophilia was confirmed in hemophilia patients with acute bleeding events as well as in transgenic hemophilia mice after needle puncture of the knee, which exhibited an extensive hematoma and a 150-fold increase of IL-6 blood levels within 7 days of the injury compared to needle-punctured control mice. Notably, IL-6 blood levels shrunk to a fourfold elevation in hemophilia mice over controls after 28 days, when the hematoma was replaced by arthrofibrosis. These findings indicate that acute-phase reactants in combination with sIL-6Rα could be sensitive biomarkers for the detection of acute and recent bleeding events in hemophilia., Competing Interests: None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative treatment modality, frequently used for patients suffering from haematological malignancies. In the last two decades, there have been multiple randomised controlled trials (RCTs), review articles, and meta-analyses addressing the efficacy of rabbit anti-thymocyte globulin (r-ATG) as a graft-versus-host disease (GvHD) prophylaxis. Nevertheless, only a few aimed to compare the effectiveness of different r-ATG formulations. Since the last article we retrieved comparing different r-ATGs in GvHD prophylaxis dates back to 2017, we performed a systematic literature review of articles published since 2017 to this day, utilising PubMed, Scopus, Cochrane, and MEDLINE, with the main endpoints being prophylaxis of acute GvHD (aGvHD) and chronic GvHD (cGvHD). We subjected to scrutiny a total of five studies, of which four compared the differences between Thymoglobulin (ATG-T) and Grafalon (ATG-G), and one discussed the impact of ATG-T dose. Overall, cGvHD, aGvHD grades II-IV, TRM, OS, NRM, LFS, relapse, overall infections, and EBV reactivation do not seem to be affected by the type of utilised rATG. However, data on aGvHD grades III-IV, GRFS, moderate-severe cGvHD, and CMV reactivation is conflicting. Through our research, we sought to summarise the most recent findings concerning r-ATGs in allo-HCT, and provide insight into the differences between the targets and origin of various ATG formulations.

Competing Interests: None declared.

Deep brain stimulation (DBS) is a relatively dated treatment procedure that emerged in the late 1980s. Nonetheless, numerous studies are being carried out to examine its influence on the human brain and develop new treatment indications. This systematic review aims to summarize the current state of knowledge referring to DBS, investigate novel insights into its indications, and discuss the technical aspects and rationale behind DBS application. In particular, we sought to subject to scrutiny the application of DBS specifically in anorexia nervosa (AN), various addiction types, depression, and obsessive-compulsive disorders (OCDs). The method is supposed to offer promising results, especially in pharmacologically resistant forms of the upper-mentioned psychiatric disorders. Moreover, further insight has been provided into the historical notions of the method and differences in the surgical approach in specific disease entities. Furthermore, we mark the possible influence of comorbidities on treatment results. Our review consists of articles and studies found on PubMed, Google Scholar, Cochrane, and Scopus, which were then analyzed with scrutiny in the identification process, including the most resourceful ones. After methodological quality and risk of bias assessment, a total of 53 studies were included. To this date, DBS's usefulness in the treatment of AN, OCDs, depression, and addictions has been proven, despite an ongoing debate concerning the technical aspects and parameters when applying DBS. To the best of our knowledge, we have not found any paper that would recapitulate the current state of DBS in the context of psychiatric disorders with an addition of technical insights., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Indian Journal of Psychiatry.)

Kidney graft failure is not a homogenous disease and the Banff classification distinguishes several types of graft rejection. The maintenance of a transplant and the treatment of its failure require specific medications and differ due to the underlying molecular mechanism. As a consequence, patients suffering from different rejection types will experience distinct side-effects upon therapy. The review is focused on comparing treatment regimens as well as presenting the latest insights into innovative therapeutic approaches in patients with an ongoing active ABMR, chronic active ABMR, chronic ABMR, acute TCMR, chronic active TCMR, borderline and mixed rejection. Furthermore, the profile of cardiovascular adverse effects in relation to the applied therapy was subjected to scrutiny. Lastly, a detailed assessment and comparison of different approaches were conducted in order to identify those that are the most and least detrimental for patients suffering from kidney graft failure.

Conjugates composed of C 2-18 fatty acid (FA) residues as a molecular carrier and 5-fluorocytosine (5-FC) as an active agent, released upon the action of intracellular esterases on the ester bond between FA and "trimethyl lock" intramolecular linker, demonstrate good in vitro activity against human pathogenic yeasts of Candida spp. The minimal inhibitory concentrations (MIC) values for the most active conjugates containing caprylic (C 8 ), capric (C 10 ), lauric (C 12 ), or myristic (C 14 ) acid residues were in the 2-64 μg mL -1 range, except for these against the least susceptible Candida krusei. The least active conjugates containing C 2 , C 16, or C 18 FA were slowly hydrolyzed by esterase and probably poorly taken up by Candida cells, as found for their analogs containing a fluorescent label, Nap-NH 2 instead of 5-FC., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Slawomir Milewski reports financial support was provided by National Science Centre Poland., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Selective therapy and controlled drug release at an intracellular level remain key challenges for effective cancer treatment. Here, we employed folic acid (FA) as a self-navigating molecule in nanoconjugates containing quantum dots (QDs) and β -cyclodextrin ( β -CD) for the delivery of antitumor unsymmetrical bisacridine compound (C-2028) to lung and prostate cancers as well as normal cells. The bisacridine derivative can form the inclusion complex with β -cyclodextrin molecule, due to the presence of a planar fragment in its structure. The stability of such a complex is pH-dependent. The drug release profile at different pH values and the mechanism of C-2028 release from QDs- β -CD-FA nanoconjugates were investigated. Next, the intracellular fate of compounds and their influence on lysosomal content in the cells were also studied. Confocal Laser Scanning Microscopy studies proved that all investigated compounds were delivered to acidic organelles, the pH of which promoted an increased release of C-2028 from its nanoconjugates. Since the pH in normal cells is higher than in cancer cells, the release of C-2028 from its nanoconjugates is decreased in these cells. Additionally, we obtained the concentration profiles of C-2028 in the selected cells treated with unbound C-2028 or nanoconjugate by the HPLC analysis.

The purpose of this article is to assess the present knowledge about chronic active (CA) T-cell mediated rejection (TCMR) of a kidney. In the research authors review current Banff diagnostic criteria used in kidney rejection, focus on their possible future evolution, and investigate the role of currently available molecular methods that could be implemented into the diagnostic scheme. Research also points out previously and currently available treatment methods applied to CA TCMR and takes into account possible side effects consequent upon the therapy. Moreover, attention is being paid to the CA TCMR coincidence with other kidney rejection types such as antibody-mediated rejection (ABMR) and its influence on the treatment approach. Authors also mark the possibility of non-HLA antibodies coexistence in patients with CA TCMR and describe its possible resonance on kidney allograft function. Nonetheless, it seems that current knowledge about CA TCMR is not sufficient and requires further investigation.

BACKGROUNDResults of many randomized trials on COVID-19 convalescent plasma (CCP) have been reported, but information on long-term outcome after CCP treatment is limited. The objectives of this extended observation of the randomized CAPSID trial are to assess long-term outcome and disease burden in patients initially treated with or without CCP.METHODSOf 105 randomized patients, 50 participated in the extended observation. Quality of life (QoL) was assessed by questionnaires and a structured interview. CCP donors (n = 113) with asymptomatic to moderate COVID-19 were included as a reference group.RESULTSThe median follow-up of patients was 396 days, and the estimated 1-year survival was 78.7% in the CCP group and 60.2% in the control (P = 0.08). The subgroup treated with a higher cumulative amount of neutralizing antibodies showed a better 1-year survival compared with the control group (91.5% versus 60.2%, P = 0.01). Medical events and QoL assessments showed a consistent trend for better results in the CCP group without reaching statistical significance. There was no difference in the increase in neutralizing antibodies after vaccination between the CCP and control groups.CONCLUSIONThe trial demonstrated a trend toward better outcome in the CCP group without reaching statistical significance. A predefined subgroup analysis showed a significantly better outcome (long-term survival, time to discharge from ICU, and time to hospital discharge) among those who received a higher amount of neutralizing antibodies compared with the control group. A substantial long-term disease burden remains after severe COVID-19.Trial registrationEudraCT 2020-001310-38 and ClinicalTrials.gov NCT04433910.FundingBundesministerium für Gesundheit (German Federal Ministry of Health).

Encephalocraniocutaneous lipomatosis (ECCL; Haberland syndrome, #613001) is an extremely rare congenital disorder that is manifested by the involvement of the skin, eyes and central nervous system (CNS). We report two cases of children with ECCL diagnosis. First was an 8-year-old girl who presented with symptomatic epilepsy, cerebral palsy and developmental delay. In 2020, she was admitted to the hospital due to the exacerbation of paresis and intensified prolonged epileptic seizures, provoked by infection of the middle ear. Diagnostic imaging revealed radiological changes suggestive of ECCL, providing a reason for the diagnosis, despite the lack of skin and eye anomalies. The second child, a 14-year-old girl, was consulted for subtle clinical signs and epilepsy suspicion. Diagnostic imaging findings were similar, though less pronounced. Based on neuroradiological abnormalities typical for Haberland syndrome, the authors discuss possible ECCL diagnosis.

The main goal of the analysis presented in this paper is to examine the dynamics of including other-sex peers in the peer networks of early adolescents, aged 11 (at T1) and 13 (at T2), and the relationship between sex heterophily and changes in the sense of peer integration. The analysis was conducted using the Latent Difference Score (LDS) model with data from a representative nationwide longitudinal study in Poland (n = 5748). With reference to the dynamics related to the heterophilic process, the research confirmed that at the beginning of grade 5 of primary school, heterophily is still relatively rare, yet towards the end of early adolescence, there is a gradual shift, more strongly in girls, towards breaking through the strictly same-sex segregation and embarking on heterophilic relationships. Importantly, the LDS model-even when controlling for different measures of peer network-showed significant and positive (among both girls and boys) relations between establishing cross-sex relationships and the sense of peer integration. The results indicate that the appearance of the opposite sex in the peer network between grades 5 and 6 will improve the sense of peer integration. The findings are discussed in relation to results from other studies in the field.

Although significant advances have been made in cancer treatment, effective methods of treatment are still limited. Classical chemotherapy is one of the main cancer treatments, but it often causes many side effects that may cause non-specific drug action. This is mainly due to the lack of significant differences between cancer and normal cells as well as drug resistance. To reduce the side effects and increase the specificity and the selectivity of chemotherapeutics to cancer cells, new methods of their delivery to tumors are being sought. One of these methods is the application of nanoparticles (NPs), e.g. Quantum Dots (QDs) as drug delivery platforms. This review describes the most popular NPs in chemotherapy, including quantum dots, gold nanoparticles, dendrimers, micelles, and liposomes. The review describes also a strategy of design and synthesis of NPs, mechanism of cellular uptake, as well as intracellular degradation and toxicity of NPs.

The article presents a new approach in the purification of chitosan (CS) hydrogel in order to remove a significant amount of endotoxins without changing its molecular weight and viscosity. Two variants of the method used to purify CS hydrogels from endotoxins were investigated using the PyroGene rFC Enzymatic Cascade assay kit. The effect of the CS purification method was assessed in terms of changes in the dynamic viscosity of its hydrogels, the molecular weight of the polymer, microbiological purity after refrigerated storage and cytotoxicity against L929 cells based on the ISO 10993-5:2009(E) standard. The proposed purification method 1 (M1) allows for the removal of significant amounts of endotoxins: 87.9-97.6% in relation to their initial concentration in the CS hydrogel without affecting the solution viscosity. Moreover, the final solutions were sterile and microbiologically stable during storage. The M1 purification method did not change the morphology of the L929 cells.

Background: Cyberbullying has recently attracted attention because of its increasing occurrence and serious consequences for victims. The purpose of the study was to examine the prevalence rates of cyberbullying and the association between cyberbullying and protective/risk factors (cognitive empathy, assertiveness, cooperation, pro-social behaviour, and social support) among Polish adolescents., Participants and Procedure: Participants (822 students, 448 girls and 374 boys, M = 12.97, SD = 1.02) completed a computer-based online questionnaire., Results: The majority of respondents did not experience cyberbul-lying in the last six months, while a significant group still experienced cyberbullying regularly (28.1%). Engaging in cyberbullying appeared to be even less common: it was reported by 12.3% of respondents. Family and peer social support appeared to be the strongest protective factor against experiencing cyberbullying while assertiveness was a characteristic that makes a person more likely to engage in cyberbullying., Conclusions: The results of our study can serve as guidance for preventive interventions against cyberbullying., (Copyright © Institute of Psychology, University of Gdansk.)

Targeted drug delivery by nanocarriers molecules can increase the efficiency of cancer treatment. One of the targeting ligands is folic acid (FA), which has a high affinity for the folic acid receptors, which are overexpressed in many cancers. Herein, we describe the preparation of the nanoconjugates containing quantum dots (QDs) and β -cyclodextrin ( β -CD) with foliate-targeting properties for the delivery of anticancer compound C-2028. C-2028 was bound to the nanoconjugate via an inclusion complex with β -CD. The effect of using FA in QDs- β -CD(C-2028)-FA nanoconjugates on cytotoxicity, cellular uptake, and the mechanism of internalization in cancer (H460, Du-145, and LNCaP) and normal (MRC-5 and PNT1A) cells was investigated. The QDs- β -CD(C-2028)-FA were characterized using DLS (dynamic light scattering), ZP (zeta potential), quartz crystal microbalance with dissipation (QCM-D), and UV-vis spectroscopy. The conjugation of C-2028 with non-toxic QDs or QDs- β -CD-FA did not change the cytotoxicity of this compound. Confocal microscopy studies proved that the use of FA in nanoconjugates significantly increased the amount of delivered compound, especially to cancer cells. QD green - β -CD(C-2028)-FA enters the cells through multiple endocytosis pathways in different levels, depending on the cell line. To conclude, the use of FA is a good self-navigating molecule in the QDs platform for drug delivery to cancer cells.

Mowat-Wilson syndrome is a rare neurodevelopmental disorder caused by pathogenic variants in the ZEB2 gene, intragenic deletions of the ZEB2 gene, and microdeletions in the critical chromosomal region 2q22-23, where the ZEB2 gene is located. Mowat-Wilson syndrome is characterized by typical facial features that change with the age, severe developmental delay with intellectual disability, and multiple congenital abnormalities. The authors describe the clinical and genetic aspects of 28th patients with Mowat-Wilson syndrome diagnosed in Poland. Characteristic dysmorphic features, psychomotor retardation, intellectual disability, and congenital anomalies were present in all cases. The incidence of most common congenital anomalies (heart defect, Hirschsprung disease, brain defects) was similar to presented in literature. Epilepsy was less common compared to previously reported cases. Although the spectrum of disorders in patients with Mowat-Wilson syndrome is wide, knowledge of characteristic dysmorphic features awareness of accompanying abnormalities, especially intellectual disability, improves detection of the syndrome., (© 2021. The Author(s).)

Purpose: To elucidate the novel molecular cause in families with a new autosomal recessive neurodevelopmental disorder., Methods: A combination of exome sequencing and gene matching tools was used to identify pathogenic variants in 17 individuals. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) and subcellular localization studies were used to characterize gene expression profile and localization., Results: Biallelic variants in the TMEM222 gene were identified in 17 individuals from nine unrelated families, presenting with intellectual disability and variable other features, such as aggressive behavior, shy character, body tremors, decreased muscle mass in the lower extremities, and mild hypotonia. We found relatively high TMEM222 expression levels in the human brain, especially in the parietal and occipital cortex. Additionally, subcellular localization analysis in human neurons derived from induced pluripotent stem cells (iPSCs) revealed that TMEM222 localizes to early endosomes in the synapses of mature iPSC-derived neurons., Conclusion: Our findings support a role for TMEM222 in brain development and function and adds variants in the gene TMEM222 as a novel underlying cause of an autosomal recessive neurodevelopmental disorder.

Background: Convalescent plasma is one of the treatment options for COVID-19 which is currently being investigated in many clinical trials. Understanding of donor and product characteristics is important for optimization of convalescent plasma., Methods: Patients who had recovered from CO-VID-19 were recruited as donors for COVID-19 convalescent plasma (CCP) for a randomized clinical trial of CCP for treatment of severe COVID-19 (CAPSID Trial). Titers of neutralizing antibodies were measured by a plaque-reduction neutralization test (PRNT). Correlation of antibody titers with host factors and evolution of neutralizing antibody titers over time in repeat donors were analysed., Results: A series of 144 donors (41% females, 59% males; median age 40 years) underwent 319 plasmapheresis procedures providing a median collection volume of 850 mL and a mean number of 2.7 therapeutic units per plasmapheresis. The majority of donors had a mild or moderate course of COVID-19. The titers of neutralizing antibodies varied greatly between CCP donors (from <1:20 to >1:640). Donor factors (gender, age, ABO type, body weight) did not correlate significantly with the titer of neutralizing antibodies. We observed a significant positive correlation of neutralization titers with the number of reported COVID-19 symptoms and with the time from SARS-CoV-2 diagnosis to plasmapheresis. Neutralizing antibody levels were stable or increased over time in 58% of repeat CCP donors. Mean titers of neutralizing antibodies of first donation and last donation of repeat CCP donors did not differ significantly (1:86 at first compared to 1:87 at the last donation). There was a significant correlation of neutralizing antibodies measured by PRNT and anti-SARS-CoV-2 IgG and IgA antibodies which were measured by ELISA. CCP donations with an anti-SARS-CoV-2 IgG antibody content above the 25th percentile were substantially enriched for CCP donations with higher neutralizing antibody levels., Conclusion: We demonstrate the feasibility of collection of a large number of CCP products under a harmonized protocol for a randomized clinical trial. Titers of neutralizing antibodies were stable or increased over time in a subgroup of repeat donors. A history of higher number of COVID-19 symptoms and higher levels of anti-SARS-CoV-2 IgG and IgA antibodies in immunoassays can preselect donations with higher neutralizing capacity., Competing Interests: Dr. Victor M. Corman is named together with Euroimmun on a patent application filed recently regarding the diagnostic of SARS-CoV-2 by antibody testing. All other authors have no conflicts of interest to declare., (Copyright © 2021 by S. Karger AG, Basel.)

Nanotechnology-based drug delivery provides a promising area for improving the efficacy of cancer treatments. Therefore, we investigate the potential of using quantum dots (QDs) as drug carriers for antitumor unsymmetrical bisacridine derivatives (UAs) to cancer cells. We examine the influence of QD-UA hybrids on the cellular uptake, internalization (Confocal Laser Scanning Microscope), and the biological response (flow cytometry and light microscopy) in lung H460 and colon HCT116 cancer cells. We show the time-dependent cellular uptake of QD-UA hybrids, which were more efficiently retained inside the cells compared to UAs alone, especially in H460 cells, which could be due to multiple endocytosis pathways. In contrast, in HCT116 cells, the hybrids were taken up only by one endocytosis mechanism. Both UAs and their hybrids induced apoptosis in H460 and HCT116 cells (to a greater extent in H460). Cells which did not die underwent senescence more efficiently following QDs-UAs treatment, compared to UAs alone. Cellular senescence was not observed in HCT116 cells following treatment with both UAs and their hybrids. Importantly, QD green/red themselves did not provoke toxic responses in cancer or normal cells. In conclusion, QDs are good candidates for targeted UA delivery carriers to cancer cells while protecting normal cells from toxic drug activities.

Aim of the Study: This study aimed to evaluate the effects of nusinersen therapy in Polish children with SMA type 1., Clinical Rationale of Study: Spinal muscular atrophy (SMA) is a neuromuscular disorder that is characterised by the loss of motor neurons, progressive muscle weakness and atrophy, leading to increased disability and mortality. Nusinersen, an antisense oligonucleotide that promotes production of the functional survival motor neuron protein is approved for the treatment of SMA 5q in the European Union. In 2017, an early access programme (EAP) for nusinersen was launched in Poland. In this study, we present the results of nusinersen treatment in Polish patients participating in the EAP., Materials and Methods: We collected prospectively clinical data including mutational analysis of SMN1 and SMN2 genes, motor function outcomes as measured on a standardized scales, ventilatory and nutritional status, on SMA type 1 patients receiving nusinersen in three EAP centres in Poland. Scores on the CHOP-INTEND scale after 18-26 months of treatment were compared to baseline., Results: We analysed data from 26 patients with SMA type 1, mean age 4.79 (2-15) years. The mutational analysis revealed two SMN2 gene copies in the majority of patients (61.54%). Three and four copies were found in 34.62% and 3.84%, respectively. Median disease duration was 21 months. Half (n = 13) of the patients required mechanical ventilation at baseline and 57.69% (n = 15) were fed by nasogastric tube or percutaneous endoscopic gastrostomy. No patient worsened during the follow-up. Mean improvement in CHOP-INTEND from baseline to the last follow-up was 7.38 points (p < 0.001). CHOP-INTEND scores did not decline for any patient. Patients with three or more SMN2 gene copies had higher scores than did the patients with two copies (p = 0.013), and they tended to show greater improvement over time, but the difference was not significant (p = 0.324). Shorter disease duration and higher CHOP-INTEND baseline score were associated with a better response (p = 0.015). Patients with a CHOP-INTEND score above the median had higher scores overall than the rest (p < 0.0013), and they improved significantly more than the rest (p = 0.037). Nusinersen was well tolerated, no new safety findings were identified., Conclusions and Clinical Implications: Our data indicates that nusinersen treatment might be effective in SMA type 1 patients, regardless of their age and functional status.

Given the high medical importance of ticks, we analyzed the most common preventive behaviors and practices adopted by medical students from Poland, Germany, and Thailand, and the level of their knowledge of ticks and tick-borne diseases. A survey consisting of 19 questions was conducted among 636 randomly selected students. The study showed that the Polish and German students preferred inspection of the body on their return home (86.9% and 63.5%, respectively) and wearing protective clothes (79.8% and 32.3%, respectively) as part of prophylaxis. The Thai students most often chose wearing protective clothes (54.7%) and preventive behavior in tick habitats (42.7%). Approximately 7% of the Polish medical students and as many as 22% of the German and Thai respondents did not use any means of prevention. Our analyses suggest that the use of preventive methods and respondents' behaviors depend on socio-demographic factors and the level of health education. The insufficient practical implementation of tick prevention measures by the medical students suggests a need for verification of health education programs in schools as well as effective popularization and educational activities. It is also necessary to develop a public health protection strategy against the effects of tick bites.

Objective: To define the risks and consequences of cardiac abnormalities in ATP1A3 -related syndromes., Methods: Patients meeting clinical diagnostic criteria for rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) with ATP1A3 genetic analysis and at least 1 cardiac assessment were included. We evaluated the cardiac phenotype in an Atp1a3 knock-in mouse (Mashl +/- ) to determine the sequence of events in seizure-related cardiac death., Results: Ninety-eight patients with AHC, 9 with RDP, and 3 with CAPOS (63 female, mean age 17 years) were included. Resting ECG abnormalities were found in 52 of 87 (60%) with AHC, 2 of 3 (67%) with CAPOS, and 6 of 9 (67%) with RDP. Serial ECGs showed dynamic changes in 10 of 18 patients with AHC. The first Holter ECG was abnormal in 24 of 65 (37%) cases with AHC and RDP with either repolarization or conduction abnormalities. Echocardiography was normal. Cardiac intervention was required in 3 of 98 (≈3%) patients with AHC. In the mouse model, resting ECGs showed intracardiac conduction delay; during induced seizures, heart block or complete sinus arrest led to death., Conclusions: We found increased prevalence of ECG dynamic abnormalities in all ATP1A3 -related syndromes, with a risk of life-threatening cardiac rhythm abnormalities equivalent to that in established cardiac channelopathies (≈3%). Sudden cardiac death due to conduction abnormality emerged as a seizure-related outcome in murine Atp1a3 -related disease. ATP1A3 -related syndromes are cardiac diseases and neurologic diseases. We provide guidance to identify patients potentially at higher risk of sudden cardiac death who may benefit from insertion of a pacemaker or implantable cardioverter-defibrillator., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Goldberg-Shprintzen syndrome (GOSHS) is caused by loss of function variants in the kinesin binding protein gene (KIFBP). However, the phenotypic range of this syndrome is wide, indicating that other factors may play a role. To date, 37 patients with GOSHS have been reported. Here, we document nine new patients with variants in KIFBP: seven with nonsense variants and two with missense variants. To our knowledge, this is the first time that missense variants have been reported in GOSHS. We functionally investigated the effect of the variants identified, in an attempt to find a genotype-phenotype correlation. We also determined whether common Hirschsprung disease (HSCR)-associated single nucleotide polymorphisms (SNPs), could explain the presence of HSCR in GOSHS. Our results showed that the missense variants led to reduced expression of KIFBP, while the truncating variants resulted in lack of protein. However, no correlation was found between the severity of GOSHS and the location of the variants. We were also unable to find a correlation between common HSCR-associated SNPs, and HSCR development in GOSHS. In conclusion, we show that reduced, as well as lack of KIFBP expression can lead to GOSHS, and our results suggest that a threshold expression of KIFBP may modulate phenotypic variability of the disease., (© 2020 The Authors. Human Mutation published by Wiley Periodicals LLC.)

Recently, it has been reported that tear osmolarity (Tosm) is correlated with plasma osmolarity and will increase during exertion. We aimed to assess whether inhaling oxygen-enriched air between exercises could significantly change the Tosm value. Thirty men aged 24.9 years were included in the study. A cycloergometer was used to perform the exercise protocol. We recorded the participants' Tosm (mOsm/L), heart rate (HR, beats/minute), oxygen saturation, and blood pressure values. After the first exhaustive exercise (T1), participants inhaled oxygen in the experimental group and a placebo in the control group. After the second exercise (T2), another set of measurements was obtained. The Tosm value before exercise was 297.4 ± 1.21 and 296.53 ± 1.11 mOsm/L (p = 0.61718) and the HR was 72.6 ± 2.59 and 73 ± 2.59 beats/minute (p = 0.39949) in the study and the control group, respectively. At T1, Tosm was 303.67 ± 1.25 and 302.2 ± 1.25 mOsm/L (p = 0.41286) and the HR reached 178.04 ± 2.60 and 176.4 ± 2.60 beats/minute (p = 0.65832), respectively. At T2, Tosm in the study group reached 305.73 ± 0.86 mOsm/L (correlation with the use of oxygen: r = -0.3818), and in the control group, it was 308.4 ± 0.86 mOsm/L (p = 0.0373), while the HR reached 172.20 ± 2.53 beats/minute in the study group and 178.2 ± 2.53 beats/minute in the control group (p = 0.057). It was concluded that inhaling oxygen before and after exercise could increase the rate of recovery after exhaustive exercise., (© 2020 Adam Wylęgała, Jan Pilch, Bartłomiej Bolek, Bogumiła Sędziak-Marcinek, Edward Wylęgała, published by Sciendo.)

Objectives: Vestibular rehabilitation leads to a gradual diminution of the subjective and objective symptoms that accompany the vestibular disorders. The aim of the study was to compare the impact of 2 different types of vestibular rehabilitation on vestibular compensation in patients with chronic unilateral vestibular dysfunction., Material and Methods: The study was conducted on a group of 58 subjects (43 females and 15 males) aged 40-64 years, who presented with chronic unilateral vestibular dysfunction and were hospitalized. The patients were randomly assigned to either of the 2 groups established. The study was conducted in a 6-week period. Group 1 consisted of patients who underwent customized group vestibular rehabilitation in an outpatient setting. The program was performed once a week for 1 h 30 min, under the supervision of a physiotherapist and a physiatrist. Group 2 was instructed to perform Cawthorne-Cooksey exercises and simple balance exercises twice a day for 15 min., Results: An improvement in the outcomes of the Dynamic Gait Index as well as the Berg Balance Scale was statistically significant for group 1. The time for fulfilling the task in the Timed Up and Go Test improved in both groups (p < 0.05). The subjective estimation of the symptoms evaluated with the use of the Dizziness Handicap Inventory and the Visual Analogue Scale revealed a statistically significant improvement in both groups, yet it was higher in group 1., Conclusions: The compensation achieved after 6 weeks of the customized, supervised outpatient rehabilitation program in group 1 was superior to the results of the home-based unsupervised Cawthorne-Cooksey and balance exercises. Int J Occup Med Environ Health. 2020;33(3):273-82., (This work is available in Open Access model and licensed under a CC BY-NC 3.0 PL license.)

The use of nanoparticles for the controlled drug delivery to cells has emerged as a good alternative to traditional systemic delivery. Quantum dots (QDs) offer potentially invaluable societal benefits such as drug targeting and in vivo biomedical imaging. In contrast, QDs may also pose risks to human health and the environment under certain conditions. Here, we demonstrated that a unique combination of nanocrystals core components (Ag-In-Zn-S) would eliminate the toxicity problem and increase their biomedical applications. The alloyed quaternary nanocrystals Ag-In-Zn-S (QD green , Ag 1.0 In 1.2 Zn 5.6 S 9.4 ; QD red , Ag 1.0 In 1.0 Zn 1.0 S 3.5 ) were used to transport new unsymmetrical bisacridine derivatives (UAs, C-2028 and C-2045) into lung H460 and colon HCT116 cancer cells for improving the cytotoxic and antitumor action of these compounds. UAs were coupled with QD through physical adsorption. The obtained results clearly indicate that the synthesized nanoconjugates exhibited higher cytotoxic activity than unbound compounds, especially toward lung H460 cancer cells. Importantly, unsymmetrical bisacridines noncovalently attached to QD strongly protect normal cells from the drug action. It is worth pointing out that QD green or QD red without UAs did not influence the growth of cancer and normal cells, which is consistent with in vivo results. In noncellular systems, at pH 5.5 and 4.0, which relates to the conditions of endosomes and lysosomes, the UAs were released from QD-UAs nanoconjugates. An increase of total lysosomes content was observed in H460 cells treated with QDs-UAs which can affect the release of the UAs from the conjugates. Moreover, confocal laser scanning microscopy analyses revealed that QD-UAs nanoconjugates enter H460 cells more efficiently than to HCT116 and normal cells, which may be the reason for their higher cytotoxicity against lung cancer. Summarizing, the noncovalent attachment of UAs to QDs increases the therapeutic efficiency of UAs by improving cytotoxicity toward lung H460 cancer cells and having protecting effects on normal cells.

The purpose of the study was to find whether there were differences in cortisol awakening response (CAR) between a neutral day and an exam day in a group of female students and to explore possible relationships between CAR, self-reported affect, and exam performance. A group of 25 female students took samples of their saliva using Salivettes at the moment of waking and after 30 min. They then described their affect using the PANAS scale. Measures were taken twice: three days before an examination and on the day of the examination. The level of free cortisol in saliva samples was determined using enzyme immunoassay. The integrated volume of cortisol (CARauc) was significantly higher on the day of the exam than on the neutral day. There were also significant differences in affect, with negative higher and positive lower on the exam day, but correlations between cortisol measures and self-reported affect were low and not significant. A negative relationship between integrated volume of cortisol (CARauc) and exam performance was also found. Anticipated exam stress caused a significant increase in CAR in female study participants when compared to a neutral day, but only in the case of integrated volume of cortisol over the waking period (CARauc). The negative relationship between this measure and exam performance can be explained by attributing CARauc to negative expectations concerning the anticipated exam.

A new method of obtaining functional foam material has been proposed. The materials were created by mixing the poly lactic acid (PLA) solution in chloroform, chitosan (CS) dissolved in water saturated with CO 2 and polyethylene glycol (PEG), and freeze-dried for removal of the solvents. The composite foams were characterized for their structural (SEM, FT-IR, density, porosity), thermal (DSC), functional (hardness, elasticity, swelling capacity, solubility), and biological (antimicrobial and cytotoxic) properties. Chitosan in the composites was a component for obtaining their foamed form with 7.4 to 22.7 times lower density compared to the neat PLA and high porosity also confirmed by the SEM. The foams had a hardness in the range of 70-440 kPa. The FT-IR analysis confirmed no new chemical bonds between the sponge ingredients. Other results showed low sorption capacity (2.5-7.2 g/g) and solubility of materials (less than 0.2%). The obtained foams had the lower T g value and improved ability of crystallization compared to neat PLA. The addition of chitosan provides the bacteriostatic and bactericidal properties against Escherichia coli and Staphylococcus aureus . Biocompatibility studies have shown that the materials obtained are not cytotoxic to the L929 cell line.

Although the link between stressful experiences and depression has been supported in numerous studies, the specific mechanisms of this relationship are still unclear. Cognitive theories of depression postulate that the influence of stress on depression may be modified by cognitive factors. The aim of the present study was to examine the interplay between negative life events, cognitive vulnerability factors, and depressive symptoms. It was hypothesized that the relationship between negative life events and symptoms of depression is shaped by rumination and cognitive biases. The study sample consisted of 108 young adults (19 men and 89 women; M = 20.31; SD = 1.84). Memory bias and attentional bias were assessed using the Attentional Blink Task and the Memory Task, respectively. Rumination and depressive symptoms were assessed via self-report questionnaires. Logistic regression and moderation analyses were conducted to examine the relationship between the study variables. Stressful life events, rumination and memory bias were found to be significantly related to depressive symptoms. Moderation analyses revealed that there is a positive relationship between negative life events and depressive symptoms but only among individuals characterized by an elevated level of rumination and among participants exhibiting negative attentional bias. The results provide further evidence for cognitive models of depression., (Copyright © 2019 Łosiak, Blaut, Kłosowska and Łosiak-Pilch.)

Physical exertion leads to the rise in tear osmolarity. However, previous studies have been conducted mostly on males and did not consider sex differences and the possible alteration in blinking during physical exercise. Sixteen women and 18 men aged 25.09 ± 1.70 were divided into equal groups with eyes open and shut. Participants performed 8-min medium-intensity exercise and 5-min intense exercise on a cycloergometer. Tear osmolarity (in mOsm/L) was evaluated before ( T0), after medium-intensity (T1) and intense exercise (T2). The blinking rate was assessed in a group with eyes open. Tear brake up time was measured in T0 and T1. With tear osmolarity measuring 305.72 ± 1.22 and 313.56 ± 1.90 for men and women, respectively, we observed significant differences in T1. In T2, tear osmolarity in men was 303.3 ± 1.28 vs. 310.87 ± 1.36 in women. The blinking rate decreased from 14.24 ± 2.54/min in T0 to 9.41 ± 2.83/min in T1. There was a statistically significant change in tear osmolarity in both groups, that is, in the group with eyes shut from 300.53 ± 1.37 in T0 to 308.06 ± 1.55 in T1 to 304.88 ± 1.54 in T2. In the group with eyes open, tear osmolarity increased from 300.29 ± 1.37 in T0 to 310.76 ± 1.55 in T1 and then dropped to 308.88 ± 1.54 in T2. Tear brake up time measured in T0 was 14.7 ± 1.43 vs. 13.53 ±1.48 in the open eyes condition. Due to physical exercise, short-term changes in tear osmolarity are partially caused by altered blinking. Sex differences in tear osmolarity in response to exertion may confirm the relationship between total body water and tear osmolarity.

Hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous neurodegenerative disorders. Numerous genes linked to HSPs, overlapping phenotypes between HSP subtypes and other neurodegenerative disorders and the HSPs' dual mode of inheritance (both dominant and recessive) make the genetic diagnosis of HSPs complex and difficult. Out of the original HSP cohort comprising 306 index cases (familial and isolated) who had been tested according to "traditional workflow/guidelines" by Multiplex Ligation-dependent Probe Amplification (MLPA) and Sanger sequencing, 30 unrelated patients (all familial cases) with unsolved genetic diagnoses were tested using next-generation sequencing (NGS). One hundred thirty-two genes associated with spastic paraplegias, hereditary ataxias and related movement disorders were analysed using the Illumina TruSight™ One Sequencing Panel. The targeted NGS data showed pathogenic variants, likely pathogenic variants and those of uncertain significance (VUS) in the following genes: SPAST (spastin, SPG4), ATL1 (atlastin 1, SPG3), WASHC5 (SPG8), KIF5A (SPG10), KIF1A (SPG30), SPG11 (spatacsin), CYP27A1, SETX and ITPR1. Out of the nine genes mentioned above, three have not been directly associated with the HSP phenotype to date. Considering the phenotypic overlap and joint cellular pathways of the HSP, spinocerebellar ataxia (SCA) and amyotrophic lateral sclerosis (ALS) genes, our findings provide further evidence that common genetic testing may improve the diagnostics of movement disorders with a spectrum of ataxia-spasticity signs.

Macrophages make important contributions to inflammation and wound healing. We show here that macrophage polarization is deregulated in haemophilia in response to macrophage colony-stimulating factor (M-CSF) and partially in response to granulocyte-macrophage colony-stimulating factor (GM-CSF). As a result, haemophilia macrophages exhibit a specific impairment of M-CSF-mediated functions involved in wound healing such as clot invasion and phagocytosis. Haemophilia monocytes express reduced amounts of the receptors for M-CSF and GM-CSF, which correlates with a failure to express tumour necrosis factor α (TNFα) and CD163 in M-CSF-treated haemophilia macrophages and reduced expression of TNFα and CD206 after treatment with GM-CSF. Protein expression in response to M-CSF was regained with respect to CD163 and CD206 after embedding haemophilia monocytes in clotted plasma suggesting that a functioning coagulation system has positive effects on macrophage M2 polarization. Mimicking the functional deficits of haemophilia macrophages in normal macrophages was possible by adding leptin, which we found to be elevated in the blood of haemophilia patients, to a monocyte cell line. The increase of leptin occurred in conjunction with C-reactive protein in a body mass index-controlled cohort suggesting that haemophilia patients harbour chronic low-grade inflammation. Together, our data indicate that impaired clotting in haemophilia patients leads to increased inflammation and a deregulation in macrophage differentiation, which may explain the commonly observed deficits in wound healing and tissue regeneration., Competing Interests: None declared., (Georg Thieme Verlag KG Stuttgart · New York.)

The aim of this study was to evaluate a novel composite material for tracheal reconstruction in an ovine model. A polymer containing various forms of carbon fibers (roving, woven, and nonwoven fabric) impregnated with polysulfone (PSU) was used to create cylindrical tracheal implants, 3 cm in length and 2.5 cm in diameter. Each implant, reinforced with five rings made of PSU-impregnated carbon-fiber roving, had three external layers made of carbon-fiber woven fabric and the inner layer formed of carbon-fiber nonwoven fabric. The inner surface of five implants was additionally coated with polyurethane (PU), to promote migration of respiratory epithelium. The implants were used to repair tracheal defects (involving four tracheal rings) in 10 sheep (9-12 months of age; 40-50 kg body weight). Macroscopic and microscopic characteristics of the implants and tracheal anastomoses were examined 4 and 24 weeks after implantation. At the end of the follow-up period, outer surfaces of the implants were covered with the tissue which to various degree resembled histological structure of normal tracheal wall. In turn, inner surfaces of the prostheses were covered only with vascularized connective tissue. Inner polyurethane coating did not improve the outcomes of tracheal reconstruction and promoted excessive granulation, which contributed to moderate to severe stenosis at the tracheal anastomoses. The hereby presented preliminary findings constitute a valuable source of data for future research on a tracheal implant being optimally adjusted for medical needs.

The HNRNPH2-associated disease (mental retardation, X-linked, syndromic, Bain type [MRXSB, MIM #300986]) is caused by de novo mutations in the X-linked HNRNPH2 gene. MRXSB has been described in six female patients with dysmorphy, developmental delay, intellectual disability, autism, hypotonia and seizures. The reported HNRNPH2 mutations were clustered in the small domain encoding nuclear localization signal; in particular, the p.Arg206Trp was found in four independent de novo events. HNRNPH1 is a conserved autosomal paralogue of HNRNPH2 with a similar function in regulation of pre-mRNAs splicing but so far it has not been associated with human disease. We describe a boy with a disease similar to MRXSB in whom a novel de novo mutation c.616C>T (p.Arg206Trp) in HNRNPH1 was found (ie, the exact paralogue of the recurrent HNRNPH2 mutation). We propose that defective function of HNRNPH2 and HNRNPH1 nuclear localization signal has similar clinical consequences. An important difference between the two diseases is that the HNRNPH1-associated syndrome may occur in boys (as in the case of our proband) which is well explained by the autosomal (chr5q35.3) rather than X-linked localization of the HNRNPH2 gene., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Research with primary human white blood cell (WBC) subpopulations requires high quantity, quality, and functionality of peripheral blood mononuclear cells (PBMCs) as a source to further characterize cellular subpopulations such as T and B lymphocytes, monocytes, or natural killer cells. Apart from buffy coats derived from whole blood, residual blood from preparative hemapheresis kits are used as a source for PBMCs, but knowledge on the yield and functionality of cells from different devices is limited., Study Design and Methods: We evaluated quantity and quality of PBMCs isolated from apheresis kits of two apheresis devices (AMICUS, Fenwal; and Trima Accel, Terumo BCT), the latter being our standard source for many years. PBMCs derived from Trima or AMICUS were tested for yield and subtype composition by flow cytometry. Functionality was assessed by cytokine induction of CD4 + and CD8 + T cells and by degranulation. Moreover, cytotoxic activity of natural killer cells was quantified by a real-time killing assay., Results: Mean numbers of isolated cells were 5.5 ± 2.4 × 10 8 for AMICUS, and 10.3 ± 6.4 × 10 8 for Trima Accel, respectively. The proportion of WBC subtypes corresponded to well-known numbers from whole blood, with minor differences between the two apheresis systems. Likewise, minor differences in cytokine induction were found in stimulated CD4 + or CD8 + T cells. Finally, PBMCs derived from the two systems showed comparable cytotoxic activity., Conclusion: PBMC derived from residual blood of the AMICUS and Trima Accel apheresis devices serve as an economic and easily accessible source for functional PBMCs with comparable quantity and quality to PBMCs derived from whole blood., (© 2018 AABB.)

PurposeIn 2012 we reported in six individuals a clinical condition almost indistinguishable from PLOD1-kyphoscoliotic Ehlers-Danlos syndrome (PLOD1-kEDS), caused by biallelic mutations in FKBP14, and characterized by progressive kyphoscoliosis, myopathy, and hearing loss in addition to connective tissue abnormalities such as joint hypermobility and hyperelastic skin. FKBP14 is an ER-resident protein belonging to the family of FK506-binding peptidyl-prolyl cis-trans isomerases (PPIases); it catalyzes the folding of type III collagen and interacts with type III, type VI, and type X collagens. Only nine affected individuals have been reported to date.MethodsWe report on a cohort of 17 individuals with FKBP14-kEDS and the follow-up of three previously reported patients, and provide an extensive overview of the disorder and its natural history based on clinical, biochemical, and molecular genetics data.ResultsBased on the frequency of the clinical features of 23 patients from the present and previous cohorts, we define major and minor features of FKBP14-kEDS. We show that myopathy is confirmed by histology and muscle imaging only in some patients, and that hearing impairment is predominantly sensorineural and may not be present in all individuals.ConclusionOur data further support the extensive clinical overlap with PLOD1-kEDS and show that vascular complications are rare manifestations of FKBP14-kEDS.

Loss-of-function mutations in the X-linked gene FLNA can lead to abnormal neuronal migration, vascular and cardiac defects, and congenital intestinal pseudo-obstruction (CIPO), the latter characterized by anomalous intestinal smooth muscle layering. Survival in male hemizygotes for such mutations is dependent on retention of residual FLNA function but it is unclear why a subgroup of males with mutations in the 5' end of the gene can present with CIPO alone. Here, we demonstrate evidence for the presence of two FLNA isoforms differing by 28 residues at the N-terminus initiated at ATG +1 and ATG +82 . A male with CIPO (c.18&#95;19del) exclusively expressed FLNA ATG +82 , implicating the longer protein isoform (ATG +1 ) in smooth muscle development. In contrast, mutations leading to reduction of both isoforms are associated with compound phenotypes affecting the brain, heart, and intestine. RNA-seq data revealed three distinct transcription start sites, two of which produce a protein isoform utilizing ATG +1 while the third utilizes ATG +82 . Transcripts sponsoring translational initiation at ATG +1 predominate in intestinal smooth muscle, and are more abundant compared with the level measured in fibroblasts. Together these observations describe a new mechanism of tissue-specific regulation of FLNA that could reflect the differing mechanical requirements of these cell types during development., (© 2017 Wiley Periodicals, Inc.)

Although over 85% of osteogenesis imperfecta (OI) cases are associated with mutations in the procollagen type I genes (COL1A1 or COL1A2), no hot spots for the mutations were associated with particular clinical phenotypes. Eight patients that were studied here, diagnosed with OI by clinical standards, are from the Polish population with no ethnic background indicated. Previously unpublished mutations were found in six out of those eight patients. Genotypes for polymorphisms (Sp1 - rs1800012 and PvuII - rs412777), linked to bone formation and metabolism were determined. Mutations were found in exons 2, 22, 50 and in introns 13 and 51 of the COL1A1 gene. In COL1A2, one mutation was identified in exon 22. Deletion type mutations in COL1A1 that resulted in OI type I had no effect on collagen type I secretion, nor on its intracellular accumulation. Also, a single base substitution in I13 (c.904-9 G>T) was associated with the OI type I. The OI type III was associated with a single base change in I51 of COL1A1, possibly causing an exon skipping. Also, a missense mutation in COL1A2 changing Gly→Cys in the central part of the triple helical domain of the collagen type I molecule caused OI type III. It affected secretion of the heterotrimeric form of procollagen type I. However, no intracellular accumulation of procollagen chains could be detected. Mutation in COL1A2 affected its incorporation into procollagen type I. The results obtained shall help in genetic counseling of OI patients and provide a rational support for making informed, life important decisions by them and their families.

Mutations in the p53 tumor suppressor are frequent in patients with castration-resistant prostate cancer but less so in patients with localized disease, and patients who have Li-Fraumeni with germline p53 mutations do not have an increased incidence of prostate cancer, suggesting that additional molecular and/or genetic changes are required for p53 to promote prostate carcinogenesis. ELL-associated factor 2 (EAF2) is a tumor suppressor that is frequently downregulated in advanced prostate cancer. Previous studies have suggested that p53 binds to EAF2, providing a potential mechanism for their functional interactions. In this study, we tested whether p53 and EAF2 could functionally interact in prostate cancer cells and whether concurrent inactivation of p53 and EAF2 could promote prostate carcinogenesis in a murine knockout model. Endogenous p53 coprecipitated with EAF2 in prostate cancer cells, and deletion mutagenesis indicated that this interaction was mediated through the C terminus of EAF2 and the DNA binding domain of p53. Concurrent knockdown of p53 and EAF2 induced an increase in proliferation and migration in cultured prostate cancer cells, and conventional p53 and EAF2 knockout mice developed prostate cancer. In human prostate cancer specimens, concurrent p53 nuclear staining and EAF2 downregulation was associated with high Gleason score. These findings suggest that EAF2 and p53 functionally interact in prostate tumor suppression and that simultaneous inactivation of EAF2 and p53 can drive prostate carcinogenesis., (Copyright © 2017 Endocrine Society.)