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Insulinomas are the most frequent type of functional pancreatic neuroendocrine tumors with a variety of neuroglycopenic and autonomic symptoms and well-defined diagnostic criteria ; however, prediction of their clinical behavior and early differentiation between benign and malignant lesions remain a challenge. The comparative studies between benign and malignant cases are limited, suggesting that short clinical history, early hypoglycemia during fasting, high proinsulin, insulin, and C-peptide concentrations raise suspicion of malignancy. Indeed, malignant tumors are larger with higher mitotic count and Ki-67 proliferative activity, but there are no accurate histological criteria to distinguish benign from malignant forms. Several signaling pathways have been suggested to affect the pathophysiology and behavior of insulinomas ; however, our knowledge is limited, urging a further understanding of molecular genetics. Therefore, there is a need for the identification of reliable markers of metastatic disease that could also serve as therapeutic targets in patients with malignant insulinoma. This opinion review reflects on current gaps in diagnostic and clinical aspects related to the malignant behavior of insulinoma.

Recent studies have linked gut microorganism composition and chronic urticaria (CU); however, the underlying mechanisms responsible for this connection are unknown. Since the human immune system is in homeostasis with microbiota, and the composition of the microbiome regulates the development and function of the immune system, it is likely that an alteration of microbiota components (a dysbiosis) could influence the course of chronic spontaneous urticaria (CSU), including disease severity, patient quality of life and treatment outcome. To date, several studies have identified changes in the gut microbiota composition of patients with CSU, though only a few have exhibited metabolic abnormalities associated with gut dysbiosis. The studies on CSU patients predominantly showed that the relative abundance of beneficial bacteria was decreased (Firmicutes and Bacteroides), while that of opportunistic bacteria was increased (Enterobacteria and Proteobacteria). In addition, serum metabolome analysis revealed that gut microbiota-associated alterations in unsaturated fatty acids and the butanoate metabolism pathway may play a role in CSU. These findings are potentially associated with inflammation mediated by the imbalance of Th1/Th2/Th17 cytokines, which might contribute to CSU pathogenesis. Further research in this field could improve clinical, diagnostic, and therapeutic approaches to patients with CSU. By applying new knowledge on gut microbial communities and metabolomics, future CSU therapies could modify the microbiota composition using agents such as probiotics or other similar agents, which, in combination with current standard therapies, could hopefully lead to a reduction in symptoms and an improved quality of life for CSU patients.

Objective. Many methods for compression and/or de-speckling of 3D optical coherence tomography (OCT) images operate on a slice-by-slice basis and, consequently, ignore spatial relations between the B-scans. Thus, we develop compression ratio (CR)-constrained low tensor train (TT) - and low multilinear (ML) rank approximations of 3D tensors for compression and de-speckling of 3D OCT images. Due to inherent denoising mechanism of low-rank approximation, compressed image is often even of better quality than the raw image it is based on. Approach. We formulate CR-constrained low rank approximations of 3D tensor as parallel non-convex non-smooth optimization problems implemented by alternating direction method of multipliers of unfolded tensors. In contrast to patch- and sparsity-based OCT image compression methods, proposed approach does not require clean images for dictionary learning, enables CR as high as 60:1, and it is fast. In contrast to deep networks based OCT image compression, proposed approach is training free and does not require any supervised data pre-processing. Main results. Proposed methodology is evaluated on twenty four images of a retina acquired on Topcon 3D OCT-1000 scanner, and twenty images of a retina acquired on Big Vision BV1000 3D OCT scanner. For the first dataset, statistical significance analysis shows that for CR≤35, all low ML rank approximations and Schatten-0 (S0) norm constrained low TT rank approximation can be useful for machine learning-based diagnostics by using segmented retina layers. Also for CR≤35, S0-constrained ML rank approximation and S0-constrained low TT rank approximation can be useful for visual inspection-based diagnostics. For the second dataset, statistical significance analysis shows that for CR≤60 all low ML rank approximations as well as S0 and S1/2 l low TT ranks approximations can be useful for machine learning-based diagnostics by using segmented retina layers. Also, for CR≤60, low ML rank approximations constrained with Sp, p∈{0, 1/2, 2/3} and one surrogate of S0 can be useful for visual inspection-based diagnostics. That is also true for low TT rank approximations constrained with Sp, p∈{0, 1/2, 2/3} for CR≤20. Significance. Studies conducted on datasets acquired by two different types of scanners confirmed capabilities of proposed framework that, for a wide range of CRs, yields de-speckled 3D OCT images suitable for clinical data archiving and remote consultation, for visual inspection-based diagnosis and for machine learning-based diagnosis by using segmented retina layers.

The proportion of oral and oropharyngeal squamous cell carcinoma (OOSCC) that can be attributed to human papillomavirus (HPV) infection is growing nowadays. A potential factor indicating the occurrence of HPV-positive OSCC is a change in the degree of methylation of gene promoters that play a key role in the immune response. In this study, we investigated the difference in the methylation of EDARADD, GBP4, HAVCR2, HLA DPB1, IL12RB1, MARCO, and SIGLEC12 gene promoters in samples of healthy oral mucosa versus samples of oral and oropharyngeal cancer. The presence of HPV infection in samples was examined earlier. To determine the difference in methylation of those gene promotors, isolated and bisulfite-modified DNA was analysed by the methylation-specific PCR method. The investigated gene promoters were found to be more hypomethylated in the oral and oropharyngeal cancer samples in comparison to normal tissue. The proportion of unmethylated gene promoters was similar in HPV-positive and HPV-negative cancers, although the data should be confirmed on a larger set of samples. To conclude, in samples of healthy oral mucosa, the investigated gene promoters were found to be methylated in a high percentage (73.3% to 100%), while in oral and oropharyngeal cancer samples, they were methylated in a low percentage (11.1% to 37%), regardless of HPV infection.

Perinatal derivatives (PnD) are drawing growing interest among the scientific community as an unrestricted source of multipotent stem cells, secretome, and biological matrices. They are useful for the treatment of diseases that currently have limited or no effective therapeutic options, but they require the development of regenerative approaches. With this development, the question of regulation of donation, processing, and distribution has therefore become more important. Within the European Cooperation in Science and Technology (COST) community, we compiled a group of international experts on PnD technologies, who revised and compared existing EU national regulations. Notably, despite clear European directives, each EU Country has developed their own implementation and standard levels for cell- and tissue-based therapies. To enable extended applications of PnD treatments within the EU community and worldwide, harmonization is highly recommended. This paper aims to provide an overview of the various options available to introduce PnD into clinical practice. For this purpose, the different aspects resulting from (1) the type of PnD, (2) the amount of available data, (3) the degree of manipulation, and (4) the intended application and the process toward a possible commercialization will be presented. In the future, it will be important to find a balance between regulatory requirements and the best medical quality of the PnD product.

Purpose The aim of this study was to analyse the postoperative corneal cross-linking results of corneal parameters and the ABCD grading system, depending on the cone location. Methods Thirty eyes of 25 patients with keratoconus (KC), who received the corneal cross-linking (CXL) treatment, were included in this study. The exclusion criteria were: patients under 18 years of age, corneal pachymetry less than 400 μm, corneal scarring, history of ocular trauma, history of ocular surgery, and corneal pathology other than KC. Patients were examined at the baseline visit, and followed-up at three, six, and twelve months after the CXL. All patients underwent visual acuity and Scheimpflug tomography at all visits. Progression parameters, keratometries, and ABCD grading were compared between the visits. Patients were classified into two groups: central and paracentral cones group (within the central 5 mm corneal zone) and peripheral cones group (outside the central 5 mm corneal zone), based on X-Y coordinates of maximal keratometry (Kmax). Results Parameter A remained relatively stable throughout the follow-up period in both groups. Parameter B and parameter C showed a significant increase in both groups postoperatively. Parameter D showed stability at the 6-month post-CXL visit in the peripheral KC group, while the central and paracentral KC group showed improvement at the 12-month post-CXL visit. Conclusion There was no significant difference in the postoperative response between different cone locations in the ABCD grading system, when classifying according to the Kmax, except an earlier recovery of the parameter D in peripherally located cones.

ObjectivesChronic graft-versus-host disease (cGvHD) is the most frequent cause of late non-relapse mortality after allogeneic haematopoietic stem cell transplantation (alloHCT). Nevertheless, established biomarkers of cGvHD are still missing. The National Institutes of Health (NIH) Consensus Development Project on Criteria for Clinical Trials in cGvHD provided recommendations for biomarker research. We evaluated to which extent studies on cellular and soluble biomarkers in cGvHD published in the last 10 years complied with these recommendations. Also, we highlight the most promising biomarker candidates, verified in independent cohorts and/or repeatedly identified by separate studies.MethodsWe searched Medline and EMBASE for “cGvHD”, “biomarkers”, “soluble” and “cells” as MeSH terms or emtree subject headings, and their variations on July 28th, 2021, limited to human subjects, English language and last ten years. Reviews, case reports, conference abstracts and single nucleotide polymorphism studies were excluded. Criteria based on the set of recommendations from the NIH group for biomarker research in cGvHD were used for scoring and ranking the references.ResultsA total of 91 references encompassing 15,089 participants were included, 54 prospective, 17 retrospective, 18 cross-sectional, and 2 studies included both prospective and retrospective cohorts. Thirty-five papers included time-matched controls without cGvHD and 20 studies did not have any control subjects. Only 9 studies were randomized, and 8 were multicentric. Test and verification cohorts were included in 11 studies. Predominantly, diagnostic biomarkers were explored (n=54). Assigned scores ranged from 5-34. None of the studies fulfilled all 24 criteria (48 points). Nevertheless, the scores improved during the last years. Three cell subsets (CXCR3+CD56bright NK cells, CD19+CD21low and BAFF/CD19+ B cells) and several soluble factors (BAFF, IL-15, CD163, DKK3, CXCL10 and the panel of ST2, CXCL9, MMP3 and OPN) had the highest potential as diagnostic and/or prognostic biomarkers in cGvHD.ConclusionDespite several limitations of this review (limited applicability for paediatric population, definition of verification, missing data on comorbidities), we identified promising candidate biomarkers for further evaluation in multicentre collaborative studies. This review confirms the importance of the NIH consensus group criteria for improving the quality and reproducibility of cGvHD biomarker research.

Perinatal derivatives are drawing growing interest among the scientific community as an unrestricted source of multipotent stromal cells, stem cells, cellular soluble mediators, and biological matrices. They are useful for the treatment of diseases that currently have limited or no effective therapeutic options by means of developing regenerative approaches. In this paper, to generate a complete view of the state of the art, a comprehensive 10-years compilation of clinical-trial data with the common denominator of PnD usage has been discussed, including commercialized products. A set of criteria was delineated to challenge the 10-years compilation of clinical trials data. We focused our attention on several aspects including, but not limited to, treated disorders, minimal or substantial manipulation, route of administration, dosage, and frequency of application. Interestingly, a clear correlation of PnD products was observed within conditions, way of administration or dosage, suggesting there is a consolidated clinical practice approach for the use of PnD in medicine. No regulatory aspects could be read from the database since this information is not mandatory for registration. The database will be publicly available for consultation. In summary, the main aims of this position paper are to show possibilities for clinical application of PnD and propose an approach for clinical trial preparation and registration in a uniform and standardized way. For this purpose, a questionnaire was created compiling different sections that are relevant when starting a new clinical trial using PnD. More importantly, we want to bring the attention of the medical community to the perinatal products as a consolidated and efficient alternative for their use as a new standard of care in the clinical practice.

Background Chronic graft-versus-host disease (cGvHD) is one of the most common life-threatening complications following allogeneic haematopoietic stem cell transplantation (alloHSCT). Understanding outcome after alloHSCT requires a full evaluation of the patient’s health status, including cGvHD and patient reported outcomes (PROs). In an effort to better understand practice patterns across European countries, a survey was initiated by the Integrated European Network on cGvHD (an EU-funded COST Action CA17138 EUROGRAFT, www.gvhd.eu) and the Transplant Complications Working Party of the European Society for Blood and Marrow Transplantation (EBMT). This report shares results of the survey, offering a snapshot view of current practice patterns in the context of long-term care of cGvHD patients. Methods Our self-designed 38-item online survey (Supplementary Material) was intended to collect data regarding transplant center characteristics, data registration practices, the use of NIH criteria in clinical routine, biopsies/biomarkers for clinical assessment, cGvHD cell-based therapies, and PROs. The survey used computer adapted testing methods and took ~10 min to complete. All centers participating in the COST Action EUROGRAFT and all EBMT centers performing alloHSCT were invited by email for participation in the survey. Data were collected between July 2019 and July 2020. Appropriate descriptive statistics were used. In case of multiple entries for a single center (n = 4), only the entry from the most senior staff member was included for the analysis. Missing data was reported as such. Findings Center characteristics Survey results are summarized in Table 1. A total of 72 centers out of 424 invited centers from 24 countries responded to the survey, representing ~17% of all alloHSCT centers and 19.6% of all transplanted patients within the EBMT network [1]. The majority of participating alloHSCT centers were from Europe with exception of three centers based in Asia and one in Latin America. Survey responses were mainly submitted by physicians and data managers. Of note, the size of the transplant programs differed between responding (mean ± SD, n = 47 ± 40 transplants/year) vs. non-responding (mean ± SD, n = 39 ± 31 transplants/year) centers (Supplementary Material).

In the last few decades, endocannabinoids, plant-derived cannabinoids and synthetic cannabinoids have received growing interest as treatment options in neurodegenerative conditions. In various experimental settings, they have displayed antioxidative, anti-inflammatory, antiapoptotic, immunomodulatory, and neuroprotective effects. However, due to numerous targets and downstream effectors of their action, the cellular and molecular mechanisms underlying these effects are rather complex and still under discussion. Cannabinoids are able to neutralize free radicals and modulate the production of reactive oxygen species and the activity of antioxidative systems acting on CB1 and CB2 cannabinoid receptors. The activation of CB1 receptors stimulates signaling pathways involved in antioxidative defense and survival (such as the phosphoinositide 3-kinase (PI3K)/Akt, mitogen-activated protein kinase (MAPK), and Nrf2 pathways) and regulates glutamatergic signaling, the activation of N-methyl-D-aspartate (NMDA) receptors, calcium influx, and the induction of Ca2+-regulated signaling cascades, whereas the neuroprotective effects mediated by CB2 receptors are due to the suppression of microglial activation and the release of prooxidative and proinflammatory mediators. This review summarizes the main molecular mechanisms and new advances in understanding the antioxidative and neuroprotective effects of cannabinoids. Because of the plethora of possible pharmacological interventions related to oxidative stress and cannabinoid-mediated neuroprotection, future research should be directed towards a better understanding of the interplay between activated signal transduction pathways and molecular targets with the aim to improve treatment options and efficacy by targeting the endocannabinoid system.

Background The incidence of carcinoma during pregnancy is reported to be 1:1000–1:1500 pregnancies with the breast carcinoma being the most commonly diagnosed. Since the fetus is most sensitive to ionizing radiation during the first two trimesters, there are mixed clinical opinions and no uniform guidelines on the use of radiotherapy during pregnancy. Within this study the pregnant female phantom in the second trimester, that can be used for radiotherapy treatment planning (as DICOM data), Monte Carlo simulations (as voxelized geometry) and experimental dosimetry utilizing 3D printing of the molds (as .STL files), was developed. Materials and methods The developed phantom is based on MRI images of a female patient in her 18th week of pregnancy and CT images after childbirth. Phantom was developed in such a manner that a pregnant female was scanned “in vivo” using MRI during pregnancy and CT after childbirth. For the treatment of left breast carcinoma, 3D conformal radiotherapy was used. The voxelized geometry of the phantom was used for Monte Carlo (MC) simulations using Monte Carlo N-Particle transport codeTM 6.2 (MCNP). Conclusions The modeled photon breast radiotherapy plan, applied to the phantom, indicated that the fetus dose is 59 mGy for 50 Gy prescribed to the breast. The results clearly indicate that only 9.5% of the fetal dose is caused by photons that are generated in the accelerator head through scattering and leakage, but the dominant component is scattered radiation from the patient’s body.

Major depressive disorder is one of the most common mental illnesses that highly impairs quality of life. Pharmacological interventions are mainly focused on altered monoamine neurotransmission, which is considered the primary event underlying the disease’s etiology. However, many other neuropathological mechanisms that contribute to the disease’s progression and clinical symptoms have been identified. These include oxidative stress, neuroinflammation, hippocampal atrophy, reduced synaptic plasticity and neurogenesis, the depletion of neurotrophic factors, and the dysfunction of the hypothalamic–pituitary–adrenal (HPA) axis. Current therapeutic options are often unsatisfactory and associated with adverse effects. This review highlights the most relevant findings concerning the role of flavonols, a ubiquitous class of flavonoids in the human diet, as potential antidepressant agents. In general, flavonols are considered to be both an effective and safe therapeutic option in the management of depression, which is largely based on their prominent antioxidative and anti-inflammatory effects. Moreover, preclinical studies have provided evidence that they are capable of restoring the neuroendocrine control of the HPA axis, promoting neurogenesis, and alleviating depressive-like behavior. Although these findings are promising, they are still far from being implemented in clinical practice. Hence, further studies are needed to more comprehensively evaluate the potential of flavonols with respect to the improvement of clinical signs of depression.

Introduction: Carbapenem-resistant Klebsiella pneumoniae is an emerging healthcare-associated pathogen with dynamic molecular epidemiology. This study presents a retrospective analysis of the distribution and antibiotic resistance patterns of ertapenem-resistant ESBL-producing K. pneumoniae strains recovered during an outbreak from 2012 to 2014 in a Croatian University hospital. Methods We aimed to estimate genetic relatedness of clinical isolates and underlying mechanisms that conferred the ertapenem- resistant phenotype. Results: Expression analysis of genes involved in the antibiotic resistance showed reduced expression of major non-selective porin channel OmpK35. Reduced expression of OmpK36 porin channel in isolates resistant to at least one more carbapenem, apart from the ertapenem, was found to a lesser degree. Pulsed-field gel electrophoresis analysis of genomic DNA revealed that almost all isolates belonged to the same genetic clone. Conclusions: Caution regarding ertapenem- resistant, carbapenemase-negative porin- deficient mutants of K. pneumoniae is required as they are widespread, and under selective pressure this could result in a local clonal outbreak.

The thymus is the organ responsible for T cell development and the formation of the adaptive immunity function. Its multicellular environment consists mainly of the different stromal cells and maturing T lymphocytes. Thymus-specific progenitors of epithelial, mesenchymal, and lymphoid cells with stem cell properties represent only minor populations. The thymic stromal structure predominantly determines the function of the thymus. The stromal components, mostly epithelial and mesenchymal cells, form this specialized area. They support the consistent developmental program of functionally distinct conventional T cell subpopulations. These include the MHC restricted single positive CD4+CD8-and CD4-CD8+cells, regulatory T lymphocytes (Foxp3+), innate natural killer T cells (iNKT), and γδT cells. Several physiological causes comprising stress and aging and medical treatments such as thymectomy and chemo/radiotherapy can harm the thymus function. The present review summarizes our knowledge of the development and function of the thymus with a focus on thymic epithelial cells as well as other stromal components and the signaling and transcriptional pathways underlying the thymic cell interaction. These critical thymus components are significant for T cell differentiation and restoring the thymic function after damage to reach the therapeutic benefits.

Contains fulltext : 244079.pdf (Publisher’s version ) (Closed access) BACKGROUND: The incidence, geographical distribution and clinical relevance of different nontuberculous mycobacteria (NTM) in Croatia are well described. There are few data on the risk factors for developing NTM pulmonary disease (NTM-PD) in this setting. METHODS: We conducted a retrospective cohort study on all Croatian residents with NTM isolated from respiratory samples in the period from 2006 to 2015 with follow-up to 2018. The American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines were used to establish NTM-PD diagnosis. Clinical, radiological and treatment data were collected from hospital records. RESULTS: Risk analysis calculations were made on the 439 isolation episodes that were classified as definitive NTM-PD (n = 137) or no disease (n = 302). Female gender, presence of bronchiectasis, low BMI and long-term systemic corticosteroid treatment were independent risk factors associated with NTM-PD. Hemoptysis and malaise were presenting symptoms independently associated with NTM-PD. Chronic obstructive pulmonary disease (COPD) and low/moderate dose inhaled corticosteroid (ICS) treatment were not associated with NTM-PD. High dose ICS treatment was a significant risk factor for developing NTM-PD (aOR = 4.73, CI 1.69-13.23 p = 0.003). CONCLUSION: The NTM-PD patients in Croatia are similar to those in other published cohorts in terms of their characteristics and risk factors. The significant dose-dependent association between ICS use and NTM-PD adds to the body of evidence suggesting that high dose ICS use is associated with NTM-PD.

We revealed that the stable gastric pentadecapeptide BPC 157, a useful peptide therapy against isoprenaline myocardial infarction, as well as against isoprenaline myocardial reinfarction, may follow the counteraction of the recently described occlusion-like syndrome, induced peripherally and centrally, which was described for the first time in isoprenaline-treated rats. BPC 157 (10 ng/kg, 10 µg/kg i.p.), L-NAME (5 mg/kg i.p.), and L-arginine (200 mg/kg i.p.) were given alone or together at (i) 30 min before or, alternatively, (ii) at 5 min after isoprenaline (75 or 150 mg/kg s.c.). At 30 min after isoprenaline 75 mg/kg s.c., we noted an early multiorgan failure (brain, heart, lung, liver, kidney and gastrointestinal lesions), thrombosis, intracranial (superior sagittal sinus) hypertension, portal and caval hypertension, and aortal hypotension, in its full presentation (or attenuated by BPC 157 therapy (given at 5 min after isoprenaline) via activation of the azygos vein). Further, we studied isoprenaline (75 or 150 mg/kg s.c.) myocardial infarction (1 challenge) and reinfarction (isoprenaline at 0 h and 24 h, 2 challenges) in rats (assessed at the end of the subsequent 24 h period). BPC 157 reduced levels of all necrosis markers, CK, CK-MB, LDH, and cTnT, and attenuated gross (no visible infarcted area) and histological damage, ECG (no ST-T ischemic changes), and echocardiography (preservation of systolic left ventricular function) damage induced by isoprenaline. Its effect was associated with a significant decrease in oxidative stress parameters and likely maintained NO system function, providing that BPC 157 interacted with eNOS and COX2 gene expression in a particular way and counteracted the noxious effect of the NOS-blocker, L-NAME.

Recurrent upper tract urothelial carcinomas (UTUCs) arise in the context of nephropathy linked to exposure to the herbal carcinogen aristolochic acid (AA). Here we delineated the molecular programs underlying UTUC tumorigenesis in patients from endemic aristolochic acid nephropathy (AAN) regions in Southern Europe. We applied an integrative multiomics analysis of UTUCs, corresponding unaffected tissues and of patient urines. Quantitative microRNA (miRNA) and messenger ribonucleic acid (mRNA) expression profiling, immunohistochemical analysis by tissue microarrays and exome and transcriptome sequencing were performed in UTUC and nontumor tissues. Urinary miRNAs of cases undergoing surgery were profiled before and after tumor resection. Ribonucleic acid (RNA) and protein levels were analyzed using appropriate statistical tests and trend assessment. Dedicated bioinformatic tools were used for analysis of pathways, mutational signatures and result visualization. The results delineate UTUC-specific miRNA:mRNA networks comprising 89 miRNAs associated with 1, 862 target mRNAs, involving deregulation of cell cycle, deoxyribonucleic acid (DNA) damage response, DNA repair, bladder cancer, oncogenes, tumor suppressors, chromatin structure regulators and developmental signaling pathways. Key UTUC- specific transcripts were confirmed at the protein level. Exome and transcriptome sequencing of UTUCs revealed AA-specific mutational signature SBS22, with 68% to 76% AA-specific, deleterious mutations propagated at the transcript level, a possible basis for neoantigen formation and immunotherapy targeting. We next identified a signature of UTUC- specific miRNAs consistently more abundant in the patients' urine prior to tumor resection, thereby defining biomarkers of tumor presence. The complex gene regulation programs of AAN-associated UTUC tumors involve regulatory miRNAs prospectively applicable to noninvasive urine-based screening of AAN patients for cancer presence and recurrence.

The knowledge on how gut microbes contribute to the inflammatory bowel disease (IBD) at the onset of disease is still scarce. We compared gut microbiota in newly diagnosed, treatment-naïve adult IBD (Crohn's disease (CD) and ulcerative colitis (UC)) to irritable bowel syndrome (IBS) patients and healthy group. Mucosal and fecal microbiota of 49 patients (13 UC, 10 CD, and 26 IBS) before treatment initiation, and fecal microbiota of 12 healthy subjects was characterized by 16S rRNA gene sequencing. Mucosa was sampled at six positions, from terminal ileum to rectum. We demonstrate that mucosal microbiota is spatially homogeneous, cannot be differentiated based on the local inflammation status and yet provides bacterial footprints superior to fecal in discriminating disease phenotypes. IBD groups showed decreased bacterial diversity in mucosa at all taxonomic levels compared to IBS. In CD and UC, Dialister was significantly increased, and expansion of Haemophilus and Propionibacterium characterized UC. Compared to healthy individuals, fecal microbiota of IBD and IBS patients had increased abundance of Proteobacteria, Enterobacteriaceae, in particular. Shift toward reduction of Adlercreutzia and butyrate-producing taxa was found in feces of IBD patients. Microbiota alterations detected in newly diagnosed treatment-naïve adult patients indicate that the microbiota changes are set and detectable at the disease onset and likely have a discerning role in IBD pathophysiology. Our results justify further investigation of the taxa discriminating between disease groups, such as H. parainfluenzae, R. gnavus, Turicibacteriaceae, Dialister, and Adlercreutzia as potential biomarkers of the disease.

Oral squamous cell carcinoma (OSCC) is frequently diagnosed in the advanced stages. The purpose of this paper is to determine the salivary values of SCCA1, SCCA2 and TROP2 in patients with T1N0M0 OSCC and to compare them with the values obtained from healthy individuals. Unstimulated (UWS) and stimulated (SWS) saliva was sampled from 29 patients with T1N0M0 OSCC and 29 sex- and age-matched healthy individuals. Statistical difference was observed in SCCA1 and SCCA2 levels both in UWS and SWS samples. TROP2 was not measurable in most of the salivary samples. Both SCCA1 and SCCA2 could represent potential biomarkers for the early-stage OSCC. Research on a larger sample and biomarker validation is needed to assess the clinical potential of SCCA1 and SCCA2 in the OSCC early diagnostics.

Introduction: The literature reviewed in this paper suggests that infertile patients present worse periodontal status, which may be causative to conception complications. This study aimed to validate an aMMP-8 point-of-care mouth rinse test in the population of women with unexplained infertility and compare it to age-matched fertile women with and without periodontitis. Furthermore, blood sampled inflammatory parameters were analyzed and compared between the two groups. It was hypothesized that the infertile women would present worse periodontal status and a greater number of positive aMMP-8 tests than fertile women, and they would have increased inflammatory blood parameters. Material and methods: The study included 50 healthy norm-ovulatory females aged 25-45 years with strictly defined unexplained (idiopathic) infertility, and 50 healthy norm-ovulatory women of the same age who had conceived and delivered naturally. Results: The sensitivity and specificity of the test for detecting periodontitis was 84% and 72% in the group of infertile patients, 88% and 68% in the group of fertile patients and 86% and 70% in the overall patient population. Infertile patients with periodontitis had less advanced periodontitis than the control group although this difference was not statistically significant. Blood inflammatory markers were significantly higher in infertile than in fertile women. Conclusion: This study has shown that infertile patients had better periodontal status and less advanced periodontitis than fertile women of the same age. Therefore, when interpreting the results of aMMP-8 tests for diagnosis of periodontitis, one should keep in mind the periodontal status of the examined population., Uvod: Literaturni podatci upućuju na to da neplodne pacijentice imaju lošiji parodontni status, što može biti uzrok komplikacijama tijekom začeća. Cilj ove studije bio je validacija aMMP-8 point-of-ca-re testa iz ispirka usne šupljine u populaciji žena s neobjašnjivom neplodnošću u usporedbi s plodnim ženama odgovarajuće dobi s parodontitisom i bez njega. Nadalje, analizirani su upalni parametri uzorkovane krvi i uspoređeni između dviju skupina. Pretpostavljali smo da će neplodne žene imati lošiji parodontni status i veći broj pozitivnih testova aMMP-8 u usporedbi s plodnima te da će im biti povišeni upalni parametri iz krvi. Materijal i metode: U istraživanje je bilo uključeno 50 zdravih žena s urednim ovulacijskim ciklusima u dobi od 25 do 45 godina i strogo definiranom neobjašnjivom (idiopatskom) neplodnošću i 50 zdravih žena iste dobi s urednim ovulacijskim ciklusima koje su zatrudnjele i rodile prirodnim putem. Rezultati: Osjetljivost i specifičnost testa za otkrivanje parodontitisa iznosila je 84 i 72 % u skupini neplodnih pacijentica, 88 i 68 % u skupini plodnih te 86 i 70 % u ukupnoj populaciji pacijentica. Neplodne pacijentice s parodontitisom imale su manje uznapredovali parodontitis od kontrolne skupine, iako ta razlika statistički nije bila značajna. Upalni parametri u krvi bili su značajno viši u neplodnih žena nego u plodnih. Zaključak: Ovo istraživanje pokazalo je da su neplodne žene imale bolji parodontni status i manje uznapredovali parodontitis od plodnih žena iste dobi. Dakle, pri tumačenju rezultata dobivenih testovima aMMP-8 za dijagnostiku parodontitisa treba imati na umu parodontni status ispitivane populacije.

Post-traumatic stress disorder (PTSD) is a trauma-related disorder. Platelet monoamine oxidase (MAO-B) is a peripheral biomarker associated with various symptoms in different psychopathologies, but its role in PTSD or different symptoms in PTSD is not clear. This study elucidated the association between platelet MAO-B activity and clinical symptoms occurring in PTSD. Platelet MAO-B activity was determined in 1053 male Caucasian subjects: 559 war veterans with PTSD (DSM-5 criteria), 62 combat exposed veterans who did not develop PTSD, and 432 non-combat exposed healthy controls. Clinical symptoms in PTSD were determined using CAPS and PANSS. Platelet MAO-B activity, controlled for the effect of smoking, was significantly increased in PTSD with severe versus mild and moderate traumatic symptoms, and was significantly decreased in PTSD subjects with severe versus mild positive, psychotic, and depressive symptoms. This finding was further confirmed with reduced platelet MAO-B activity in PTSD veterans with severe versus mild individual items of the PANSS-depressed, PANSS-psychotic, and PANSS-positive subscales. Altered platelet MAO-B activity, controlled for the possible confounders, was associated with the development and severity of different symptoms occurring in PTSD. These findings confirmed the role of platelet MAO-B activity as a peripheral marker of various psychopathological symptoms.

Background This study evaluated the prevalence ofspreading pathways in nontuberculous mycobacteria(NTM) pulmonary infections according to nodulardistribution patterns seen on chest computed tomog-raphy (CT). Methods This study included 63 patients diagnosedwith NTM lung infections who underwent CT at ourinstitution. A retrospective analysis of CT images fo-cused on the presence and distribution of nodules, presence of intrathoracic lymphadenopathy and thepredominant side of infection in the lungs. The find-ings were classified into five groups ; centrilobular(bronchogenic spread), perilymphatic (lymphangiticspread), random (hematogenous spread), combinedpattern and no nodules present. The groups werethen compared according to other CT findings. Results Among 51 (81%) patients identified with anodular pattern on chest CT, 25 (39.8%) presentedwith centrilobular, 7 (11.1%) with perilymphatic, 6(9.5%) with random and 13 (20.6%) with combinednodular patterns but located in different areas of thelungs. The right side of the lungs was predominantin 38 cases (60.3%). Intrathoracic lymphadenopa-thy was evident in 20 patients (31.7%). Significantdifferences in distributions of nodular patterns wereseen in patients infected withMycoplasma aviumcomplex(MAC) associated with centrilobular pat-tern (p= 0.0019) andM. fortuitumassociated withrandom pattern (p= 0.0004). Some of the findingswere related to perilymphatic nodules between otherisolated species of NTM (p= 0.0379). Conclusion The results of this study showed a highproportion of perilymphatic nodules and right-sidedpredominance in the upper lobe, which, combinedwith intrathoracic lymphadenopathy is highly sugges-tive of the lymphangitic spread of lung NTM infec-tions.

Background High energy electron linear accelerators (LINACs) producing photon beams with energies higher than 10 MeV are widely used in radiation therapy. In these beams, fast neutrons are generated, which results in undesired contamination of the therapeutic beam. In this study, measurements and Monte Carlo (MC) simulations were used to obtain neutron spectra and dose equivalents in vicinity of linear accelerator. Materials and methods LINAC Siemens Oncor Expression in Osijek University Hospital is placed in vault that was previously used for 60Co machine. Then, the shielding of the vault was enhanced using lead and steel plates. Measurements of neutron dose equivalent around LINAC and the vault were done using CR-39 solid state nuclear track detectors. To compensate energy dependence of detectors, neutron energy spectra was calculated in measuring positions using MC simulations. Results The vault is a source of photoneutrons, but a vast majority of neutrons originates from accelerator head. Neutron spectra obtained from MC simulations show significant changes between the measuring positions. Annual neutron dose equivalent per year was estimated to be less than 324 μSv in the measuring points outside of the vault. Conclusions Since detectors used in this paper are very dependent on neutron energy, it is extremely important to know the neutron spectra in measuring points. Though, patient dosimetry should include neutrons, estimated annual neutron doses outside the vault were far below exposure limit of ionizing radiation for workers.

PURPOSE: To monitor the changes in the ABCD grading system during a one-year follow-up after a corneal cross-linking (CXL) procedure. METHODS: This prospective study included 30 eyes of 25 patients with keratoconus, who received the CXL treatment. The patients with a history of ocular trauma or surgery and other corneal pathology were excluded from the study. The patients were examined at the baseline visit and followed up at 3, 6, and 12 months after the CXL. All the patients underwent a standard CXL procedure with visual acuity and Scheimpflug tomography testing at each visit. The corneal parameters and ABCD grading were monitored throughout the follow-up period. RESULTS: There were no significant changes of parameter A and anterior radius curvature (ARC) in the ABCD grading system. Parameters B and D showed progression postoperatively, with an improvement of parameter D on the final visit. Parameter C showed a statistically significant increase at all three post-CXL visits, but a constant gradual decrease in the value over time. CONCLUSION: The ABCD grading system can be very useful in monitoring the progression of keratoconus (KC), but it can also help in monitoring the efficacy of corneal cross-linking. The anterior surface parameters in the ABCD grading system did not show progression in the post-CXL period, and parameters C and D showed improvement and stability a year after the procedure.

Background and objectives: This study aimed to evaluate prognostic factors for post-recurrence survival in local and locally advanced colorectal cancer patients. Materials and Methods: A total of 273 patients with stage III and high-risk stage II colorectal cancer were prospectively enrolled. All patients underwent operative treatment of the primary tumor and adjuvant fluorouracil-based chemotherapy. Results: Over the three-year period (2008–2010), a cohort of 273 patients with stage III and high-risk stage II colorectal cancer had been screened. During follow up, 105 (38.5%) patients had disease recurrence. Survival rates 1-, 3- and 5-year after recurrence were 53.9, 18.2 and 6.5%, respectively, and the median post-recurrence survival time was 13 months. Survival analysis showed that age at diagnosis (p &lt, 0.01), gender (p &lt, 0.05), elevated postoperative Ca19-9 (p &lt, 0.01), tumor histology (adenocarcinoma vs. mucinous vs. signet ring tumors, p &lt, 0.01) and tumor stage (II vs. III, p &lt, 0.05) had a significant influence on post-recurrence survival. Recurrence interval and metastatic site were not related to survival following recurrence. Multivariate analysis showed that older age (HR 2.43), mucinous tumors (HR 1.51) and tumors expressing Ca19-9 at baseline (HR 3.51) were independently associated with survival following recurrence. Conclusions: Baseline patient and tumor characteristics largely predicted patient outcomes after disease recurrence. Recurrence intervals in local and locally advanced colorectal cancer were not found to be prognostic factors for post-recurrence survival. Older age, male gender, stage III and mucinous histology were poor prognostic factors after the disease had recurred. Stage II patients had remarkable post-recurrence survival compared to stage III patients.

Simple Summary The process of HPV-mediated oncogenesis in HNSCCs is not fully understood. DLG1 and SCRIB protein expression levels and localization changes were evaluated in a number of HPV16-positive and HPV-negative OPSCCs and seem to be associated with malignant transformation. Moreover, loss of SCRIB expression inversely correlates with higher grade tumors, and this is much more evident in the presence of HPV16 E6. This could serve as a potential marker in predicting development of OPSCCs. Abstract The major causative agents of head and neck squamous cell carcinomas (HNSCCs) are either environmental factors, such as tobacco and alcohol consumption, or infection with oncogenic human papillomaviruses (HPVs). An important aspect of HPV-induced oncogenesis is the targeting by the E6 oncoprotein of PDZ domain-containing substrates for proteasomal destruction. Tumor suppressors DLG1 and SCRIB are two of the principal PDZ domain-containing E6 targets. Both have been shown to play critical roles in the regulation of cell growth and polarity and in maintaining the structural integrity of the epithelia. We investigated how modifications in the cellular localization and protein expression of DLG1 and SCRIB in HPV16-positive and HPV-negative histologic oropharyngeal squamous cell carcinomas (OPSCC) might reflect disease progression. HPV presence was determined by p16 staining and HPV genotyping. Whilst DLG1 expression levels did not differ markedly between HPV-negative and HPV16-positive OPSCCs, it appeared to be relocated from cell–cell contacts to the cytoplasm in most samples, regardless of HPV16 positivity. This indicates that alterations in DLG1 distribution could contribute to malignant progression in OPSCCs. Interestingly, SCRIB was also relocated from cell–cell contacts to the cytoplasm in the tumor samples in comparison with normal tissue, regardless of HPV16 status, but in addition there was an obvious reduction in SCRIB expression in higher grade tumors. Strikingly, loss of SCRIB was even more pronounced in HPV16-positive OPSCCs. These alterations in SCRIB levels may contribute to transformation and loss of tissue architecture in the process of carcinogenesis and could potentially serve as markers in the development of OPSCCs.

In recent years, interest in natural products such as alternative sources of pharmaceuticals for numerous chronic diseases, including tumors, has been renewed. Propolis, a natural product collected by honeybees, and polyphenolic/flavonoid propolis-related components modulate all steps of the cancer progression process. Anticancer activity of propolis and its compounds relies on various mechanisms: cell-cycle arrest and attenuation of cancer cells proliferation, reduction in the number of cancer stem cells, induction of apoptosis, modulation of oncogene signaling pathways, inhibition of matrix metalloproteinases, prevention of metastasis, anti-angiogenesis, anti-inflammatory effects accompanied by the modulation of the tumor microenvironment (by modifying macrophage activation and polarization), epigenetic regulation, antiviral and bactericidal activities, modulation of gut microbiota, and attenuation of chemotherapy-induced deleterious side effects. Ingredients from propolis also ”sensitize“ cancer cells to chemotherapeutic agents, likely by blocking the activation of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). In this review, we summarize the current knowledge related to the the effects of flavonoids and other polyphenolic compounds from propolis on tumor growth and metastasizing ability, and discuss possible molecular and cellular mechanisms involved in the modulation of inflammatory pathways and cellular processes that affect survival, proliferation, invasion, angiogenesis, and metastasis of the tumor.

Posttraumatic stress disorder (PTSD) is frequently associated with cognitive disturbances and high prevalence of smoking. This study evaluated cognition in war veterans with PTSD and control subjects, controlled for the effect of smoking and brain derived neurotrophic factor (BDNF) rs6265 and rs56164415 genotypes/alleles. Study included 643 male war veterans with combat related PTSD and 120 healthy controls. Genotyping was done by real time PCR. Cognitive disturbances were evaluated using the Positive and Negative Syndrome Scale (PANSS) cognition subscale and the Rey-Osterrieth Complex Figure (ROCF) test scores. Diagnosis (p &lt, 0.001), BDNF rs56164415 (p = 0.011) and smoking (p = 0.028) were significant predictors of the cognitive decline in subjects with PTSD. BDNF rs56164415 T alleles were more frequently found in subjects with PTSD, smokers and non-smokers, with impaired cognition, i.e., with the higher PANSS cognition subscale scores and with the lower ROCF immediate recall test scores. Presence of one or two BDNF rs56164415 T alleles was related to cognitive decline in PTSD. The T allele carriers with PTSD had advanced cognitive deterioration in smokers and nonsmokers with PTSD, and worse short-term visual memory function. Our findings emphasize the role of the BDNF rs56164415 T allele and smoking in cognitive dysfunction in war veterans with PTSD.

There is a lot of evidence showing that lipid peroxidation plays very important role in development of various diseases, including neurodegenerative diseases and brain tumors. Lipid peroxidation is achieved by two main pathways, by enzymatic or by non-enzymatic oxidation, respectively. In this paper, we focus on non-enzymatic, self-catalyzed chain reaction of poly-unsaturated fatty acid (PUFA) peroxidation generating reactive aldehydes, notably 4-hydroxynonenal (4-HNE), which acts as second messenger of free radicals and as growth regulating factor. It might originate from astrocytes as well as from blood vessels, even within the blood-brain barrier (BBB), which is in case of brain tumors transformed into the blood-brain-tumor barrier (BBTB). The functionality of the BBB is strongly affected by 4-HNE because it forms relatively stable protein adducts thus allowing the persistence and the spread of lipid peroxidation, as revealed by immunohistochemical findings. Because 4-HNE can act as a regulator of vital functions of normal and of malignant cells acting in the cell type- and concentration-dependent manners, the bioactivities of this product of lipid peroxidation be should further studied to reveal if it acts as a co-factor of carcinogenesis or as natural factor of defense against primary brain tumors and metastatic cancer.

Infertility is one of the major medical problems nowadays. Couples who opt for In Vitro Fertilization (IVF) face a great deal of stress which certainly affects the outcome of the procedure. Therefore, we aimed to reduce the stress during the oocyte retrieval procedure by applying midazolam. Total oxidant (TOC) and antioxidant (TAC) capacities of serum, as well as glutathione (GSH) content and catalase activity, were measured in both control and midazolam groups. Follicular fluid was also tested for oxidant capacity and IL1β. Results implied that the midazolam group increased TAC at the end of the procedure. At the same time, the control group decreased GSH at the beginning of the procedure, and both groups decreased catalase activity at the end of the procedure. The results imply that stress during the procedure affects oxidative and antioxidative parameters of the patients, but did not affect the frequency of the pregnancy at the end of this pilot study. Yet, the results imply that oxidative and antioxidative mechanisms during IVF should be investigated in detail as they could affect the outcome of IVF.

Objective Сhronic rhinosinusitis with nasal polyps (CRSwNPs) is a distinct entity within the chronic rhinosinusitis group of diseases, which are chronic upper airway diseases with several pheno- and endotypes. Oxidative stress plays an important role in the pathogenesis of CRSwNPs. The aim was to assess the association between expression of the aryl hydrocarbon receptor (AhR) and 4-hydroxynonenal (4-HNE) in patients with CRSwNPs. Methods The study included 26 patients who underwent endoscopic sinus surgery: Fourteen patients with CRSwNPs, and 12 controls with healthy sinus mucosa. Expression of AhR and 4-HNE was assessed in tissue samples using immunohistochemistry. The level of 4-HNE in serum samples was measured using the ELISA assay. Total oxidative capacity (TOC) was assessed by measuring the peroxidase activity. Results Higher levels of 4-HNE expression were observed in tissues (3, range 1–3 vs. 0, range 0–0 p2O2 eq., p = 0.848). Patients with bronchial asthma (57%) had abundant eosinophil in tissue samples. Patients with recalcitrant CRSwNPs had higher 4-HNE serum levels, compared to non-recalcitrant cases (27.3 vs 24.2 pmol/mg, p = 0.339). Conclusion Patients suffering from CRSwNPs have oxidative stress–mediated overexpression of AhR, which is linked to a chronic inflammatory response in the paranasal sinus tissues.

Obsessive-compulsive disorder (OCD) was considered one of the less common mental disorders, but in fact about 2-3% of people in the population have obsessive-compulsive disorder. OCD belongs to the group of anxiety disorders, and is characterized by the appearance of obsessive thoughts and compulsive actions. People who suffer from this disorder understand the irrationality of their actions and find them uncomfortable, but cannot prevent them. Consequently, all aspects of life can be affected (work, school, interpersonal relationships), and many activities limited. The changes in daily routines caused by the pandemic cause's anxiety in everyone, it can be especially disturbing for people who suffer from mental disorders. Social structures and relationships are components of mental and physical health, and their sudden disappearance is especially difficult for those who use them to maintain balance in the fight against mental difficulties. An additional problem is the fear of many unknowns and an uncertain future. In this paper we aim to present the main characteristics of OCD and also changes in the way it is observed during the pandemic of corona virus.

Introduction: in rheumatoid arthritis, inflammation and damage lead to functional impairment. as the hand is a typical site of involvement, lower grip strength is often found in patients with rheumatoid arthritis. in these patients it is necessary to evaluate the hand grip impairment in a more detailed way. The aim of this study was to analyze a new method for measuring hand grip. Methods: an expert electronic measuring system for obtaining dynamic time series of hand grip force was developed. We tested it in a sample of 24 participants, 12 patients with rheumatoid arthritis and 12 age- and sex-matched healthy controls. The main dynamometric parameters obtained were: maximum grip force, fatigue, grip velocity, and functional potential. These were measured at the baseline and at 60, 120, and 180 days. Results: compared to the control group, at baseline the patients with rheumatoid arthritis had a significantly lower maximum grip force (68.2 vs. 97.3), earlier occurrence of fatigue (22.4 vs. 24.9), as well as lower grip velocity (14.8 vs. 22.2) and functional potential (808.2 vs. 1876.3). a significant improvement in all measured variables was observed during the follow-up period. Conclusion: in our pilot study we tested a newly developed electrodynamometer measuring system and found that it can provide an objective and detailed description of the hand condition. This system has the potential to be used as a relevant indicator of hand function in patients with rheumatoid arthritis as well as to help tailor their rehabilitation.

The aim of this review is to provide a brief overview of some current approaches regarding diagnostics, pathologic features, treatment, and genetics of prostate carcinoma (PCa). Prostate carcinoma is the most common visceral tumor and the second most common cancer-related cause of death in males. Clinical outcomes for patients with localized prostate cancer are excellent, but despite advances in prostate cancer treatments, castrate-resistant prostate cancer and metastatic prostate cancer patients have a poor prognosis. Advanced large-scale genomic studies revealed a large number of genetic alterations in prostate cancer. The meaning of these alterations needs to be validated in the specific prostate cancer molecular subtype context. Along these lines, there is a critical need for establishing genetically engineered mouse models, which would include speckle type BTB/POZ protein and isocitrate Dehydrogenase (NADP (+)) 1 mutant, as well as androgen receptor neuroendocrine subtypes of prostate cancer. Another urgent need is developing highly metastatic prostate cancer models, as only up to 17% of available models dis- play bone metastases and exhibit a less typical neuroendocrine prostate cancer or sarcomatoid carcinoma. Moreover, androgen deprivation and relapse should be mimicked in the genetically engineered mouse models, as androgen independence may yield a better model for metastatic castrate-resistant prostate cancer. The development of such refined animal models should be guid- ed by comparative genomics of primary versus corresponding metastatic tumors. Such an approach will have the potential to illuminate the key genetic events associated with specific molecular prostate cancer subsets and indicate directions for effective therapy.Conclusion. Despite excellent results in the treatment of localized prostatic carcinoma, castrate-resistant prostate can- cer and metastatic prostate cancer have a poor prognosis. Advanced large-scale genomic studies revealed a large number of ge- netic alterations in PCa. Experimental models of prostate carcinoma in genetically modified mice could provide new data about the genetic changes in such cancers and help in developing better animal models for treatment resistant prostate carcinomas.

Negative symptoms of schizophrenia, including anhedonia, represent a heavy burden on patients and their relatives. These symptoms are associated with cortical hypodopamynergia and impaired striatal dopamine release in response to reward stimuli. Catechol-O-methyltransferase (COMT) and monoamine oxidase type B (MAO-B) degrade dopamine and affect its neurotransmission. The study determined the association between COMT rs4680 and rs4818, MAO-B rs1799836 and rs6651806 polymorphisms, the severity of negative symptoms, and physical and social anhedonia in schizophrenia. Sex-dependent associations were detected in a research sample of 302 patients with schizophrenia. In female patients with schizophrenia, the presence of the G allele or GG genotype of COMT rs4680 and rs4818, as well as GG haplotype rs4818-rs4680, which were all related to higher COMT activity, was associated with an increase in several dimensions of negative symptoms and anhedonia. In male patients with schizophrenia, carriers of the MAO-B rs1799836 A allele, presumably associated with higher MAO-B activity, had a higher severity of alogia, while carriers of the A allele of the MAO-B rs6651806 had a higher severity of negative symptoms. These findings suggest that higher dopamine degradation, associated with COMT and MAO-B genetic variants, is associated with a sex-specific increase in the severity of negative symptoms in schizophrenia patients.

Prognostic, diagnostic or predictive biomarkers are urgently needed for assessment of chronic graft-versus-host disease (cGvHD), a major risk for patients undergoing allogeneic hematopoietic stem cell transplantation. The main goal of this review generated within the COST Action EUROGRAFT “Integrated European Network on Chronic Graft Versus Host Disease” was to identify potential novel biomarkers for cGvHD besides the widely accepted molecular and cellular biomarkers. Thus, the focus was on cellular biomarkers, alloantibodies, glycomics, endothelial derived particles, extracellular vesicles, microbiome, epigenetic and neurologic changes in cGvHD patients. Both host-reactive antibodies in general, and particularly alloantibodies have been associated with cGvHD and require further consideration. Glycans attached to IgG modulate its activity and represent a promising predictive and/or stratification biomarker for cGVHD. Furthermore, epigenetic changes such as microRNAs and DNA methylation represent potential biomarkers for monitoring cGvHD patients and novel targets for developing new treatment approaches. Finally, the microbiome likely affects the pathophysiology of cGvHD; bacterial strains as well as microbial metabolites could display potential biomarkers for dysbiosis and risk for the development of cGvHD. In summary, although there are no validated biomarkers currently available for clinical use to better inform on the diagnosis, prognosis or prediction of outcome for cGvHD, many novel sources of potential markers have shown promise and warrant further investigation using well characterized, multi-center patient cohorts.

A recent comparison of clinical and inflammatory parameters, together with biomarkers of oxidative stress, in patients who died from aggressive COVID-19 and survivors suggested that the lipid peroxidation product 4-hydroxynonenal (4-HNE) might be detrimental in lethal SARS-CoV-2 infection. The current study further explores the involvement of inflammatory cells, systemic vascular stress, and 4-HNE in lethal COVID-19 using specific immunohistochemical analyses of the inflammatory cells within the vital organs obtained by autopsy of nine patients who died from aggressive SAR-CoV-2 infection. Besides 4-HNE, myeloperoxidase (MPO) and mitochondrial superoxide dismutase (SOD2) were analyzed alongside standard leukocyte biomarkers (CDs). All the immunohistochemical slides were simultaneously prepared for each analyzed biomarker. The results revealed abundant 4-HNE in the vital organs, but the primary origin of 4-HNE was sepsis-like vascular stress, not an oxidative burst of the inflammatory cells. In particular, inflammatory cells were often negative for 4-HNE, while blood vessels were always very strongly immunopositive, as was edematous tissue even in the absence of inflammatory cells. The most affected organs were the lungs with diffuse alveolar damage and the brain with edema and reactive astrocytes, whereas despite acute tubular necrosis, 4-HNE was not abundant in the kidneys, which had prominent SOD2. Although SOD2 in most cases gave strong immunohistochemical positivity similar to 4-HNE, unlike 4-HNE, it was always limited to the cells, as was MPO. Due to their differential expressions in blood vessels, inflammatory cells, and the kidneys, we think that SOD2 could, together with 4-HNE, be a potential link between a malfunctioning immune system, oxidative stress, and vascular stress in lethal COVID-19.

Rak dojke je maligna bolest u žena koja predstavlja značajan javno-zdravstveni i klinički problem. Sama dijagnoza raka dojke započinje anamnezom i kliničkim pregledom. Kod dijagnostike je važno naglasiti važnost samopregleda koji žena provodi, a koji ima ključno značenje u ranom otkriću bolesti. Dijagnostika se obavlja putem mamografije, ultrazvučnog pregleda, magnetske rezonancije biopsije i dr. Po saznanju raka dojke, kreće se s liječenjem. Samo liječenje iziskuje puno napora kod pacijentice zbog operativnog zahvata, zračenja, kemoterapije, hormonske terapije te imunoterapije. Liječenje se započinje nakon biopsije. Najvažniji kriterij prognoze je svakako zahvaćenost limfnih čvorova. Što je veći broj zahvaćenih limfnih čvorova metastazama prognoza je lošija. Važnost zdravstvene njege kod pacijentice oboljele od karcinoma dojke stoga je neupitna, a uloga prvostupnice sestrinstva je pravovremeno uočavanje potreba i promjena zdravstvenog stanja pacijentice, fizička i psihološka podrška te sukladno time izrada plana zdravstvene njege. Cilj ovog završnog rada je kroz prikaz slučaja jedne pacijentice izraditi i analizirati sestrinske dijagnoze i pripadajuće intervencije kod osoba oboljelih od maligne bolesti dojke. Breast cancer is a malignant disease in women that represents a significant public health and clinical problem. The diagnosis of breast cancer itself begins with a history and clinical examination. When diagnosing, it is important to emphasize the examination that the woman does herself, which is of central importance in the early detection of the disease. Diagnosis is performed through mammography, ultrasound examination, magnetic resonance biopsy, etc. Upon learning of breast cancer, he moves on to treatment. The treatment itself requires a lot of effort in the patient from surgery, radiation, chemotherapy, hormone therapy, and immunotherapy. Treatment is started after the biopsy. The most important prognostic criterion is certainly lymph node involvement. The higher the number of lymph node metastases affected, the worse the prognosis. The health care of a patient with breast cancer is unquestionable, so health professionals, nurses-technicians have a big role in all this. The nurse-technician observes and recognizes the nurse's diagnoses, and accordingly works out a health care plan. The role of the nurse-technician is to create an intervention plan through the patient's diagnoses. The purpose of this paper is to analyze and explain nursing diagnoses and interventions in diagnostic and therapeutic procedures in persons with breast malignancy.

Febrilne konvulzije najčešći su neuropedijatrijski problem, a pojavljuju se između tri mjeseca i 5 godina života te se povezuju s febrilitetom, no ne mogu se dokazati intrakranijalna infekcija ili točan uzrok napadaja. Rad prikazuje istraživanje, u koje je uključeno 108 pacijenata s postavljenom dijagnozom febrilnih konvulzija, a hospitaliziranih na Odjelu za pedijatriju, u Jedinici veće djece i dojenčadi u trogodišnjem razdoblju (1. siječnja 2016. – 31. prosinca 2018.). Cilj istraživanja bio je prikazati značajke febrilnih konvulzija kod ispitanika te ih usporediti sa spoznajama iz literature. Deskriptivnom statističkom analizom dobiveni su sljedeći rezultati: najčešće se konvulzije pojavljuju kod muške djece, u dobi od 1 do 2 godine te pri temperaturi od 38,0-38,9°C. U najvećem su postotku FK jednostavne i događaju se prvi put te se rijetko ponavljaju. Uzroci su febrilnih konvulzija obično infekcije gornjih dišnih puteva te gastroenterokolitis. Trajanje bolničkog liječenja obično je 3,0±1,3 dana, a troškovi boravka na Odjelu u prosjeku iznose 3675,00 kuna za jedno dijete. Febrile seizures are the most common neuropediatric problem, usually occurring between three months and five years of age and associated with fever but without evidence of intracranial infection or defined cause. This retrospective study included 108 patients diagnosed with febrile seizures and hospitalized at the Department of Pediatrics in the three-year-period (January 1st 2016 - December 31st. 2018). The aim of the study was to present the characteristics of febrile seizures in our hospitalized patients and to compare them with similar studies found in the literature. Descriptive statistical analysis results were obtained - seizures occur mostly in male children, aged 1 to 2 years and at a temperature of 38.0-38.9° C. They are mostly simple, they mostly happen once and are rarely repeated. The causes of febrile seizures are usually upper respiratory tract infections and gastroenterocolitis. The duration of hospital treatment was usually 3.0 ± 1.3 days, and the cost of hospital stay was approximately 3675,00 Croatian kunas/child.

Background: Chronic Graft-versus-Host disease (cGvHD) is the leading cause of late non- relapse morbidity and mortality following allogeneic hematopoietic stem cell transplantation (alloHSCT). Metabolic bone disease is frequently seen after alloHSCT and is related to vitamin D deficiency and to GvHD – especially corticosteroids therapy and gastrointestinal (GIT) involvement. Elevated parathyroid hormone levels (PTH>6 pmol/L) were noticed alongside vitamin D deficiency presumably causing excessive bone resorption. However, high PTH level could be also a marker of systemic inflammation in cGvHD. In this study we investigated an association of cGvHD and vitamin D with PTH levels among long-term alloHSCT survivors. Methods: Data were collected on a prospective cross-sectional study protocol in patients who underwent alloHSCT and were evaluated by the institutional multidisciplinary cGvHD team from 6/2013 to 11/2019. Laboratory tests and detailed history were obtained, and patients with cGvHD were evaluated according to NIH 2005 criteria. Exclusion criteria were active acute GvHD, and for non-cGvHD group of patients also ongoing immunosuppressive treatment. Results: Study population consisted of 89 alloHSCT survivors (46% female), median age 48 (11-72) years, median of 672 (77-9478) days after alloHSCT. 62 (69.7%) had cGvHD and were evaluated at median of 376 (0-8869) days after the diagnosis was established. Majority of cGvHD patients had severe (38.7%) or moderate (38.7%) NIH global score, 41.9% had active cGvHD by clinician impression, and 58.1% were receiving systemic immunosuppression (41.6% of them corticosteroids). Median number of organs involved by cGvHD was 3, and most frequently involved organs were skin (58.0%), eyes (53.2%), and mouth (51.6%). GIT was involved in 11.3% of the patients. There was significantly more patients with history of acute GvHD (p

Environments polluted with excessively high levels of antibiotics released from manufacturing sites can act as a source of transferable antibiotic resistance (AR) genes to human commensal and pathogenic bacteria. The aim of this study was to evaluate AR of bacteria isolated from the Sava river sediments (Croatia) at the discharge site of effluents from azithromycin production compared to those from the upstream site and isolates collected in Croatian hospitals. A total of 228 environmental strains of azithromycin-resistant bacteria were isolated and identified, with 124 from the discharge site and 104 from the upstream site. In addition, a total of 90 clinical, azithromycin-resistant streptococcal and staphylococcal isolates obtained from the Croatian Reference Center for Antibiotic Resistance Surveillance were analyzed. PCR screening of isolates on 11 relevant macrolide- resistance genes (MRGs) showed that discharge isolates had greater detection frequencies for 4 gene targets (ermB, msrE, mphE and ermF) compared to upstream isolates. Among clinical isolates, the most frequently detected gene was ermB, followed by msrD, mefE and mefC. The discharge site demonstrated a greater abundance of isolates with co-occurrence of two different MRGs (predominantly msrE-mphE) than the upstream site, but a lower abundance than the clinical sources (most commonly msrD-mefE). The simultaneous presence of three or even four MRGs was specific for the discharge and clinical isolates, but not for the upstream isolates. When MRG results were sorted by gene mechanism, the ribosomal methylation (erm) and protection genes (msr) were the most frequently detected among both the discharge and the clinical isolates. Following sequencing, high nucleotide sequence similarity was observed between ermB in the discharge isolates and the clinical streptococcal isolates, suggesting a possible transfer of the ermB gene between bacteria of clinical and environmental origin. Our study highlights the importance of environmental bacterial populations as reservoirs for clinically relevant macrolide- resistance genes.

Thymus regenerative therapy implementation is severely obstructed by the limited number and expansion capacity in vitro of tissue-specific thymic epithelial stem cells (TESC). Current solutions are mostly based on growth factors that can drive differentiation of pluripotent stem cells toward tissue-specific TESC. Target-specific small chemical compounds represent an alternative solution that could induce and support the clonal expansion of TESC and reversibly block their differentiation into mature cells. These compounds could be used both in the composition of culture media designed for TESC expansion in vitro, and in drugs development for thymic regeneration in vivo. It should allow reaching the ultimate objective - autologous thymic tissue regeneration in paediatric patients who had their thymus removed in the course of cardiac surgery.

Antipsychotic drugs target primarily dopaminergic system which makes catechol-O-methyltransferase (COMT) an interesting target in studies searching for treatment response predictors in schizophrenia. The study assessed the association of the COMT rs4680 and rs4818 polymorphisms with therapeutic response to olanzapine, risperidone, clozapine or other antipsychotic medication after 8 weeks of monotherapy in patients with schizophrenia. 521 Caucasian patients with schizophrenia received a monotherapy with olanzapine (10–20 mg/day; N = 190), risperidone (3–6 mg/day; N = 99), or clozapine (100–500 mg/day; N = 102). The fourth group (N = 130) consisted of patients receiving haloperidol (3–15 mg/day), fluphenazine (4–25 mg/day) or quetiapine (50–800 mg/day). Treatment response was defined as a 50% reduction from the baseline positive and negative syndrome scale (PANSS) total and subscale scores, but also as an observed percentage reduction from the initial PANSS0–6 total and subscale scores. Carriers of the COMT rs4680 A allele and carriers of the COMT rs4680–rs4818 C-A haplotype block had greater reduction in the PANSS total scores following olanzapine treatment, compared to carriers of the COMT rs4680 GG genotype and other COMT rs4680–rs4818 haplotypes. The COMT rs4680 A allele, and COMT rs4680–rs4818 C-A haplotype, were significantly associated with therapeutic response in patients treated with olanzapine, but not in patients treated with other antipsychotics.

The role of T regulatory lymphocytes (Treg) particularly in cancer is well known. The goal of the present study was to determine the contribution of these lymphocytes in the regulation of anti-tumor immunity of CBA/HZgr mice against MC-2 fibrosarcoma (4th generation of methylcholanthrene induced tumor). The levels of T lymphocytes (CD4+, CD8+ and CD4+CD25+) were determined 8 and 20 days after tumor transplantation. Further, the role of CD4+CD25+ (Tregs) in tumor-host interaction was evaluated in vitro and in vivo by using specific monoclonal antibodies. We found that splenocytes of both control and Treg depleted tumor bearing mice strongly but differently inhibited growth of tumor cells in vitro. While splenocytes of untreated mice exhibited significant decrease of this activity (from 74.4% to 62.6% and 32.95%), the splenocytes of Treg depleted mice showed increase of this activity (from 79.5% to 84.3% and 86.2%) from day 6 to day 13 and day 21 after tumor grafting, respectively. Further, upon i.v. injecting specific monoclonal anti-Treg antibody tumor immediately prior to tumor cell intracutaneous transplantation, the tumor was rejected after initial growth. In treated mice, the incidence of Treg cells was very low initially, reaching normal values two weeks later. These animals were shown to be resistant to tumor transplantation four months later., Uloga T regulatornih limfocita dobro je poznata, osobito kod tumora. Cilj ovoga istraživanja bio je utvrditi doprinos ovih limfocita u regulaciji antitumorske imunosti CBA/HZgr miševa protiv MC-2 fibrosarkoma (4. generacija metilkolantrenom izazvanog tumora). Razine T limfocita (CD4+, CD8+ and CD4+CD25+) određivale su se 8 i 20 dana nakon transplantacije tumora. Nadalje, uloga CD4+CD25+ T limfocita (Treg) u interakciji tumora i domaćina procijenjena je in vitro i in vivo primjenom specifičnih monoklonskih protutijela. Utvrdili smo da splenociti kako kontrolnih miševa tako i miševa s tumorom bez Treg snažno, ali različito suzbijaju rast tumorskih stanica in vitro. Dok su splenociti netretiranih miševa pokazivali značajno smanjenje ove aktivnosti (sa 74,4% na 62,6% i 32,95%), splenociti miševa bez Treg pokazivali su porast ove aktivnosti (sa 79,5% na 84,3% i 86,2%) od 6. do 13. i 21. dana nakon transplantacije tumora. Uz to, nakon i.v. injektiranja specifičnog monoklonskog anti-Treg tumorskog protutijela neposredno prije intrakutane transplantacije tumorskih stanica, nakon početkog rasta nastupilo je odbacivanje tumora. Kod tretiranih miševa incidencija Treg stanica bila u početku vrlo niska i dostigla je normalne vrijednosti dva tjedna kasnije. Nakon četiri mjeseca pokazalo se da su ove životinje otporne na transplantaciju tumora.

Proinflammatory counterworks are important at different stages of tumor development, particularly during invasion and metastasis. Immune cells and their signal molecules can influence all stages of tumor progression, as well as therapeutic intervention. Proinflammatory cytokines are known triggers of growth in gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). In this study, we explored the immunohistochemical expression of tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), IL-2, and IL-6 in tissues from 43 GEP-NEN patients with tumors of gastric, duodenal, ileal, appendical, and colonic origin. The immunohistochemical expression of TNF-α was increased in tumor groups with high proliferation rates (Ki67; p = 0.034), as well as in those with higher tumor grades (p = 0.05). Moreover, the immunohistochemical expression of TNF-α positively correlated with death outcomes (p = 0.016). Expression of IL-6, IL-1β, and IL-2 displayed similar immunohistochemical expression patterns regardless of Ki67, although the expression between the ILs differed. Most GEP-NENs had high levels of IL-6 and lower levels of IL-1β and IL-2. Although further comprehensive studies are required for a complete understanding of activated mechanisms in proinflammatory protumoral microenvironment of GEP-NENs, TNF-α is a potential marker in the prognosis of those tumors.

International audience; In order to address the recent concerns over a possible increasing in brain tumour mortality among interventional radiologists and cardiologist, this work evaluated the exposure conditions of the operator’s brain during interventional procedures using Monte Carlo simulations with anthropomorphic phantoms. The absorbed doses in several predefined segments of the operator’s brain were estimated in a typical interventional radiology irradiation scenario. The doses were normalized to the KAP values simulated for ten X-ray beam qualities and four projections (PA, RAO 25°, LAO 25° and CRA 25°). For the interventional radiology scenario, because of the position of the operator, no difference was found in the exposure between the left and right regions of the brain for the first operator, while for the second operator standing at a farer distance from the tube, the exposure of the left part of the brain is up to two times higher than that of the right part. The results are in agreement with dose measurements reported in the literature. The conversion factors, obtained as the absorbed dose per KAP, can be used to obtain a first estimate of the exposure of the brain of the operators during interventional procedures

Cilj: Prema prijedlogu Cooke i suradnika (BBMT, 2017) kliničke manifestacije kronične bolesti presatka pro-tiv primatelja (engl. chronic graft versus host disease – cGVHD) mogu se grupirati ovisno o dominantnom fenotipu (infl amatorni i sklerotični) te sukladno tome imaju i distinktne podležeće patofi ziološke procese. Cilj ovog istraživanja jest ispitati odražavaju li laboratorijski pokazatelji infl amacije koje koristimo u svakodnevnoj kliničkoj praksi imunološke procese pojedinog fenotipa.Metode: Pedeset sedam bolesnika (78 uzoraka) liječenih alogeničnom transplantacijom krvotvornih matič- nih stanica (aloTKMS), obrađeno je u Multidisciplinarnom cGVHD timu u KBC Zagreb (4/2017. – 12/2019., HRZZ projekt IP-2016-06- 8046), od kojih je u 46 potvrđen cGVHD, a preostalih 11 su bile kontrole (bolesnici nakon aloTKMS a bez cGVHD-a). Prema kliničkim manifestacijama, bolesnici su razvrstani su u infl amatorni (n=16), sklerotični (n=15) i mješoviti fenotip (n=15) cGVHD-a (prilagođeno prema Cooke i sur., BBMT, 2017). Bolesnici s istovremenim sklerotičnim i infl amatornim manifestacijama su miješovitog fenotipa. Laboratorijska obrada je uključila pokazatelje infl amacije povezane s cGVHD-om (Grković i sur. Leukemia, 2011).Rezultati: U cGVHD skupini je medijan dobi 47 godina, 59% je bilo ženskog spola ; 71% liječeno je zbog AML/MDS/ALL, a 47% bolesnika u trenutku pregleda nije primalo imunosupresivnu terapiju. Nije bilo značajne razlike prema dobi, spolu i imunosupresiji među fenotipskim skupinama cGVHD-a. Ukupni leukociti (p=0, 003), monociti (p=0, 016), neutrofi li (p=0, 007), eozinofi li (p=0, 007) i trombociti (p=0, 018) bili su statistički značajno viši u cGVHD skupini nego u kontrola, dok razlike u navedenim pokazateljima nisu nađene između fenotipskih skupina cGVHD-a. Nije bilo razlike u bazofi lima, limfocitima, albuminu i ukupnim proteinima, komplementu, te sedimentaciji eritrocita između cGVHD skupina kao niti u odnosu na kontrolnu skupinu. Feritin je bio stati-stički značajno snižen u sklerotičnoj skupini (p=0, 005), kao i u odnosu na kontrole, dok je CRP neočekivano bio značajno najniži u infl amatornom obliku cGVHD-a (medijan 2, 1 mg/L vs. miješoviti 4, 9 mg/L i sklerotični 5, 4 mg/L ; kontrola 7, 3 mg/L, p=0, 013). Osjetljivost (78, 3% AUC) i specifi čnost (65, 9% AUC) prema CRP-u su nedo-statne za diskriminaciju cGVHD-a i ne-cGVHD-a, kao i između fenotipskih skupina cGVHD-a.Zaključak: Ispitivani laboratorijski pokazatelji infl amacije u našem istraživanju nisu se pokazali dostatnim za diskriminaciju različitih kliničkih fenotipskih skupina cGVHD-a te su potrebna daljnja istraživanja specifi č-nih biomarkera za pojedini fenotip

Background: Symptomatic remission is an achievable goal in the treatment of schizophrenia. The type of antipsychotic medication and particular genetic variants of the dopaminergic system might be associated with remission. Potential pharmacogenetic markers of the treatment response to antipsychotic medication are missing. This study assessed the possible association between dopamine receptor type 2 (DRD2 rs1800497) and dopamine transporter (DAT1 rs28363170) gene variants with symptomatic remission in schizophrenia. Subjects and methods: Olanzapine (5-20 mg/d) monotherapy was administered for 6 months to 150 male Caucasian subjects with schizophrenia. Remission was evaluated according to "Remission in Schizophrenia Working Group" criteria. Genotyping was performed by PCR- RFLP. Results: Symptomatic remission was found in 31% of patients. DRD2 rs1800497 and DAT1 rs28363170 gene variants were not significantly associated with symptomatic remission. The limitations are a relatively small sample size of patients with schizophrenia (N=150), especially of group with symptomatic remission (N=45). However, the study had moderate but adequate sample sizes for most of the comparisons. Only two dopaminergic polymorphisms were analyzed, and plasma concentration of olanzapine was not determined. Conclusion: These results revealed a lack of association between DRD2 rs1800497 and DAT1 rs28363170 genetic variants and symptomatic remission in male patients treated with olanzapine, suggesting that these genetic variants could not be used to predict symptomatic remission to olanzapine monotherapy. Negative results should be further confirmed or rejected in the larger samples, including haplotype analyses, to detect clinically useful and easy obtainable pharmacogenetic markers that might predict therapeutic response or remission in schizophrenia.

Lung cancer is the leading cause of cancer-related deaths worldwide. Despite growing efforts for its early detection by screening populations at risk, the majority of lung cancer patients are still diagnosed in an advanced stage. The management of lung cancer has dramatically improved in the last decade and is no longer based on the “one-fits-all” paradigm or the general histological classification of non-small cell versus small cell lung cancer. Emerging options of targeted therapies and immunotherapies have shifted the management of lung cancer to a more personalized treatment approach, significantly influencing the clinical course and outcome of the disease. Molecular biomarkers have emerged as valuable tools in the prognosis and prediction of therapy response. In this review, we discuss the relevant biomarkers used in the clinical management of lung tumors, from diagnosis to prognosis. We also discuss promising new biomarkers, focusing on non-small cell lung cancer as the most abundant type of lung cancer.