Search

This paper explores the physiological consequences of decreased expression of GD3 synthase (GD3S), a biosynthetic enzyme that catalyzes the synthesis of b-series gangliosides. GD3S is a key factor in tumorigenesis, with overexpression enhancing tumor growth, proliferation, and metastasis in various cancers. Hence, inhibiting GD3S activity has potential therapeutic effects due to its role in malignancy-associated pathways across different cancer types. GD3S has also been investigated as a promising therapeutic target in treatment of various neurodegenerative disorders. Drugs targeting GD3 and GD3S have been extensively explored and underwent clinical trials, however decreased GD3S expression in mouse models, human subjects, and in vitro studies has demonstrated serious adverse effects. We highlight these negative consequences and show original mass spectrometry imaging (MSI) data indicating that inactivated GD3S can generally negatively affect energy metabolism, regulatory pathways, and mitigation of oxidative stress. The disturbance in several physiological systems induced by GD3S inhibition underscores the vital role of this enzyme in maintaining cellular homeostasis and should be taken into account when GD3S is considered as a therapeutic target.

Silk, traditionally acclaimed as the “queen of fiber,” has been widely used thanks to its brilliant performance such as gentleness, smoothness and comfortableness. Owing to its mechanical characteristics and biocompatibility silk has a definitive role in biomedical applications, both as fibroin and fabric. In this work, the simultaneous dyeing and functionalization of silk fabric with pigments from Streptomyces anulatus BV365 were investigated. This strain produced high amounts of orange extracellular pigments on mannitol-soy flour agar, identified as actinomycin D, C2 and C3. The application of purified actinomycins in the dyeing of multifiber fabric was assessed. Actinomycins exhibited a high affinity towards protein fibers (silk and wool), but washing durability was maintained only with silk. Acidic condition (pH5) and high temperature (65°C) facilitated the silk dyeing. The morphologies and chemical components of the treated silk fabrics were analyzed using scanning electron microscopy and Fourier transform infrared spectroscopy. The results showed the pigments bind to the silk through interaction with the carbonyl group in silk fibroin rendering the functionalized, yet surface that does not cause skin irritation. The treated silk exhibited a remarkable antibacterial effect, while the biocompatibility test performed with 3D-reconstructed human epidermis model indicated safe biological properties, paving the way for future application of this material in medicine.

The aim of this study was to investigate how sociodemographic and health factors contribute cognitive abilities in the older population of the Republic of Serbia, using data from the 2019 national health survey. The study included 3,743 participants, of whom 2,061 (55.1%) were women and 1,682 (44.9%) were men. The median age of all participants was 72 (10) years. Study used logistic regression on cross-sectional data to analyze how education, social support, and healthcare access affect cognitive abilities, while adjusting for demographic variables. The results revealed negative associations between higher levels of education and lower odds of experiencing memory and concentration problems, while recent visits to specialists were positively associated with increased risk for the same. The highest percentage of participants (22.6%) reporting major difficulties in memory and concentration were in the age group of 85–89 years (p

IntroductionLeiomyosarcoma (LMS), together with smooth muscle tumors of uncertain malignant potential (STUMP) and benign leiomyomas, belongs to a heterogeneous group of uterine neoplasms. According to the World Health Organization, tumors originating from uterine smooth muscle fibers are the second most frequent tumors. It is challenging to distinguish between STUMP and LMS because of an overlap of symptoms, lack of a precise definition, and unequivocal information obtained using imaging diagnostic methods. Following myomectomy or hysterectomy with laparoscopic or laparotomy surgery and a definitive histological diagnosis of STUMP, the course of treatment is determined by the need to preserve fertility. In 2014, the U.S. Food and Drug Administration published an alert that unprotected laparoscopic morcellation is correlated with a 3-fold higher likelihood of dissemination of malignant cells and disease progression. Unprotected morcellation was independently associated with a higher risk of disease recurrence after demolition or conservative surgery, with a relative risk of 2.94.ConclusionHematoperitoneum resulting from the spontaneous rupture of a uterine tumor is a rare gynecological emergency, with very few cases reported in the last decade.

BackgroundCorynebacterium, Nocardia, Rhodococcus, Mycobacterium, as well as Gordonia genera belongs to the genus Gordonia, Actinomycetia class. Gordonia bronchialis is a nitrate-reducing, urease-producing, non-motile, force aerobe with a rod-like figure that is known to arrangement into sessile, cord-like groups. This systematic review aimed to establish whether and what invasive infections in humans were caused by Gordonia bronchialis, and to evaluate outcomes of administered antibiotic treatment.MethodsWe have registered this systematic review in PROSPERO database of systematic reviews and meta-analyses with the number CRD42022369974.ResultsA total of 24 publications were included (22 case reports and two case series) with 28 individual cases. The oldest patients had 92 years, and the youngest patients had 13 years. Clinical signs of infection were present in six patients (21%). All isolates were susceptible to ciprofloxacin, imipenem, and amikacin. Vancomycin was the most frequently used antibiotic with nine cases followed by ciprofloxacin, ceftriaxone, and amoxicillin/clavulanic acid.ConclusionAlthough there are no standardized recommendations to date, successful treatment with a favorable outcome has most often been carried out with fluoroquinolones, vancomycin with or without aminoglycosides, as well as carbapenems.

Background: Cardiovascular phantoms for patient education, pre-operative planning, surgical training, haemodynamic simulation, and device testing may help improve patient care. However, currently used materials may have different mechanical properties compared to biological tissue.Methods/Aim: The aim of this study was to investigate the mechanical properties of 3D-printing and silicone materials in comparison to biological cardiovascular tissues. Uniaxial cyclic tension testing was performed using dumbbell samples from porcine tissue (aorta, pulmonary artery, right and left ventricle). Flexible testing materials included 15 silicone (mixtures) and three 3D-printing materials. The modulus of elasticity was calculated for different deformation ranges.Results: The modulus of elasticity (0%–60%) for the aorta ranged from 0.16 to 0.18 N/mm2, for the pulmonary artery from 0.07 to 0.09 N/mm2, and for the right ventricle as well as the left ventricle short-axis from 0.1 to 0.16 N/mm2. For silicones the range of modulus of elasticity was 0.02–1.16 N/mm2, and for the 3D-printed materials from 0.85 to 1.02 N/mm2. The stress-strain curves of all tissues showed a non-linear behaviour in the cyclic tensile testing, with a distinct toe region, followed by exponential strain hardening behaviour towards the peak elongation. The vessel samples showed a more linear behaviour comparted to myocardial samples. The silicones and 3D printing materials exhibited near-linearity at higher strain ranges, with a decrease in stiffness following the initial deformation. All samples showed a deviation between the loading and unloading curves (hysteresis), and a reduction in peak force over the first few cycles (adaptation effect) at constant deformation.Conclusion: The modulus of elasticity of silicone mixtures is more in agreement to porcine cardiovascular tissues than 3D-printed materials. All synthetic materials showed an almost linear behaviour in the mechanical testing compared to the non-linear behaviour of the biological tissues, probably due to fibre recruitment mechanism in the latter.

Spontaneous coronary artery dissection (SCAD), although in the majority of cases presents as an acute coronary syndrome (ACS), has different pathophysiology from atherosclerosis that influences specific angiography findings and enables most patients to be solved by optimal medical therapy rather than percutaneous coronary intervention (PCI). Therefore, accurate diagnosis is essential for adequate treatment of each patient as management of SCAD differs from that of ACS of atherosclerotic aetiology. So far, invasive coronary angiography remains the most important diagnostic tool in suspected SCAD. However, there are ambiguous cases that can mimic SCAD. In this review, the authors summarize current knowledge about the diagnostic algorithms, particularly angiographic features of SCAD, pitfalls of angiography, and the role of intracoronary imaging in the context of SCAD diagnosis. Finally, apart from the pathognomonic angiographic features of SCAD that are thoroughly discussed in this review, the authors focus on obscure angiography findings and findings that can mimic SCAD as well. Differential diagnosis and the timely recognition of SCAD are crucial as there are differences in the acute and long-term management of SCAD and other causes of ACS.

Spontaneous coronary artery dissection (SCAD) is a rare cause of acute coronary syndrome that is often overlooked, misdiagnosed, and maltreated. Medical treatment poses a significant challenge because of the lack of randomized studies to guide treatment. The initial clinical presentation should guide medical and interventional management. Fibrinolytic agents and anticoagulants should be avoided because they could favor hematoma propagation. In patients with SCAD, antiplatelet therapy should be prescribed especially dual antiplatelet therapy (DAPT) consisting of aspirin and clopidogrel, whereas potent P2Y12 inhibitors, e.g., ticagrelor and prasugrel, should be avoided. If a stent was used, DAPT should be continued for 12 months. Aspirin only can be an option for patients without “high-risk” angiographic features—thrombus burden, critical stenosis, and decreased coronary flow. Beta-blocking (BB) agents should be used to prevent recurrence of SCAD. There is a general agreement that angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, mineralocorticoid antagonists, and loop diuretics should be used in patients with SCAD experiencing the symptoms of heart failure and a decrease in left ventricular ejection fraction below 50%. Although without firm evidence, statins can be used in SCAD due to their pleiotropic properties. The results of a randomized trial on the use of BB and statins are awaited. Aggregation of data from national registries might point out truly beneficial medications for patients with SCAD.

We present a case of a 42-year-old man who suffered an iatrogenic injury to his left circumflex (Cx) coronary artery after mitral valve (MV) repair surgery. After the patient suffered from myocardial infarction without ST-segment elevation following minimally invasive MV surgery, we performed repeated coronary angiography and optical coherence tomography (OCT), which revealed severe coronary stenosis of the dominant Cx caused by intramural hematoma. In addition, we proceeded with percutaneous coronary intervention and stent implantation.

Introduction/backgroundCourse evaluation in health education is a common practice yet few comprehensive evaluations of health education exist that measure the impact and outcomes these programs have on developing health graduate capabilities.Aim/objectivesTo explore how curricula contribute to health graduate capabilities and what factors contribute to the development of these capabilities.MethodsUsing contribution analysis evaluation, a six-step iterative process, key stakeholders in the six selected courses were engaged in an iterative theory-driven evaluation. The researchers collectively developed a postulated theory-of-change. Then evidence from existing relevant documents were extracted using documentary analysis. Collated findings were presented to academic staff, industry representatives and graduates, where additional data was sought through focus group discussions - one for each discipline. The focus group data were used to validate the theory-of-change. Data analysis was conducted iteratively, refining the theory of change from one course to the next.ResultsThe complexity in teaching and learning, contributed by human, organizational and curriculum factors was highlighted. Advances in knowledge, skills, attitudes and graduate capabilities are non-linear and integrated into curriculum. Work integrated learning significantly contributes to knowledge consolidation and forming professional identities for health professional courses. Workplace culture and educators’ passion impact on the quality of teaching and learning yet are rarely considered as evidence of impact.DiscussionCapturing the episodic and contextual learning moments is important to describe success and for reflection for improvement. Evidence of impact of elements of courses on future graduate capabilities was limited with the focus of evaluation data on satisfaction.ConclusionContribution analysis has been a useful evaluation method to explore the complexity of the factors in learning and teaching that influence graduate capabilities in health-related courses.

BackgroundPast research indicates a higher prevalence, incidence, and severe clinical manifestations of alpha-synucleinopathies in men, leading to a suggestion of neuroprotective properties of female sex hormones (especially estrogen). The potential pathomechanisms of any such effect on alpha-synucleinopathies, however, are far from understood. With that aim, we undertook to systematically review, and to critically assess, contemporary evidence on sex and gender differences in alpha-synucleinopathies using a bench-to-bedside approach.MethodsIn this systematic review, studies investigating sex and gender differences in alpha-synucleinopathies (Rapid Eye Movement (REM) Behavior Disorder (RBD), Parkinson’s Disease (PD), Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA)) from 2012 to 2022 were identified using electronic database searches of PubMed, Embase and Ovid.ResultsOne hundred sixty-two studies were included; 5 RBD, 6 MSA, 20 DLB and 131 PD studies. Overall, there is conclusive evidence to suggest sex-and gender-specific manifestation in demographics, biomarkers, genetics, clinical features, interventions, and quality of life in alpha-synucleinopathies. Only limited data exists on the effects of distinct sex hormones, with majority of studies concentrating on estrogen and its speculated neuroprotective effects.ConclusionFuture studies disentangling the underlying sex-specific mechanisms of alpha-synucleinopathies are urgently needed in order to enable novel sex-specific therapeutics.

BackgroundThe presence of visual imagery in dreams of congenitally blind people has long been a matter of substantial controversy. We set to systematically review body of published work on the presence and nature of oneiric visuo-spatial impressions in congenitally and early blind subjects across different areas of research, from experimental psychology, functional neuroimaging, sensory substitution, and sleep research.MethodsRelevant studies were identified using the following databases: EMBASE, MEDLINE and PsychINFO.ResultsStudies using diverse imaging techniques and sensory substitution devices broadly suggest that the “blind” occipital cortex may be able to integrate non-visual sensory inputs, and thus possibly also generate visuo-spatial impressions. Visual impressions have also been reported by blind subjects who had near-death or out-of-body experiences.ConclusionDeciphering the mechanistic nature of these visual impression could open new possibility in utilization of neuroplasticity and its potential role for treatment of neurodisability.

BackgroundMyocardial ischemia is caused by epicardial coronary artery stenosis or atherosclerotic disease affecting microcirculation. Trimetazidine (TMZ), promotes glucose oxidation which optimizes cellular energy processes in ischemic conditions. Small studies demonstrated protective effects of TMZ in terms of reducing myocardial injury after percutaneous coronary intervention (PCI), its effect on microcirculation using contemporary investigative methods has not been studied. The aim of the study was to examine effects of trimetazidine, given before elective PCI, on microcirculation using invasively measured index of microcirculatory resistance (IMR).MethodsThis was prospective, single blinded, randomized study performed in a single university hospital. It included consecutive patients with an indication for PCI of a single, de novo, native coronary artery lesion. Patients were randomly assigned to receive either TMZ plus standard therapy (TMZ group) or just standard therapy. Coronary physiology indices fractional flow reserve (FFR), coronary flow reserve (CFR) and index of microcirculatory resistance (IMR) were measured before and after PCI using coronary pressure wire.ResultsWe randomized 71 patients with similar clinical characteristics and risk profile, previous medications and coronary angiograms. Patientshad similar values of Pd/Pa, FFR and CFR prior to PCI procedure. After PCI, FFR values were higher in TMZ group, while IMR values were lower in this group respectively (FFR TMZ + 0.89 ± 0.05 vs. TMZ – 0.85 ± 0.06, p = 0.007; CFR TMZ + 2.1 ± 0.8 vs. TMZ- 2.3 ± 1.3, p = 0.469; IMR TMZ + 18 ± 9 vs. TMZ- 24 ± 12, p = 0.028). In two-way repeated measures ANOVA PCI was associated with change in FFR values (TMZ p = 0.050; PCI p

IntroductionIntracerebroventricularly (icv) injected streptozotocin (STZ) is a widely used model for sporadic Alzheimer’s disease (sAD)-like pathology, marked by oxidative stress-mediated pathological progression. Intermittent theta burst stimulation (iTBS) is a noninvasive technique for brain activity stimulation with the ability to induce long-term potentiation-like plasticity and represents a promising treatment for several neurological diseases, including AD. The present study aims to investigate the effect of the iTBS protocol on the animal model of STZ-induced sAD-like pathology in the context of antioxidant, anti-inflammatory, and anti-amyloidogenic effects in the cortex, striatum, hippocampus, and cerebellum.MethodsMale Wistar rats were divided into four experimental groups: control (icv normal saline solution), STZ (icv STZ—3 mg/kg), STZ + iTBS (STZ rats subjected to iTBS protocol), and STZ + Placebo (STZ animals subjected to placebo iTBS noise artifact). Biochemical assays and immunofluorescence microscopy were used to evaluate functional and structural changes.ResultsThe icv STZ administration induces oxidative stress and attenuates antioxidative capacity in all examined brain regions. iTBS treatment significantly reduced oxidative and nitrosative stress parameters. Also, iTBS decreased Aβ-1-42 and APP levels. The iTBS enhances antioxidative capacity reported as elevated activity of its enzymatic and non-enzymatic components. In addition, iTBS elevated BDNF expression and attenuated STZ-induced astrogliosis confirmed by decreased GFAP+/VIM+/C3+ cell reactivity in the hippocampus.DiscussionOur results provide experimental evidence for the beneficial effects of the applied iTBS protocol in attenuating oxidative stress, increasing antioxidant capacity and decreasing reactive astrogliosis in STZ-administrated rats.

ObjectivesThe study aimed to identify differences and compare anatomical and biomechanical features between elective and ruptured abdominal aortic aneurysms (AAAs).MethodsData (clinical, anatomical, and biomechanical) of 98 patients with AAA, 75 (76.53%) asymptomatic (Group aAAA) and 23 (23.46%) ruptured AAA (Group rAAA), were prospectively collected and analyzed. Anatomical, morphological, and biomechanical imaging markers like peak wall stress (PWS) and rupture risk equivalent diameter (RRED), comorbid conditions, and demographics were compared between the groups. Biomechanical features were assessed by analysis of Digital Imaging and Communication in Medicine images by A4clinics (Vascops), and anatomical features were assessed by 3Surgery (Trimensio). Binary and multiple logistic regression analysis were used and adjusted for confounders. Accuracy was assessed using receiving operative characteristic (ROC) curve analysis.ResultsIn a multivariable model, including gender and age as confounder variables, maximal aneurysm diameter [MAD, odds ratio (OR) = 1.063], relative intraluminal thrombus (rILT, OR = 1.039), and total aneurysm volume (TAV, OR = 1.006) continued to be significant predictors of AAA rupture with PWS (OR = 1.010) and RRED (OR = 1.031). Area under the ROC curve values and correct classification (cc) for the same parameters and the model that combines MAD, TAV, and rILT were measured: MAD (0.790, cc = 75%), PWS (0.713, cc = 73%), RRED (0.717, cc = 55%), TAV (0.756, cc = 79%), rILT (0.656, cc = 60%), and MAD + TAV + rILT (0.797, cc = 82%).ConclusionBased on our results, in addition to MAD, other important predictors of rupture that might be used during aneurysm surveillance are TAV and rILT. Biomechanical parameters (PWS, RRED) as valuable predictors should be assessed in prospective clinical trials. Similar studies on AAA smaller than 55 mm in diameter, even difficult to organize, would be of even greater clinical value.

Atherosclerosis is a widespread disease affecting coronary arteries. Diffuse atherosclerotic disease affects the whole vessel, posing difficulties in determining lesion significance by angiography. Research has confirmed that revascularization guided by invasive coronary physiology indices improves patients' prognosis and quality of life. Serial lesions can be a diagnostic challenge because the measurement of functional stenosis significance using invasive physiology is influenced by a complex interplay of factors. The use of fractional flow reserve (FFR) pullback provides a trans-stenotic pressure gradient (ΔP) for each of the lesions. The strategy of treating the lesion with greater ΔP first and then reevaluating another lesion has been advocated. Similarly, non-hyperemic indices can be used to assess the contribution of each stenosis and predict the effect of lesion treatment on physiology indices. Pullback pressure gradient (PPG) integrates physiological variables of coronary pressure along the epicardial vessel and characteristics of discrete and diffuse coronary stenoses into a quantitative index that can be used to guide revascularization. We proposed an algorithm that integrates FFR pullbacks and calculates PPG to determine individual lesion importance and to guide intervention. Computer modeling of the coronaries and the use of non-invasive FFR measurement together with mathematical algorithms for fluid dynamics can make predictions of lesion significance in serial stenoses easier and provide practical solutions for treatment. All these strategies need to be validated before widespread clinical use.

Background: Adipose tissue is a dynamic endocrine organ, a highly active metabolic tissue, and an important source of cytokines. Inflammatory factors play an important role in visceral obesity associated with insulin resistance (IR), metabolic syndrome (MS), hypertension, non-alcoholic fatty liver disease (NAFLD), diabetes mellitus type 2 (DM2), endothelial dysfunction (ED) and atherosclerosis.Objectives: To examine corelation of siMS score, as a quantification method for metabolic syndrome (MS), with insulin resistance, glucoregulation parameters, as with other co-founding factors of MS, inflammation and thrombosis factors, microalbuminuria, uric acid, fatty liver index (FLI) and homocysteine.Methods: The study included 451 obese individuals with pre–metabolic syndrome (pre-MS) and MS (age 16–75, body mass index (BMI) > 25kg/m2) classified into two groups: I-age 10–30 (167 patients); II-age 31–75 (284 patients). International Diabetes Federation (IDF) classification was applied for diagnosing metabolic syndrome. Patients with less than three criteria indicated below were considered pre-metabolic syndrome. siMS risk score was used.Results: siMS score increased with age: I-3.03 ± 0.87, II-3.27 ± 0.90. siMS score correlated with associated factors of MS: hyperinsulinemia and IR, ALT, gama-GT, FLI, uric acid in both groups and CRP (p < 0.01) in group I. Correlations in II group: siMS score with PAI-1 (p = 0.01), microalbuminuria (p = 0.006), homocysteine ​​(p = 0.076).Conclusion: Correlation of siMS score with HOMA-IR confirmed that hyperinsulinism and insulin resistance are in the basis of MS. Correlation of siMS score with parameters of NAFLD, CRP, PAI-1, uric acid, microalbuminuria and homocysteine indicates that they are significant co-founding factors of MS. Correlation of siMS score with PAI-1, microalbuminuria, homocysteine, indicates higher risk for progression of endothelial dysfunction and atherosclerosis with age.

Smallholder poultry production is a significant source of food and income for many rural households in Kenya, but poultry products can be contaminated with Salmonella and Campylobacter spp. Household members have different roles in poultry production, with women and youth more actively involved in the earlier steps of the value chain, such as poultry production and processing, particularly at the farm level. This literature review summarizes current knowledge and practices on the roles of women and youth in food safety in the smallholder poultry value chain in Kenya. Of the 19 articles identified, a majority referenced gender roles in the poultry value chain but few referenced youth or the roles of women and youth in ensuring food safety. Women and youth were found to be the primary smallholder poultry producers on-farm. Due to their direct involvement in poultry handling and production, women and youth may have higher potential risk of exposure to foodborne pathogens. Men, women, and youth were all found to participate in slaughtering and transportation of poultry products. It was also found that, although women may be the owners and caretakers of chickens, they may not have decision-making power on the use of income from the poultry, and poultry product sales. Therefore, women and youth may have limited decision-making power or access to resources, such as training, to increase food safety. Further research is needed to address the factors important to women and youth empowerment to ensure food safety in the smallholder poultry value chain and reduce the risks of foodborne disease (FBD) in Kenya.

Objectives: To describe COVID-19 information-seeking behavior (CISB) during the first stage of the pandemic in Switzerland and identify its determinants.Methods: We conducted an online cross-sectional survey (4 May to 6 July 2020). Participants self-reported their CISB (information sources and frequency), personal COVID-19 situation (e.g., perception about having had COVID-19), sociodemographic information, and completed validated measures of health literacy, and worry and anxiety. Data were analyzed using descriptive statistics and logistic regressions.Results: We included 1,505 participants (24.7% male; mean age = 43.0 years, SD = 13.9). Most participants reported searching for information daily (n = 1,023, 68.0%) and referring to multiple information sources (mean 3.7, SD = 1.5). Commonly used sources were official websites (n = 1,129, 75.0%) and newspapers (n = 997, 66.2%). Participants with higher health literacy were more likely to seek information daily and use online resources, but less likely to use personal networks than those with lower health literacy. We did not find any association between CISB and worry and anxiety.Conclusion: More opportunities for personal dialogue and education about reliable online information resources should be encouraged to optimize the CISB of groups with lower health literacy.

IntroductionPatients with Cushing’s syndrome (CS) represent a highly sensitive group during corona virus disease 2019 (COVID-19) pandemic. The effect of multiple comorbidities and immune system supression make the clinical picture complicated and treatment challenging.Case reportA 70-year-old female was admitted to a covid hospital with a severe form of COVID-19 pneumonia that required oxygen supplementation. Prior to her admission to the hospital she was diagnosed with adrenocorticotropic hormone (ACTH)-dependent CS, and the treatment of hypercortisolism had not been started yet. Since the patient’s condition was quickly deteriorating, and with presumend immmune system supression due to CS, we decided on treatement with intraveonus immunoglobulins (IVIg) that enabled quick onset of immunomodulatory effect. All comorbidities were treated with standard of care. The patient’s condition quickly stabilized with no direct side effects of a given treatment.ConclusionTreatment of COVID-19 in patients with CS faces many challenges due to the complexity of comorbidity effects, immunosupression and potential interactions of available medications both for treatment of COVID-19 and CS. So far, there are no guidelines for treatment of COVID-19 in patients with active CS. It is our opinion that immunomodulating therapies like IVIg might be an effective and safe treatment modality in this particularly fragile group of patients.

BackgroundHyperlactatemia is a biological marker of tissue hypoperfusion with well-known diagnostic, prognostic, and therapeutic implications in shock states. In daily clinical practice, it is difficult to find out the exact mechanism underlying hyperlactatemia. Central venous to arterial CO2 difference (pCO2 gap) is a better parameter of tissue hypoperfusion than the usual ones (clinical examination and mixed venous saturation). Furthermore, the ratio between the pCO2 gap and p(v–a)CO2/C(a–v)O2 may be a promising indicator of anaerobic metabolism, allowing for the identification of different causes of tissue hypoxia and hyperlactatemia. The main aim of the study is to demonstrate that initial hemodynamic resuscitation based on an algorithm integrating the pCO2 gap and p(v–a)CO2/C(a–v)O2 ratio vs. usual clinical practice in acute circulatory failure improves lactate clearance.MethodsLACTEL is a randomized, prospective, multicentric, controlled study. It compares the treatment of hyperlactatemia using an algorithm based on the pCO2 gap and P(v–a)CO2/C(a–v)O2 ratio vs. usual clinical practice in acute circulatory failure. A total of 90 patients were enrolled in each treatment group. The primary endpoint is the number of patients with a lactate clearance of more than 10% 2 h after inclusion. Lactate levels were monitored during the first 48 h of treatment as hemodynamic parameters, biological markers of organ failure, and 28-day mortality.DiscussionpCO2 derivate indices may be of better interest than routine clinical indices to differentiate causes of hyperlactatemia and diagnose anaerobiosis. LACTEL results will provide clinical insights into the role of these indices in the early hemodynamic management of acute circulatory failure in the ICU.Clinical Trial Registrationwww.clinicaltrials.gov; identifier: NCT05032521.

During the COVID-19 pandemic, universities across the world transitioned rapidly to remote education. Engaging with a curriculum that has been transitioned from in-person to remote education mode is likely to impact how students and educators adapt to the changes and uncertainties caused by the pandemic. There is limited knowledge about individual differences in students' and educators' adaptability to remote education in response to the pandemic. This paper explored healthcare students' and educators' adaptability experiences to remote education. Drawing on pragmatism, a convergent mixed-methods design was adopted. Data were collected between May and August in 2020 using an online survey, followed by interviews with students and educators of five large health courses at an Australian research-intensive University. Data included 476 surveys and seven focus group interviews with 26 students, and 95 surveys and 17 individual interviews with educators. Results were interpreted through an integration of quantitative and qualitative elements from student and educator experiences. Findings indicated that students were less adaptable than educators. Whilst remote learning was less appealing than in-person learning, some students adapted well to the new learning environment. Limited social learning, transmissive pedagogy, and lack of technical and non-technical skills were identified as factors that impacted upon the experience of students and educators. Navigating the challenges associated with remote education provided students and educators with a unique opportunity to improve adaptability—an attribute critical for future uncertainties in healthcare practice.

BackgroundThe aims of our study are related to examining the relevance of teachers' attitudes toward the implementation of inclusive education. In addition, its subject is related to the implications on inclusive education policies, limitations of the existing study along with the recommendations for our future research endeavors.MethodsThe research is a cross-sectional study type. The sample included 64 primary school teachers in the lower grades of primary school (grades 1–4), selected by using simple random sampling, in three primary schools on the territory of Belgrade, Serbia in 2021 (26, 17, and 21 primary school teachers). The Questionnaire for Teachers, which was used as a research instrument, was taken from the Master's Thesis Studen Rajke, which was part of the project “Education for the Knowledge Society” at the Institute for Educational Research in Belgrade. Dependent variables measured in the study referred to the attitudes of primary school teachers toward inclusive education. Categorical variables are represented as frequencies and the Chi-square test was used to determine if a distribution of observed frequencies differed from the expected frequencies.ResultsOne in three teachers (32.8%) thought that inclusion was useful for children with disabilities (29.7%), of them thought that schools did not have the conditions for inclusive education, whereas one in four teachers (25.0%) believed that inclusion was not good. No statistically significant differences were found in the attitudes of professors, when observed in terms of their gender, age and length of service.ConclusionInvesting more resources and time in developing and implementing special education policies can promote successful inclusive education.

Neurodegeneration implies progressive neuronal loss and neuroinflammation further contributing to pathology progression. It is a feature of many neurological disorders, most common being Alzheimer’s disease (AD). Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive stimulation which modulates excitability of stimulated brain areas through magnetic pulses. Numerous studies indicated beneficial effect of rTMS in several neurological diseases, including AD, however, exact mechanism are yet to be elucidated. We aimed to evaluate the effect of intermittent theta burst stimulation (iTBS), an rTMS paradigm, on behavioral, neurochemical and molecular level in trimethyltin (TMT)-induced Alzheimer’s-like disease model. TMT acts as a neurotoxic agent targeting hippocampus causing cognitive impairment and neuroinflammation, replicating behavioral and molecular aspects of AD. Male Wistar rats were divided into four experimental groups–controls, rats subjected to a single dose of TMT (8 mg/kg), TMT rats subjected to iTBS two times per day for 15 days and TMT sham group. After 3 weeks, we examined exploratory behavior and memory, histopathological and changes on molecular level. TMT-treated rats exhibited severe and cognitive deficit. iTBS-treated animals showed improved cognition. iTBS reduced TMT-induced inflammation and increased anti-inflammatory molecules. We examined PI3K/Akt/mTOR signaling pathway which is involved in regulation of apoptosis, cell growth and learning and memory. We found significant downregulation of phosphorylated forms of Akt and mTOR in TMT-intoxicated animals, which were reverted following iTBS stimulation. Application of iTBS produces beneficial effects on cognition in of rats with TMT-induced hippocampal neurodegeneration and that effect could be mediated via PI3K/Akt/mTOR signaling pathway, which could candidate this protocol as a potential therapeutic approach in neurodegenerative diseases such as AD.

BackgroundChanging daily habits such as diet, hygiene and physical activity may be some of the consequences of the COVID-19 pandemic. The aim of the study was to analyze the effect of this pandemic on lifestyle, physical activity, eating and hygiene habits among students.MethodsThis cross-sectional study involved 171 students from the Faculty of Medical Sciences, University of Kragujevac, Serbia. Data were statistically analyzed using Wilcoxon Signed-Rank test, Marginal homogeneity test and Chi-square test. The differences were considered statistically significant when p ≤ 0.05.ResultsIn this study, it was observed that the most common physical activity before the pandemic was walking, while during the pandemic was home exercising. Compared to the period before the pandemic, there was no difference in the time spent engaging in daily physical activity (p = 0.334). However, there was a significant increase in sitting time during the pandemic (p = 0.005). Difference was noticed in the use of breakfast, the number of meals, and the type of fat in the diet before and during the pandemic (p = 0.000). During the pandemic, there was an increase in the use of fruits (p = 0.000), vegetables, and nuts (p = 0.001), while the use of fast food and alcohol have decreased. During the COVID-19 pandemic, a significant increase in the use of dietary supplements was observed (40.2%), (p = 0.008).ConclusionsGiven that the COVID-19 pandemic is ongoing, certain changes in lifestyle observed in this study should be confirmed in more extensive population studies.

BackgroundThere is conflicting and limited information regarding factors that influence undergraduate nursing students' academic and clinical performance prior to entry to practice.ObjectiveTo identify factors influencing the academic and clinical performance of undergraduate nursing students throughout the course.DesignMixed methods study utilizing a retrospective cohort and a qualitative study.SettingMonash University, Melbourne, Australia.ParticipantsLongitudinal existing data of nursing undergraduate students who commenced in 2017 (n = 176) and 2018 (n = 76), and two focus groups with final year nursing students were analyzed.MethodsRetrospective students' records were used to determine the students' academic and clinical performance using the weighted average mark (WAM) of the theoretical and clinical components of the curriculum, separately. The WAM considered the year level of each unit and was scored out of 100. Multivariate linear regression was used to determine predictor factors of academic and clinical performance. Variables include entry cohort (with no previous nursing qualification vs. diploma of nursing), admission category (domestic vs. international), campus (metropolitan vs. outer metropolitan), and secondary school (year 12) results. Two focus group discussions were conducted and thematically analyzed.ResultsMore than two-thirds of the students were aged 18–20 years and mainly female. Almost 20% of the participants were international students. Students with higher secondary school (year 12) results and studying at the outer metropolitan campus achieved a higher academic performance while international students had significantly lower academic performance compared to domestic students. Students with a previous diploma of enrolled nursing and international students had lower clinical performance. Students identified that a comprehensive orientation, interactive curriculum, formal and informal support structure, and educator qualities influenced their academic and/or clinical performance.ConclusionsA supportive educational environment with an interactive curriculum may enhance students' academic and clinical performance and readiness for practice. Furthermore, targeted interventions for international students, those with lower secondary school (year 12) results, and those with a former diploma of nursing may be required to increase academic and clinical performance.

This study was designed in a rat model to determine the hallmarks of possible permanent behavioral and structural brain alterations after a single moderate hypoxic insult. Eighty-two Wistar Han (RccHan: WIST) rats were randomly subjected to hypoxia (pO2 73 mmHg/2 h) or normoxia at the first postnatal day. The substantially increased blood lactate, a significantly decreased cytochrome-C-oxygenase expression in the brain, and depleted subventricular zone suggested a high vulnerability of subset of cell populations to oxidative stress and consequent tissue response even after a single, moderate, hypoxic event. The results of behavioral tests (open-field, hole-board, social-choice, and T-maze) applied at the 30–45th and 70–85th postnatal days revealed significant hyperactivity and a slower pace of learning in rats subjected to perinatal hypoxia. At 3.5 months after hypoxic insult, the histochemical examination demonstrated a significantly increased number of specific extracellular matrix—perineuronal nets and increased parvalbumin expression in a subpopulation of interneurons in the medial and retrosplenial cingulate cortex of these animals. Conclusively, moderate perinatal hypoxia in rats causes a long-lasting reorganization of the connectivity in the cingulate cortex and consequent alterations of related behavioral and cognitive abilities. This non-invasive hypoxia model in the rat successfully and complementarily models the moderate perinatal hypoxic injury in fetuses and prematurely born human babies and may enhance future research into new diagnostic and therapeutic strategies for perinatal medicine.

Phytogenics are plant-based feed additives utilized in animal nutrition to support animal growth and health. Worldwide restrictions and bans on the use of antibiotic growth promoters resulted in an increased demand for in-feed alternatives including phytogenics. However, several challenges remain for technology readiness in animal industry, especially regarding the standardization of the ingredients as well as our knowledge on the cellular mechanisms underlying their biological effects. In the present study, 32 weaned piglets were allocated for 28 days to four experimental diets, a control diet, a phytogenic feed additive (PFA) diet, or the same two diets but with the addition of oxidized oil (OO) at 10%. The last two diets aimed at evaluating the antioxidant properties of PFA. At the end of the trial, the ileum and the liver of the pigs were sampled, and RNA were isolated for profiling their transcriptome via RNA sequencing (RNA-Seq). In the ileum, the gene set enrichment analysis showed that the activity of several immune pathways (NF-kB, interferon α/β, antimicrobial peptide, and collagen pathways) was reduced in piglets fed PFA compared to the control piglets. As expected, the addition of OO induced strong effects on the liver transcriptome and most likely accounted for the significant growth impairment. The likelihood ratio test across the four diets revealed a global response driven by the oxidative stress challenge with hundreds of genes associated with fatty acid β-oxidation and peroxisome in the liver. The expression levels of those genes in the piglets fed OO+PFA were much less affected by the challenge. Collectively, the effects seen at day 28 suggest that substances in the PFA formulation provide anti-inflammatory and antioxidant properties. The use of RNA-Seq in animal nutrition allows exploring and deciphering novel mechanisms of natural growth promoters.

Background: Renalase has been implicated in chronic heart failure (CHF); however, nothing is known about renalase discriminatory ability and prognostic evaluation. The aims of the study were to assess whether plasma renalase may be validated as a predictor of ischemia in CHF patients stratified to the left ventricular ejection fraction (LVEF) and to determine its discriminatory ability coupled with biomarkers representing a range of heart failure (HF) pathophysiology: brain natriuretic peptide (BNP), soluble suppressor of tumorigenicity (sST2), galectin-3, growth differentiation factor 15 (GDF-15), syndecan-1, and cystatin C.Methods: A total of 77 CHF patients were stratified according to the LVEF and were subjected to exercise stress testing. Receiver operating characteristic curves were constructed, and the areas under curves (AUC) were determined, whereas the calibration was evaluated using the Hosmer-Lemeshow statistic. A DeLong test was performed to compare the AUCs of biomarkers.Results: Independent predictors for ischemia in the total HF cohort were increased plasma concentrations: BNP (p = 0.008), renalase (p = 0.012), sST2 (p = 0.020), galectin-3 (p = 0.018), GDF-15 (p = 0.034), and syndecan-1 (p = 0.024), whereas after adjustments, only BNP (p = 0.010) demonstrated predictive power. In patients with LVEF 45%.Conclusion: Plasma renalase concentration provided significant discrimination for the prediction of ischemia in patients with CHF and appeared to have similar discriminatory potential to that of BNP. Although further confirmatory studies are warranted, renalase seems to be a relevant biomarker for ischemia prediction, implying its potential contribution to ischemia-risk stratification.

Background: Papillary fibroelastomas are rare benign heart tumors, and is most likely to involve the cardiac valves. We will present an extremely rare localization of a large Valsalva sinus fibroelastoma, with occasional left coronary artery ostial obstruction presented as an acute coronary syndrome. The tumor was removed surgically and histologically confirmed as papillary fibroelastoma. This review points to the crucial importance of multidisciplinary team decision and multimodality imaging methods for diagnosing the fibroelastoma, determination of size, and localization, which avoided complications of fatal embolization during an invasive procedure.Case Summary: A healthy 55-year-old male with vigorous physical daily training and exercise was admitted to the acute coronary syndrome emergency department. Shortly after admission, expert transthoracic echocardiography was performed. Computed tomography of the chest observed a large irregular hypodense tumor-like lesion in the bulbar aorta that was occasionally prolapsing into the left main coronary artery ostium and which corresponded to fibroelastoma. A few hours after admission, an emergency cardiac surgery was performed with the excision of a Valsalva sinus tumor (size 2 × 2 cm) located between the right and left coronary cusp of the aortic valve.Conclusions: Focus cardiac ultrasound should be performed for any acute coronary syndrome because of the possible Valsalva sinus fibroelastoma etiology. Its localization next to the left main coronary artery ostium is rare, and dangerous. The timely diagnosis can be made by the multimodality imaging method, however, the final diagnosis will be made pathohistologically. Early cardiac surgery may be a necessitated recourse for these patients in order to prevent a fatal outcome.

With the epidemic of human obesity, dietary fats have increasingly become a focal point of biomedical research. Epidemiological studies indicate that high-fat diets (HFDs), especially those rich in long-chain saturated fatty acids (e.g., Western Diet, National Health Examination survey; NHANES ‘What We Eat in America’ report) have multi-organ pro-inflammatory effects. Experimental studies have confirmed some of these disease associations, and have begun to elaborate mechanisms of disease induction. However, many of the observed effects from epidemiological studies appear to be an over-simplification of the mechanistic complexity that depends on dynamic interactions between the host, the particular fatty acid, and the rather personalized genetics and variability of the gut microbiota. Of interest, experimental studies have shown that certain saturated fats (e.g., lauric and myristic fatty acid-rich coconut oil) could exert the opposite effect; that is, desirable anti-inflammatory and protective mechanisms promoting gut health by unanticipated pathways. Owing to the experimental advantages of laboratory animals for the study of mechanisms under well-controlled dietary settings, we focus this review on the current understanding of how dietary fatty acids impact intestinal biology. We center this discussion on studies from mice and rats, with validation in cell culture systems or human studies. We provide a scoping overview of the most studied diseases mechanisms associated with the induction or prevention of Inflammatory Bowel Disease in rodent models relevant to Crohn’s Disease and Ulcerative Colitis after feeding either high-fat diet (HFD) or feed containing specific fatty acid or other target dietary molecule. Finally, we provide a general outlook on areas that have been largely or scarcely studied, and assess the effects of HFDs on acute and chronic forms of intestinal inflammation.

The main form of COVID-19 transmission is via “oral-respiratory droplet contamination” (droplet: very small drop of liquid) produced when individuals talk, sneeze, or cough. In hospitals, health-care workers wear facemasks as a minimum medical “droplet precaution” to protect themselves. Due to the shortage of masks during the pandemic, priority is given to hospitals for their distribution. As a result, the availability/use of medical masks is discouraged for the public. However, for asymptomatic individuals, not wearing masks in public could easily cause the spread of COVID-19. The prevention of “environmental droplet contamination” (EnvDC) from coughing/sneezing/speech is fundamental to reducing transmission. As an immediate solution to promote “public droplet safety,” we assessed household textiles to quantify their potential as effective environmental droplet barriers (EDBs). The synchronized implementation of a universal “community droplet reduction solution” is discussed as a model against COVID-19. Using a bacterial-suspension spray simulation model of droplet ejection (mimicking a sneeze), we quantified the extent by which widely available clothing fabrics reduce the dispersion of droplets onto surfaces within 1.8 m, the minimum distance recommended for COVID-19 “social distancing.” All textiles reduced the number of droplets reaching surfaces, restricting their dispersion to

High-affinity monoamine transporters are targets for prescribed medications and stimulant drugs of abuse. Therefore, assessing monoamine transporter activity for candidate medications and newly-emerging drugs of abuse provides essential information for industry, academia, and public health. Radiotracer binding and uptake inhibition are the gold standard assays for determining drug–transporter interaction profiles. The combined results from such assays yield a unique biochemical fingerprint for each compound. Over time, different assay methods have been developed to assess transporter activity, and the comparability of data across various assay platforms remains largely unclear. Here, we compare the effects of six well-established stimulants in two different cell-based uptake inhibition assays, one method using adherent cells and the other using suspended cells. Furthermore, we compare the data from transfected cell lines derived from different laboratories and data reported from rat synaptosomes. For transporter inhibitors, IC50 values obtained by the two experimental methods were comparable, but using different transfected cell lines yielded disparate results. For transporter substrates, differences between the two cell lines were less pronounced but the drugs displayed different inhibition potencies when evaluated by the two methods. Our study illustrates the inherent limitations when comparing transporter inhibition data from different laboratories and stresses the importance of including appropriate control experiments with reference compounds when investigating new drugs of interest.

BackgroundTranscranial direct current stimulation (tDCS) is used for various chronic pain conditions, but experience with tDCS for acute postoperative pain is limited. This study investigated the effect of tDCS vs. sham stimulation on postoperative morphine consumption and pain intensity after thoracotomy.MethodsThis is a single-center, prospective, randomized, double-blind, sham-controlled trial in lung cancer patients undergoing thoracotomy under general anesthesia. All patients received patient-controlled (PCA) intravenous morphine and intercostal nerve blocks at the end of surgery. The intervention group (a-tDCS, n = 31) received anodal tDCS over the left primary motor cortex (C3-Fp2) for 20 min at 1.2 mA, on five consecutive days; the control group (n = 31) received sham stimulation. Morphine consumption, number of analgesia demands, and pain intensity at rest, with movement and with cough were recorded at the following intervals: immediately before (T1), immediately after intervention (T2), then every hour for 4 h (Т3–Т6), then every 6 h (Т7–Т31) for 5 days. We recorded outcomes on postoperative days 1 and 5 and conducted a phone interview inquiring about chronic pain 1 year later (NCT03005548).ResultsA total of 62 patients enrolled, but tDCS was prematurely stopped in six patients. Fifty-five patients (27 a-tDCS, 28 sham) had three or more tDCS applications and were included in the analysis. Cumulative morphine dose in the first 120 h after surgery was significantly lower in the tDCS [77.00 (54.00–123.00) mg] compared to sham group [112.00 (79.97–173.35) mg, p = 0.043, Cohen’s d = 0.42]. On postoperative day 5, maximum visual analog scale (VAS) pain score with cough was significantly lower in the tDCS group [29.00 (20.00–39.00) vs. 44.50 (30.00–61.75) mm, p = 0.018], and pain interference with cough was 80% lower [10.00 (0.00–30.00) vs. 50.00 (0.00–70.00), p = 0.013]. One year after surgery, there was no significant difference between groups with regard to chronic pain and analgesic use.ConclusionIn lung cancer patients undergoing thoracotomy, three to five tDCS sessions significantly reduced cumulative postoperative morphine use, maximum VAS pain scores with cough, and pain interference with cough on postoperative day 5, but there was no obvious long-term benefit from tDCS.

Clostridioides difficile (CD) is a spore-forming bacterium that causes life-threatening intestinal infections in humans. Although formerly regarded as exclusively nosocomial, there is increasing genomic evidence that person-to-person transmission accounts for only 72%) employed the same (one-of-six) culture strategy. Because the prevalence was also meta-analytically similar across six culture strategies reported, all studies were integrated using three meta-analytical methods. At the study level (n = 79), the four-decade global cumulative-prevalence of CD in the human diet was 4.1% (95%CI = −3.71, 11.91). At the food-set level (n = 232, mean 12.9 g/sample, similar across regions p > 0.2; 95%CI = 9.7–16.2), the weighted prevalence ranged between 4.5% (95%CI = 3–6%; all studies) and 8% (95%CI = 7–8%; only CD-positive-studies). Risk-ratio ranking and meta-regression showed that milk was the least likely source of CD, while seafood, leafy green vegetables, pork, and poultry carried higher risks (p < 0.05). Across regions, the risk of CD in foods for foodborne exposure reproducibly decreased with Earth latitude (p < 0.001). In conclusion, CD in the human diet is a global non-random-source of foodborne exposure that occurs independently of laboratory culture methods, across regions, and at a variable level depending on food type and latitude. The latitudinal trend (high CD-food-prevalence toward tropic) is unexpectedly inverse to the epidemiological observations of CD-infections in humans (frequent in temperate regions). Findings suggest the plausible hypothesis that ecologically-richer microbiomes in the tropic might protect against intestinal CD colonization/infections despite CD ingestion.

Academic engagement describes students’ involvement in academic learning and achievement. This paper reports the psychometric properties of the University Student Engagement Inventory (USEI) with a sample of 3992 university students from nine different countries and regions from Europe, North and South America, Africa, and Asia. The USEI operationalizes a trifactorial conceptualization of academic engagement (behavioral, emotional, and cognitive). Construct validity was assessed by means of confirmatory factor analysis and reliability was assessed using Cronbach’s alpha and McDonald’s omega coefficients. Weak measurement invariance was observed for country/region, while strong measurement invariance was observed for gender and area of graduation. The USEI scores showed predictive validity for dropout intention, self-rated academic performance, and course approval rate while divergent validity with student burnout scores was also evident. Overall, the results indicate that the USEI can produce reliable and valid data on academic engagement of university students across the world.

Thy-1 is a small membrane glycoprotein and member of the immunoglobulin superfamily of cell adhesion molecules. It is abundantly expressed in many cell types including neurons and is anchored to the outer membrane leaflet via a glycosyl phosphatidylinositol tail. Thy-1 displays a number of interesting properties such as fast lateral diffusion, which allows it to get in and out of membrane nanodomains with different lipid composition. Thy-1 displays a broad expression in different cell types and plays confirmed roles in cell development, adhesion and differentiation. Here, we explored the functions of Thy-1 in neuronal signaling, initiated by extracellular binding of αVβ3 integrin, may strongly dependent on the lipid content of the cell membrane. Also, we assort literature suggesting the association of Thy-1 with specific components of lipid rafts such as sialic acid containing glycosphingolipids, called gangliosides. Furthermore, we argue that Thy-1 positioning in nanodomains may be influenced by gangliosides. We propose that the traditional conception of Thy-1 localization in rafts should be reconsidered and evaluated in detail based on the potential diversity of neuronal nanodomains.

Streptomyces sp. NP10 was previously shown to synthesize large amounts of free fatty acids (FFAs). In this work, we report the first insights into the biosynthesis of these fatty acids (FAs) gained after genome sequencing and identification of the genes involved. Analysis of the Streptomyces sp. NP10 draft genome revealed that it is closely related to several strains of Streptomyces griseus. Comparative analyses of secondary metabolite biosynthetic gene clusters, as well as those presumably involved in FA biosynthesis, allowed identification of an unusual cluster C12-2, which could be identified in only one other S. griseus-related streptomycete. To prove the involvement of identified cluster in FFA biosynthesis, one of its three ketosynthase genes was insertionally inactivated to generate mutant strain mNP10. Accumulation of FFAs in mNP10 was almost completely abolished, reaching less than 0.01% compared to the wild-type strain. Cloning and transfer of the C12-2 cluster to the mNP10 mutant partially restored FFA production, albeit to a low level. The discovery of this rare FFA biosynthesis cluster opens possibilities for detailed characterization of the roles of individual genes and their products in the biosynthesis of FFAs in NP10.

Trichinella spiralis, as well as its muscle larvae excretory–secretory products (ES L1), given either alone or via dendritic cells (DCs), induce a tolerogenic immune microenvironment in inbred rodents and successfully ameliorate experimental autoimmune encephalomyelitis. ES L1 directs the immunological balance away from T helper (Th)1, toward Th2 and regulatory responses by modulating DCs phenotype. The ultimate goal of our work is to find out if it is possible to translate knowledge obtained in animal model to humans and to generate human tolerogenic DCs suitable for therapy of autoimmune diseases through stimulation with ES L1. Here, the impact of ES L1 on the activation of human monocyte-derived DCs is explored for the first time. Under the influence of ES L1, DCs acquired tolerogenic (semi-matured) phenotype, characterized by low expression of HLA-DR, CD83, and CD86 as well as moderate expression of CD40, along with the unchanged production of interleukin (IL)-12 and elevated production of IL-10 and transforming growth factor (TGF)-β, compared to controls. The interaction with DCs involved toll-like receptors (TLR) 2 and 4, and this interaction was mainly responsible for the phenotypic and functional properties of ES L1-treated DCs. Importantly, ES L1 potentiated Th2 polarizing capacity of DCs, and impaired their allo-stimulatory and Th1/Th17 polarizing properties. Moreover, ES L1-treated DCs promoted the expansion of IL-10- and TGF-β- producing CD4+CD25hiFoxp3hi T cells in indolamine 2, 3 dioxygenase (IDO)-1-dependent manner and increased the suppressive potential of the primed T cell population. ES L1-treated DCs retained the tolerogenic properties, even after the challenge with different pro-inflammatory stimuli, including those acting via TLR3 and, especially TLR4. These results suggest that the induction of tolerogenic properties of DCs through stimulation with ES L1 could represent an innovative approach for the preparation of tolerogenic DC for treatment of inflammatory and autoimmune disorders.

Cellular therapies with CD4+ T regulatory cells (Tregs) hold promise of efficacious treatment for the variety of autoimmune and allergic diseases as well as posttransplant complications. Nevertheless, current manufacturing of Tregs as a cellular medicinal product varies between different laboratories, which in turn hampers precise comparisons of the results between the studies performed. While the number of clinical trials testing Tregs is already substantial, it seems to be crucial to provide some standardized characteristics of Treg products in order to minimize the problem. We have previously developed reporting guidelines called minimum information about tolerogenic antigen-presenting cells, which allows the comparison between different preparations of tolerance-inducing antigen-presenting cells. Having this experience, here we describe another minimum information about Tregs (MITREG). It is important to note that MITREG does not dictate how investigators should generate or characterize Tregs, but it does require investigators to report their Treg data in a consistent and transparent manner. We hope this will, therefore, be a useful tool facilitating standardized reporting on the manufacturing of Tregs, either for research purposes or for clinical application. This way MITREG might also be an important step toward more standardized and reproducible testing of the Tregs preparations in clinical applications.

Reduced cognitive abilities are often characterized by an impairment of flexibility, i.e., the ability to switch from learned rules or categories that were important in certain contexts to different new modalities that rule the task. Drugs targeting the dopamine transporter (DAT) are widely used for their potential to enhance cognitive abilities. However, commercially available drugs are of limited specificity for DAT, blocking also noradrenaline and serotonine transporters, that can lead to unwanted side effects in healthy subjects. Therefore, we tested a newly synthetized compound (CE-123) with higher specificity for DAT in male rats in an attentional set-shifting task (ASST), that proves for cognitive flexibility and a 5-choice serial-reaction time task (5-CSRTT) assessing visuospatial attention and impulsivity. Treated rats at a dose of 0.3 and 1.0 but not 0.1 mg/kg bodyweight showed reduced extra-dimensional shifts in the ASST compared to controls indicating increased cognitive flexibility. Rats treated with R-Modafinil, a commercially available DAT inhibitor at a dose of 10 mg/kg bodyweight showed increased premature responses, an indicator of increased impulsivity, during a 10 s but not a 2.5, 5, or 7.5 s intertrial interval when compared to vehicle-treated rats in the 5-CSRTT. This was not found in rats treated with CE-123 at the same dose as for R-Modafinil. Visuospatial attention, except premature responses, did not differ between R-Modafinil and CE-123-treated rats and their respective controls. Thus, CE-123 increased cognitive flexibility with diminished impulsivity.