Autoantibodies related to ataxia and other central nervous system manifestations of gluten enteropathy

Gluten ataxia and other central nervous system disorders could be linked to gluten enteropathy and related autoantibodies.In this narrative review,we focus on the various neuro-logical manifestations in patients with gluten sensitivity/celiac disease,immunological and autoimmune mechanisms of ataxia in connection to gluten sensitivity and the autoantibodies that could be used as a biomarker for diagnosing and following.We focused on the anti-gliadin antibodies,antibodies to different isoforms of tissue transglutaminase(TG)(anti-TG2,3,and 6 antibodies),anti-glycine receptor antibodies,anti-glutamine acid decarboxylase antibodies,anti-deamidated gliadin peptides antibodies,etc.Most studies found a higher prevalence of these antibodies in patients with gluten sensitivity and neurological dysfunction,presented as different neurological disorders.We also discuss the role of a gluten-free diet on the clinical improvement of patients and also on imaging of these disorders.

Role of children in the Bulgarian COVID-19 epidemic:A mathematical model study

BACKGROUND The coronavirus disease 2019(COVID-19)pandemic affects all aspects of our lives,including children.With the advancement of the pandemic,children under five years old are at increased risk of hospitalization relative to other age groups.This makes it paramount that we develop tools to address the two critical aspects of preserving children's health–new treatment protocols and new predictive models.For those purposes,we need to understand better the effects of COVID-19 on children,and we need to be able to predict the number of affected children as a proportion of the number of infected children.This is why our research focuses on clinical and epidemiological pictures of children with heart damage post-COVID,as a part of the general picture of post-COVID among this age group.AIM To demonstrate the role of children in the COVID-19 spread in Bulgaria and to test the hypothesis that there are no secondary transmissions in schools and from children to adults.METHODS Our modeling and data show with high probability that in Bulgaria,with our current measures,vaccination strategy and contact structure,the pandemic is driven by the children and their contacts in school.RESULTS This makes it paramount that we develop tools to address the two critical aspects of preserving children's health–new treatment protocols and new predictive models.For those purposes,we need to understand better the effects of COVID-19 on children,and we need to be able to predict the number of affected children as a proportion of the number of infected children.This is why our research focuses on clinical and epidemiological pictures of children with heart damage post-COVID,as a part of the general picture of post-Covid among this age group.CONCLUSION Our modeling rejects that hypothesis,and the epidemiological data supports that.We used epidemiological data to support the validity of our modeling.The first summer wave in 2020 from the listed here school proms endorse the idea of transmissions from students to teachers.

Method“Monte Carlo”in healthcare

In public health,simulation modeling stands as an invaluable asset,enabling the evaluation of new systems without their physical implementation,experimentation with existing systems without operational adjustments,and testing system limits without real-world repercussions.In simulation modeling,the Monte Carlo method emerges as a powerful yet underutilized tool.Although the Monte Carlo method has not yet gained widespread prominence in healthcare,its technological capabilities hold promise for substantial cost reduction and risk mitigation.In this review article,we aimed to explore the transformative potential of the Monte Carlo method in healthcare contexts.We underscore the significance of experiential insights derived from simulated experimentation,especially in resource-constrained scenarios where time,financial constraints,and limited resources necessitate innovative and efficient approaches.As public health faces increasing challenges,incorporating the Monte Carlo method presents an opportunity for enhanced system construction,analysis,and evaluation.

Artificial intelligence as a tool in drug discovery and development

The rapidly advancing field of artificial intelligence(AI)has garnered substantial attention for its potential application in drug discovery and development.This opinion review critically examined the feasibility and prospects of integrating AI as a transformative tool in the pharmaceutical industry.AI,encompassing machine learning algorithms,deep learning,and data analytics,offers unprecedented opportunities to streamline and enhance various stages of drug development.This opinion review delved into the current landscape of AI-driven approaches,discussing their utilization in target identification,lead optimization,and predictive modeling of pharmacokinetics and toxicity.We aimed to scrutinize the integration of large-scale omics data,electronic health records,and chemical informatics,highlighting the power of AI in uncovering novel therapeutic targets and accelerating drug repurposing strategies.Despite the considerable potential of AI,the review also addressed inherent challenges,including data privacy concerns,interpretability of AI models,and the need for robust validation in realworld clinical settings.Additionally,we explored ethical considerations surrounding AI-driven decision-making in drug development.This opinion review provided a nuanced perspective on the transformative role of AI in drug discovery by discussing the existing literature and emerging trends,presenting critical insights and addressing potential hurdles.In conclusion,this study aimed to stimulate discourse within the scientific community and guide future endeavors to harness the full potential of AI in drug development.

Harnessing immunity:Immunomodulatory therapies in COVID-19

An overly exuberant immune response,characterized by a cytokine storm and uncontrolled inflammation,has been identified as a significant driver of severe coronavirus disease 2019(COVID-19)cases.Consequently,deciphering the intricacies of immune dysregulation in COVID-19 is imperative to identify specific targets for intervention and modulation.With these delicate dynamics in mind,immunomodulatory therapies have emerged as a promising avenue for miti-gating the challenges posed by COVID-19.Precision in manipulating immune pathways presents an opportunity to alter the host response,optimizing antiviral defenses while curbing deleterious inflammation.This review article compre-hensively analyzes immunomodulatory interventions in managing COVID-19.We explore diverse approaches to mitigating the hyperactive immune response and its impact,from corticosteroids and non-steroidal drugs to targeted biologics,including anti-viral drugs,cytokine inhibitors,JAK inhibitors,convalescent plasma,monoclonal antibodies(mAbs)to severe acute respiratory syndrome coronavirus 2,cell-based therapies(i.e.,CAR T,etc.).By summarizing the current evidence,we aim to provide a clear roadmap for clinicians and researchers navigating the complex landscape of immunomodulation in COVID-19 treatment.CS Glucocorticoids are among the most widely prescribed drugs with their immune-suppressive and anti-inflammatory effect[84].The current guidelines for the treatment of COVID-19 recommend against the use of dexamethasone or other systemic CS in non-hospitalized patients in the absence of another indication[70].The RECOVERY trial demonstrates the reduced 28-d mortality among hospitalized patients with COVID-19 using dexamethasone compared to the usual standard of care,along with other investigators,such as Ahmed and Hassan[85].The benefit of dexamethasone was seen only among participants receiving either oxygen alone or invasive mechanical ventilation at randomization but not among those receiving no respiratory support at enrollment[85].In a systematic review and meta-analysis,Albuquerque et al[86]showed that in comparison to tocilizumab,baricitinib,and sarilumab are associated with high probabilities of similar mortality reductions among hospitalized COVID-19 concurrently treated with CS.As a result of the absence of SARS-CoV-2-specific antiviral medications,the effectiveness of COVID-19 treatments is reduced.Several COVID-19 therapies are now under investigation.However,the majority of them lack specificity,efficacy,and safety[87].Immunotherapy is a ground-breaking medical treatment that manipulates the immune system to fight diseases.Translational research is rapidly progressing,recognized as a significant breakthrough in 2013[88].Among the immunotherapeutic options for treating COVID-19 are Immunoglobulin,CP,antibodies,mAbs(mAbs),NK cells,T cells,TLR,cytokine therapies and immune modulators.

Secretion of immunoregulatory cytokines by mesenchymal stem cells

According to the minimal criteria of the International Society of Cellular Therapy, mesenchymal stem cells(MSCs) are a population of undifferentiated cells defined by their ability to adhere to plastic surfaces when cultured under standard conditions, express a certain panel of phenotypic markers and can differentiate into osteogenic, chondrogenic and adipogenic lineages when cultured in specific inducing media. In parallel with their major role as undifferentiated cell reserves, MSCs have immunomodulatory functions which are exerted by direct cell-to-cell contacts, secretion of cytokines and/or by a combination of both mechanisms. There are no convincing data about a principal difference in the profile of cytokines secreted by MSCs isolated from different tissue sources, although some papers report some quantitative but not qualitative differences in cytokine secretion. The present review focuses on the basic cytokines secreted by MSCs as described in the literature by which the MSCs exert immunodulatory effects. It should be pointed out that MSCs themselves are objects of cytokine regulation. Hypothetical mechanisms by which the MSCs exert their immunoregulatory effects are also discussed in this review. These mechanisms may either influence the target immune cells directly or indirectly by affecting the activities of predominantly dendritic cells. Chemokines are also discussed as participants in this process by recruiting cells of the immune systems and thus making them targets of immunosuppression. This review aims to present and discuss the published data and the personal experience of the authors regarding cytokines secreted by MSCs and their effects on the cells of the immune system.

Treg/Th17 cell balance and phytohaemagglutinin activation of T lymphocytes in peripheral blood of systemic sclerosis patients

AIM To investigate T-cell activation, the percentage of peripheral T regulatory cells(Tregs), Th17 cells and the circulating cytokine profile in systemic sclerosis(SSc).METHODS We enrolled a total of 24 SSc patients and 16 healthy controls in the study and divided the patients as having diffuse cutaneous SSc(dc SSc, n = 13) or limited cutaneous SSc(lc SSc, n = 11). We performed a further subdivision of the patients regarding the stage of the disease-early, intermediate or late. Peripheral venous blood samples were collected from all subjects. We performed flow cytometric analysis of the activationcapacity of T-lymphocytes upon stimulation with PHA-M and of the percentage of peripheral Tregs and Th17 cells in both patients and healthy controls. We used ELISA to quantitate serum levels of human interleukin(IL)-6, IL-10, tissue growth factor-β1(TGF-β1), and IL-17 A.RESULTS We identified a decreased percentage of CD3+CD69+ cells in PHA-stimulated samples from SSc patients in comparison with healthy controls(13.35% ± 2.90% vs 37.03% ± 2.33%, P < 0.001). However, we did not establish a correlation between the down-regulated CD3+CD69+ cells and the clinical subset, nor regarding the stage of the disease. The activated CD4+CD25+ peripheral lymphocytes were represented in decreased percentage in patients when compared to controls(6.30% ± 0.68% vs 9.36% ± 1.08%, P = 0.016). Regarding the forms of the disease, dc SSc patients demonstrated lower frequency of CD4+CD25+ T cells against healthy subjects(5.95% ± 0.89% vs 9.36% ± 1.08%, P = 0.025). With regard to Th17 cells, our patients demonstrated increased percentage in comparison with controls(18.13% ± 1.55% vs 13.73% ± 1.21%, P = 0.031). We detected up-regulated Th17 cells within the lc SSc subset against controls(20.46% ± 2.41% vs 13.73% ± 1.21%, P = 0.025), nevertheless no difference was found between dc SSc and lc SSc patients. Flow cytometric analysis revealed an increased percentage of CD4+CD25-Foxp3+ in dc SSc patients compared to controls(10.94% ± 1.65% vs 6.88% ± 0.91, P = 0.032). Regarding the peripheral cytokine profile, we detected raised levels of IL-6 [2.10(1.05-4.60) pg/m L vs 0.00 pg/m L, P < 0.001], TGF-β1(19.94 ± 3.35 ng/m L vs 10.03 ± 2.25 ng/m L, P = 0.02), IL-10(2.83 ± 0.44 pg/m L vs 0.68 ± 0.51 pg/m L, P = 0.008), and IL-17 A [6.30(2.50-15.60) pg/m L vs 0(0.00-0.05) pg/m L, P < 0.001] in patients when compared to healthy controls. Furthermore, we found increased circulating IL-10, TGF-β, IL-6 and IL-17 A in the lc SSc subset vs control subjects, as it follows: IL-10(3.32 ± 0.59 pg/m L vs 0.68 ± 0.51 pg/m L, P = 0.003), TGF-β1(22.82 ± 4.99 ng/m L vs 10.03 ± 2.25 ng/m L, P = 0.031), IL-6 [2.08(1.51-4.69) pg/m L vs 0.00 pg/m L, P < 0.001], and IL-17 A [14.50(8.55-41.65) pg/m L vs 0.00(0.00-0.05) pg/m L, P < 0.001]. Furthermore, circulating IL-17 A was higher in lc SSc as opposed to dc SSc subset(31.99 ± 13.29 pg/m L vs 7.14 ± 3.01 pg/m L, P = 0.008). Within the dc SSc subset, raised levels of IL-17 A and IL-6 were detected vs healthy controls: IL-17 A [2.60(0.45-9.80) pg/m L vs 0.00(0.00-0.05) pg/m L, P < 0.001], IL-6 [2.80(1.03-7.23) pg/m L vs 0.00 pg/m L, P < 0.001]. Regarding the stages of the disease, TGF-β1 serum levels were increased in early stage against late stage, independently from the SSc phenotype(30.03 ± 4.59 ng/m L vs 13.08 ± 4.50 ng/m L, P = 0.017).CONCLUSION It is likely that the altered percentage of Th17 and CD4+CD25-Fox P3+ cells along with the peripheral cytokine profile in patients with SSc may play a key role in the pathogenesis of the disease.

Preliminary in vitro evaluation of neuroprotective and monoamine oxidase type B inhibitory effects of newly synthesized 8-aminocaffeines

The expected growth of the elderly population at highest risk for Parkinson’s disease(PD)in the next decades makes the identification of factors that promote or prevent the disease an important goal.In addition,new therapies-aiming to delay the progression of PD are also needed(Prediger,2010).However,there have been few clinical trials designed to investigate neuroprotection.Thus the application of an appropriate in vitro model such as the neuroblastoma SH-SY5Y cell line is extremely helpful.These cells were selected due to its human origin,catecholaminergic neuronal properties,and ease of maintenance(Xicoy et al.,2017).

Light and electron microscopic study of the medial collateral ligament epiligament tissue in human knees

AIM To examine the normal morphology of the epiligament tissue of the knee medial collateral ligament(MCL) in humans. METHODS Several samples of the mid-substance of the MCL of the knee joint from 7 fresh human cadavers(3 females and 4 males) were taken. Examination of the epiligament tissue was conducted by light microscopy and photomicrography on semi-thin sections of formalin fixed paraffin-embedded blocks that were routinely stained with haematoxylin and eosin, Mallory stain and Van Gieson's stain. Electron microscopy of the epiligament tissue was performed on ultra-thin sections incubated in 1% osmium tetroxide and contrasted with 2.5% uranyl acetate, lead nitrate, and sodium citrate.RESULTS The current light microscopic study demonstrated that the epiligament of the MCL consisted of fibroblasts, fibrocytes, adipocytes, neuro-vascular bundles and numerous multidirectional collagen fibers. In contrast, the ligament body was poorly vascularised, composed of hypo-cellular fascicles which were formed of longitudinal groups of collagen fibers. Moreover, most of the vessels of the epiligament-ligament complex were situated in the epiligament tissue. The electron microscopic study revealed fibroblasts with various shapes in the epiligament substance. All of them had the ultrastructural characteristics of active cells with large nuclei, well developed rough endoplasmic reticulum, multiple ribosomes, poorly developed Golgi apparatus, elliptical mitochondria and oval lysosomes. The electron microscopy also confirmed the presence of adipocytes, mast cells, myelinated and unmyelinated nerve fibers and chaotically oriented collagen fibers.CONCLUSION Significant differences exist between the normal structure of the ligament and the epiligament whose morphology and function is to be studied further.

Evaluation of the combined activity of benzimidazole arylhydrazones as new anti-Parkinsonian agents:monoamine oxidase-B inhibition,neuroprotection and oxidative stress modulation

Neuroprotective drugs and selective monoamine oxidase inhibitors can slow down the progression and improve symptoms of Parkinson’s disease(PD).Since there is an implication of oxidative stress in the pathophysiological mechanisms of the disease,the compounds possessing an ability to reduce the oxidative stress are prime candidates for neuroprotection.Thereby our current study is focused on the development of new multi-target PD drugs capable of inhibiting the activity of monoamine oxidase-B while exerting neuroprotective and antioxidant properties.A small series of benzimidazole derivatives containing hydroxy and methoxy arylhydrazone fragments has been synthesized and the neurotoxicity of the compounds has been evaluated in vitro on neuroblastoma SH-SY5Y cells and on isolated rat brain synaptosomes by measuring the cell viability and the levels of reduced glutathione and a good safety profile has been shown.The 2-hydroxy-4-methoxy substituted arylhydrazone 7 was the least toxic on neuronal SH-SY5Y cells and showed the lowest neurotoxicity in rat brain synaptosomes.The neuroprotective properties of the test compounds were further assessed using two models:H2O2-induced oxidative stress on SH-SY5Y cells and 6-hydroxydopamine-induced neurotoxicity in rat brain synaptosomes.Compound 7 showed more pronounced neuroprotective activity on SH-SY5Y cells,compared to the referent melatonin and rasagiline.It also preserved the synaptosomal viability and the reduced glutathione levels;the effects were stronger than those of rasagiline and comparable to melatonin.All the tested compounds were capable to inhibit human monoamine oxidase-B enzyme to a significant extent,however,compound 7 exerted the most prominent inhibitory activity,similar to selegiline and rasagiline.The carried out molecular docking studies revealed that the activity is related to the appropriate molecular structure enabling the ligand to enter deeper in the narrow and highly lipophylic active site pocket of the human monoamine oxidase-B and has a favoring interaction with the key amino acid residues Tyr326 and Cys172.Since much scientific evidence points out the implication of iron dyshomeostasis in PD,the compounds were tested to reduce the ferrous iron induced oxidative molecular damage on biologically important molecules in an in vitro lecithin containing model system.All the investigated compounds denoted protection effect,stronger than the one of the referent melatonin.In order to support the assignments of the significant neuroprotective and antioxidant pharmacological activities,the radical-scavenging mechanisms of the most promising compound 7 were evaluated using DFT methods.It was found that the most probable free radicals scavenging mechanism in nonpolar phase is the hydrogen atom transfer from the amide group of compound 7,while in polar medium the process is expected to occur by a proton transfer.The current study outlines a perspective leading structure,bearing the potential for a new anti-PD drug.All performed procedures were approved by the Institutional Animal Care Committee of the Medical University of Sofia(Bulgarian Agency for Food Safety with Permission№190,approved on February 6,2020).

Renal cell carcinoma presented with a rare case of icteric Stauffer syndrome:A case report

BACKGROUND Paraneoplastic syndromes remain poorly understood and manifest as multifaceted clinical symptoms,making their diagnosis difficult.Cholestasis can be observed in various malignancies.In rare cases,it can be a paraneoplastic manifestation,most often associated with renal cell carcinoma and other urogenital tumors,as well as with bronchial carcinoma.The classical form of Stauffer syndrome presents with a reversible anicteric increase of cholestatic liver function tests,thrombocytosis,coagulation impairment,and hepatosplenomegaly,without any proven hepatobiliary obstruction or metastases.CASE SUMMARY We report a patient who presented with elevated liver enzymes,cholestatic jaundice,weight loss and pruritus,in whom renal cell carcinoma was incidentally found during hospitalization.Clinical,laboratory,and imaging tests excluded primary hepatic cause or metastatic disease.Jaundice and laboratory abnormalities reversed completely a few months after nephrectomy.This case is an example of the many sides of renal cell carcinoma,and it focuses the clinicians’attention on the differential diagnosis of cholestasis,including Stauffer syndrome and its variant.Thus,the correct diagnosis can be straightforward and the associated malignancy can be treated promptly.All cases should be followed up with a multidisciplinary team.Interleukin(IL)-6 is proposed to contribute to the pathophysiology of the condition.The probable mechanism is proinflammatory activity by the IL-6 cytokine,causing elevation of C-reactive protein and haptoglobin and inhibition of hepatobiliary transporter gene expression,impairing biliary outflow.CONCLUSION Despite being rare,Stauffer syndrome is a potentially reversible paraneoplastic condition,when the primary cause is treatable.This syndrome should be considered by clinicians because of the remediable liver disturbance,after successful treatment of the underlying malignancy.

Protective Effects of Saponin Mixture, Isolated from <i>Astragalus monspessulanus</i>subsp. <i>monspessulanus</i>on Tert-Butyl Hydroperoxide—Induced Oxidative Stress in Isolated Rat Hepatocytes

Saponin mixture, obtained from Astragalus monspessulanus subsp. monspessulanus (Fabaceae) was investigated for possible protective effect on tert-butyl hydroperoxide (t-BuOOH)-induced cytotoxicity using primary isolated rat hepatocytes. The cells were isolated by two-stepped col-lagenase perfusion. Liver damage was induced by one hour incubation with t-BuOOH (75 μmol·L-1) and discerned by decreased cell viability, increased lactate dehydrogenase (LDH) leakage into the medium, increased production of malondialdehyde (MDA) and depletion of the cell protector glutathione (GSH). Cell pre-incubation with the saponin mixture (1 mg/mL and 5 mg/mL) significantly (p < 0.05) ameliorated t-BuOOH-induced liver damage, judged by preserved cell viability, decreased activity of LDH, decreased MDA production and restoration of GSH. The effect was concentration-dependent, more pronounced in the highest concentration and comparable with those of silymarin, used as a positive control. The observed cytoprotective effect could be explained by the influence of the saponins on the mitochondrial function, disturbed by t-BuOOH toxic metabolites.

Vaccine equity: The need of the hour in the face of emerging SARS-CoV-2 variants

Equity is not equality.The word‘equity’focuses on the individual and takes a need-based approach,whereas‘equality’treats everyone equally irrespective of the rationale.Vaccine equity aims to provide equal access to vaccines to people all around the globe[1].The World Health Organization(WHO)had set a target for each country for vaccinating 40%of their population by the end of this year,but many countries are far off from the target[1].Low-and middle-income countries(LMIC),with some exceptions,suffer from a polarisation of vaccinations rates,with the latter suffering the most[1,2].

Role of GM3 ganglioside in the pathology of some progressive human diseases and prognostic importance of serum anti-GM3 antibodies

Glycosphingolipids(gangliosides)have been characterized as important biological molecules with a key role as regulators in many physiological processes on cellular,tissue,organ,and organism levels.The deviations in their normal amounts,production,and metabolism are very often related to the development of many multi-factor socially important diseases.GM3 ganglioside,as a small molecule,plays important roles in the cascade regulatory pathways in the pathology of many disorders like neurodegenerative diseases,autoimmune diseases,inflammation,diabetes,malignant transformation,and others.Ganglioside GM3 and its derivatives are membrane-bound glycosphingolipids composed of an oligosaccharide head structure containing one sialic acid residue.These molecules transduce signals involved in cell surface events,including the phosphorylation of transmembrane receptors.This ganglioside is the most widely distributed among tissues,and it serves as a precursor for most of the more complex ganglioside species.GM3 inhibits the function of fibroblast growth factor receptor,and cell growth is regulated by GM3-enriched microdomain.GM3 is thought to inhibit immunologic functions,such as the proliferation and production of cytokines by T cells.On the other hand,the anti-ganglioside antibodies(AGAs)are important in many acquired demyelinating immunemediated neuropathies,like Multiple sclerosis(MS),Guillain–Barrésyndrome(GBS)and its variation,Miller–Fisher syndrome(MFS)and could be suggested as important diagnostic and prognostic markers about the describe diseases and their etiology.We show that the complexes of anti-ganglioside antibodies to GM3(detected by ELISA)may be useful diagnostic and prognostic tool markers for autoimmune diseases,neurodegenerative disorders,malignancy,diabetes,and inflammation.Our pilot studies suggest increased serum IgG anti-GM3 antibodies titers in patients with secondary progressive MS(SPMS),throat cancer,elder people with diabetes(89–96 years),old Lewis rats(30–33 months),and in the serum of subjected on lead intoxication BALB/c mice treated by salinomycin.We observed no changes in the titers in healthy elder people(89–96 years),in 70-year-old woman on dialysis,in relapsing-remitting MS(RRMS)patients on long-term treatment with Glatiramer acetate,Laquinimod,and Interferons,as well as in 18–22 months old Wistar rats and subjected on lead intoxication BALB/c mice treated by monensin and dimercaptosuccinic acid(DMSA).Considerable decrease of serum GM3 in early MS correlate with early damage and severe destruction of the blood–brain barrier,which provides impetus to initiate early therapy.

Improving <i>in Silico</i>Prediction of Epitope Vaccine Candidates by Union and Intersection of Single Predictors

The in silico prediction of peptide binding affinities to MHC proteins is a very important first step in the process of epi-tope-based vaccine design and development. Five MHC class II binding prediction servers were combined in different ways and the resulting performance of these combinations was evaluated using a test set, which consisted of 4540 known HLA-DRB1 binders. The five servers were: NetMHCIIpan, NetMHCII, ProPred, RANKPEP, and EpiTOP. The top 5% of the ranked predictions from each server were combined using union and intersection operators. The outputs were evaluated in terms of sensitivity and positive predictive value (PPV). The union operator showed high sensitivity (65-79%) and low PPVs (6-8%), while intersection outputs had low sensitivities (4-41%) yet significantly higher PPVs (14-31%). Thus there is a defining trade-off between sensitivity and PPV for each combination. The union of outputs from different servers brings more “noise” than “signal” to the resulting set of predicted binders. Conversely, selecting only commonly predicted binders increases the probability that an identified binder is a true binder.

Pharmacotherapy Cost of Controlled Ovarian Hyperstimulation of <i>in Vitro</i>Fertilization—A Real Life Study

The aim of the current study is to analyze the cost of controlled ovarian hyperstimulation (COH) of in vitro fertilization (IVF) during the period 2009-2013 in a specialized gynecology clinic. It is a prospective, observational study and bottom up cost analysis of the COH pharmacotherapy of IVF. The data was collected for all women admitted to the clinic, therapeutic COH protocols, prescribed medicines and doses, average length of therapy and its cost. Statistical analysis is applied towards the pharmacotherapy and cost data. On average 136 (SD 21.92) women were admitted varying from 105 to 179 for 10.7 (SD 1.47) days. 11% were on long (GnRH agonist containing) therapeutic COH protocol and all other on short (GnRH antagonist containing). Therapeutic protocols include Follitropin-α IU (103 women at average dose of 1171 IU (SD 314.16));Follitropin-β IU (299 women at average dose of 1634 IU (SD 423.5));Urofollitropin 75 IU amp (243 women at average dose of 21.3 IU (SD 7.37));urFSH + urLH 75IU:75IU/amp (354 women at average dose of 23.4 IU (SD 8.8));cetrorelix amp 0.25 mg prescribed at 264 women at average dose of 3.84 IU (SD 1.32);ganirelix amp 0.25 mg for 299 women at average dose of 4.01 mg (SD 1.32);Human chorion gonadotropin for 535 women at average dose of 6752.52 IU (SD 1216.23);Nafarelin mcg/ml for 8 women at dose of 17,700 mcg (SD 10,725);triptorelinacetat 0.1 mg amp - 63 women at doses of 5.5 (SD 3.25) mg at 14 women and average dose of 7.5 mg (SD 2.5);clomiphen citrate and letrozole for 15 women at average dose of 8 mg (SD 2.4). The average cost of COH pharmacotherapy is varying among the years with highest value of 1803.776 (SD - 624.89) BGN in 2009. Controlled ovarian hyperstimulation of in vitro fertilization is cost and resource consuming procedure in regards to pharmacotherapy. Age and reason of infertility influence significantly the cost.

Immunohistochemical Localization of Some Neurotrophic Factors and Their Receptors in the Rat Carotid Body

The carotid body (CB) is a small neural crest-derived organ that registers oxygen and glucose levels in blood and regulates ventilation. The most abundant cell type in the CB glomeruli is glomus or type I cells, which is enveloped by processes of sustentacular or type II cells. Growth and neurotrophic factors have been established as signaling molecules played an important role in the development of the CB. To gain insight whether these signaling molecules are present in the adult rat CB, we examined the expression and cellular localization of some neurotrophic factors and their corresponding receptors in this organ by immunohistochemistry. The results showed the presence of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF) as well as p75NTR, tyrosine kinase A receptor (TrkA), tyrosine kinase B receptor (TrkB) and GDNF family receptor alpha1 (GFRα1) in the adult CB. At the light-microscopical level, the immunoreactivity for NGF and both its low-affinity (p75) and high-affinity (TrkA) receptors was detected in the majority of glomus cells and also in a subset of sustentacular cells. BDNF and its receptors, p75 and TrkB, were observed in the glomus cells, too. Remarkably, the immunohistochemical analysis revealed that the neuron-like glomus cells, but not the glial-like sustentacular cells, expressed GDNF and GFRα1. Taken together with prior results, it can be inferred that neurotrophins may be involved in the CB cell differentiation and survival in adulthood, and may exert a potent glomic protective action as well. It is also presumable that GDNF production by glomus cells plays a pivotal role in permitting long-term viability of CB grafts, which permits their potential applicability in cell therapy as a promising tool in neurodegenerative disorders.

Bioethics in the Training and Management of Sport

The aim of this paper is to examine the opportunities and problems presented by the increasing availability of technologies which is capable of enhancing sporting performance and identifying the risks in sports for creating educational and sports management practices to lead with justice, honesty, and beneficence. A questionnaire is developed to ascertain the social determinants and risks of health aspects of sports in a sample of professionals and amateurs. Descriptive and correlation analysis were used for data analysis. The study identifies health risks connected with the intensive loading of locomotors system, poor working conditions which cause working trauma and diseases as well as low level of health culture regarding the effects of performance-enhancing drugs including anabolic steroids, stimulants, human growth hormone, and supplements. There are arguments that the quality of sport education will be achieved by addressing the study of sports ethics coupled with a study of management and law.

Islet transplantation-immunological challenges and current perspectives

Pancreatic islet transplantation is a minimally invasive procedure aiming to reverse the effects of insulin deficiency in patients with type 1 diabetes(T1D)by transplanting pancreatic beta cells.Overall,pancreatic islet transplantation has improved to a great extent,and cellular replacement will likely become the mainstay treatment.We review pancreatic islet transplantation as a treatment for T1D and the immunological challenges faced.Published data demonstrated that the time for islet cell transfusion varied between 2 and 10 h.Approximately 54%of the patients gained insulin independence at the end of the first year,while only 20%remained insulin-free at the end of the second year.Eventually,most transplanted patients return to using some form of exogenous insulin within a few years after the transplantation,which imposed the need to improve immunological factors before transplantation.We also discuss the immunosuppressive regimens,apoptotic donor lymphocytes,anti-TIM-1 antibodies,mixed chimerism-based tolerance induction,induction of antigen-specific tolerance utilizing ethylene carbodiimide-fixed splenocytes,pretransplant infusions of donor apoptotic cells,B cell depletion,preconditioning of isolated islets,inducing local immunotolerance,cell encapsulation and immunoisolation,using of biomaterials,immunomodulatory cells,etc.

Gastrointestinal mucosal immunity and COVID-19

As the gastrointestinal tract may also be a crucial entry or interaction site of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the role of the gut mucosal immune system as a first-line physical and immunological defense is critical.Furthermore,gastrointestinal involvement and symptoms in coronavirus disease 2019(COVID-19)patients have been linked to worse clinical outcomes.This review discusses recent data on the interactions between the virus and the immune cells and molecules in the mucosa during the infection.By carrying out appropriate investigations,the mucosal immune system role in SARS-CoV-2 infection in therapy and prevention can be established.In line with this,COVID-19 vaccines that stimulate mucosal immunity against the virus may have more advantages than the others.