Nonspecific Effects Research Articles

Prospects on Repurposing a Live Attenuated Vaccine for the Control of Unrelated Infections.

Live vaccines use attenuated microbes to acquire immunity against pathogens in a safe way. As live attenuated vaccines (LAVs) still maintain infectivity, the vaccination stimulates diverse immune responses by mimicking natural infection. Induction of pathogen-specific antibodies or cell-mediated cytotoxicity provides means of specific protection, but LAV can also elicit unintended off-target effects, termed non-specific effects. Such mechanisms as short-lived genetic interference and non-specific innate immune response or long-lasting trained immunity and heterologous immunity allow LAVs to develop resistance to subsequent microbial infections. Based on their safety and potential for interference, LAVs may be considered as an alternative for immediate mitigation and control of unexpected pandemic outbreaks before pathogen-specific therapeutic and prophylactic measures are deployed.

Mitochondrial thioredoxin system is required for enhanced stress resistance and extended longevity in long-lived mitochondrial mutants

Mild impairment of mitochondrial function has been shown to increase lifespan in genetic model organisms including worms, flies and mice. To better understand the mechanisms involved, we analyzed RNA sequencing data and found that genes involved in the mitochondrial thioredoxin system, trx-2 and trxr-2, are specifically upregulated in long-lived mitochondrial mutants but not other non-mitochondrial, long-lived mutants. Upregulation of trx-2 and trxr-2 is mediated by activation of the mitochondrial unfolded protein response (mitoUPR). While we decided to focus on the genes of the mitochondrial thioredoxin system for this paper, we identified multiple other antioxidant genes that are upregulated by the mitoUPR in the long-lived mitochondrial mutants including sod-3, prdx-3, gpx-6, gpx-7, gpx-8 and glrx-5. In exploring the role of the mitochondrial thioredoxin system in the long-lived mitochondrial mutants, nuo-6 and isp-1, we found that disruption of either trx-2 or trxr-2 significantly decreases their long lifespan, but has no effect on wild-type lifespan, indicating that the mitochondrial thioredoxin system is specifically required for their longevity. In contrast, disruption of the cytoplasmic thioredoxin gene trx-1 decreases lifespan in nuo-6, isp-1 and wild-type worms, indicating a non-specific detrimental effect on longevity. Disruption of trx-2 or trxr-2 also decreases the enhanced resistance to stress in nuo-6 and isp-1 worms, indicating a role for the mitochondrial thioredoxin system in protecting against exogenous stressors. Overall, this work demonstrates an important role for the mitochondrial thioredoxin system in both stress resistance and lifespan resulting from mild impairment of mitochondrial function.

Functional in-vitro evaluation of the non-specific effects of BCG vaccination in a randomised controlled clinical study

Bacille Calmette-Guérin (BCG), the only currently licenced tuberculosis vaccine, may exert beneficial non-specific effects (NSE) in reducing infant mortality. We conducted a randomised controlled clinical study in healthy UK adults to evaluate potential NSE using functional in-vitro growth inhibition assays (GIAs) as a surrogate of protection from four bacteria implicated in infant mortality. Volunteers were randomised to receive BCG intradermally (n = 27) or to be unvaccinated (n = 8) and were followed up for 84 days; laboratory staff were blinded until completion of the final visit. Using GIAs based on peripheral blood mononuclear cells, we observed a significant reduction in the growth of the Gram-negative bacteria Escherichia coli and Klebsiella pneumonia following BCG vaccination, but no effect for the Gram-positive bacteria Staphylococcus aureus and Streptococcus agalactiae. There was a modest association between S. aureus nasal carriage and growth of S. aureus in the GIA. Our findings support a causal link between BCG vaccination and improved ability to control growth of heterologous bacteria. Unbiased assays such as GIAs are potentially useful tools for the assessment of non-specific as well as specific effects of TB vaccines. This study was funded by the Bill and Melinda Gates Foundation and registered with ClinicalTrials.gov (NCT02380508, 05/03/2015; completed).

Reappraising the variability of effects of antipsychotic medication in schizophrenia: a meta-analysis.

It is common experience for practising psychiatrists that individuals with schizophrenia vary markedly in their symptomatic response to antipsychotic medication. What is not clear, however, is whether this variation reflects variability of medication-specific effects (also called "treatment effect heterogeneity"), as opposed to variability of non-specific effects such as natural symptom fluctuation or placebo response. Previous meta-analyses found no evidence of treatment effect heterogeneity, suggesting that a "one size fits all" approach may be appropriate and that efforts at developing personalized treatment strategies for schizophrenia are unlikely to succeed. Recent advances indicate, however, that earlier approaches may have been unable to accurately quantify treatment effect heterogeneity due to their neglect of a key parameter: the correlation between placebo response and medication-specific effects. In the present paper, we address this shortcoming by using individual patient data and study-level data to estimate that correlation and quantitatively characterize antipsychotic treatment effect heterogeneity in schizophrenia. Individual patient data (on 384 individuals who were administered antipsychotic treatment and 88 who received placebo) were obtained from the Yale University Open Data Access (YODA) database. Study-level data were obtained from a meta-analysis of 66 clinical trials including 17,202 patients. Both individual patient and study-level analyses yielded a negative correlation between placebo response and treatment effect for the total score on the Positive and Negative Syndrome Scale (PANSS) (ρ=-0.32, p=0.002 and ρ=-0.39, p<0.001, respectively). Using the most conservative of these estimates, a meta-analysis of treatment effect heterogeneity provided evidence of a marked variability in antipsychotic-specific effects between individuals with schizophrenia, with the top quartile of patients experiencing beneficial treatment effects of 17.7 points or more on the PANSS total score, while the bottom quartile presented a detrimental effect of treatment relative to placebo. This evidence of clinically meaningful treatment effect heterogeneity suggests that efforts to personalize antipsychotic treatment of schizophrenia have potential for success.

ASD/OCD-Linked Protocadherin-10 Regulates Synapse, But Not Axon, Development in the Amygdala and Contributes to Fear- and Anxiety-Related Behaviors.

The Protocadherin-10 (PCDH10) gene is associated with autism spectrum disorder (ASD), obsessive-compulsive disorder (OCD), and major depression (MD). The PCDH10 protein is a homophilic cell adhesion molecule that belongs to the δ2-protocadherin family. PCDH10 is highly expressed in the developing brain, especially in the basolateral nucleus of the amygdala (BLA). However, the role of PCDH10 in vivo has been debatable: one paper reported that a Pcdh10 mutant mouse line showed changes in axonal projections; however, another Pcdh10 mutant mouse line was reported to have failed to detect axonal phenotypes. Therefore, the actual roles of PCDH10 in the brain remain to be elucidated. We established a new Pcdh10 KO mouse line using the CRISPR/Cas9 system, without inserting gene cassettes to avoid nonspecific effects, examined the roles of PCDH10 in the brain, and studied the behavioral consequences of Pcdh10 inactivation. Here, we show that Pcdh10 KO mice do not show defects in axonal development. Instead, we find that Pcdh10 KO mice exhibit impaired development of excitatory synapses in the dorsal BLA. We further demonstrate that male Pcdh10 KO mice exhibit reduced anxiety-related behaviors, impaired fear conditioning, decreased stress-coping responses, and mildly impaired social recognition and communication. These results indicate that PCDH10 plays a critical role in excitatory synapse development, but not axon development, in the dorsal BLA and that PCDH10 regulates anxiety-related, fear-related, and stress-related behaviors. Our results reveal the roles of PCDH10 in the brain and its relationship to relevant psychiatric disorders such as ASD, OCD, and MD.SIGNIFICANCE STATEMENTProtocadherin-10 (PCDH10) encodes a cell adhesion molecule and is implicated in autism spectrum disorder (ASD), obsessive-compulsive disorder (OCD), and major depression (MD). PCDH10 is highly expressed in the basolateral nucleus of the amygdala (BLA). However, the phenotypes of previously published Pcdh10 mutant mice are debatable, and some are possibly because of the nonspecific effects of the LacZ/Neo cassette inserted in the mice. We have generated a new Pcdh10 mutant mouse line without the LacZ/Neo cassette. Using our new mouse line, we reveal the roles of PCDH10 for excitatory synapse development in the BLA. The mutant mice exhibit anxiety-related, fear-related, and stress-related behaviors, which are relevant to ASD, OCD, and MD, suggesting a possible treatment strategy for such psychiatric disorders.

Use of non-thermal plasma for decontamination of titanium implants

Non-thermal plasma (NTP) has a non-specific bactericidal effect as a result of the synergistic activity of biologically active components contained in the plasma torch. As part of this work, we investigated the potential of using NTP for the antibacterial treatment of titanium implants. Applying samples made of the VT6 titanium alloy used to create implants and a strain of antibiotic-resistant staphylococcus MRSA, we showed that 1) plasma pretreatment of the sample surface led to the formation of a film containing titanium oxides which have a weak bactericidal effect reducing the colonization of the surface with staphylococcus; 2) direct plasma treatment of a polished titanium disk for 120 seconds reduced the contamination of S. aureus by 563 times; 3) the relief of the titanium surface itself plays an important role in the effectiveness of decontamination: the bacteria on the rough surface were less susceptible to the effects of NTP than the bacteria on the polished surface. In total, the data obtained indicate the need to continue research aimed at increasing the effectiveness of the bactericidal activity of NTP against bacteria on the surface of titanium implants.

Health effects of utilising hospital contacts to provide measles vaccination to children 9\u201359\u2009months\u2014a randomised controlled trial in Guinea-Bissau

BackgroundMeasles vaccination coverage in Guinea-Bissau is low; fewer than 80% of children are currently measles vaccinated before 12 months of age. The low coverage hampers control of measles. Furthermore, accumulating evidence indicates that measles vaccine has beneficial non-specific effects, strengthening the resistance towards other infections. Thus, even if children are not exposed to measles virus, measles-unvaccinated children may be worse off. To increase vaccination coverage, WHO recommends that contacts with the health system for mild illness are utilised to vaccinate. Currently, in Guinea-Bissau, curative health system contacts are not utilised.MethodsBandim Health Project registers out-patient consultations and admissions at the paediatric ward of the National Hospital in Guinea-Bissau. Measles-unvaccinated children aged 9–59 months consulting for milder illness or being discharged from the paediatric ward will be invited to participate in a randomised trial. Among 5400 children, randomised 1:1 to receive standard measles vaccine or a saline placebo, we will test the hypothesis that providing a measles vaccine at discharge lowers the risk of admission/mortality (composite outcome) during the subsequent 6 months by 25%. All enrolled children are followed through the Bandim Health Project registration system and through telephone follow-up. The first 1000 enrolled children are furthermore followed through interviews on days 2, 4, 7 and 14 after enrolment.DiscussionUtilising missed vaccination opportunities can increase vaccination coverage and may improve child health. However, without further evidence for the safety and potential benefits of measles vaccination, these curative contacts are unlikely to be used for vaccination in Guinea-Bissau.Trial registrationwww.ClinicalTrials.gov NCT04220671. Registered on 5 January 2020.

Can Bacillus Calmette-Guérin (BCG) treat localized prostate cancer?

The Bacillus Calmette-Guérin (BCG) vaccine has been used for a century to prevent tuberculosis and non-specific effects of BCG vaccination have provided a degree of protection from other non-mycobacterial pathogens and even some cancers. As such, intravesical BCG instillation is an accepted and well tolerated immunotherapy for non-muscle-invasive bladder cancer. Notably, during BCG instillations there is commonly reflux of urine from the prostatic urethra into the prostatic ducts and most men develop an asymptomatic granulomatous prostatitis in the peripheral zone of the prostate, typically where prostate cancer occurs. In the United States, prostate cancer is the most common diagnosed cancer in men; and most men are diagnosed over age sixty. There are several treatment options for localized intermediate-risk prostate cancer; they include active surveillance, radical prostatectomy, radiotherapy, and androgen deprivation therapy. However, these treatments can cause urinary, sexual, and rectal toxicities; as such, some older men defer treatment and instead choose watchful waiting, which is associated with a worse survival outcome compared to treatment options. We posit that intravesical BCG can target prostate cancer directly by refluxing from the prostatic urethra via ducts into the peripheral zone of the prostate and at that location initiate a robust immunologic anti-tumor response. Moreover, there is evidence that a prior BCG vaccination will augment the immune response from intravesical BCG therapy. Hence, we hypothesize that BCG vaccination followed by intravesical BCG instillation might be a treatment option for localized intermediate-risk prostate cancer, will have limited side effects, and be particularly suited for older men who have chosen watchful waiting. We have suggested how this hypothesis can be safely tested.

Anticancer nanomedicines harnessing tumor microenvironmental components

Introduction Small-molecular drugs are extensively used in cancer therapy, while they have issues of nonspecific distribution and consequent side effects. Nanomedicines that incorporate chemotherapeutic drugs have been developed to enhance the therapeutic efficacy of these drugs and reduce their side effects. One of the promising strategies is to prepare nanomedicines by harnessing the unique tumor microenvironment (TME). Areas covered The TME contains numerous cell types that specifically express specific antibodies on the surface including tumor vascular endothelial cells, tumor-associated adipocytes, tumor-associated fibroblasts, tumor-associated immune cells and cancer stem cells. The physicochemical environment is characterized with a low pH, hypoxia, and a high redox potential resulting from tumor-specific metabolism. The intelligent nanomedicines can be categorized into two groups: the first group which is rapidly responsive to extracellular chemical/biological factors in the TME and the second one which actively and/or specifically targets cellular components in the TME. Expert opinion In this paper, we review recent progress of nanomedicines by harnessing the TME and illustrate the principles and advantages of different strategies for designing nanomedicines, which are of great significance for exploring novel nanomedicines or translating current nanomedicines into clinical practice. We will discuss the challenges and prospects of preparing nanomedicines to utilize or alter the TME for achieving effective, safe anticancer treatment.

Cannabis as medicine, aura and valebo - a new perspective on self-medication and medical support for chronic diseases

It is known from medical practise that patients and physicians can have positive experiences with little-researched and unapproved interventions. Under certain circumstances, effects even go beyond the placebo effect. Based on casuistics of chronic pain patients, the question of whether self-medication in the context of a good doctor-patient relationship can optimize the efficacy of cannabinoids and reduce dose and undesirable side effects is investigated. Using medicinal cannabis as an example, a new view on self-medication and medical support is proposed. The casuistics show that daily requirements (average of approximately 75 mg) for Δ9tetrahydocannabinol (THC) doses can be reduced. An unaccompanied and risky self-medication can be transformed into an effective therapy with significantly less medical cannabis. The approach consists of tracing the self-medication that has taken place to date and picking up the patient where he has "discovered" something for himself. The specific mode of action of cannabis in chronic diseases can be explained by mechanisms in the endocannabinoid system. Cannabinoids relieve patients in the context of stress, anxiety and depression, which are always involved in chronic diseases. In their physical as well as psychological sensations, patients are strengthened and eventually guided into self-efficacy. If the patient has "discovered" cannabis as medicine for himself and can draw on positive experiences, something very powerful can emerge. In addition to the specific effects demonstrated by studies, there are non-specific effects or contextual factors at work that tend to be neglected in evidence-based medicine. These non-specific effects include, above all, those factors through which a patient gives a (subjective) meaning to a specific intervention. A new view on self-medication and medical support in chronic diseases is needed.

LONG-TERM EFFECTS OF SHAM SURGERY ON PHAGOCYTE FUNCTIONS IN RATS

Animal models of inflammatory disorders, including those of the nervous system are commonly used to explore the pathophysiological role of immune cell response in disease triggering and course and to develop biotechnology products for therapeutic use. Modeling some of these disorders, particularly neurodegenerative diseases, implies surgical manipulations for the intracerebral introduction of disease-initiating substances (toxins, amyloids etc.). Design of these experiments involves the use of sham-operated animals as a control of non-specific intrinsic side-effects elicited by surgical manipulations per se, including local and systemic inflammation, where phagocytic cells are key participants. Short-term post-surgical immunomodulatory effects are widely reported. However, no study thus far has examined the long term effects of sham-surgery on phagocyte functions. The purpose of this study was to evaluate the effect of sham-surgery, commonly used for modeling neurodegenerative diseases, on phagocyte functions in the far terms after the surgical manipulations. Materials and Methods. Adult male Wistar rats were used in the study. Sham surgery consisted of stereotactic unilateral injection of saline solution into the median forebrain bundle (sham-operated 1, SO1) or directly into the substantia nigra (sham-operated 2, SO2). Before the placebo surgery, animals were anaesthetized using nembutal and ketamine/xylazine correspondingly. Functional characteristics (phagocytic activity, oxidative metabolism, CD80/86 and CD206 expression) of phagocytes (microglia, peritoneal macrophages, circulating monocytes and granulocytes) were examined by flow cytometry. Differential leukocyte count was conducted using hematological analyzer. Results. Phagocytes from animals underwent of different protocols of placebo surgery, demonstrated various patterns of functional changes on day 29 after the manipulations. In animals from SO1 group, we observed signs of residual neuroinflammation (pro-inflammatory shift of microglia functional profile) along with ongoing resolution of systemic inflammation (anti-inflammatory metabolic shift of circulating phagocytes and peritoneal macrophages). In rats from SO2 group, pro-inflammatory polarized activation of peritoneal phagocytes was registered along with anti-inflammatory shift in microglia and circulating phagocytes. Conclusions. Sham surgery influences functions of phagocytic cells of different locations even in the far terms after the manipulations. These effects can be considered as combined long-term consequences of surgical brain injury and the use of anesthetics. Our observations evidences, that sham associated non-specific immunomodulatory effects should always be taken into consideration in animal models of inflammatory central nervous system diseases.

ОТДЕЛЬНЫЕ АСПЕКТЫ ЛЕЧЕНИЯ ПАЦИЕНТОВ С ВПЕРВЫЕ ВЫЯВЛЕННЫМ ТУБЕРКУЛЕЗОМ ЛЕГКИХ С МНОЖЕСТВЕННОЙ ЛЕКАРСТВЕННОЙ УСТОЙЧИВОСТЬЮ В СОЧЕТАНИИ И ХРОНИЧЕСКОЙ ОБСТРУКТИВНОЙ БОЛЕЗНЬЮ ЛЕГКИХ: В ФОКУСЕ ИНГАЛЯЦИОННЫЕ ГЛЮКОКОРТИКОСТЕРОИДЫ

Introduction. The problem of treating tuberculosis (TB) remains relevant, due to the growth of drug-resistant forms of mycobacterium tuberculosis and an increase in the incidence of TB in persons with comorbid bronchopulmonary pathology, which requires comprehensive management of this category of patients, with mandatory drug correction of concomitant pathology. Aim. The aim of this study was to assess the effect of inhaled glucocorticosteroids (budesonide / formoterol 160 / 4.5 in an Inhaler device) on the efficacy of TB therapy in patients with newly diagnosed multidrug-resistant tuberculosis (MDR) who developed in the presence of chronic obstructive pulmonary disease (COPD). Material and methods. A simple, prospective, comparative study in accordance with the inclusion criteria included 40 patients admitted to an anti-tuberculosis dispensary with newly diagnosed MDR tuberculosis with COPD. The diagnosis of TB and COPD was confirmed using radiographic, functional and laboratory research methods. Group 1, age Me (25; 75) 55.5 (46; 58) years - 22 patients with MDR + COPD tuberculosis who, simultaneously with TB chemotherapy, received a short-acting M-anticholinergic blocker, 2 inhalations 4 times a day, group 2, age 54.5 (51; 58) years - 18 patients with MDR + COPD tuberculosis, simultaneously with TB chemotherapy received a combination of ICS with a long-acting bronchodilator (beta-2-agonist (LABA)), budesonide + formoterol 160 / 4.5 μg dose - 2 inhalations 2 times a day (in an inhaler device). Duration of observation is 9 months. Results and discussion. After 9 months of observation, closure of decay cavities in 63.6% in group 1 and 83.3% in group 2 (χ² = 0.3; p = 0.581), smear negativity in 90.9% of cases in group 1 and in 100, 0% in group 2, respectively (χ² = 0.04 p = 0.834), abacillated 63.3% and 100.0% in groups 1 and 2, respectively (χ² = 0.46; p = 0.496). Against the background of the use of ICS in the intensive phase of TB chemotherapy simultaneously with antibiotic therapy, there was a decrease in the time of abacillation and closure of decay cavities in comparison with the group that did not receive ICS. At the same time in broncholics, the use of ICS made it possible to quickly stop the broncho-obstructive syndrome, improve the quality of life and compliance with long-term anti-tuberculosis therapy. An additional nonspecific anti-inflammatory effect of ICS promoted the active resorption of infiltrative changes and the cure of a specific process, reducing the duration of the main course of treatment, including in patients with MDR. Conclusion. Patients of the anti-tuberculosis dispensary with concomitant bronchopulmonary pathology need complex treatment aimed at correcting comorbid conditions, simultaneously with chemotherapy for tuberculosis. The use of ICS in addition to long-acting bronchodilators (LABA, LDAH) in patients with COPD for the correction of broncho-obstructive syndrome in the intensive phase of TB treatment can reduce the time of smear negativity, abacillation and closure of decay cavities.

265 The design of a virtual museum to address social disconnection and pain among individuals with chronic pain (IWCP)

OBJECTIVES/GOALS: Engagement with art may reduce the social disconnection that accompanies chronic pain. Disaggregating specific from non-specific effects of arts-based programs is challenging. This study creates an experimental virtual museum to identify the separate and joint effects of art and social connection. METHODS/STUDY POPULATION: Two x two factorial experiment with repeated measures: (1) Artwork present condition is a virtual exhibition featuring paintings from the Google Arts &amp; Culture collection; (2) Artwork absent condition is the same exhibition space but with the paintings removed; (3) Social connection condition asks participants to write about a situation in which they felt more socially connected to others; (4) Social disconnection conditions asks participants to write about a situation in which they felt more socially disconnected from others. Participants: (1) English language proficiency; (2) ≥18 years; (3) Chronic moderate to severe pain; (4) Lonely; (5) Has electronic device with internet connection. RESULTS/ANTICIPATED RESULTS: Participants will be recruited through a 3-month social media campaign conducted by StudyPages, a clinical trial recruitment and management platform. This study will evaluate the effects of virtual art exposure and social connectivity priming on pain and social disconnection reduction among lonely IWCP. Pre-intervention scores for pain intensity, pain unpleasantness, and perceived social disconnection will be compared to post-intervention scores. Secondary outcome measures include (a) Museum visit data (e.g., user movement, click, object interaction, open comments) and (b) perceptions about artwork. DISCUSSION/SIGNIFICANCE: Psychosocial support for IWCP may improve pain-related outcomes. This studys data will help to optimize virtual museum interventions and provides the first data we are aware of to evaluate the specific effects of art in virtual museum engagement to reduce pain and social disconnection among IWCP.

Evaluation of the pharmacological activity of hybrid organotin compounds in a B16 melanoma model in the classical and metronomic administration modes

Introduction: In modern medical chemistry, much attention is paid to the search for new antimetastatic agents based on metal compounds. Organotin compounds promise to be good candidates as the treatment of malignant neoplasms. In order to reduce a possible nonspecific toxic effect of tin compounds and to expand the intended therapeutic use, the paper presents hybrid tin (IV) complexes with Sn-S bond containing a fragment of 2,6-di-tert-butylphenol. The aim of the study was to evaluate the antitumor and antimetastatic effects of bis (3,5-di-tert-butyl-4-hydroxyphenylthiolate) dimethylolol (Me3) and (3,5-di-tert-butyl-4-hydroxyphenylthiolate) triphenylolol (Me5) in a model of transplanted melanoma tumor in B16 mice in classical and metronomic administration mode.&#x0D; Materials and methods: The efficacy of organotin compounds was studied in a model of a transplanted tumor with spontaneous metastasis of C57Bl/6 (female) melanoma B16 mice using the following indicators: average life expectan­cy, inhibition of tumor growth by weight, tumor mass, and metastasis inhibition index.&#x0D; Results and discussion: The most pronounced antimetastatic effect (54% and 36%) is achieved with a five-fold in­traperitoneal injection of Me3 and Me5 at the total doses of 375 mg/kg and 250 mg/kg. The comparable results of the efficacy were obtained in the classical and metronomic modes of the injection of hybrid organotin compounds. With an increase in the injected dose, there is an effect of activating the tumor process with the generalized metastasis.&#x0D; Conclusion: Bis dimethylolol (Me3) and triphenylolol (Me5) compounds demonstrate both a pronounced antimetastatic activity and a multidirectional effect on the growth of the primary focus and the metastasis in lungs, depending on an injected dose.

Metabolism testing methods as exemplified by selected new psychoactive substances (NPSs)

Detailed assessment of the biotransformation of compounds and the activity of their metabolites is an extremely important element in the safety evaluation of a substance, both in preclinical and clinical studies. It should be noted that the metabolite may differ from the parent compound in terms of physicochemical properties and consequently pharmacological and toxicological properties. The purpose of the biotransformation of xenobiotics is to increase their hydrophilicity, which allows excretion in the urine. the metabolites of biotransformation phase I show undesirable pharmacological or toxic effects much more often. according to U.S. Food and Drug administration (FDA) guidance, if a metabolite in the human body accounts for more than 10% of the total amount of metabolites, its safety should be thoroughly assessed. Metabolites can interact more strongly or weakly, or to the same degree, with the same or a different molecular target as the parent compound. they can also display non-specific effects by, for example, damaging macromolecules (e.g. proteins, nucleic acids) in the way that free radicals do. In the case of new psychoactive substances (NPSs), the pharmacological properties, including metabolism, are largely unknown until they are traded illegally and their users begin to appear in departments of toxicology or forensic medicine. It is in this way that the activity profile and probable metabolic pathways of NPSs are determined. to determine the metabolites of NPSs is also an important toxicological skill in the forensic testing of biological samples (blood/urine/tissue) collected from victims, in which metabolites, not parent compounds, are usually found. Using examples from the authors’ research and the available literature, the article aims to present alternative methods of metabolism testing for NPSs. In vitro methods (application of microsomes, S9 fraction, hepatocytes, cytosol) are discussed and comparisons are made between the results of in vivo tests on animals and analyses of autopsy material. The experiments and the literature review demonstrate that by using in vitro methods the metabolism of NPSs can be predicted with high probability. By improving existing methods of metabolism research and creating new and alternative ones it will be possible to better understand metabolic pathways and better identify the NPS metabolites formed in the human body. This will contribute not only to the development of better methods of treating NPS poisoning, but will also be of use when compiling forensic and medical reports for the judiciary.

The Effects of Working Memory versus Adaptive Visual Search Control Training on Executive Cognitive Function.

There is considerable debate about whether Working Memory (WM) training specifically results in far-transfer improvements in executive cognitive function (ECF) rather than improvements on tasks similar to the training tasks. There has also been recent interest in whether WM training can improve ECF in clinical populations with clear deficits in ECFs. The current study examined the effects of WM training compared with non-WM adaptive Visual Search (VS) control training (15 sessions over 4 weeks) on various measures of ECF, including delay discounting (DD) rate, inhibition on flanker, color and spatial Stroop tasks, and drinking in a community-recruited sample with Alcohol Use Disorder (AUD, 41 men, 41 women, mean age = 21.7 years), who were not in treatment or seeking treatment, and non-AUD healthy controls (37 men, 52 women, mean age = 22.3 years). Both WM and VS training were associated with improvements on all ECF measures at 4 weeks and 1-month follow-up. WM and VS training were associated with reductions in both DD rates and interference on Stroop and Flanker tasks in all participants, as well as reductions in drinking in AUD participants that remained apparent one month post training. The results suggest that nonspecific effects of demanding cognitive training, as opposed to specific WM training effects, could enhance ECF, and that such enhancements are retained at least one-month post-training.

General non-specific effects of balneofactors of Truskavets’ spa on parameters of neuroendocrine regulation, metabolism, immunity and microbiota in patients with chronic pyelonephritis and cholecystitis

Background. Earlier in experiments on rats, it was shown that drinking mineral water, regardless of their mineralization and chemical composition, have similar (nonspecific) course effects on a number of parameters of metabolism and neuroendocrine-immune complex. The aim of this study is to identify such parameters in patients of Truskavets’ spa who received complex drinking balneotherapy. Materials and Methods. The object of clinical-physiological observation were 34 men aged 23-70 years, who underwent rehabilitation treatment of chronic cholecystitis and pyelonephritis in remission. The examination was performed twice, before and after a 7-10-day course of balneotherapy. All patients received bioactive water Naftussya, therewith, 11 men additionally drank sulfate-chloride sodium-magnesium water "Khrystyna" (5 g/L), and the other 11 men - water "Myroslava" with a similar chemical composition, but twice the mineralization. The object of the study were the parameters of the electroencephalogram, heart rate variability (HRV), hormones, metabolism, immunity, microbiota and cholekinetics. Results. The complex balneotherapy by interval use of Naftussya water with sulfate-chloride sodium-magnesium mineral waters causes similar significant changes in the constellation of 10 EEGs, 10 metabolic, 10 microbiota and 4 immune parameters as well as total power and entropy of HRV, calcitonin and testosterone plasma levels and cholecystokinetics activity index. Conclusion. Balneofactors of Truskavets’ spa causes non-specific modulating effects on parameters of neuroendocrine regulation, metabolism, immunity, microbiota and cholekinetics in patients with chronic pyelonephritis and cholecystitis.

The efficacy and safety of immunobiological therapy of atopic dermatitis in children

The review shows atopic dermatitis (AD) as a chronic inflammatory skin disease that develops in early childhood in infants with a hereditary predisposition. The inflammatory response type 2, including a complex interaction of type 2 T-helpers (Th2), congenital lymphoid cells, granulocytes (including eosinophils, mast cells and basophils), cytokines (IL-4, IL-5, IL-13 etc.) and immunoglobulin E (IgE) underlie at the base of the AD pathogenesis. IL-4 and IL-13 deserve special attention since they affect several links of pathogenesis at once. Both cytokines interact with receptors. Their critical subunit is the alpha chain of the IL-4 receptor. This molecule is the target for dupilumab, the first genetically engineered biologically active drug that demonstrated the high efficacy in the treatment of AD in 6 to 18-year children patients. At the same time, the data available in the literature indicates the drug to have both nonspecific (soreness at the injection site, allergic response) and specific (conjunctivitis, secondary herpetic infections, eosinophilia) adverse effects, which should be taken into account by practitioners when prescribing immunobiological therapy. Conclusion. In randomised, double-blind, placebo-controlled trials in children of different ages with the moderate to severe course of AD, immunobiological therapy with dupilumab has demonstrated high clinical efficacy in the form of a rapid remission of the disease and exemplary safety.

Autoantibodies directed against glutamate decarboxylase interfere with glucose-stimulated insulin secretion in dispersed rat islets.

Islet autoantibodies, including autoantibodies directed against the 65kDa isoform of glutamate decarboxylase (GAD65Ab), are present in the majority of patients with newly diagnosed type 1 diabetes (T1D). Whereas these autoantibodies are historically viewed as an epiphenomenon of the autoimmune response with no significant pathogenic function, we consider in this study the possibility that they impact the major islet function, namely glucose-stimulated insulin secretion. Two human monoclonal GAD65Ab (GAD65 mAb) (b78 and b96.11) were investigated for uptake by live rat beta cells, subcellular localization and their effect on glucose-stimulated insulin secretion. The GAD65 mAbs were internalized by live pancreatic beta cells, where they localized to subcellular structures in an epitope-specific manner. Importantly, GAD65 mAb b78 inhibited, while GAD65 mAb b96.11 enhanced, glucose-stimulated insulin secretion (GSIS). These opposite effects on GSIS rule out non-specific effects of the antibodies and suggest that internalization of the antibody leads to epitope-specific interaction with intracellular machinery regulating insulin granule release. The most likely explanation for the alteration of GSIS by GAD65 Abs is via changes in GABA release due to inhibition or change in GAD65 enzyme activity. This is the first report indicating an active role of GAD65Ab in the pathogenesis of T1D.

Nonspecific Effects of Normal Aging on Taxonomic and Thematic Semantic Processing

ABSTRACT Objective This study aimed to assess the effect of normal aging on the processing of taxonomic and thematic semantic relations. Method We used the Visual-World-Paradigm coupled with eye-movement recording. We compared performance of healthy younger and older adults on a word-to-picture matching task in which participants had to identify each target among semantically related (taxonomic or thematic) and unrelated distractors. Results Younger and older participants exhibited similar patterns of gaze fixations in the two semantic conditions. The effect of aging took the form of an overall reduction in sensitivity to semantic competitors, with no difference between the taxonomic and thematic conditions. Moreover, comparison of the proportions of fixations between the younger and older participants indicated that targets were identified equally quickly in both age groups. This was not the case when mouse-click reaction times were analyzed. Conclusions Findings argue in favor of nonspecific effects of normal aging on semantic processing that similarly affect taxonomic and thematic processing. There are important clinical implications, as pathological aging has been repeatedly shown to selectively affect either taxonomic or thematic relations. Measuring eye-movements in a semantic task is also an interesting approach in the elderly, as these seem to be less impacted by aging than other motor responses.