Hypothalamic regulation of reproduction under the chronic influence of toluene and melatonin

Experiments on chronic administration of melatonin with and without chronic inhalation of toluene dosed at both maximal permissible concentration (50 mg/ml) and limited chronical range (500 mg/m3) have been carried out on female rats to discover their effects on biogenic amines system in hypothalamic structures related to gonadoliberin synthesis and secretion - preoptic area (PA) and median eminence (ME). Contents of biogenic amines in ME and especially in PA have been shown to have circadian variations with maximum in the morning in control group of rats.The chronic effect of synchronizing agent melatonin (administered dissolved in drinking water in concentration of 10 pg/m l, at night during 2 months) on neotransmitters and their circadian variations in both hypothalamic structures proved surprisingly to be much alike the effect of toluene. Both chemicals cause the disturbances of normal circadian variations o f norepinephrine, dopamine and serotonine in PA and dopamine in ME. The simultaneous administration of toluene and melatonin showed likewise no synchronizing ability of the latter under the conditions described.

Effect of Metformin on the Kidney Histology of Rats in Gentamicin Induced Toxicity

Acknowledgment: We are indebted to Dr. Rashad Hussain from department of animal sciences, Quaid-i-Azam University, Islamabad for his consistent support and guidance for the write up of this manuscript. Study’s background and aim: Metformin, an oral antidiabetic agent has been studied in the past for its protective effects in aminoglycoside induced renal injuries. We hypothesized that the use of metformin may be protective in the aminoglycoside mediated acute renal failure. We thus tried two doses of metformin (M1; 75mg/kg/day) (M2; 150mg/kg/day) to evaluate this preventive potential on gentamicin induced acute renal failure in rats. Study Design: Randomized controlled trial Place of Study: Animal House of National Institute of Health Islamabad/ Department of Pharmacology, AL Nafees Medical College and Hospital, Islamabad, duration was 1stAugust 2018 to 31stJanuary 2019. Materials and Methods: The rats were divided into three main groups (n=10) kept under similar conditions for food and temperature. Renal failure was induced by injecting gentamicin (80mg/kg/day) intraperitonealy (ip) for eight days with simultaneous administration of oral metformin for 28 days.Slides of rats’ kidneys were prepared for histological comparison at the last day of study. Results: In gentamicin induced renal failure and simultaneous administration of metformin, the histological findings of rat kidneys showed remarkable tissue necrosis in control group and prevention in metformin treated groups. Conclusion: Based on the histological results of our study it was concluded that metformin at a dose of 150mg/kg showed a nephroprotective effect in gentamicin induced renal injuries in Sprague-Dawley rats. Keywords: Metformin, Gentamicin, Nephrotoxicty, Renal injuries, Nephroprotective effect

Influence of immunomodulators of viral or bacterial origin and vaccine against Aujeszky’s disease on the proportion of peripheral blood B cells in growing pigs

The consequences of infection by Suid herpesvirus type 1 (SuHV-1) that causes Aujeszky’s disease (AD) are well studied, however, the effects of immunomodulators (IMs) of microbial origin (viral and bacterial) when administered solely or in combination with the attenuated SuHV-1 vaccine are less known. The effects of parenteral administration of IMs, inactivated Parapoxvirus ovis (P. ovis) or a combination of inactivated Propionibacterium granulosum (P. granulosum) and detoxified Escherichia coli lipopolysaccharide (LPS) and attenuated SuHV-1, strain Bartha, on the proportion of peripheral blood CD3- CD21+ B cells were analysed in 30 crossbred, 3-month old pigs using flow cytometry (FCM). Specific antibodies for gE and gB of SuHV- 1 were detected using the enzyme-linked immunosorbent assay (ELISA). Data were compared among six experimental groups: (1) pigs that separately received the vaccine, (2) IM of bacterial origin, (3) IM of viral origin, (4) simultaneous administration of the vaccine and bacterial IM, (5) simultaneous administration of the vaccine and viral IM, and (6) the control group of untreated pigs. Comparison of B cell proportions and the detection of specific antibodies in blood samples of vaccinated pigs on Day 11 of the experiment showed a transient decrease in B cell contents, though this could not be assumed to be related since the control group showed a decrease in B cell proportion on the same day. The results showed that the use of IMs alone or in combination with the attenuated SuHV-1 vaccine did not have a significant impact on the proportion of peripheral blood B cells in growing pigs.

Cell Therapy of Pathological Gastrointestinal Lesions in Modeled NSAID-Induced Enterocolitis

Wistar rats with NSAID-induced (dexketoprofen) chronic enterocolitis of the gastrointestinal tract were treated with a cultured allogeneic cell suspension consisting of mononuclear cells (40 millions) and multipotent mesenchymal stromal cells (10 millions). The suspension was transplanted intraperitoneally, 2 times with an interval of 30 days. Cultured allogeneic fractions of bone marrow cells accelerate the regeneration of long-term non-healing gastrointestinal lesions by reducing the duration and severity of the inflammatory phase and activating the regenerative phase of the ulcerative process. It was found that the simultaneous administration of the studied cultured stem cells can be used for the treatment of chronic, long-term non-healing, poorly-scarring ulcerative necrotic gastrointestinal pathologies.

σ2 Receptor and Its Role in Cancer with Focus on a MultiTarget Directed Ligand (MTDL) Approach

Sigma-2 (σ2) is an endoplasmic receptor identified as the Endoplasmic Reticulum (ER) transmembrane protein TMEM97. Despite its controversial identity, which was only recently solved, this protein has gained scientific interest because of its role in the proliferative status of cells; many tumor cells from different organs overexpress the σ2 receptor, and many σ2 ligands display cytotoxic actions in (resistant) cancer cells. These properties have shed light on the σ2 receptor as a potential druggable target to be bound/activated for the diagnosis or therapy of tumors. Additionally, diverse groups have shown how the σ2 receptor can be exploited for the targeted delivery of the anticancer drugs to tumors. As the cancer disease is a multifactorial pathology with multiple cell populations, a polypharmacological approach is very often needed. Instead of the simultaneous administration of different classes of drugs, the use of one molecule that interacts with diverse pharmacological targets, namely MultiTarget Directed Ligand (MTDL), is a promising and currently pursued strategy, that may overcome the pharmacokinetic problems associated with the administration of multiple molecules. This review aims to point out the progress regarding the σ2 ligands in the oncology field, with a focus on MTDLs directed towards σ2 receptors as promising weapons against (resistant) cancer diseases.

Vaccination coverage estimates and utilization patterns of inactivated enterovirus 71 vaccine post vaccine introduction in Ningbo, China

Background In China, enterovirus 71 (EV71) is the major etiological agents of hand foot mouth disease that poses severe risks to children’s health. Since 2015, three inactivated EV71 vaccines have been approved for use. Previous studies indicated the high willingness of EV71 vaccination in eastern China. However, few studies have assessed coverage and utilization patterns of EV71 vaccine in China. Methods Children born during 2012–2018 were sampled and their records were abstracted from Ningbo childhood immunization information management system. Descriptive statistics characterized the study population and assessed coverage and timeliness for EV71 vaccination. Simultaneous administration patterns as well as type of EV71 vaccine used were also evaluated. Bivariate and multivariable analysis was used to examine the relationship of socio-demographic characteristics with vaccination coverage and timeliness. Results Of 716,178 children living in Ningbo. One hundred seventy-two thousand two hundred thirty-six received EV71 vaccine with a coverage rate of 24.05% and only 8.61% received vaccination timely. 21.97% of children received the complete two dose EV71 series but only 6.49% completed timely. Vaccination coverage and timeliness increased significantly from 2012 birth cohort to 2018 birth cohort. Relatively higher coverage and timeliness were observed in resident children, Inner districts, high socioeconomic areas and large-scaled immunization clinics. Of 329,569 doses of EV71 vaccine, only 5853(1.78%) doses were administered at the same day as other vaccines. Conclusions There is a need for increasing EV71 vaccination coverage and timeliness as well as eliminating disparities among different populations. Our study highlights the importance of simultaneous administration to increasing coverage and timeliness of EV71 vaccination.

OP0166 DISEASE ACTIVITY IN CHILDREN WITH JUVENILE IDIOPATHIC ARTHRITIS AFTER SIMULTANEOUS PCV13 AND HIB VACCINATION: A COHORT STUDY

Background:The safety of vaccination of children with rheumatic diseases is determined not only by the risk of adverse events but also by the risk of exacerbation of the disease. The simultaneous administration of several vaccines can increase the likelihood of these events.Objectives:To evaluate the clinical and laboratory signs of disease activity in children with juvenile idiopathic arthritis (JIA) after simultaneous vaccination against pneumococcal and Haemophilus influenzae type b (Hib) infections.Methods:We included hospitalized patients with JIA ages 2 through 18 without serious comorbidity, immunized with polysaccharide conjugate vaccines against pneumococcal (PCV13) and Hib infections. Vaccines were administered (0.5 ml each) concurrently subcutaneously into the deltoid area. In all children before and 3 weeks after vaccination, clinical (joints with active arthritis, uveitis activity) and laboratory signs (increased ESR, concentrations of highly sensitive C-reactive protein – hsCRP, and calprotectin) of JIA activity were assessed. Serum hsCRP and calprotectin were quantified by ELISA. The upper limit of the reference interval for hsCRP was considered (according to the manufacturer’s instructions) a value of 8.2 mg/L, for calprotectin – 2.9 μg/ml, and for ESR – > 10 mm/h.Results:The study included 430 patients with JIA (girls 60.9%), median (IQR) age – 11.1 years (7.3 to 14.4), onset of JIA – 4.7 years (2.4 to 8.6). Patients with persistent oligoarticular JIA numbered 149 (34.7%), polyarticular RF-negative – 148 (34.4%), systemic – 101 (23.4%), enthesitis-related – 20 (4.7%), and polyarticular RF-positive JIA – 12 (2.8%). Biologic disease-modifying antirheumatic drugs (DMARDs) were administered to 278 (64.7%), non-biologic DMARDs (mostly methotrexate) – 282 (65.6%), corticosteroids – 45 (10.5%), and NSAIDs – 18 (4.2%) patients. Three weeks after vaccination, out of 100 (23.3%) patients with initially active joints, signs of active arthritis remained in 96 patients, of which 16 patients had a decrease in the median (IQR) number of active joints by 4 (2 to 8). Among patients without active joints at baseline, signs of active arthritis were not subsequently detected. Before vaccination, 9 patients had uveitis in the exacerbation phase, 7 - in the subactive phase, and 41 - in the remission phase. After vaccination, exacerbation of uveitis persisted in 4 patients. There were no new cases of uveitis or its exacerbation. The dynamics of laboratory signs of JIA activity are presented in Table 1. Initially, the high concentration of calprotectin was found in 191 (44.4%) patients, and after vaccination – in 220 (51.2%) patients; the difference was 6.7% (95% CI 1.0 - 12.5); hsCRP - in 34 (7.9%) and 51 (11.9%) patients; the difference was 4.0% (95% CI 0.6 - 7.3); high ESR – in 76 (17.7%) and 41 (9.5%) patients; the difference was -8.1% (95% CI -11.6 to -4.7), respectively. An independent predictor of new cases of high concentration of hsCRP (n = 36), but not new cases of high concentration of calprotectin (n = 94), was the initial number of joints with active arthritis – odds ratio 2.37 (95% CI 1.14 - 4.93).Table 1.Laboratory signs of JIA activity after simultaneous administration of vaccines against pneumococcal (PCV13) and Hib-infectionsVariablesBaselineAfter 3 weeksRatio*p**Geometric mean (95% CI)Calprotectin, μg/ml2.93 (2.70 – 3.17)3.15 (2.92 – 3.40)1.08 (0.99 – 1.17)0.087hsCRP, mg/L0.69 (0.60 – 0.78)0.79 (0.69 – 0.90)1.15 (0.99 – 1.33)0.073ESR, mm/h4.4 (4.0 – 4.8)3.7 (3.4 – 4.0)0.84 (0.78 – 0.90)0.001Note. CI – confidence interval. * Ratios of paired observations (95% CI). ** P-value calculated in paired samples t-test.Conclusion:Simultaneous vaccination against pneumococcal (PCV13) and Hib-infections in children with JIA produced no negative dynamics of the traditional indicators of disease activity (joint activity, uveitis, high ESR). At the same time, 3 weeks after vaccination, an increase in the concentration of calprotectin and hsCRP was found in a small number of patients (<10%).Disclosure of Interests:None declared

COVID19 pandemic is a «pandemic» of antimicrobial therapy

The article presents a critical analysis of antibiotic usage tactics in the treatment of patients with COVID-19 existing in Russian and foreign healthcare, and discusses the possible causes of unjustified antibiotic aggression in this category of patients. The potential negative consequences of the widespread use of antibiotics in patients carrying a new coronavirus infection are analyzed: life-threatening cardiotoxicity in patients with the simultaneous administration of such a «popular» candidate etiologic therapy as a combination of azithromycin and hydroxychloroquine, the potential development of other serious adverse drug reactions (in particular, the development of an antibiotic-associated pseudomembranous colitis, etc.), the expected dramatic increase in the secondary drug resistance of potentially pathogenic microorganisms to widely and often prescribed antibiotics.