Eco-friendly Synthesis and Molecular Modelling of 2-Phenylimidazo[1,2-b]pyridazine Derivatives: In Vitro and In Vivo Studies for Lead Optimization.

7-methyl-2-phenylimidazo[1,2-b]pyridazin-3-carboxylic acid (DM1) and 6-methoxy-2-phenylimidazo[1,2-b]pyridazin-3-carboxylic acid (DM2) have been shown to act as human (h) Cav voltage-gated calcium channel blockers with promising in vivo anti-absence activity, positioning them as potential antiepileptic drugs. The primary aim of this work was to develop cost-effective and environmentally friendly synthetic procedures for preparing 2-phenylimidazo[1,2-b]pyridazine derivatives. After optimizing the synthesis of this compound class using efficient and green techniques such as microwaves and ultrasound irradiation, we further evaluated the antiepileptic effects of DM1 and DM2 in two animal models: CD-1 ICR mice after pentylenetetrazol administration and DBA/2 mice with seizures induced by audiogenic stimuli.

The Insulin-Degrading Enzyme from Structure to Allosteric Modulation: New Perspectives for Drug Design.

The insulin-degrading enzyme (IDE) is a Zn peptidase originally discovered as the main enzyme involved in the degradation of insulin and other amyloidogenic peptides, such as the β-amyloid (Aβ) peptide. Therefore, a role for the IDE in the cure of diabetes and Alzheimer's disease (AD) has been long envisaged. Anyway, its role in degrading amyloidogenic proteins remains not clearly defined and, more recently, novel non-proteolytic functions of the IDE have been proposed.

Tetrasubstituted Pyrrole Derivative Mimetics of Protein-Protein Interaction Hot-Spot Residues: A Promising Class of Anticancer Agents Targeting Melanoma Cells.

A new series of tetrasubstituted pyrrole derivatives (TSPs) was synthesized based on a previously developed hypothesis on their ability to mimic hydrophobic protein motifs. The resulting new TSPs were endowed with a significant toxicity against human epithelial melanoma A375 cells, showing IC values ranging from 10 to 27 μM, consistent with the IC value of the reference compound nutlin-3a (IC = 15 μM). In particular, compound (IC = 10 μM) resulted as both the most soluble and active among the previous and present TSPs.

The role of NOS3 (rs2070744) and GNB3 (rs5443) genes' polymorphisms in endothelial dysfunction pathway and carotid intima-media thickness in hypertensive patients.

The mechanisms orchestrating the balance between nitric oxide and endothelium-derived contracting factors, and genetic predisposition to endothelial dysfunction in hypertensive patients remain to be determined. One-hundred hypertensive patients participated in the case-control study to clarify the risk of endothelial dysfunction and carotid "intima media" thickness (IMT) changes depending on NOS3 (rs2070744) and GNB3 (rs5443) genes' polymorphisms. It is found that presence of NOS3 gene's С-allele significantly elevates the risk of atherosclerotic plaques on carotid arteries (OR95%CI: 1.

Surgical Resection Combined with Adjuvant Radiotherapy and Non-Steroidal Anti-Inflammatory Drugs in the Treatment of Heterotopic Ossification Following Total Hip Arthroplasty.

Heterotopic ossification (HO) is a well-known complication following total hip arthroplasty (THA), with an average incidence of 30%. Patients are classified according to Brooker's staging system. In advanced stages (III and IV), HO may limit hip motion and cause intolerable pain.

Antireflux surgery is required after endoscopic treatment for Barrett's esophagus.

<b>Introduction:</b> Barrett's esophagus is an acquired condition that develops as a result of transformation of normal stratified squamous epithelium in the lower part of the esophagus into columnar epithelium. Barrett's esophagus is considered to be a complication of gastroesophageal reflux disease (GERD). Various endoscopic techniques have been shown to be successful in the treatment of this condition.

Surgical treatment of acute cholecystitis in obese patients.

<b>Introduction:</b> In today's technological climate, science and medicine have entered a new era. At the level of technological progress, we have identified millennia of "new" problems and diseases. If earlier diseases had a certain individuality then, in the third millennium, we face compliance and synergistic influence of diseases.

Tonic GABAergic inhibition, via GABA receptors containing αβƐ subunits, regulates excitability of ventral tegmental area dopamine neurons.

The activity of midbrain dopamine neurons is strongly regulated by fast synaptic inhibitory γ-Aminobutyric acid (GABA)ergic inputs. There is growing evidence in other brain regions that low concentrations of ambient GABA can persistently activate certain subtypes of GABA receptor to generate a tonic current. However, evidence for a tonic GABAergic current in midbrain dopamine neurons is limited.

Surgical treatment of acute cholecystitis in obese patients.

<b>Introduction:</b> In today's technological climate, science and medicine have entered a new era. At the level of technological progress, we have identified millennia of "new" problems and diseases. If earlier diseases had a certain individuality then, in the third millennium, we face compliance and synergistic influence of diseases.

The cytochrome 11B2 aldosterone synthase gene rs1799998 single nucleotide polymorphism determines elevated aldosterone, higher blood pressure, and reduced glomerular filtration, especially in diabetic female patients.

Objective: The cytochrome 11B2 aldosterone synthase gene (CYP11B2) that links to aldosterone synthase enzyme synthesis changes and blood pressure regulation is of particular interest among the renin-angiotensin-aldosterone system encoding genes.

Methods: One-hundred hypertensive patients with target-organ damaging (2nd stage), moderate, high or very high cardiovascular risk were involved in the case-control study. Mean age was 59.

Features of the course of acute pancreatitis in patients with obesity.

Purpose: The purpose of the study is to investigate the course of acute pancreatitis in obese patients, the development of local and systemic complications and mortality rates.

Materials And Methods: We took and analyzed 482 histories of acute pancreatitis treated at Kyiv Regional Clinical Hospital from January 1, 2011 to February 2, 2019. The data were statistically processed in the Excel 2010 program using a descriptive method applying relative, absolute numbers, mean square deviations and their errors.

[HEMOSTASIOLOGIC INDICES AFTER LAPAROSCOPIC CHOLECYSTECTOMY FOR AN ACUTE CHOLECYSTITIS].

The indices of coagulometry and thromboelastography (THEG) were determined in 60 patients, suffering various forms of an acute cholecystitis. Preoperatively the coagulometry indices have had a hypercoagulation tendency while the disease severity enhances. After performance of laparoscopic cholecystectomy the most essential changes of indices were observed.

Better consenting for thyroidectomy: who has an increased risk of postoperative hypocalcaemia?

Hypocalcaemia is the most common complication following thyroidectomy. This study aimed to establish the factors associated with increased risk of hypocalcaemia on day 1 following thyroidectomy. All patients who underwent thyroidectomy under a single consultant during a 5-year period were included.

SPECIFIC FEATURES OF CHRONORHYTH- MOLOGIC CHANGES OF THE ION-REGU- LATING FUNCTION OF THE KIDNEYS UN- DER THE HYPOFUNCTION OF THE PINEAL GLAND.

The paper investigates the specific features of chronorhythmologic changes of the ion-regulating function of the kidneys under the hypofunction of the pineal gland. For the study of hypofunction of the pineal gland, animals were maintained under constant light stimulation during 7 days. It has been established that the hypofunction epiphysis point out disturbances of the phasic structure of the ion-regulating function in relation to chronograms of the intact group of rats.

PATHOPHYSIOLOGICAL ASPECTS OF PLEIOTROPIC EFFECTS OF GASTROINTESTINAL HORMONES.

The unique properties and a great therapeutic potential of incretin drugs allowed them to win a firm place in modern algorithms of treatment of type 2 diabetes in an unprecedented short period of time. Due to discovery of the incretin effect and introduction of the increrin mimetics into clinical practice, an interest of the researchers was growing to study the plelotropic effects of gastrointestinal hormones. In experimental and clinical studies in recent years there has been shown the cytoprotective and cytoproliferative effects of a number of intestinal hormones, namely giucagon-like peptide-1 (GLP-1), ghrelin, and obestatin when administered systemicallyThis review presents an analysis of the currently available results of fundamental and clinical research on the plelotropic potential of the gastrointestinal peptides, and also determines the relevance of further research on the metabolic effects of bariatric surgery.

[ANALYSIS OF COMPLICATIONS POSTOPERATIVE CAUSES AND MORTALITY AFTER RADICAL TREATMENT FOR TUMORS OF THE LEFT ANATOMICAL SEGMENT OF THE PANCREAS].

Radical surgery for tumors of the left anatomical and surgical segment of the pancreas proved for distal resection in various versions, central resection and enucleation of tumors. The causes of early postoperative complications and mortality in 129 patients aged from 14 to 81 years, operated on for neoplastic lesions of the left anatomical segment of the pancreas in the period from 2009 to 2014 were analysed. The influence of various factors of risk of complications and mortality were studied in particular, extended resection, for tumor invasion of adjacent organs, and adjacent vessels.

[Cephalometric findings in patients with TMJ anterior disk displacement without reduction].

Objective of the study was to determine representative cephalometric signs for the patients with TMJ anterior disk displacement without reduction (ADWoR). Twenty one female patients with ADWoR, which was confirmed by MRI, were included in the study. Cephalometric parameters described by Arnett-McLaughlin and Jarabak were measured by means of lateral cephalograms and computed tomograms (CT) to determine the growth pattern of the facial skeleton.

[APPLICATION OF LARGE SUBCUTANEOUS VEIN AS MATERIAL FOR DISTAL SHUNTING IN CRITICAL ISCHEMIA OF THE LOWER EXTREMITY TISSUES].

While performing autologous reconstruction of distal arteries in 24 patients in chronic critical ischemia of the lower extremity tissues the method of a large subcutaneous vein mobilization, using a ring-like desobliterator,was applied. This have permitted to reduce the procedure traumaticity, comparing with a standard method. Additional application of pharmacological vasodilatation of venous transplant have permitted to avoid the risk, connected with impact of hydraulic vasodilatation on the venous wall functional state.

[SURGICAL TREATMENT OF TUMORS OF THE LEFT PANCREATIC ANATOMICAL SEGMENT].

The results of treatment of 231 patients, suffering tumoral affection of pancreatic left anatomical segment in period of 2009-2013 yrs were analyzed. Individualized approach, using modern technologies, was applied. Radical operations were performed in 129 patients, ageing 14-81 yrs old, including pancreatic distal resections in various modifications, central resection and tumoral enucleation.

[Pancreatic resection using laparoscopic access].

Experience of their own on performance of pancreatic resection interventions, using laparoscopic access, conducted in the clinic in 2009 - 2013 yrs, was presented. In 8 patients laparoscopic distal pancreatic resection was conducted, in 5--laparoscopic enucleation of pancreatic tumor, in 1--laparoscopic pancreaticoduodenal resection. The results were compared with such after open operations, performed in this period of time.

[Effect of streptozotocin-induced diabetes and transient global brain ischemia on apoptosis in the thymus of rats].

The influence of incomplete global ischemia-reperfusion of the brain on the activity of pro- and antiapoptotic processes in the thymocytes by the intensity of p53 and Bcl-2 - proteins expressions has been investigated. It has been shown that in the cortical zone of thymus of rats with a four-month diabetes, as well as in the control rats and rats with diabetes mellitus after brain ischemia, the antiapoptotic processes are dominated. In the medullar zone of the gland in rats with diabetes, complicated and uncomplicated with brain ischemia-reperfusion the antiapoptotic mechanisms predominate too, but to a lesser extent than in the cortical zone.

[Morphological analysis of the results of injection of the autologous stromal marrow-derived stem cells into the uterine scar in rats].

The results of injection of the autologous stromal (mesenchymal) marrow-derived stem cells (ASMSC) transfected with green fluorescent protein (GFP) gene into the rat uterine scar were studied by methods of light microscopy. One week after ASMSC injection into the formed scar on the right side (2 months after the uterine horn ligation), large groups of blood vessels containing the formed elements of blood were found, while these were absent in the uterine scar on the opposite side. The study of the unstained sections in the reflected ultraviolet light demonstrated bright luminescence in the vessel endothelium and adventitia in the uterine horn scar only at the side of ASMSC injection.

[Dynamic biliary manometry: display modelling and graphic interpretation].

Tendencies of development of biliary manometry have been analyzed. Key advantages and problems of manometric investigation of biliary tracts have been summarized. New method of graphic registration and pressure monitoring in biliary tracts called biliary manometry has been suggested.